Archive January 2019

Screening-based approach to discover effective platinum-based chemotherapies for cancers with poor prognosis

Screening-based approach to discover effective platinum-based chemotherapies for cancers with poor prognosis

Contributed equally to this work with: Hristo P. Varbanov, Fabien Kuttler Roles Data curation, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – review & editing Affiliation Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ⨯ Roles Formal analysis, Software, Writing – review & editing Affiliation Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ⨯ Roles Funding acquisition, Resources, Writing – review & editing Affiliation Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ⨯ Roles Conceptualization, Funding acquisition, Resources, Visualization, Writing – review & editing * E-mail: (HV); (PD) Affiliation Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ⨯ Screening-based approach to discover effective platinum-based chemotherapies for cancers with poor prognosis Hristo P. Varbanov, Figures Abstract
Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success. The synergistic combinations identified during the screening were validated by synergy quantification using the combination index method and via high content fluorescent microscopy analysis. New promising synergistic combinations discovered using this approach include compounds currently not used as anticancer drugs, such as cisplatin or carboplatin with hycanthone and cisplatin with spironolactone in pancreatic carcinoma, and carboplatin and deferoxamine in non-small cell lung cancer. Strong synergy between cisplatin or carboplatin and topotecan in PANC-1 cells, compared to A549 cells, suggests that this combination, currently used in lung cancer treatment regimens, could be applied to pancreatic carcinoma as well. Several drugs used to treat diseases other than cancer, including pyrvinium pamoate, auranofin, terfenadine and haloprogin, showed strong cytotoxicity on their own and synergistic interactions with platinum drugs. This study demonstrates that non-obvious drug combinations that would not be selected based on complementary mechanisms can be identified via high-throughput screening.
Citation: Varbanov HP, Kuttler F, Banfi D, Turcatti G, Dyson PJ (2019) Screening-based approach to discover effective platinum-based chemotherapies for cancers with poor prognosis. PLoS ONE 14(1): e0211268. https://doi.org/10.1371/journal.pone.0211268
Editor: Irina V. Lebedeva, Columbia University, UNITED STATES
Received: July 20, 2018; Accepted: January 10, 2019; Published: January 29, 2019
Copyright: © 2019 Varbanov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: H.V. is indebted to the Austrian Science Fund (FWF) for the financial support (Schrödinger fellowship, Project number: J3577-B13). We acknowledge the Swiss National Center for Competence (NCCR) in Chemical Biology for providing access to the chemical libraries and screening facilities.
Competing interests: The authors have declared that no competing interests exist. Introduction
Cancer, one of the leading causes of death, is a term used to describe a large group of related diseases featuring over 100 subtypes, which differ significantly in terms of incidence, mortality and prevalence [ 1 – 4 ]. Advances in treatment strategies together with earlier diagnosis have systematically increased the survival of cancer patients [ 5 , 6 ]. Amongst these advances, the introduction of cisplatin has arguably led to one of the key improvements. For example, the cure rate of patients diagnosed with testicular cancer increased from 10 to over 95% after the introduction of cisplatin (FDA approval in 1978) [ 7 – 9 ]. At present, cisplatin and its analogues carboplatin and oxaliplatin ( Fig 1 ) are extensively used in cancer chemotherapy, usually in combinations with other drugs [ 8 , 10 – 12 ]. Indeed, 36 of 75 anticancer treatment regimens listed in Martindale drug reference book are platinum-based [ 13 ], while Pt drugs are prescribed to nearly halve of the patients undergoing chemotherapy in Australia [ 12 ]. Furthermore, preclinical and clinical efficacy of new anticancer drug candidates is commonly trialed in combination with platinum chemotherapeutics [ 11 , 14 ]. Download: https://doi.org/10.1371/journal.pone.0211268.g001
The clinically used platinum-based drugs are neutral Pt(II) complexes with a cis square planar geometry bearing so-called carrier ligands (i.e. two ammines or chelating diamine) and leaving groups (two chlorides or chelating dicarboxylate) [ 7 , 14 – 16 ]. Their mechanism of action includes intracellular activation by aquation and subsequent covalent binding to DNA bases, which primarily leads to cell death by apoptosis [ 7 , 15 ]. The main limitations to their use include severe side effects and resistance (intrinsic in some tumors or acquired during chemotherapy) [ 11 , 15 , 17 ].
Cisplatin-resistant cancer types usually have poor prognosis and a high mortality. Pancreatic adenocarcinoma, for example, has a 5-years survival rate for patients of only 2.4% [ 4 , 18 , 19 ]. Surgical resection offers the only potentially curative treatment, but in the majority of the cases the disease is inoperable and metastatic at the time of diagnosis. Therefore, chemotherapy (i.e. gemcitabine-based combinations) remains the standard-of-care in most countries, as it improves the overall survival and quality of life of patients [ 19 ]. Pancreatic cancer does not respond well to Pt drugs, although cisplatin and oxaliplatin are sometimes used in the combination therapy [ 19 – 21 ].
Lung carcinoma is the leading cause of cancer death worldwide [ 4 , 22 ], despite the number of treatment regimens available [ 13 , 21 ]. Pt drugs are amongst the most useful agents used to treat lung cancer and first-line chemotherapy typically involves cisplatin or carboplatin in combination with other antineoplastic drugs (e.g. paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan or pemetrexed) [ 20 , 21 , 23 ]. Nevertheless, gains in overall survival are marginal (5-year survival of 10%) [ 18 ] and development of more effective platinum-based combinations is necessary. Recently, targeted therapies have also been introduced for lung cancer treatment. Epidermal growth factor receptor (EGFR) inhibitors have been successfully used as co-drugs to improve the prognosis of non-small cell lung cancer (NSCLC) expressing EGFRs. Although the subset of NSCLCs responding to this treatment is small, the results demonstrate that improvements can be made by tailoring therapy in a cancer type specific manner [ 24 , 25 ].
We have recently shown that new potential chemotherapeutics for the treatment of problematic malignancies such as lung and pancreatic cancers can be identified by screening libraries containing drugs already approved for other applications [ 26 ]. A key advantage of such an approach (often referred to as drug repurposing or repositioning) [ 27 ] is that all recognized hits are compounds with confirmed safety and bioavailability in humans and subsequently clinical development costs are lower, with shorter approval times and higher approval rates [ 27 , 28 ]. We have further expanded our methodology with the aim of identifying drug-like molecules that can synergistically potentiate the cytotoxic effects of clinically applied Pt drugs (see Fig 1 ) against cancers with poor prognosis. This is of particular utility, as anticancer chemotherapies typically employ drug cocktails, rather than a single agent. The selection of anticancer agents for combination therapy is usually done based on the complementary mechanisms of the drugs and non-overlapping toxic side-effects, while sometimes established regimens are adapted from one cancer type to another [ 29 , 30 ].
In this study, we present an alternative, screening-based approach that identifies promising and previously unidentified anticancer drug combinations for platinum-based treatments of specific cancer types. High-throughput screening (HTS) assay was applied to chemoresistant A549 (NSCLC) and PANC-1 (pancreatic carcinoma) cell lines and has demonstrated that novel combination therapies may be able to overcome resistance mechanisms to Pt drugs. Potential synergistic combinations identified during the screening were confirmed and further validated, e.g. synergy quantification using the combination index (CI) method of Chou and Talalay [ 31 ] and High Content Analysis (HCA) using automated fluorescent microscopy. Selected combinations were further examined in HCT116 (colorectal carcinoma) cells, as well as in healthy counterparts of carcinoma models, such as MRC-5 (normal lung fibroblasts) and BJ (normal foreskin fibroblasts) cell lines. The data suggests that for certain drug combinations, doses could be lowered without compromising efficacy, potentially reducing the side effects. Although extrapolation from cell culture to in vivo models often requires further optimization, in vitro drug combination studies could provide valuable information in the development of new treatment regimens [ 32 ]. The methodology presented herein has considerable potential for optimizing Pt drug anticancer therapy including the possibility to obtain new combination treatments for chemoresistant cancers. Results and discussion
Combinations of Pt drugs (see Fig 1 ) and other known drugs, which act synergistically against PANC-1 and A549 cells were identified in this study following a step-wise protocol (summarized in Fig 2 ). The method can easily be applied to other cancer cell types that grow in culture. Download: original image Fig 2.
Schematic overview of the workflow used in this study : 1) Screening of Prestwick Chemical Library (PCL) alone and in combination with one of the approved Pt drugs against PANC-1 and A549 cells to identify hit combinations (HCs); 2) Re-testing the PCL compounds identified in HCs during the primary study alone and in combination with the Pt drug to exclude false-positive HCs; 3) HCs studies in dose-response manner and synergy quantification; 4) Secondary assay, based on HCA. https://doi.org/10.1371/journal.pone.0211268.g002 Primary HT screening–identification of HCs
The primary screening step comprises a commercial library of approved drugs to be screened in combination with Pt drugs for activity against specific cancer cell lines. The PCL [ 33 ], which is composed of 1280 chemically and pharmacologically diverse compounds (ca. 90% being FDA-approved drugs) was selected. Experimental conditions (i.e., number of cells per well, concentration of the library compounds, drugs exposure time, volumes of the reagents used) for the screening assays were adapted from an established and validated protocol for screening of PCL against PANC-1 and A549 cells [ 26 ]. The PCL compounds (at a 10 μM single point concentration) are screened alone and in combination with cisplatin, carboplatin or oxaliplatin ( Fig 1 ), at concentrations chosen to correspond to their IC 50 and IC 20 values (as determined in the preliminary assays, see S1 Fig ). The assay protocols were optimized in order to minimize any detrimental effects of DMSO (from the PCL stock solutions) on the activity of the Pt drugs [ 34 , 35 ]. Thus, PCL compounds were dispensed first into empty plates, followed by addition of the cell suspension and then the Pt drug last (freshly prepared in water or PBS stocks, diluted with medium). The final concentration of DMSO was therefore 0.1% and its direct interaction with the Pt drugs was limited by the high dilution in medium (see also S2 Fig ). The screening experimental protocol is summarized in Table 1 and depicted in S3 Fig . Download: https://doi.org/10.1371/journal.pone.0211268.t001
The results from every screen plate were normalized to the controls obtaining HTS scores, where a score of 0 corresponds to the average fluorescence intensity of the negative control wells (cells + 0.1% DMSO) and a score of 1 to that of the positive control wells (cells + 10 μM Doxorubicin) for each plate. In the case of the PCL-Pt combination plates, a fixed concentration of the respective Pt drug is added to every well (including those with positive and negative controls). Subsequently, the calculation of the scores is based on normalization to the effect of the Pt drug alone (at its IC 20 or IC 50 value). This approach allows potential synergistic combinations between the Pt drugs and the PCL compounds to be identified from the direct comparison between the scores of the PCL compounds alone and their combinations with the respective Pt drugs. A higher score of a PCL compound in combination with certain Pt drug, compared to the score of the PCL compound alone suggests more than cumulative cytotoxicity (i.e. synergistic), and such drug combinations are marked as ‘hit-combinations’ (HCs). Over 25 HCs for PANC-1 cells and 50 HCs in A549 cells were identified during the primary screen ( S4 Fig ). In a few cases, an effect on cell viability was noticed only in the presence of a Pt drug (HTS scores, higher than the average of the negative controls + 3 x SD were detected only in the PCL-Pt combination plates). All HCs found during the primary screen were subjected to a confirmation screen (to exclude false-positive HCs), employing the same experimental protocol used in the primary screen. In the cases where synergistic interactions could not be revealed due to the high activity of the library drug on its own (primary scores > 0.9; e.g. anthracyclines, cardiac glycosides, disinfectants), the experimental setting was modified and the respective PCL compounds were tested at 12 times lower concentration (0.83 μM instead of 10 μM). Confirmation screening
About 60% of the HCs identified during the primary screening step were confirmed in the confirmation screening (see Table 2 for list of the confirmed HCs). In addition, the lower concentration setting enabled the identification of HCs with very active PCL compounds, i.e. daunorubicin and camptothecine. Many of the false-positive primary HCs, which were not confirmed during the confirmation screen, could be explained with the very steep concentration-effect relationships and/or large variability of the response for some PCL compounds, e.g. thiostreptone, verteporfin, haloprogin, tegaserod (see also ref. [ 26 ]). It should also be noted that not all synergistic combinations identified for cisplatin could be found for carboplatin (and vice versa), despite both drugs having the same spectrum of anticancer activity. This finding can be attributed to the different rates and mechanisms of activation of cisplatin and carboplatin, reflected in different cellular pharmacokinetics. Download: https://doi.org/10.1371/journal.pone.0211268.t002 Combinations with known anticancer drugs.
Cytotoxic antibiotics, such as the positive control doxorubicin, are the most cytotoxic anticancer agents included in the library [ 26 ]. They caused significant to complete inhibition of cell viability (scores > 0.9 ) in both cell lines at the primary screening concentration setting. Re-testing them at 12-times lower concentration allowed the identification of HCs between cisplatin/carboplatin and daunorubicin in both cell lines ( S5 Fig ). Anthracyclines, such as daunorubicin and doxorubicin, are used and have been trialed in a number of combination chemotherapy regimens against a wide range of malignancies including lung cancer [ 13 , 21 , 22 , 36 , 37 ]. Moreover, cisplatin and doxorubicin in combination are part of treatment regimens for ovarian, stomach and bladder cancers [ 13 , 22 ]. Our results support that combination therapies featuring Pt drugs and anthracyclines may have potential to improve existing treatment options for pancreatic and lung cancers.
Several HCs involving antimetabolites, e.g. azacytidine-5, cladribine, cytarabine and gemcitabine, and one or more of the Pt drugs were detected in A549 cells. Most of these HCs were validated during the confirmation screen (see S6 Fig ) and the following dose-response studies (see below). Antimetabolites are S-phase specific chemotherapeutic agents, frequently employed together with Pt drugs in the treatment regimens of various cancers [ 13 , 22 ]. Indeed, chemotherapy schedules for lung and pancreatic cancers also include combinations of Pt drugs and antimetabolites, particularly gemcitabine [ 21 ]. However, no HCs including antimetabolites were detected in PANC-1 cells during the screens, emphasizing the need for new therapeutic approaches to treat pancreatic cancer.
The topoisomerase I inhibitors camptothecine and topotecan synergize with the platinum drugs in both PANC-1 and A549 cells. Higher cytotoxicity of cisplatin in combinations with camptothecines and anthracyclines in lung cancer cells was demonstrated also by recent studies [ 38 , 39 ]. Indeed, topotecan is used in combination with cisplatin or carboplatin in chemotherapeutic regimens for lung (and other) cancers [ 13 , 21 ]. Thus, the results from the screens confirm the synergistic basis for the use of gemcitabine-platinum and topotecan-platinum regimens for treatment of lung cancer and reflect the applicability of the screening approach and A549 cells as a model. Furthermore, the data obtained in PANC-1 cells (see Fig 3 and “synergy quantification”, Table 3 ) suggest that topotecan-platinum treatments could be expanded to pancreatic cancer. Download: original image Fig 3. HTS scores of topotecan and hycanthone alone and in combinations with cisplatin, obtained from the confirmation screen in PANC-1 cells.
Data is presented as means ± SDs from 2 replicates. Statistical significance is determined by ordinary one-way ANOVA followed by Dunnett’s multiple comparison test (**p < 0.01 and ***p < 0.001) using GraphPad Prism 7. Chemical structures of topotecan and hycanthone (right). https://doi.org/10.1371/journal.pone.0211268.g003
Other confirmed HCs include the protein kinase inhibitor erlotinib [ 40 ] and oxaliplatin in A549 cells, and the histone deacetylase inhibitor (HDACi) vorinostat and cisplatin in both cell lines. Vorinostat is used for the treatment of cutaneous T cell lymphoma and is currently undergoing early-phase clinical trials for lung and pancreatic cancers [ 41 – 43 ]. Moreover, recent studies found an enhanced antitumor effect for the combination of vorinostat with cisplatin in lung cancer models [ 38 , 44 , 45 ].
Surprisingly, the plant alkaloids paclitaxel and docetaxel, which are commonly employed in platinum-based treatment regimens [ 13 ], showed decreased scores in the presence of the Pt drugs (less than additive effect) in the screens. A similar effect was observed also for other mitotic inhibitors not currently used in cancer therapy, i.e. colchicine and podophyllotoxin. The lower scores obtained for combinations between taxanes and Pt drugs might be linked to the reverse mode of the screening assay, as the mode of action of mitotic inhibitors may vary for attached cells and for cell suspensions and in some cases even from the concentration used. Furthermore, taxanes are usually applied at much lower concentrations than these used in the assay (IC 50 values are commonly in the nanomolar range [ 26 , 31 ]). Combinations with non-anticancer drugs.
The discovery of HCs with drugs used to treat diseases other than cancer is of interest due to the possibility of repositioning existing non-cytotoxic drugs in novel combinations with Pt drugs. Such combinations can be translated to cancer therapy relatively rapidly and at lower cost than introducing new anticancer drugs [ 27 ].
Cardiac glycosides and their aglycones represent the most active class of non-anticancer drugs in the PCL, exhibiting strong cytotoxic effects in both cell lines that are retained at the lower concentration setting of the confirmation screen. The potential of cardiac glycosides as anticancer drugs, and their main limitations associated with their narrow therapeutic indices and low maximum tolerated dose (MTD)s, have been reported [ 46 – 49 ]. In this context, synergistic combinations with other drugs that can decrease the required doses of cardiac glycosides are needed to access their antitumor effects for clinical relevance. Indeed, Felth et al. reported additive to slightly synergistic interactions between different cardiac glycosides and 5-FU, cisplatin or oxaliplatin in colon cancer cells [ 49 ]. Nevertheless, HCs between the Pt drugs and cardiac glycosides could not be identified under the high-throughput conditions employed in our study due to the strong cytotoxic effects of cardiac glycosides on their own, even at the low concentration setting. Further dose-effect combination studies with the cardiac glycosides aglycones digoxigenin and digitoxigenin and the Pt drugs revealed additive to antagonistic interactions in PANC-1 and A549 cells; however, the steep dose-response curves of digoxigenin and digitoxigenin impeded accurate synergy quantification.
The anthelmintic, pyrvinium pamoate, appeared in HCs with all Pt drugs in both cell lines in the primary and confirmation screens. Unfortunately, further dose-response studies for synergy quantification were impeded by solubility problems and precipitation of the drug after cell seeding. Similar solubility-related issues were observed with haloprogin and terfenadine. Another antiparasitic drug, the schistosomicide hycanthone, showed enhanced cytotoxicity in PANC-1 cells in combination with cisplatin ( Fig 3 ) and carboplatin and these combinations were subjected to further dose-response studies (see next paragraphs). Interestingly, no HCs featuring the collection of benzimidazole athelmintics (some of which are currently being repositioned as anticancer drugs) [ 26 , 50 , 51 ] were found during the screens. Moreover, in most of these cases (e.g., parbendazole, albendazole, mebendazole), the anthelmintic drugs displayed lower scores in the presence of Pt drugs.
The antirheumatic agent, auranofin, synergizes with all three Pt drugs in A549 cells. Auranofin is a gold complex, which potential as anticancer drug was demonstrated in several preclinical studies and it is currently examined in clinical trials for treatment of leukemia and some advanced solid tumors [ 52 – 54 ], and has also been show to synergize with ruthenium anticancer drug candidates [ 55 ].
Other PCL compounds identified and confirmed in HCs with one or more of the Pt drugs and advanced to further validation studies include the acridine derivative, aminacrine, the saponine mixture, beta-escin, the iron chelator, deferoxamine, the anti-hyperlipidemic drug, fluvastatin and the peripheral vasodilatator, suloctidil. (see Table 2 )
Several corticosteroid drugs showed higher scores in the presence of oxaliplatin and/or carboplatin in A549 cells, while in some cases cytotoxicity was observed only in the PCL-Pt combination plates. Most of the steroid drugs found in the confirmed HCs showed only marginal and dose-independent cytotoxicity in A549 cells when tested alone [ 26 ]. The ability to potentiate the cytotoxicity of Pt drugs towards A549 cells was further evaluated for some of them (see below). Corticosteroids are included in several cancer chemotherapy regimens [ 56 ], and combination of a Pt(IV) complex, satraplatin, and the corticosteroid, prednisone, was investigated in clinical trials for the treatment of prostate cancer [ 57 ].
The potassium-sparing diuretic with steroid structure, spironolactone ( S7 Fig ), enhances the activity of cisplatin against PANC-1 cells, without displaying activity on its own under the screening conditions. Our findings are in agreement with recent reports on the ability of spironolactone to sensitize ovarian and colon cancer cells by inhibition of different DNA repair mechanisms [ 58 , 59 ]. Spironolactone shows no cytotoxic activity in a large panel of cancer cell lines [ 60 ], however, it exhibits some anti-angiogenic properties [ 61 ]. Its effects on the activity of cisplatin in PANC-1 cells were further evaluated. Dose-effect combination studies (synergy quantification)
Quantification of synergism for the confirmed HCs was assessed using the median-effect principle—combination index (MEP-CI) method with a diagonal constant ratio experimental design [ 31 , 32 , 62 ]. The results from the combination analysis are summarized in Tables 3 and 4 and selected diagrams and isobolograms are shown in Figs 4 – 6 and in the ESI ( S8 – S10 Figs). As synergism and antagonism usually differ at different dose/effect levels, the CI values for the tested combinations are presented at high effect levels, which are in principle of higher therapeutic relevance for cancer chemotherapy [ 31 ]. Download: original image Fig 4. Cytotoxic effects of vorinostat and cisplatin in PANC-1 cells, alone and in combination at concentrations: 1 (7.5 and 10 μM), 2 (15 and 20 μM) and 3 (30 and 40 μM) after 72 h of exposure.
Data is presented as means ± SDs from 4 replicates (vorinostat and combination) or 8 replicates (cisplatin) per concentration. Dose-reduction index (DRI) plot is shown on the right. original image Fig 5. Synergistic combinations between carboplatin and antimetabolites in A549 cells.
Classical isobolograms at 0.5, 0.7 and 0.9 effect level (IC 50 , IC 75 and IC 90 concentrations, respectively) for the combinations of carboplatin with azacytidine-5, 1:0.37 (left), and with gemcitabine, 1:0.001 (right); markers for the actual combination points are pattern filled. original image Fig 6. Synergistic combination of carboplatin and deferoxamine (1:0.12) in A549 cells.
Classical isobologram at 0.5, 0.7 and 0.9 effect level (IC 50 , IC 75 and IC 90 concentrations, respectively); markers for the actual combination points are pattern filled; chemical structures are shown on the right. https://doi.org/10.1371/journal.pone.0211268.t004
Dose-effect combination studies confirmed synergism for most of the combinations tested. Prominent synergistic interactions between camptothecines, namely camptothecine and topotecan, and Pt drugs (especially cisplatin and carboplatin) were determined in PANC-1 cells ( S8 Fig ). However, these effects were much less pronounced in A549 cells, and the combination between oxaliplatin and topotecan even appears to be slightly antagonistic. Other promising combinations in terms of synergism in PANC-1 cells include cisplatin+vorinostat, carboplatin+aminacrine and carboplatin+hycanthone ( Fig 4 , S8 and S9 Figs). The combination of vorinostat and cisplatin at their IC 50 values caused 98% inhibition of cell viability. This value corresponds to an 8-fold reduction of the dose of cisplatin and 34-fold reduction of that of vorinostat compared with the doses of each drug alone needed to cause such effect. Vorinostat and cisplatin showed strong synergistic interactions also in A549 cells ( Table 4 ). These findings demonstrate that the cisplatin-vorinostat combination could show promise in the treatment of pancreatic and lung cancers.
The highest degree of synergism determined in A549 cells was for the combinations between antimetabolites, namely azacytidine-5, cladribine, cytarabine and gemcitabine, with cisplatin or carboplatin. Interestingly, gemcitabine was found to act antagonistically with oxaliplatin in A549 cells. Combination regimens including gemcitabine and cisplatin or carboplatin are commonly used in the chemotherapy of NSCLC. CI analysis revealed that certain Pt drug-antimetabolite combinations exhibit stronger synergism than the clinically applied regimens ( Table 4 , Fig 5 and S10 Fig ), and could provide alternatives to the current treatment options. Another combination that displays promising synergistic effects in A549 cells consist of carboplatin and the iron chelator deferoxamine ( Fig 6 ).
Daunorubicin was shown to act synergistically with cisplatin (PANC-1 cells) and carboplatin (in both cell lines). However, sequential deletion analysis (S.D.A.) showed high variability of the CI values, particularly in the A549 cells, and, therefore, the determined degrees of synergism must be taken with caution. Similarly, synergistic interactions between some compounds, for example the gold drug auranofin or beta-escin and the Pt drugs, could not be confirmed unambiguously due to large variations of the cellular response and the steep dose-response curves. In the case of combinations featuring pyrvinum pamoate, terfenadine, suloctidil or haloprogin, synergy quantification was not possible due to high deviations between the replicates and/or low conformity of the median effect plots (r < 0.85). As already mentioned, in some cases these problems could be attributed to the low water solubility of the PCL compound and precipitation after dilution with cell medium.
The combination effects between Pt drugs (i.e., carboplatin and oxaliplatin) and corticosteroids in A549 cells could not be evaluated with the CI method of Chou-Talalay as the flat dose-response curves (fa ≈ 0.3–0.5 in the range 0.1–100 μM) of the steroids did not allow determination of the parameters required for the analysis (D m and m). However, the fractional product method of Webb [ 63 ] revealed no synergistic interactions between the Pt drugs and the steroid drugs at the concentrations tested (see Fig 7 , S11 and S12 Figs). As a proof of principle, the same methodology was applied also to evaluate the synergistic combinations cisplatin+vorinostat and carboplatin+topotecan in PANC-1 cells as well as the cisplatin+palcitaxel combination in A549 cells. The fractional product method confirmed the synergy for cisplatin+vorinostat and carboplatin+topotecan combinations and suggested antagonistic interactions between cisplatin and paclitaxel in A549 cells at most of the concentrations tested ( S12 Fig ) in good agreement with the results obtained from the screens. Download: Fig 7. Concentration effect curves of oxaliplatin, alone and in combination with corticosteroids: prednicarbate (at concentration range 1.5–20 μM) and fludrocortisone (at fixed concentration of 10 μM) in A549 cells after 72 h of exposure.
Curves fitting and graphs are prepared with GraphPad Prism 7. https://doi.org/10.1371/journal.pone.0211268.g007
Spironolactone (see S7 Fig for chemical structure) is inactive at a concentration of 10 μM, but potentiates the cytotoxicity of cisplatin in PANC-1 cells, resulting in a 2.5-fold decrease of the IC 50 and a 3-fold decrease of IC 90 values ( Fig 8 ). This supports the work of Coin et al . [ 59 ] on the repositioning of spironolactone as an adjuvant in platinum-based therapy, particularly for highly chemoresistant pancreatic carcinoma. Further experiments showed that spironolactone can enhance the activity of cisplatin to certain extent also in other cancer cells and in some cases also in non-cancer cell lines (see S13 Fig ). Download: original image Fig 8. Cytotoxicity of cisplatin alone and in combination with spironolactone in PANC-1 cells after 72 h of exposure.
Left: concentration effect curves and Right: bar graphs of selected concentrations. Data is presented as mean ± SD from 4 replicates (combination) or 8 replicates (drugs alone) per concentration (****p < 0.0001, ***p 95%) was confirmed by 1 H NMR spectroscopy and elemental analysis prior to use. Stock solutions were prepared directly before experiments either in water (carboplatin and oxaliplatin) or in PBS (cisplatin) and filtered through sterile membrane filter (0.22 μM) prior use. The PCL was purchased from Prestwick Chemicals (Washington, DC) and contains 1280 molecules, supplied as 10 mM stock solutions in DMSO. Compounds were stored in the dark, at– 20°C under dry air, using an automated storage system and their chemical integrity was controlled regularly by HPLC-MS. Cell lines and culture conditions
A549 (human non-small cell lung adenocarcinoma), PANC-1 (human pancreatic adenocarcinoma), HCT116 (human colorectal carcinoma), BJ (human normal foreskin fibroblasts) and MRC-5 (human normal lung fibroblasts) cell lines were purchased from ATCC and were used between passage numbers 10 and 35. All cell culture media, buffers and reagents were obtained from Gibco Life Technologies. Cells were grown as adherent monolayer cultures in 75 cm 2 culture flasks (TPP) without antibiotics using the following growth media, supplemented with 10% heat-inactivated fetal bovine serum (FBS, Invitrogen 10101–145): Dulbecco’s Modified Eagle medium/F-12 Nutrient mixture (Ham) (DMEM/F-12 + GlutaMAX, 31331–028) for A549 cells, Dulbecco’s Modified Eagle’s Medium (DMEM, high glucose, GlutaMAX, Pyruvate, 31966–021) for PANC-1 cells, McCoy5a Medium (McCoy5a, GlutaMAX, 36600–021) for HCT116 cells and Eagles’s Minimum Essential Medium (EMEM, low glucose, L-Glutamine, 11095–080) for BJ and MRC-5 cells. Cultures were maintained at 37°C in a humidified CO 2 incubator.
Cells were subcultured 2 to 3 times per week. Briefly, the cells were harvested with Trypsin 0.05%-EDTA (Life Technologies 25300062) and diluted with growth medium (1:3 to 1:5 for PANC-1, BJ and MRC-5 cells, 1:5 to 1:20 for A549 and HCT116 cells). Cells used for the assays were harvested from culture when the level of confluence was between 60% and 80%, while cell viability was > 90%. Primary HTS assay
The compounds from the PCL were dispensed into sterile, basic flat-bottom, culture-treated, transparent, barcoded 384-well plates (Corning 3701), using an acoustic liquid handler Echo 550 (Labcyte Inc. Sunnyvale, CA). Each drug was added once (one well per compound), volume 30 nl, yielding a final concentration of the compound of 10 μM and final DMSO concentration of 0.1%. The first two columns of every plate were used as negative control (no PCL drug added) and filled with an equivalent volume of DMSO (30 nl/well) while the last two columns were filled with doxorubicin (10 μM with DMSO, 0.1%) for the positive control; the entire PCL can be processed on four such plates (see ref.[ 26 ]). Cells were harvested by tripsinization and seeded in complete growth medium into the plates in volumes of 25 μl/well using a multi-drop dispenser (Thermo Scientiffic Multidrop Combi) at medium speed. A seeding density of 2000 cells/well was used for both A549 and PANC-1 cells to ensure exponential growth of untreated controls throughout the experiment and a satisfactory quality of the assay. Next, Pt drugs (in concentration corresponding to their IC 50 or IC 20 ) diluted in medium were added to each well of the PCL-Pt combination plates in volumes of 5 μl/well using a multi-drop dispenser. In the PCL-only plates, equivalent amounts of PBS (respectively water) diluted in medium were added also to all the wells. After a post-plating incubation step at room temperature for 20 min, which ensures a more homogeneous repartition of the cells at the bottom of the wells, plates were transferred to an incubator (37°C, 5% CO 2, saturated moist atmosphere) for 72 h (PANC-1 cells) or 50 h (A549 cells). Subsequently, 3 μL of PrestoBlue reagent (Life Technologies, Switzerland) was added to each well and the plates were returned to the cell incubator for 1 h. The fluorescence intensity (bottom-read) was measured using a multiwell plate reader (Tecan Infinite F500) at excitation 560/10 nm, emission 590/10 nm and a fixed gain. The experimental protocol for the screen is summarized in Table 1 and S3 Fig . The screening was performed for each cell line with the full PCL alone or in combination with each of the Pt drugs, tested in two final concentrations; all conditions were assayed in duplicate. Data analysis.
The BSF in-house Laboratory Information Management System (LIMS) was used for basic data processing, management, visualization and statistical validation. Data was normalized according to the fluorescence signals of control wells located in the first two and last two columns of every plate and presented as HTS scores, where a score of 0 was assigned to the average fluorescence intensity of the negative control wells and 1 to that of the positive control wells [ 26 ]. In the case of the PCL-Pt combination plates, calculation of the scores is based on normalization to the effect of the Pt drug alone as the respective Pt drug (at fixed concentration) is added to every well (including the controls). For each screen plate, HTS scores were considered only when their value is higher than the average of the negative controls + 3 x SD. HTS scores were calculated as mean ± SD from two replicates (every screen plate was ran in duplicate). A higher mean score of a PCL compound in combination with certain Pt drug, compared to the mean score of the PCL compound alone (Mean PCL+Pt + SD PCL+Pt > Mean PCL —SD PCL ) suggests more than cumulative cytotoxicity (i.e. synergistic); such drug combinations were marked as ‘hit-combinations’ (HCs).
Assay quality was assessed by calculation of the screening window coefficient (Z’-factor) for every screen plate. The Z’-factor was determined according to the formula: Z’ = 1–3(SD pos + SD neg )/|Av pos −Av neg |, where SD and Av are the standard deviation and the average, respectively, of the fluorescence signals of the negative and positive control wells [ 66 ]. For the combination plates (PCL compounds plus Pt drugs at their IC 50 ), a narrower dynamic range and separation band were observed as a result from the lower fluorescence of the negative controls, a consequence of the decreased cell metabolism and viability, caused directly by the Pt drug. The quality of the assay was considered sufficient when Z’ >0.4–0.5 Confirmation screening.
The PCL compounds identified in HCs during the primary screening assay were dispensed (cherry picked) into 384-well plates using the acoustic liquid handler Echo 550 (Labcyte Inc. Sunnyvale, CA). Library compounds were added in volumes of 30 nl or 2.5 nl (for compounds with scores > 0.85 in the primary screen) to yield final concentrations of 10 μM or 0.83 μM, respectively. The plate layout was redesigned to accommodate the lower number of samples and avoid any edge effect (no controls or compounds in the edge wells). Cell seeding, addition of Pt drugs (or PBS/water), incubation, cell viability determination and data evaluation were as described for the primary screening. All conditions were assayed in duplicate. Combination studies and synergy quantification
Confirmed HCs were further evaluated using the CI method of Chou and Talalay with a diagonal constant ratio experimental design [ 31 , 32 ]. Two-fold serial dilutions were performed for each drug alone and for their mixtures at a fixed concentration ratio (e.g. at (IC 50 ) Pt drug /(IC 50 ) PCL compd ratio) to yield 5 concentrations ranging from ¼ x IC 50 to 4 x IC 50 (see S24 Fig for the plate layout). PCL compounds were dispensed into 384-well plates using the Echo 550 acoustic liquid handler (Labcyte Inc. Sunnyvale, CA) before seeding the cells. Pt drugs were added either also by the acoustic liquid handler (carboplatin, oxaliplatin) before cell seeding or manually (cisplatin and in some cases oxaliplatin) after cell seeding in order to minimize interactions with the DMSO solvent used in the PCL compounds stocks (see S2 Fig ). Cell seeding (2000 cells/well for PANC-1 cells and 1200 cells/well for A549 cells), incubation (72 h for both cell lines) and cell viability determination were accomplished as described for the screening assays. Data was normalized to the controls (20 μM Doxorubicin.HCl and 0.2% DMSO, respectively) and presented as fraction of effect affected (fa). All compound concentrations and combinations were tested in 4 replicates (i.e. 2 wells/plate, every plate in duplicate) and mean fa values and their standard deviations were calculated. Combination effects analysis and CI calculation were performed using CompuSyn software [ 62 ]. Linear regression was used to fit the logarithmic form of the median effect equation to the experimental data for each drug and their combinations, allowing the potency, D m (corresponding to the IC 50 ), and the shape (sigmoidicity) of the dose-response curve, m, to be determined. The linear correlation coefficient, r, was determined as conformity for goodness of fit and r > 0.85 for both single drugs and combinations was required for a successful analysis. The D m and m values for each drug and their combinations were used to calculate CI as a quantitative measure of the drug interactions in terms of synergism (CI 1) for a given endpoint of the effect measurement. Sequential deletion analysis (S.D.A.) was used as a measure of the variability of the CI values at presented effect levels. Mean ± 95% confidence intervals were calculated at the specified effect levels after an iterative sequential deletion of one concentration of a drug at a time for repetitive CI calculations [ 31 , 62 ]. Combinations with carboplatin in PANC-1 cells were studied at non-equipotency fixed ratios, due to its low activity (IC 50 ~ 180 μM) towards PANC-1 cells; the highest concentration of carboplatin used (192 μM) resulted in cell viability inhibition, fa = 0.53. Nevertheless, conformity of analysis for carboplatin and its combinations in PANC-1 cells was good (r > 0.9).
Additional combination experiments with fixed concentrations (e.g., 0.1, 1 or 10 μM) of some PCL compounds (corticosteroids, spironolactone) and the Pt drugs in concentrations, ranging from ¼ x IC 50 to 4 x IC 50 , were also performed. Evaluation of the combination effects in certain cases was assessed by the fractional product method of Webb [ 63 , 67 ]. The cell survival fractions (fu = 1—fa) of the drugs alone were used to calculate the expected additive effects as a product of the individual fractional effects (fu A+B calc = fu A x fu B ) for specific concentrations. A synergistic interaction was assumed when 0.7 x fu A+B calc —Mean (fu A+B det ) ≥ 3 x SD (fu A+B det ); when Mean (fu A+B det )– 1.3 x fu A+B calc ≥ 3 x SD (fu A+B det ), the combination was considered as antagonistic. HCA using automated fluorescence microscopy assays
Experiments were performed using sterile, black/clear tissue culture treated, 384-well plates with flat bottom (BD Falcon Imaging plates 353962). Selected PCL and Pt drugs (alone and in combinations at four different concentrations, two wells per condition) were added using the Echo acoustic dispenser (PCL compounds) or manually after cell seeding (Pt drugs). Cells were seeded (in medium and at volume of 30 μl/well) into the plates using a multidrop dispenser, medium speed at density of 2100 cells/well for PANC-1 cells, 1100 cells/well for A549 cells, 2000 cells/well for BJ and MRC-5 cells and 3000 cells/well for HCT116 cells. The plates were then incubated at 37°C and 5% CO 2 for 24, 48 and 72 h prior staining. The staining solution was prepared freshly by diluting DMSO stocks of Calcein AM (Invitrogen C3100MP) and Hoechst 33342 (Sigma B2261), and aqueous stock solution of propidium iodide (PI, Fluka 81845) in PBS, and added to the cells manually at volumes of 10 μl/well. The final concentrations of the dyes were as follows: 2 μg/ml for Hoechst, 0.16 μg/ml for Calcein AM and 6.66 μg/ml for PI in the case of A549, BJ and MRC-5 cells and double diluted for PANC-1 and HCT116 cells. Plates were then returned to the incubator for another 30 minutes for full staining. Microscopy reading was performed in an environmental chamber (37°C, 5% CO 2 ) using a GE Healthcare IN Cell Analyzer 2200. Imaging was performed with a 20X/0.75 objective. For each well 9 field of view were acquired, each with 3 channels. Hoechst, PI and Calcein AM signals were imaged using the filter combinations 390/18-432/48, 542/27-597/45, 475/28-512/23, respectively. Exposure times were set respectively at 80, 5 and 100 ms for PANC-1 cells, 100, 5 and 100 ms for A549 cells, 80, 50, and 8 ms for BJ and MRC-5 cells and 60, 10 and 40 ms for HCT116 cells. Images were analyzed using Cell Profiler and Cell Profiler analyst software [ 64 , 65 ]. Supporting information S1 Fig. Time/concentration dependent cytotoxicity of the Pt drugs and doxorubicin hydrochloride in PANC-1 and A549 cells. Experiments were performed in 96-well format; cell viability was determined by the PrestoBlue fluorescence assay. A) Dose response curves of PANC-1 cells after continuous drug exposure for 48 h, 72 h and 96 h (cell seeding density at 7500, 6000 and 5000 cells/well, respectively). B) Dose response curves of A549 cells after continuous drug exposure for 24 h, 48 h, 72 h and 96 h (cell seeding density at 10000, 6000, 4000 and 2500 cells/well, respectively). C) 50% inhibitory concentrations (IC 50 ) determined for the investigated compounds in PANC-1 (left) and A549 (right) cells after different exposure times; IC 50 values are plotted as mean ± SDs from at least two independent experiments.

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PERSONAL HEALTH

<h1>PERSONAL HEALTH</h1>

PERSONAL HEALTH

LEAD: MILLIONS of American women who are trying to prevent osteoporosis by increasing their calcium intake may be ignoring the most important cause of the disease: the decline of estrogens after menopause.

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Nora Ephron’s Final Act

<h1>Nora Ephron’s Final Act</h1>

Nora Ephron’s Final Act

The play “Lucky Guy,” Nora Ephron’s last completed work, is about a journalist who kept striving to do his best work even as he was dying of cancer. He was her inspiration to do the same.

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Personal Health: Too Much Medicine, and Too Few Checks

Personal Health: Too Much Medicine, and Too Few Checks

My 92-year-old aunt was a walking pharmacy, and a month ago it nearly killed her. The episode also cost the American medical system several hundred thousand dollars. Overmedication of the elderly is an all too common problem, a public health c…

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PROPOSALHow To Make a Thesis relyibidTo see examples of such mappings, search online for “learning cycle Zull Kolb”.the teacher’s assignments look for a high level of analysis or synthesis on the3breaking the teacher out of a familiar but undesirable cognitiveviBack to the Brainsame conceptused. Do use subheads throughout.sosubsection. Don’t worry now about being totally and perfectly accurate in the outline. Certainlycontribution to the body ofideas to practices in the teacher’s field of study (or everyday life) you riskThis chapter, however, should not merely string together what other researchers have found. Rather, youcycle onto our understanding of cognition would, plus other relevant documents.
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The BrainShould one bring up ideas like “rehearsal” and “redundancy” with a teacherstudents!Discuss applied and scientific contributions.anwithinthesis. It is even better if the thDo your thesis carefully; you never know whr instance, under “Education” and “Psychology.”self—streamlined or expanded.D. Hypotheses (in broad sense of the term; alself! Tell yourself that you’veUndertaking aThe defense is scheduled when the thesis has been completed successfully–becomessurelyfive-mile run.Chapter I. INTRODUCTION.previous paragraph, but even then you risk running afoul of anothersurprise, since our
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DOZENS OF FACTORS CRITICAL IN BONE LOSS AMONG ELDERLY

DOZENS OF FACTORS CRITICAL IN BONE LOSS AMONG ELDERLY

LEAD: WHILE calcium wars rage in pharmacies,health food stores and supermarkets throughout the country, research in osteoporosis is revealing that only a minority of cases of this bone-wasting disorder result from diets deficient in calcium.

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Diabetes Mellitus Study Guide

Diabetes Mellitus Study Guide

DIABETES MELLITUS * Chronic multisystem dz , abnormal insulin production / spoiled utilization * Disorder of glucose metamorphosis related to absent/ insuff insulin bring or poor utilization of inslin thats available * 7th leading pay off of dying * leading private road of blindness, ESRD, lower limb amputation * contri entirelying ingredient for heart dz/ stroke stake 2-4 x gameer than without DM * INSULIN ductless gland produced by cells in islets of Langerhans of pancreas.Normal continously into telephone circuitstream ( basal rate), or increased w/ meals (bolus) * Normal glucose range 70-120 mg/dL, average insulin secreted day-by-day 40-50 U 0. 6 U/kg * Glucagon, epinephrin, GH, cortisol oppose effects of insulin counterregulatory hormones they rent glucose lebels, get chthonian ones skin glucose production by liver-colored, movement of glucose into cells. Insulin released from cells as precursor / proinsulin thru liver enzymes realize insulin &038 C-peptide ( C-peptide in serum &038 urine indicator of cell function) * in germ plasm insulin subsequently meal storage of glucose as glycogen in liver/ muscle, isoniazidibits gluconeogenesis, plummet de carriage, protein synthesis * Nl over iniquity fasting release of stored gucose from liver, protein from muscle, fat from adipose create from raw material * Skeletal muscle &038 adipose tissue receptors for insulin insulin-dependent tissues reference I Diabetes Juvenile infringement, insulin-dependent, s/s abrupt but dz suffice present for several yrs, 5-10%, absent or momentimal insulin production, computer virus/toxins, under 40, 40% before 20 yr * s/s thirst( polydipsia), polyuria, polyphagia ( hunger), fatigue, wt bolshie, Kussmaul respirations * tolerant mediated dz T-cells attack &038 destroy cells * genetic predisposition &038 exposure to virus * Idiopathic diabetes not atoimmune, strongly isoniaziderited, in small pt w/ type I DM , Afri hatful/Asian * Predisposition HLAs tender leukocyte ntigens when exposed to viral transmission cells destroyed * commodious preclinical period, s/s develop when pancreas can no longer produce competent insulin to maintain nl glucose takes * Req. insulin from outside source exogenous insulin eg. enterion * No insulin diabetic ketoacidosis (DKA) life threatening, results in metabolous acidosis * honeymoon period newely diagnosed pts, tx initiated pt experience remissions req little insulin because cells produce suff amount of insulin lasts 3-12 mths then req permanent insulin Prediabetes * attemptiness for develop diabetes glucose take aims high but not high enough for diabetes diagnosis * impaired fasting glucose IGF 100-125 mg/dL * 2 hr ad-lib exam glucose security deposit test OGTT 140-199 mg/dL * HgB A1C 5. 7%-6. 4% take a chance for diabetes * Increased jeopardize for evolution DM type II if no interdictive measures develop DM in 10 yrs * Long circumstance damage to organic structure heart, phone line vessels occur in prediabetes * Usually no symptoms * Maintain healthy weight, consumption incessantly, healthy diet take chances of developing diabetes persona II Diabetes * Adult onset, non-insulin dependent, 90% * > 35, overweight, tendency to run n families * African Am, Asian, Hispanics, Amerian Indians Some insulin is produced but either insufficient for body inevitably / poorly utilized * Gradual onset, many yrs undetected hyperglycemia, 500- universal gravitational constantmg/dL * advance(prenominal) usu. asymptomatic high risk pt screen each year * Fatigue, recurrent inf, vaginal yeast inf, candida inf, procrastinateed wound healing, visual changes * Risk factor obesity ( abdominal/ visceral ) * 4 major metabolic abnormalities * insulin defense > tissue no rejoinder to insulin / unresp receptors receptors argon located on gaunt muscles, fat &038 liver * ability of pancreas to produce insulin fatigued from compensatory prod of insulin, ell volt aic pile lost * inappropriate glucose by liver too much glucose for body take ons type II * altered prod. of hormones &038 cytokines by adipose tissue ( adipokines) role in glucose &038 fat metabolism type II. Two adipokines ( adiponectin &038 leptin ) displace insulin sensitivity altered mechanism in type I &038 I * Metabolic syndrome > risk for type II &038 cardio dz, cluster of abnormalities, insulin resistance, insulin levels, triglycerides, HDLs, LDLs, HTN * Risk factors for metabolic syndrome central obesity, sedentary lifestyle, urbanization, westernization Gestational Diabetes During pregnancy, 7% of pregnancies * High risk flagitious obesity, prior hx of gestational DM, glycosuria, polycystic ovary syndrome, family hx of DM II screened at 1st antepartum visit * Average risk OGTT at 24-28 wks of gestation * Higher risk of cesarean delivery, perinatal death, neonatal complications * Will have nl glucose levels within 6 wks canpartum but risk of DM II in 5-10 yrs * nutritional therapy 1st line , if doesnt work insulin therapy Other specific types of diabetes * delinquent to other medical condition or treatment causes abn blood glucose levels * injure , injury, destruction of cell function Cushings, hyperthyroidism, pancreatitis, cystic fibrosis, hemochromatosis, TPN * Meds > corticosteroid (prednisone), thiazides, phenytoin(Dilantin), antipsychotics clozapine * Tx underlying condition, stop meds Diagnostic studies * A1C > 6. 5 % great convenience, no fasting req, less day to day alterations during focussing/ illness * FPG &gt126 no thermal intake for 8 hrs prior interrogatory confirmed by repeat testing other day if has s/s and FPG&gt126 further testing OGTT not req * 2 hr OGTT &gt200, glucose load 75g accuracy depends on pt preparation, and factors that influence results.False negative > impaired GI dousing, falsely elevated> onerous restrictions of carbs, discerning illness, meds corticosteroids, contraceptives, bed r est * IFG impaired fasting glucose &038 IGT > prediabetes, 100-125 mg/dL, IGT 2 hr > 140-199 * Glycosylated HgB HgB A1C > amount of glucose attached to HgB molecules over lifespan ( RBC 90-120 years ) DM pts should soften it habituely, arrogatee to monitor success of tx / make changes to tx s/s, promote strong being, prevent acute complications, prevent/ hinder onset/ forward motion met when pt maintain glucose level as near to nl, daily decisions about food for thought intake, blood glucose testing meds, exercise * Rapid acting insulin lispro (Humalog), aspart (NovoLog) onset 0-15 min, tallness 60-90 min, dur. -4 hrs , clear, give 15 min before meals bolus * Short acting languid (Humulin R, Novolin R) onste ? -1 hr, stature 2-3hr, dur 3-6 hrs, injected 30-45 min before meals bolus * Intermediate acting NPH, basal insulin, onset 2-4hrs, peak 4-10hrs can result in hypoglycaemia, dur. 10-16 hrs, can be tangled w/ short &038 fast, cloudy, must be agitated before adm. Long acting glargine (Lantus), detemir ( Levemir) addition to meal clip insulin, type I, to control glucose between meals &038 overnight, without it risk of developing DKA, no peak risk of hypoglycemia , not diluted or intricate, clear onset 1-2 hrs, dur. 24hrs +, basal * Combination > pt dont want 2 separate injections, 2 type of insulin mixed together, not same control of glucose levels as with basal-bolus ahort/ fast mixed w/ ntermediate cater both mealtime &038 basal coverage * Storage > vials room temperature 4 wks, set off &038 freezing alter insulin, between 32-86 F annul direct exp to sunlight, otiose insulin in fridge/ traveling-thermos, Prefilled syringes sight impaired, manual dexterity syringes w/ cudy solution in vertical position needle up to avoid clumping of suspension, rolled gently, warm before injection. * Injection > a bdomen fastest absorption arm, thigh, buttock, rotate within 1 particular order never into site thats about to be exercised (heat = absorption &038 onset), vial 1ml=100U, SQ 90 degrees * Needles ? 5/16 inch (short children, thin adults) gauges 28,29,30,31 higher gauge = smaller diam = more comfortable injection * Recapping done except by soul using syringe, never recap syringe used by pt alcohol swabs in health care facility before inj to HAI, at home soap &038 water * Insulin pump continuous subq insulin infusion 24 hr/d basal rate , loaded w/ rapid acting insulin via plastic tubing to catheter in subq tissue.At meal time bolus . (+) roiled glucose control, standardized to nl physiologic pattern, nl lifestyle, more flexibility (-) infection at site, risk of DKA, cost Problems w/ insulin therapy * Hypoglycemia * Allergic rxn itching, erythema, burning around inj. site, whitethorn improve w/ low dose antihistamine rxns to Zinc, protamine, latex , rubber stoppers on vials * Lipodystrophy atrophy of subq tissue if same inj site used Somogyi effect cringe effect, overdose of insulin induces undetected hypoglycemia in hrs of sleep, produces glucose decline in response to too much insulin s/s headaches, night sweats, nightmares if in first light glucose adcised to check glucose levels at 2-4am if hypoglycemia present at that time.If it is insulin dosage in affecting morning blood glucose is reduced TX less insulin * Dawn phenomenon hyperglycemia on awakening in the morning due to release counterregulatory hormones in predawn hrs ( possibly GH/cortisol) adolescence/ young TX adjustment in timing of insulin adm. or in insulin. Predawn fasting glucose levels insulin production from pancreas , s. ff > wt gain, hypoglycemia * Meglitinides repaglinide(Prandin) insulin prod, less likely cause hypoglycemia because more rapidly absorbed/eliminated, cause wt gain, take 30 min before meal, not if skipped * Biguanides Metformin > glucose lowering, first choice DM II/prediabetes, obese &038 starch blockers slow down carbs absorption, taken with first flake, effectiveness> check 2 hr postprandial glucose levels * Thiazolidinediones Avandia > insulin sensitizers, for pts w/ insulin resistance, dont insulin Production, not cause hypoglycemia risk of MI, stroke , not for pt w/ HF * DPP4 inhibitor Januvia > new class, slow inactivation of incretin hormones DDP4 inh are glucose dependent = risk of hypoglycemia, no wt gain * Incretin mimetics exenatide (Byetta) > stimulate incretin horm which are in DM II, stim. of insulin, Suppress glucagon, satiety = caloric intake, slows gastric change prefilled pen * Amylin analog > Amylin hormone secreted by cells, co secreted w/ insulin Pramlintide (Symlin) is synthetic substance , type I &038 II when glucose level not achieved w/ insulin at mealtimes , subq thigh or abdomen NOT arm , not mixed w/ insulin cause severe hypoglycemia * blockers &8212 masks s/s of hypoglycemia, prolong hypoglycemic effects of insulin * Thiazide / loop diuretic &8212 hyperglycemia, K Nutrition Type I > meal en mucklening, exercise, developed w/ pts alimentation habits &038 legal action pattern in mind, day to day consistency in timing &038 amount of food eaten * Type II > wt privation = change insulin resistance, total fats &038 simple sugars = calorie &038 carbs intake Spacing meals , wt loss 5-7% = glycemic control, regular exercise * Carbohydrates > sugar, starches, fiber whole grains, fruits, veggies, low fat take out include min 130g/d * Glycemic index GI > describe blood glucose levels 2 hrs after(prenominal) carb meal , GI of 100 = 50g glucose * Fiber intake 14g/1000 kcal * Fats 7% of total calories , inhibits gluconeogenesis ( breakdown of glycogenglucose) by liver severe hypoglycemia in pt on insuli n / oral hypoglycemic dx.Moderate alcohol consumption 150 min/wk moderate intensity aerophilous DM II resistance training 3 x wk, virtually adults should 30 min moderate intensity activity 5 x or so days * Exercise > insulin resistance, blood glucose, wt loss which insulin resistance ( may need less meds), triglycerides, LDL, HDL, BP, circulation * Start slowly w/ progression. Insulin, sulfonylureas, meglitinides &gtrisk of hypoglycemia with increase physical activity esp if exercise at peak of dx or no food intake.Effect may last 48 hrs post exercise Exercise 1 hr after meal, have 10-15g carb eat every 30 min. during exercise (prevent hypoglycemia). Before exercise glucose immediate selective information about glucose levels can make adjustments diet, activity, meds * Recomm. for all insulin-treated pts * Multiple insulin injections 3 or more x day, done before meals, before &038 after exercise esp in type I, whenever hypoglycemia suspected, when ill (stress), 2 hrs after become of meal if effective Pancreas transplantation * For pt w/ ESRD, plan to have kidney transplant * Pancreas transplanted following kidney transplant, pancreas alone rare * Pancreas alone only if hx of severe metabolic complications, emotional roblems w/ exogenous insulin, failure of insulin-based centering * Improve quality of life, no exogenous insulin need, no dietary restrictions * scarce partially able to reverse renal &038 neurologic complications * Need long immunosuppression to prevent rejection * Pancreatic islet cell transplantation in observational stage, islets from deceased pancreas via catheter into abdomen portal vein Nursing management * Pt active participant in management of diabetes regimen * Few/no episodes of acute hyper/hypoglycemic episodes, maintain glucose level near nl * Prevent/ delay inveterate complications * Adjust lifestyle to accommodate DM regimen w/ min. stress Nursing assessment Past hx mumps, rubella, viral inf, recent trauma, stress, pregnancy, baby&gt9lbs, Cushing, acromegaly, family hx of DM * Meds > compliance w/ insulin, OA corticosteroids, phenytoin, diuretics * Eyes > drop eyeballs, vitreal hemorrhages, cataract * Skin > dry, warm, inelastic, pigmented lesions on legs, ulcers(feet), loss of hair on toes * Respiratory > Kussmaul rapid, deep * Cardio > hypotension, weak rapid pulse * GI > dry mouth, vomiting, fruity breath * Neuro > altered reflexes, restlessness, confusion, stupor * MS > muscle wasting * Also electrolyte abnormalities, fasting glucose level &gt126, tolerance test> 200, leukocytosis, BUN, creatinine, triglycerides, cholesterol, LDL, HDL, A1C 45yrs without risk factors for diabetes Acute intervention * Hypoglycemia, DK A, HHS hypersmolar hyperglycemic syndrome * Stress f acute illness/ surgery > counterregulatory hormones > hyperglycemia ( even minor upper resp infection or flu can cause this) * Continue regular diet, noncaloric fluids (broth, water, diet gelatin, decaffeinated), take OA/insulin as prescribed, monitor glucose Q4H * Acutely ill DM I , glucose&gt240 test urine for ketones Q3-4H , medium/large report to MD * Ill > eat than normal > continue OA meds/ insulin as prescribed + bread containing fluids (soup, juices, decaffeinated) * Unable to prevail fluids/ food down MD * Dont stop insulin when ill counterregulatory mechanisms will glucose level * Food intake heavy body needs extra energy to deal w/ stress Extra insulin may be needed to meet this demand, prevent DKA in DM I * Intraoperative > IV fluids &038 insulin before, during, after sx when theres no oral intake In DM II w/ OA pardon its temporary measure, doesnt mean worsening of DM * If personal line of credit med ium (w/iodine) > Metformin discontinued 1-2 days before sx, resumed 48 hrs after sx risk of acute renal failure.Resume after kidney function nl ( creatinine checked &038 is nl) * Insulin adm > school proper administration, adjustments, side effects, assess response to insulin tx, if new to insulin assess ability to manage tx safely, cognitive status, ability to recognize/ tx hypoglycemia, if cognitive skill another responsible person must be assigned diff to self inject/ afraid of needles * Follow ups > inspect injection sites ( lipodystrophy ) * Short term warehousing deficit > OA or short acting OA cuz doesnt cause hypoglycemia * OA w/ diet &038 activity, not take extra pill when overindulge * Diligent skin care &038 dental > aily brushing/ flossing, inform dental practitioner about DM * Foot care scrapes, burns treated immediately &038 monitored > nonirritating antiseptic ointment > dry sterile pad> not start to heal in 24 hrs or infection > MD * fix eye e xams * Travel sedentary > walk Q2H to prevent DVT &038 prevent glucose , assoil snacks, extra insulin COMPLICATIONS Diabetic Ketoacidosis DKA * Diabetic coma Profound deficiency of insulin > hyperglycemia, ketosis, acidosis, dehydration * Most likely in DM I pts, but sometimes in DM II ( severe illness/ stress) * Causes > illness, infection, undiagnosed DM I, inadeq insulin dosage, poor self management, neglect * Insulin glucose cant be mightily used for energy fat broken for fuel ketones (by product) serious when ebullient in blood alter pH, cause metabolic acidosis ketonuria (in urine) &038 electrolyes humiliated impaired protein synthesis, nitrogen lost from tissues * Untreated depletion of Na, K, Cl, Mg, phosphate hypovolemiarenal failure/ guardianship of ketones &038 glucose shockcoma (result of dehydration, lytes &038 acidosis)death * s/s > dehydration, poor turgor, dry mm, HR, orthostatic hypotension, Kussmaul , abdominal pain, sunken eyeballs, acetone fruity odor, early s/s > lethargy,weakness * blood glucose &gt250, arterial blood pH IV access begin fluid/ electrolyte transposition NaCL 0. 45% or 0. 9% to restore urine output 30-60 ml/hr &038 BP * glucose level approach 250 5% grape sugar added * Incorrect fluid repl > sudden Na &038 cerebral edema * Obtain K level before insulin started insulin > further K * Insulin withheld until fluid resuscitation &038 K&gt3. 5 * alike rapid IV fluids &038 rapid lowering of glucose cerebral edema Hypersmolar hyperglycemic syndrome HHS * disembodied spirit threatening, able to produce insulin to prevent DKA but not enough to prevent severe hyperglycemia, osmotic diuresis, ECF depletion * Less common than DKA * Often > 60, in DM II Causes > UTI, pneumonia, sepsis, acute illness, new DM II * asymptomatic in early stages > so glucose can rise very high &gt600mg/dL * The higher glucose > in serum osm > neurologic manifestations somnolence, coma, seizures, hemiparesis, aphasia * Rese mble fortuity (stroke) determine glucose level for correct dx * Ketones absent in urine * Tx similar to DKA * First IV 0. 45% or 0. 9% NS, regular insulin given up after fluid replacement * Glucose fall to 250 add glucose 5% dextrose * Hypokalemia not as significant as in DKA * HHs require greater fluid replacement * Assess VS, I&038O, turgor, labs, cardiac / renal observe related to hydration &038 electrolyte levels, mental status, serum osm Hypoglycemia Low blood glucose glucagon &038 epinephrine > defense against hypoglycemia * s/s of epinephrine > shaking, palpitations, nervousness, diaphoresis, anxiety, hunger, pallor * wag req constant supply of glucose > when > affect mental functioning > LOC, diff speaking, visual disturbances, confusion, coma, death * Hypoglycemis unawareness > no warning signs until glucose reach critical point > incoherent, combative, LOC > lots elderly w/ beta blocker meds * When very high glucose level falls too rapidly, too vigoro us management of hyperglycemia * mismatch in timing of food intake &038 peak of isulin/ OA * Can be quickly reversed Check glucose levels, if contain fat that glucose absorption check glucose in 15 min * Still 70 eat regular meal/snack low peanut butter, bread, cheese, crackers, check glucose in 45 min * No significant imptovement after 2-3 doses of 15g carb MD * Pt not alert to swallow 1mg glucagon IM in deltoid muscle ( nausea, vomiting repercussion hypoglycemia) * Hospital setting > 20-50ml of 50% dextrose IV push * chronic COMPLICATIONS OF DM Angiopathy * end organ dz from damage to blood vessels (angiopathy) 2nd to chronic hyperglycemia * leading cause of diabetes-related deaths, 68% deaths due to cardio, 16% strokes * causes accumul.Of glucose metabolism by products (sorbitol) damage to nerve cells, abnormal glucose molecules in basement tissue layer of small blood vessels (eye,kidney), derangement in RBCs oxygenation to tissues * DM I > keep blood glucose levels near to normal retinopathy &038 nephropathy (complications of microvascular complications) Macrovascular complications * Dz of large, medium size blood vessels , earlier onset in pt w/ diabetes * W > 4-6x risk of cardiovascular dz, M > 2-3 x * risk factors > obesity, smoking, HTN, fat intake &038 sedentary lifestyle * Smoking injurious to pt w/DM, risk for blood vessel dz, CV dz, stroke, lower termination amputations * Maintain BP control bar of CV / renal dz Microvascular complication * Thickening of vessel membranes in capillaries/ arterioles in response to chronic hyperglycemia * Are specific to diabetes Eyes ( retinopathy ), kidneys ( nephropathy ), skin (dermopathy ) * Some changes present w/DM II at time of dx, but s/s not appear until 10-20 yrs after onset of DM * Diabetic retinopathy microvascular damage to retina, most common cause of blindness 20-74 yrs old. Nonproliferative> most common, partial occlusion of small blood vesselin retina microaneurysms, Proloferative& gt most severe, involves retina &038 vitreous neovasculization ( form new blood vessels to compensate) if macula involved vision is lost * DM II > dilated eye exam at time of diagnosis &038 annually, DM I within 5 yrs after DM onset * Laser photocoagulation * Virectomy * Glaucoma Nephropathy microvascular complication, damage to small blood vessels that supply glomeruli / kidney.Leading cause of ESRD in US same risk for DM I &038 II > HTN, smoking, genetic predisposition, chronic hyperglycemia * Screen for nephropathy annually w/ measurement albumin / creatinine ratio * If micro/macroalbuminuria > ACE inh ( lisinopril ) or angiotensin II rec antagonist ( Cozaar ) tx HTN &038 delay progression of nephropathy * Aggressive BP management &038 tight glucose control Neuropathy Sensory neuropathy (PNS) loss of protective sensation in lower extremities amputations * Hyperglycemia > sorbitol &038 fructose take in in nerves damage * Distal symmetric polyneuropathy > hand/ feet bil aterally * Loss of sensation to touch/ temperature * Pain > burning, cramping, crushing, tearing , at night * Paresthesias > tingling , burning, itching * At times skin too small (hyperesthesia) * Foot injury &038 ulcerations without having pain TX blood glucose control, topical creams capsaicin ( Zostrix ) 3-4 X/d pain in 2-3 wks, selective serotonin, norepinephrine reuptake inh ( Cymbalta ), pregabali ( Lyrica ), gabapentin involuntary neuropathy can affect all body systems &038 lead to hypoglycemic unawareness, bowel incontinence, diarrhea, urinary retention Complications * Delayed gastric emptying ( gastroparesis ) anorexia, n/v, reflux, fullness, can trigger hypoglycemia by delaying food absorption * Cardiovascular abnormalities , postural hypotension assess change from lying, sitting, standing, painless MI, resting tachycardia HR * Risk for falls * inner dysfunction > ED in diabetic men > 1st s/s of autonomic failure * Neurogenic bladder > urinary retention, diff. voiding, weak stream empty bladder Q3H in sitting position, Crede maneuver ( work lower abdomen) * Cholinergic agonists > benthanechol Feet &038 lower extremities Risk for theme ulcerations &038 lower extremity amputations * Sensory neuropathy > major rosk for amputations due to loss of protective sensations LOPS * Unaware of foot injury, improper footwear, stepping on objects w/ bare feet * Screening using microfilament > insensitivity to 10g Semmes-Weinstein > risk for ulcers * Proper footwear, avoid injuries, diligent skin care, inspect feet daily * expand risk for amputations due to blood flow to lower extremities * PAD s/s > intermittent claudication, pain at rest, cold feet, loss of hair, cap refill, dependent rubor ( redness when extr in dependent position ) * DX ankle brachial index ABI &038 angiography * Casting to redistribute weight on plantar surface * Wound control > debridement, dressings, vacuum, skin grafting etcetera Charcots foot > ankle &0 38 foot changes joint deformity need fitted footwear * Acanthosis nigricans dark, coarse, thickened skin in flexures &038 neck * Necrobiosis lipoidica diabeticorum DM I, red-yellow lesions w/ atrophic skin , shiny &038 transparent revealing blood vessels under the surface young women * Granuloma annulare DM I, autoimmune, partial rings of papules, dorsal surface of hands/ feet Infection Candida albicans, boils, furuncles, bladder infections (glycosuria) antibiotics Gerentologic * reduction in cells, insulin sensitivity, altered carbohydrate metabolism * 20 % > 65 YO * of conditions treated w/ meds that impair insulin action (

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When I was taking enough prednisone, I didn’t need any mestinon. Usually the doctors want us to take just enough prednisone so that with some mestinon we can control our symptoms. Mestinon was very helpful for me at first, but I didn’t like the cramps, sweating, etc, and so aimed for enough prednisone to not need mestinon. I know when I was at 20 mg of prednisone (tapering down) I still didn’t need Mestinon. If I took it, I felt worse — twitchy muscles and so on.
Good Luck
Russ

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Jackson's Health Summary

<h1>Jackson's Health Summary</h1>

Jackson’s Health Summary

3/1/11: Born (37w 2d csection. 8lbs 9ozs)3/3: Vesicostomy surgery (caudel block did NOT work.)3/5: Home3/14: recheck w/ Sumfest for fussiness, red vesicostomy, white D/C from site3/16: Home nurse – no wt gain3/18: Dr recheck (fussy, maintained wt)3/19:Dr recheck (mottled, fussy, urine thick/cloudy)3/19: ICU at Hershey Na 108, K 9.8 Dx. urosepsis ( Enterobactor UTI, Enterococcus Blood ), dehydration, shock treated w/ Gent/Vanco, blood transfusion & dobutamine3/31: D/C from Geisinger on Salt 4meQ QID4/20: routine labs (platelets now high (489) creat 0.5)5/4: 2 month appt – shots with fever x 24’6/8: Nephro appt (Creat 0.4, platelets 560) F/U in 6 mos6/22: pink (Right) eye, rx. eye gtts6/27: fussy x 2 days dx.UTI ( Staph Epidermis ) rx. Augmentin6/28: more tired, CBC/BMP ok, recheck with Dr7/7: fever and diarrhea, last (10th) day of Augmentin, saw Dr, urine/c-diff stool OK.7/8: 4 month appt – shots with fever x 48′ (no more diarrhea)7/13: bad pink eye (Right) rx. Amox x 10d7/18: dx UTI ( E.Coli ), fever 101 x 3 days, happy D/C Amoxil, rx Augmentin7/19: Dr recheck, fever still 101, D/C Augmentin rx Bactrim, Dr NOT concerned w/ platelets7/29: Admit LGH dx UTI ( Enterobator )/pyelo/dehyd WBC 27k, cr 0.5, BUN 22. IM Rocephin x 3d7/31: D/C8/1: f/u ped – rx Cipro x 10d for UTI, decrease intake, Udip neg, fever 100, looks sick, conts D8/9: sleepy but happy, u dip +WBC, culture sent at Dr appt (cult neg)8/12: sudden fever 100.2, sort of fussy, u dip +, Dr appt, dx UTI rx Cipro8/13: admit to GMC dx UTI ( E.Coli ) (cr 0.4, BUN 10, Na 140, WBC norm) IM Rocephin x3 then Bactrim BID x 4d then start Bactrim proph. Uro f/u 6 wk; Nephro f/u 4 mos. rx Prevacid9/7: 100.1, udip +WBC, protein, blood, ER @ HOL d/t weather dx UTI ( Enterococcus Faecalis ) (WBC 17.2k, K+ 7.1, cr 0.5) Rocephin IM9/8: f/u @peds Rocephin shot, rx Augmentin x 8d. (Uro/Nephro N’d GMC closed d/t weather). No fever.9/12: 6 month appt – shots held for 5 days. Vomitting, weird coloring, no fever, urine dip neg. GHP n’d 2nd opinion.9/21: admit LGH dx UTI/pyelo ( E.Coli – resistant to Bactrim) IM Rocephin x2, rx Suprax WBC 13.7, cr 0.5, BUN 30, K4.4.9/25: 6 mos shots and flu shot – fever x24’9/28: Appt w/Sumfest – surgery 10/13.10/3: Fussy, no fever, Udip +WBC, protein & blood. Dr appt (DR Curry)- cult sent “Wait and see” “cont Suprax” (Day 12 of 14)10/4: 101.3, Udip +, Dr Sumfest N’d direct admit to GMC. dx UTI ( Enterococcus species) D/C Suprax, Rocephin IM x2, WBC: Na+ WNL BUN 16 Cr 0.4. US showed debris in B/L ureters. Ucult resist to Rocephin10/8: D/C from GMC after neg urine cult. Rx Amoxicillan x 14 days10/13: Urethral Reconstruction Surgery. PUV snipped, Urethral stricture dilated, Vesicostomy reversed. Croup and D.10/15: D/C’d from GMC with decreased input, D & abd cramping. WBC 18.22. Rx Tylenol #3 and “cont with Amox (day 12of14)”10/15: PM suddenly cath bloody, not draining – to HOLRMC ER for irriagation (sm clot). xfer to GMC ER. Uro Resident irrigated ALOT and did US.Contd with decrease input & D. D/C’d ER at 0500 10/16 10/17: Direct admit to LGH for D/dehydration/? UTI (cult neg). No CBC done. Na/K WNL. Glucose 52, CO2 16, BUN 8, cr 0.6.10/18: D/C from LGH. Rx Omnicef and Amox.10/19: Sumfest d/c cath. Rx ONLY Bactrim. Ped Rx Soy formula x 1 month10/25: Slimy D, decreased input, wt loss, fussy – Dr appt “ok”… Flu shot10/27: 103 fever – LGH ER. UA, CBC, BMP & CXR WNL. Cr 0.610/28: 102.7 fever, whiny, tired. Direct admit LGH for 1 night. Labs/UA WNL cr 0.5. Dx virus10/30: No fever, blotchy rash. Dx Roseola D/C’d Prevacid11/7: Urology Appt at John Hopkins11/15: decreased intake (Jaylee has bad cold) – Dr appt, u cult sent. (NEG) prob teething.11/28: conts with only trace amt protein in U dips, happy as can be, eats 30 ozs/day + table food, crawling and pulling himself up12/15: 9 month well visit. Hep B shot. Teething (top 4)12/19: STINKY urine when he woke (+leuks/trace protein) – rx Augmentin, cult sent (NEG) abx d/c’d1/5/12: “straining” more to pee x 2 wks. Had 1 episode in AM of no void x 2′. Woke from sleep screaming, then peed intermitt lg amts x 7 mins. Uro N – cysto in OR scheduled 1/11. (*Also 2 weeks of teething – 100′ intermitt D, drooling, diaper rash.)1/6: Pre-op H&P appt at Drs office.1/11: OR day: Stricture fixed, cystogram shows NO REFLUX, bladder almost a full circle now, hypospadia repair done. Rx Bactrim and Tyelonl #3. (18lb 10oz)1/12: 7pm spiked 103 fever & tachypneic – to LGH ER. CBC, BMP, CXR OK. D/C’d (cr 0.4, Na+ 138, BUN 7, WBC11)1/13: NOT eatting, 102.5′. Direct admit to LGH dx. Dehydration. BMP OK(cr 0.5, BUN 11) UA dirty, IV fluids, Rocephin1/14: NOT eatting, 102′ U cult was lost, cont Rocephin, dx. RSV+.1/15: eats a little, no fever, Rocephin D/C’d, D, D/C’d from LGH @ 1700 after being playful.1/16: fussy, Ped removed cath, wt 19lb 0oz1/17: Post-op appt at GMC. f/u 4 mos Wet cough, diarrhea1/19: in PM: Cold (96.5′), pale, fussy, out of it – LGH ER ?pneumonia?UTI (cult sent); offered admit to “observe” D/C 02001/20: 0600 to HOLRMC ER for cold (97.2′), fussy & dry diaper. flu (neg) – D/C. wt 18lb2 oz. then 0950 Ped appt for decreased input, cold, wt loss. CBC, BMP, bld cult (WBC 12.8 – viral, Na+ 141, cr 0.4) ?R otitis media – “just watch for now”1/25: 6 top teeth coming in -fussy, runny nose, still has wet cough. saw Dr to check ears – A OK!2/9: Fever x 2d w/ D,pulling at ears, udip WNL – Dr appt, dx. viral GI 20lbs2/12: Direct adm to LGH for UTI/dehyd (dip + for everything), N,V,D 103 fever. ( UTI E.Coli, ?Strep A Blood) WBC 14.4, cr 0.5, BUN ???26, Na 138. IV ceftriaxone. 19lbs2oz2/14: D/C’d. no fever, pleasant2/16: pm started with fever 101, some nasal stuffiness2/17: 0300 spiked 102.6 fever, Dr appt in afternoon for fevers around 102 – CBC, BMP, Bld & urine cult – called with results at 5pm and told to go directly to LGH for direct admit (WBC 22.2, BUN 16, cr 0.5, NA 138, Urine OK. eatting OK, fevers to 103.3 with Tylenol ?virus? 19.4lbs.2/19: D/C’d dx bacterial infection with unknown source. IV Ceftriaxone effective Rx. Augmentin x 5d. + diarrhea, started soy formula. Urine and blood cult neg.2/23: F/U appt with Dr. Give saline drops for snoring, 18lbs 12 ozs (not worried) I mailed paperwork to LGH to access health records. Udip WNL at home, feels cool, clammy often. Walking, 2 molars coming in on top.3/1: 1 year old birthday!! Weight over past few days at home 19lb 7 oz to 19 lb 3.5oz to today 19lb 1oz. Udip WNL yest b/c waking everyother night x 2 nights.3/7: Well check up. 19lb 9oz, got 3 shots, Sleep study scheduled for snoring/apnea, started on Soy milk, has molars popping through, great spirits, Sumfest N’d straining and drippy then hard urine stream- not concerned.3/16: Fever 100.3 x 3d. Teething, NOT sleeping well x 10d, clingy. On Whole milk – 40-48oz/day- pale pasty poo .20 lbs. Walking well, says Milk, Dada, Mama, Bird. Dx pharyngitis (viral). Pee-sized lump L throat. Udip WNL. good urine stream x 1 today (dripping only alot x 10d)3/19: ER LGH 0400 for udip +leuk, blood. (N,V,D x 24 hours prior). dx. UTI ( E.Coli ) Rocephim IM rx. Omnicef. Cont with V all day, so Dr appt in pm for IM Rocephin repeat. Rx Zofran (effective). CBC WNL, cr 0.53/21: acting well. Udip conts with lg blood, sm leuks, + protein. Sumfest N’d – cult results faxed to him, conts to Strian periodically with voids.3/22: Udip WNL3/27: Sumfest finally received cult results – wants f/u 4/11. Udip WNL. Still not eatting foods well, prefers milk bottle (32-40 ozs/day) 19lbs 13 ozs. Hershey called re. sleep study – scheduled 5/10.3/29: Dental appt “gingivitis”. Wt 19lb 13 ozs… saw Ped for eatting advice. “Max 16 ozs milk qday, + 8oz Pediasure if not eatting well each day” They are not worried. Udip WNL4/3: Yeast diaper rash – Lotrimin QID x 3d. Restarted Prevacid 7.5mg since watching his sleeping, and he seems to have reflux a lot while sleeping.4/6: Teething with 4 teeth – pleasant, some loose stools. Eatting better, tol Pediasure/Milk mixture. 19lb 14 ozs. Says Baa, hi, ball, bird. Tries to jump. Loves outside.4/9: after a whiny weekend at Liounis’, + Udip (lg bact, lg blood, + protein) No fever, to LGH ER – dx. UTI ( E.Coli ) IM Rocephin, rx Omnicef. Tylenol for discomfort.4/10: Ped appt – rx. Miraalax, Pediasure BID, stop Bactrim, see Speech therapy, Early Intervention, & OT for refual to eat. 19 lbs 14 ozs. dx. Failure to Thrive. WIC notified.4/11: GMC Uro appt – US no changes in kidney/ureter size, bladder empty, Xray “No constipation” that could be causing UTIs, D/C Bactrim and Miraalax. Unknown reason WHY UTIs now since hypospadia repair. Will do Cysto in OR and repair any strictuers, possibly make urthra opening bigger, but he doubts it is the cause, since bladder is empty. Suspects Ureters are the issue – Ureter surgery is TOO risky at this point and unwarranted since kidneys show no damage from UTIs. Jackson in good spirits – ate chips and pizza!4/12: Udip WNL, snacking more!4/13: Speech therapy eval – “prob bad reflux” will see weekly x 2 to be sure. Ate more than usual today, Udip WNL.4/14: eatting food better x 2.5 days (cheese, chips, baby jars, pickles.) Also 16 oz Pediasure and 24 oz whole milk. Bad diaper rash – ? yeast, Lotrimin applied.4/20: 20lbs 5ozs. Done abx – no daily abx now, eatting more – variety, textures. Conts with acidic D. Teething bottom I teeth. Talking a lot. Pediasure – 2 cans/day + 20 ozs milk. U dip WNL. Peeing without straining. Speech therapy “focus on pureed”.4/27: 20lb 1 oz… not eatting or drinking as much. Teething bad. Tylenol Q4-6. Increased reflux s/s. Speech therapy was a big fight – she states it’s common with teething kids. low grade fever. Udip x 2 WNL. Straining some to pee, but pees into cup on demand.4/28: increased Prevacid to whole tab (15mg) Qday.4/30: Woke w/ vomitting… Udip +lg everything. Dr appt. dx UTI ( E.Coli ) Roephin IM and rx. Omnicef x 10d. rx. Zofran Sumfest N’d- OK with June surgery.5/2: WIC – Pediasure approved 2/day.5/3: Nutritionist – needs 900cc fluid, 1200 calories/day. Plan: 3 can Pediasure, 6-8 ozs H20, 2-4 ozs Cranberry Juice. Eat as wanted… push calories, not food.5/4: Speech – ate better, dipping foods.5/6: Possible antifreeze ingest. – LGH ER, labs OK (cr 0.4). Muchant notified.5/8: 3′ Early Intervention Appt – OT with S June Center on June 17th5/9: Dr f/u appt: Labs OK, GI referral given (May 25th)5/10: Sleep study- had episodes of resps down to 9 or 12 (normal 24-30), results in 1-3 weeks. BP 98/54.5/11: teething/drooling, eatting down to 14 ozs Pediasure/milk mix, udip WNL5/18: croupy with runny nose. Udip WNL. No fever. eatting less. 20lb 12 ozs.5/20: No sympotms. Udip + lg leuk, trace blood – HOL ER. dx UTI ( Enterococcus Faecalis ). Rocephin IM, rx Omnicef. 20lb 3ozs. Eats only Pediasure. sleeping through night. Talking a lot, running, climbing, horse/ATV riding.5/21: ENT apt – had nasal scope!! Everything WNL. Sleep study – mild sleep apnea not needing intervention. No f/u. Suggests have GI reflux study done. Teething – bottom four eye & molars.5/22: Udip still +lg leuk, trace blood. Cult shows resistance to Omnicef – rx. Amox x 10d. Sumfest N’d. + D. Speech: ate a whole yogurt and a pepperoni!! He cries and fights eatting so bad.5/25: Udip trace leuks, 20lb 7ozs. GI appt: Cont Prevacid 15mg, start Carafate QID x 14d then call with improvement or no change status. Will prob scope/biopsy Jackson with Uro surgery – now moved to July 17th. Awaiting Carafate pre-Auth.5/26: Carafate d/c’d 2′ gagging (smells aweful) started Maalox 10cc QID x 10d.6/5: 15 mos appt. WIC rx for 3 Pediasure/day. 2 shots – no fever. (-)PPD6/7: Nephro appt. Stop NaCl x 7 day then blood work. f/u 6 mos. BP 94/? “hopefully surgery will stop the infections” eatting more the past few days. D x 2 days w/ diaper rash.top canine teeth, interested in eatting. Hugs, kisses, tries to jump, runs, shakse “no”.6/14: +D, low grade fever, +MMR rash. Udip WNL. BMP done. Speech Therapy cancelled.6/15: OT visit – Food Play. cr. 0.5 BUN 26 Na 141 (?dehyd?). GI Dr “Maalox x 2 more days, may stop Prevacid in 2 wks if you want, f/u in August, NO scope!”6/17: a lil fussy – Udip +lg leuks/bld – to HOLRMC ER dx UTI (Strep) rx. Amox x10d.6/18: Dr f/u appt. Wt 21 lb. Udip still +lg blood,leuks. WIC appt – 3 Ped/day.6/19: Dr Sumefst and Muchant n’d UTI. Conts with decreased PO intake. Udip +Mod leuks.6/26: Udip WNL, “bratty” x 5 days. Dr Muchant not worried until BUN is 60+7/2: Pre-op appt. 21lbs 7oz. Asks to eat a variety of foods. 2-3bottles Pediasure/day.7/16: OR Cysto: 22lb3oz, BP 90s/50s, No strictures/valves, No reflux, Tiny stricture scar sliced, No catheter, Udip barely + leuk/blood, No pain meds needed7/18: 102 fever. Udip WNL. Dr appt dx. Hand-Foot-Mouth Dz7/24: OT appt – taste buds dull, decrease Pediasure amt. 22lbs7/30: Udip conts with spec grav 1.030, yellow urine.8/14: Nurtition appt – 21lb 13 ozs. (gaining lower end of appropriately). Decrease Pediasure to 20 ozs/day. Stimulate taste buds. Requests GFR w/ next labs. Appeal mailed to GHP.8/17: Intermit coughing spells 2-3 x’s a night (10 mins each) – sounds like whooping cough. No cold s/s. Started 8/3 in Seattle. Ped notified. OT visit… play “mouth games” more. Restarted Maalox until GI visit – ? reflux at night??8/28: repeat BMP: BUN 19, cr 0.5, Na 140. GFR est online of 64. Udip WNL. Appt 9/4 for night cough.9/4: Ped appt for night cough x 5 weeks LCTA. CXR: asthma vs viral. Per Dr, not whoop cough9/5: CHOP – Dr Shukla “needs Urodynamics and Mag 3 to see how the urine is flowing thru kidneys and how the bladder is actually working.” Dr Meyers “Kidneys ok right now, just sit and wait”9/12: Fever and cough all night 101.4-102.4, mottled, c/o right eye and belly pain. Drooling, red spot on tongue x weeks, increased apnea, cough during naps now. Udip WNL, eatting bottles, Dr appt and WIC appt.9/13: 102.5 fevers, front top gum RED and swollen. Peds sent us to HOLRMC ER. CXR “viral bronchiolitis” RSV (-) Pox not done. Taking bottles only, vomits with meds.9/14: did not seelp at all, in ovious pain ?abd pain, tooting, Zofran adm. 1400 F/U appt – dx Hand Foot Mouth dz and viral URI. Benadryl QHS for cough.9/21: OT appt – cont to play with food.9/25: Nutrition appt: only gained 3kg/day (should be 6-10). Only give full strength Peidasure – atleast 3 bottles daily. Push proteins, follow meals with 4 oz Pediasure. No longer coughing at night.10/22: Dx croup, rx. Prednisone x2d. Udip WNL, 24lb4oz, 18 ozs Pedia/day plus 10 bites food11/20: Interested in eatting, 24+ lbs, decreasing Pediasure – now in sippy cups except for bed. Udips WNL.11/27: Conts with dry hacking cough every day, worse at night and after exercise. No wheezing. Dr Knox-Lee ordered STAT xrays to r/o foreign body. Xrays repeated next day due to not being done right. Xrays OK, f/u with her- Probable Pulmon. referral or MDI trial.11/30: Nutrition appt – Max 16 ozs Pediasure, try to get bottles out of bed. try down to 1 bottle by Feb.12/5: croupy all night (not bad though)12/7: worse cold s/s.- constant hacking wet nonprod cough with coarse lung sounds. Benadryl and Maalox not effective.12/10: Dr appt, only runny nose now. prob reflux – f/u with GI. GI emailed… “if cough conts try Prevacid x 2 weeks, see me if no improvement,” Not coughing.12/18: 23lbs 9ozs – eatting more, down to 8ozs Pediasure and 8 ozs Milk – Nutritionist emailed.12/19: Dr appt for Terrible croup all night. states throat very irritated – prob refluxing badly which can cause the croup. Rx: Prevacid, Flovent 2 puffs BID (when not sick Qday), Steroids x 2 days. Will also do 10d Maalox QID for throat healing. 23lbs 15ozs.12/31: No longer coughing, taking 2+ full bottles of Pediasure at night time plus one for naps. WIC paperowrk filled out. MDI Qday and Prevacid only now. Talking in 2 word sentences. Straining to pee sometimes. Udips WNL.1/22/13: Hardly eatting food. 3-4 btls Pediasure. Dx3d, pleasant1/23: GMC for labs/US/appts… CKD stage ONE now, labs WNL – cr 0.4 BUN17. US showed inprovement in hydro. Down to 1/3 chance he’ll need transplant. Bladder still thick… ? try Ditropan IF probs with potty training next year. Nephro doesn’t care about eatting – not kidney related -as long as he’s growing, she’s happy. BP 96/?. F/U 1 year.1/25: Dx6d now, cont to be happy, not sick. 24lb 13 ozs. Dr N – + culturelle daily.1/28: OT: “reflux kids have a hard time getting back to eatting” Cont with food play.2/5: Up all night screaming in pain with vomitting… lasted 8 hours only2/8: Nutrition: needs 1200 cal/day. 25lb 1 oz, 33.6″. Happy with growth. Cont to get in 3 bottles Pediasure for cals, since he’ll only eat junk. + Daily vit. for ice cravings. F/U with GI re. ?celiac dz and need for scope.2/21: 4 BMs No D, woke Q1′ all night screaming in pain. Gas med – no relief. No V,D. c/o Booboo, points to belly. Conts to hardly eat food.2/22: c/o bellypain in early am with 3 BMS no D, drank Pediasure ok. GI Dr appt made – 3/29.2/23: c/o intermitt belly pain – Dx2. Dx over phone OU Pink Eye, rx Cipro gtts x 7d. Right worse than left. Right top molar thru.2/24: Dx3. less c/o’s belly pain. Ate some food today! Eyes less red, goopy.2/25: 1 BM then Dx1. up until 0230 c/o throat pain. +wet cough. Vx2 with cough.2/26: Dr appt: dx GI bug – talked with GI – appt now 3/1. Cont 3-4 bottles Pediasure/day.3/1: GI appt: prob. medical, needs scope with biopsy to check reflux, eosinophiliac esophagitis and celiacs. Liquid Prevacid NOT covered by insurance ($200/month). Scope 3/27.3/13: noon sudden screaming & rolling in pain. c/o leg pain then abd pain. 8pm spike 103.3 fever… Ped said to go to ER at LGH. Abd US ok, no intususseption and less hydro. Abd xray shows gas. No other tests or exam done. Vicodin x1 effective. Suggests Barium swallow to r/o Dyspgia w/ Aberrant subclavian artery .3/14: home from ER at 0330. Woke 0630 screaming in pain, 103.8 fever. Glycerin suppos and Tylenol given. Dr appt 1045. Dx. Flu B. (Strep neg)3/15: Much improvement, no fevers3/22: Woke 0600 screaming in pain – Vx2. 0900 Tylenol for leg and abd pain. Lg BM, No D. No fever. Conts with MDI BID. Still has dry cough without wheezing with exercise. 6 oz Pediasure at 2030, vomitted it all at 0130.3/23:c/o leg/belly pain thru day – obvious discomfort. Tylenol Q4′ helpful. norm BM. No fever. Ate little. 8 oz Pediasure at 2000- then vomitted it all at 0100. Udip WNL.3/24: less c/o’s slept thru night.3/27: GI scope by Dr Peters @West Shore Surgery Center. Everything looked good except for possible delayed stomach emptying. Biopsy results 5 days or so. 24lb 12oz. 107/71, HR 108, 99%. I D/C’d Prevacid and Flovent.4/2:Nutrition: needs min 1200 cal. Conts with good growth. Try meal at midnight feeds. Per GI Dr Kuhn: Biopsy shows reflux – cont Prevacid. Duodenum biopsy “some intraepithelial lymphocytes” suggests possible Celiacs but doesn’t reach enough criteria to diagnose… need blood work. No eosinophelic esophagitis. Did not mention GI delayed emptying.4/3: blood work at LGH (CBC, BMP, Thryoid, Celiac markers,Lipase) (cr 0.5, BUN 21, wbc 13.6) AST 51, ALT 48- liver results not mentioned.4/16: Tried Omeprazole for reflux but he picked the medicine balls out of his ice cream4/30: 1 week of 1/2 strength Pediasure/whole milk just caused D, no increase in eatting. Per Dr Kuhn… “try with Lactaid, he may have milk intolerance” 25lb 15 ozs5/5: Cold s/s x 5d +runny nose, wet cough, D, pleasant. No fever. Tried 1/2 Pediasure/Lactaid.9/3: Still picky eater but we can force him to take a bite now. Still no real interest in eating. 2 bottles of Pediasure a day ave. (usually 1/2 Lactaid.) Tells us before he has to pee if he is naked. Pees outside if not in a diaper. Randomly tells us that it hurts to pee. No meds for months now. At beach last week, had minor issues with sand and cold. Also c/o tummy pain with foot pain x 2 days at beach, but then acted fine 10 mins later – ?.9/26: 30 month checkup… 28 lbs. “Don’t worry about his eating!” start teeth brushing and potty training.10/27: 4 days of fevers 104. c/o mouth pain and foot pain. Strep neg, UA WNL (sm ketones). Tylenol brings fever down to 101/102 only. Prob hand/foot/mouth dz. Then this am started with obvious croup… LGH ER – Rocemic Epi Neb and Orapred 30mg and rx x 5d. Given Tyenol w/ Codeine at home b/c screaming about mouth pain.10/28: F/U with Ped (Take Orapred 15mg x 2d only) restart Flovent Qd (BID when sick)10/31: 101 again… to Ped. “Throat so red” Strep neg, CXR neg, CBC OK (Metamyelocyte high 1%), CMP: BUN 28, cr 0.5, ratio 56. K+ 5.6 (tough draw), AST 56, ALT 42. Rocephin 2 shots. 27lb 12oz.11/1: Cont with 101 fever. Dx Flu B.1/9/2014: 28lb 4 oz. 4-5 bottles Pediasure daily. Per nutrition phone consult “Do not push milk b/c high renal load” suggests seeing Sandra, Speach therapist again. Labs drawn for GMC appts (Renal panel, CBC) Still PICKY eater. Potty training… with no diaper on will potty almost every time. Must double/triple void. Pees every 20 minutes or so. Hides when he poops his diaper. Randomly stopped using his paci!!! Conts to randomly c/o foot/leg pain. Has short hair cut… looks “sick” to me over past few weeks. Has dry skin around mouth- hydrocortisone improving it.1/10: AST/ALT high, per Dr Muchant (Labs ran by mistake at LGH). Ped appt on 1/14 for f/u- will need to see GI again. WBC “slightly high” cr. 0.5 BUN 23.1/14: Dr Cook thinks viral hepatitis from Flu in Oct/Nov. ordered labs, not overly concerned.1/15: Uro appt at GMC… “dramatic improvement of US” – less hydro b/l, megaureters hardly seen on US, bladder wall still thick “cont trying with potty training”. F/U 1 yr.1/16: Nephro appt – Dr. very pleased. No diet restrictions, BUN in 20s is fine (worry when in 60s). BP 100/64 (“ok, but watch”). F/U 1 yr. GI appt – norm kids AST/ALT is 50s. Not overly concerned b/c not all liver enzymes hi “prob related to a virus”. Large amt blood work ordered for 3 weeks or so “Just to be sure, since you are having metemyelocytes rechecked anyway” Referred to GMC feeding clinic though (April 28th) “He will prob just grow out of it”.1/29: Labs at LGH (Metamyelocytes ZERO, AST/ALT down to almost normal, BUN 23 and cr 0.5, Hepatitis neg. Jason forcing him to take bites of dinner, sometimes gags himself.2/18: Dr Kuhn agreed to 2-4 week trial of Periactin (appetite stimulant).3/17:Dr Kuhn notified of Periactin success “cont! if it stops working, we’ll stop and restart. Cancel feeding clinic”. Down to 2 bottles Pediasure daily. Eating more, feels hunger. still picky. Well visit w/ Dr Cooke… 31 lbs, 94/58… only give 1 bottle Pediasure daily, see ENT asap for restless sleep at night with snoring/apnea (appt 3/24). POTTY TRAINED!!!3/24: ENT Kevin, PA appt… “nasal swelling”… try Nasonex x 1 month and see if improvement. in 3 weeks, get Adenoid xray. Tonsils are tiny.3/30: He HATES Nasonex but he is not tossing and turning nearly as bad. Also is not picking nose anymore. Weight down to 28 lbs(down 3 lbs) with 1 bottle Pediasure daily… will increase to 2 bottles.4/23/: Dx sinusitis w/ wheezing (fever 103 x 2d, wet/croupy/whoopy cough). abx x 10d/steroid/nebs.?/?/: ENT f/u D/C spray since he hates it, could do sleep study, but he’d end up with a mask probably – I declined. Xray WNL.6/15: Admit at HOLRMC dx: pyelo ( morganella morgani ). IV Rocephin x2, fluids, tylenol, zofran (fever, c/o “tough guy scar hurts”, scream with void, nausea, bloody urine) WBC 18.1, cr 0.5, BUN 18, NA 1356/16: D/C’d6/17: Ped f/u. rx Bactrim x 10d. f/u Sumfest for prohylact abx? VCUG? US? cystoscope for stricture?nothing? Muchant wants cr repeat next week, Sumfest emailed – on vaca until next week.6/26: Creatnine 0.8 BUN 23 BMP WNL US shows obvious mega ureters. No s/s. Muchant will see us tomorrow. Sumfest N’d.6/27: Muchant “?” Repeat labs in 2 weeks. Had US done at GMC for better imaging: R kidney down to 5.5cm from 6.5 cm plus there is a 0.5cm mass on it (?lymphnode) Left 7cm. Sumfest NOT worried about mass. “Maybe he’s not voiding all the way.” We put Jack back in diaper so he can void freely, he had started to laek a little before getting to potty, thought he was too busy to go to potty.7/2: Uroflowmetry Test WNL with no residual at GMC. “? what’s going on… will go to OR to check it out.” Spoke with Kerry NP @ CHOP… will transfer care there and start Bactrim 2.5cc/day awhile.7/5: LGH labs: cr 0.7, BUN 207/9: Diapers ordered with rx. GMC med records done to CHOP. CHOP apt 7/14. GMC OR 7/24. UA WNL.7/14: CHOP Shukla “OR for cysto/check VUR/suprapubic cath. 7-10d later, MAG3 & urodyn.” “I think the issue is the bladder.” Kaplan “US dx Duplicated Kidney. Pediasure is just fine. No mass on right kidney. Kidneys small, echogenicity says there is damage. Kidneys function 56%. Dx. Pseudo prune belly. F/u 1 mos w/ labs.”9/4: Anesthesia phone call pre-surgery. Wt 33lb 1oz. decreased po and pediasure input. X 4 weeks. D/c’d Periacton. c/o headache intermitt. trying to push fluids.9/6: croupy through night. No fever, LCTA. Albuterol Neb BID Prednisone 15mg x 2d (home treatment). Drs N9/9: CHOP cysto (no urethral obstruction, lg badder) and suprapubic cath placed (clamped, in a dsg) inserted. Creatinine 0.4 BUN 17 despite no po x 17′. 9/10: requires Tylenol #3 and Ditropan for bad bladder spasms. Urine more bloody, CHOP N’d “prob bladder spasms, not UTI. Drain cath PRN”9/11: Keflex for possible UTI. cult sent from Dr Cook. SP Tube to be left open to drain. Ditropan causes him to be very flushed. He is terrirified of the tube. 9/15: mag 3 (right 30%, left 70%). VUDS (bladder divereticulum; held 130 cc, emptied tic completely; no reflux) Suprapubic cath d/c’d; urine cult neg d/c keflex cont Bactrim x 1 year10/29: Neph appt. PTh down to 72, no treatment at this time. BUN 21, cr 0.5, Na 137. Spoke with nutritionist “offer Pediasure only after solids”12/22: U/S and Uro appt: No change. better at potty training, and eatting more! 33lb 15 oz. f/u 6 mos. 12/26: croupy, vomit x4 in 2 hours. No fever. Urine WNL. flu neg. Dx croup, rx predisolone. 1/7/2015: woke mid night w/ 103 fever. Vomit X1. C/o and pain, later c/o right ear pain. Dx OM R ear with large hard wax pellet removed by Dr. Rx augmentin. 2/28: Abd pain with pale BMs and D on/off for a few weeks. Today c/o abd pain x 10 hrs then V. No fever. Udip WNL. 3/3: well visit. 35 lb. stool tests for ongoing and pain. PPD. 3/4: stool spec to LGH 3/5: cont with random hrs c/o umbilical and lower abd pain w/ V. Then fine thru day. Cries in sleep. Ped and GI Nd – warm compresses, 5cc maalox. Tried Ditropan, no effect. Udip WNL. 4/22: GI issues slowly went away. Periactin effective. Has “good” eating days. + 4 bottles Pediasure. Trying Nasonex again for restlessness. Has good potty training days, other days dribbles constantly.5/11: CHOP Nephro Dr Baluarte. F/u 1 year- labs after GI appt. 5/21: CHOP GI Dr Flick. Change Periactin to 3 wks on/1off. Blood work done (CBC, CMP, PTH, Celiacs). If blood ok, go to Hershey feeding clinic. “Prob was a health prob younger and now is behavioral results.” Cont 4 pediasure daily (gives 960 cal). Needs 1300 cal. Results: celiac neg, CBC OK 5/27: results from Nephro. cr 0.6 (up from growth spurt?) BUN 20, PTH WNL 52. Labs in 6 mos, f/u 1 year. 6/22: Uro at CHOP. D/C bactrim is ok! F/u 6 mos 7/2: c/o r ear pain x 2d. Dx ROM rx Augmenting 7/9: 104.4 fever x 24′. Patchy sore throat. HOLRMC ER. Dx virus 7/10: 3rd day of fever 104+ 7/23: Open Fx right thumb; rx Keflex. Eating better on his own still 4 pediasure. “Good” at potty training when his pants are off 7/25: thumb still oozing. Saw Ped for wound check-see Ortho on Monday7/27: Saw Ortho Dr Battista – f/u 2 weeks for X-ray. OK to swim, etc. 9/26: flu shot 12/11: CHOP Uro: potty training going well but also dribbles some. eating well + 2 Pediasures. Counts Periactin cycles. 35.5 lb. US “unchanged”. “Worry about potty training in 2 years.” Creatinine 0.5. BUN 17. Glucose 60. Signed up for PreK 3/4: we’ll visit. Stopped Pediasure on 3/1. 38 lbs. ER check in 2 months. Day time potty trained. 3/8: croup. Prednisone x 2d 3/21: still little, picky eating. Wants milk all day. Solids pushed. Prefers ice cream, pudding, yogurt, cheese, Cheezits. 34lb. Pediasure restarted 1 daily. Udip TRACE PROTEIN x 2 wks. 4/25: CHOP US URO 37lbs 41″ 96/64. Eating!! 1 Pediasure daily. Pee accidents when playing-behavioral? “Drops just come out” sleeps with PM diaper and pad to keep bed dry. Dr wants suprapubic/Urodynamics in Sept – Jason said no. F/u 6 mos for spot, US, uroflow and re eval need for Urodynamics. US showed a little more pee in kidneys/ureters but bladder was full too. Start potty chart 5/3: ENT says adenoids and tonsils must come out “tonsils large” “+3” and no need for sleep study. Uro notified- will do procedures at same time in Fall. 5/23: Ped, Nephro and Dentist say tonsils NOT large. ped ordered Sleep Study at CHOP, before surgery. Cont 1 Pediasure daily- wt 39 lbs. eating OK. Cr up to 0.6 – recheck at Urondynamic appt. “cont to sit and watch and wait”. 7/23: sleep study went well. “Mild apnea” apnea 3.1 times/hr, pox >90. 8/11: ped ordered adenoid X-ray b/c tonsils only +1. ? Only adenoids out? X-ray: “13mm” “large/normal” “nasal passage open” “same size as 2014”. ENT NP N: surgery cancelled f/u different ENT 8/31. Uro N to schedule surgery in Oct. no Pediasure x 1 month… Eating more foods!!8/31: New ENT DR… no ENT surgery needed! mild sleep apnea… no intervention. 9/27: flu shot. Surgery 11/9. Tests 11/23. 1 Pediasure/day to increase at. Wants to stay full day at kindergarten 9/29: Full day kindergarten! Eats1 Pediasure after lunch. still damp undies most times.11/9: CHOP: cysto with Suprapubic cath. No valves or structures. Creat 0.6 11/23: CHOP urodynamics, tube removal. No changes, diverticulum still big. Empties pretty well. “Pee twice each time!” Creat 0.7- he has not eaten or drank x 2 was since suprapubic hurts him a lot. He didn’t dribble at all bc the cath made it hurt, he peed small ants frequently and we drained his cath mostly d/t pain. 5/1: CHOP. U/S unchanged. Creatinine 0.6 (0.5 normal now). Biofeedback went “well”. Void 130cc, retained 30cc. Bought WOBL Watch. 5/17: vomitted X1. UA WNL. C/o butt itch. Dx anal strep. Rx keflex x 10d, Zofran 2 mg prn 5/30: rx Bactroban TID X 7d to get ride of remaining anal strep. 6/13: Dx anal fungal infection. Lotrimin x 10d 7/11: cont c/o a lot of pain with BMs. Saw Dr. 42lb. Exam WNL. Referral to LGH nutrition. Prob anal fissure. Stated Fiber gummy and 1 tsp miraalax. 8/15: Nutritionist @LGH : needs 1800 cal/day to grow/gain wt. pediasure each appx 200 calls- good to give. No daily vit if 2 pediasure/day. Needs 50 ozs liquid every day. Increase protein rich foods. “No Thankyou bite”. F/u 2-3 months. Email 2 wk food log. 10/6: CHOP. US showed a little worse kidneys and ureters, L kidney cyst bigger now. Biofeedback went “well” I forget #s but he did retain. Nothing to do about drips- eventually cath. F/u 3 months Biofeedback. 10/23: Poison Ivy rash x 5d. Treated with Clobestol ointment, now Jason tells me the rx is bad for kidneys. Dr appt. 12:8: CHOP URO Biofeedback. Bladder held 60cc, 20cc post void residual. “Don’t focus on wet pants- him peeing is preserving his kidneys.” Keep strict diary to figure out when he’s leaking. Start Ditropan (to help bladder hold more) 2cc BID- AM and after school. It puts bladder “to sleep” so voiding every other hour is very important. F/u in 3-4 months. Will prob need Cathed in his leftime:( 2/27/18: c/o sore throat and HA, dx strep. Rx Augmentin x 10d. 3/2: 7 yo we’ll visit. 46.5lb 46”. Everything looks good. She wants a CBC done to check Hgb. Dr Cook retiring:( Ditropan working well, no leaks when he takes it. 3/8: 3rd day of generalized intermittent and pain/squeezing. Random N. Some D yest AM, now soft unformed BM. And unremarkable on assess. Pain Kept waking him. Zofran 2mg at 0315 while in bath. Saw Dr at 1pm for bad abd pain with nausea. Zofran 2 mg at 10:30am somewhat effective. Dr said he’s ok, maybe bc of Augmentin that I dc’d on 3/5 (day8) d/t abd pain. Suggested gas meds. V XL amt at 10pm with No fever. Lost 2 lbs since 3/2, 45lbs now. Urine dipped WNL on 3/7. 5/9: chip fracture right middle finger on field trip from being smashed by 2 logs. Very swollen. Tylenol and splint x 3 wks. 9/10: auto appt, US, change rx to Oxybutinin 5mg extend release QHS. 10/2: left school with fever, painful urination, flank pain & sore throat. Udip WNL and strep neg at Dr with Nan (I’m in Hawaii). Abx started until culture results. 10/5: urine and strep cultures neg, feeling better. Abx d/c’d. 10/11: up x 2 in night c/o calf pain. Tylenol and hot baths help. 1/22/19: dx staph impitego infection to finger tip, nostril and left eye area. Rx keflex x 5d, rx abx pint x 7d. 1/28/19: to Ortho Dr for 6 months of intermittent right shin pain that wakes him appx 3 xs a week. Pain is relieved by a 10 minute hot bath. Was dx by Ped in Nov by ortho thought it best to evaluate him. X-ray done. Summary from his admission 7/29/11: “The patient was born at 37 weeks and 2 days to a G5 P3 mother by low-transverse c-section. Prenatal course was complicated by suspected pseudo-prune belly syndrome. At 19 weeks the bladder was very massively enlarged, and there was oligohydramnios, and, therefore, bladder decompression in utero had to be performed. The patient was born with apgar scores of 8 and 9 and with birthweight of 3.917 kg and was large for gestational age. He underwent unsuccessful urethral catheterization while in Geisinger NICU and, therefore, urethral stricture was eventually diagnosed. He had to undergo a vesicostomy at Geisinger on day of life #3. He was discharged then to home but was admitted at 2 weeks of life to hershey med and had a diagnosis of urosepsis with Enterobactor cloacae sensitive only to Gent growing out of his urine. He also had septic shock and required dobutamine drip, and his blood culture grew out Enterococcus faecalis that was sensitive to Ampicillin. He required intubation temporarily for a central line at that point and was severely hyponatremic and hyperkalemic, which had to be corrected. He had been seen by Ped Infectious Disease and nephrology while at hershey Med and was subsequently transferred to Geisinger for further care. The pt has continued to be followed as an outpatient by Geisinger ped Uro and Nephro. His formal diagnosis are bilateral hydronephrosis, hydroureters urethral stricture/bladder outlet obstruction, bladder wall thinkening, hypospadias, chronic kidney disease stage 2, and the appendicovesicostomy. The urinary system abnormalities do give him a diagnosis of pseudo-prune belly sysndrome.”

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