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1.  Histone deacetylase inhibitors as novel anticancer therapeutics 
Current Oncology  2008;15(5):237-243.
Histone deacetylase inhibitors represent a promising new class of compounds for the treatment of cancer. Inhibitors of this kind currently under clinical evaluation mainly target the classical (Rpd3/Hda1) family of histone deacetylases. Of particular note, the U.S. Food and Drug Administration recently approved the first histone deacetylase inhibitor (Zolinza: Merck and Co., Whitehouse Station, NJ, U.S.A.) for the treatment of cutaneous T-cell lymphoma. Dozens of such inhibitors are now in phase ii–iii clinical trials, sometimes in combination with other chemotherapy drugs, for diverse cancer types, including both hematologic and solid tumours. In this mini-review, we provide an overview of the histone deacetylase superfamily, highlight the positive results of deacetylase inhibitors in cancer clinical trials, and comment on the prospects for the next generation of such inhibitors.
PMCID: PMC2582508  PMID: 19008999
Histone deacetylase; tubulin acetylation; Hsp90; vorinostat; trichostatin A; tubacin; chromatin; epigenetics
2.  A comparison of expressed sequence tags (ESTs) to human genomic sequences. 
Nucleic Acids Research  1997;25(8):1626-1632.
The Expressed Sequence Tag (EST) division of GenBank, dbEST, is a large repository of the data being generated by human genome sequencing centers. ESTs are short, single pass cDNA sequences generated from randomly selected library clones. The approximately 415 000 human ESTs represent a valuable, low priced, and easily accessible biological reagent. As many ESTs are derived from yet uncharacterized genes, dbEST is a prime starting point for the identification of novel mRNAs. Conversely, other genes are represented by hundreds of ESTs, a redundancy which may provide data about rare mRNA isoforms. Here we present an analysis of >1000 ESTs generated by the WashU-Merck EST project. These ESTs were collected by querying dbEST with the genomic sequences of 15 human genes. When we aligned the matching ESTs to the genomic sequences, we found that in one gene, 73% of the ESTs which derive from spliced or partially spliced transcripts either contain intron sequences or are spliced at previously unreported sites; other genes have lower percentages of such ESTs, and some have none. This finding suggests that ESTs could provide researchers with novel information about alternative splicing in certain genes. In a related analysis of pairs of ESTs which are reported to derive from a single gene, we found that as many as 26% of the pairs do not BOTH align with the sequence of the same gene. We suspect that some of these unusual ESTs result from artifacts in EST generation, and caution researchers that they may find such clones while analyzing sequences in dbEST.
PMCID: PMC146621  PMID: 9092672
3.  Projected Heat-Related Mortality in the U.S. Urban Northeast 
Increased heat-related mortality is projected to be among the major impacts of climate change on human health, and the United States urban Northeast region is likely to be particularly vulnerable. In support of regional adaptation planning, quantitative information is needed on potential future health responses at the urban and regional scales. Here, we present future projections of heat-related mortality in Boston, New York and Philadelphia utilizing downscaled next-generation climate models and Representative Concentration Pathways (RCPs) developed in support of the Intergovernmental Panel on Climate Change (IPCC)’s Fifth Assessment Report (AR5). Our analyses reveal that heat-related mortality rates per 100,000 of population during the baseline period between 1985 and 2006 were highest in Philadelphia followed by New York City and Boston. However, projected heat-related mortality rates in the 2020s, 2050s and 2080s were highest in New York City followed by Philadelphia and Boston. This study may be of value in developing strategies for reducing the future impacts of heat and building climate change resilience in the urban Northeast region.
PMCID: PMC3881138  PMID: 24300074
heat-related mortality; climate change; New York; Boston; Philadelphia
4.  Salmon lice (Lepeophtheirus salmonis) showing varying emamectin benzoate susceptibilities differ in neuronal acetylcholine receptor and GABA-gated chloride channel mRNA expression 
BMC Genomics  2013;14:408.
Caligid copepods, also called sea lice, are fish ectoparasites, some species of which cause significant problems in the mariculture of salmon, where the annual cost of infection is in excess of €300 million globally. At present, caligid control on farms is mainly achieved using medicinal treatments. However, the continued use of a restricted number of medicine actives potentially favours the development of drug resistance. Here, we report transcriptional changes in a laboratory strain of the caligid Lepeophtheirus salmonis (Krøyer, 1837) that is moderately (~7-fold) resistant to the avermectin compound emamectin benzoate (EMB), a component of the anti-salmon louse agent SLICE® (Merck Animal Health).
Suppression subtractive hybridisation (SSH) was used to enrich transcripts differentially expressed between EMB-resistant (PT) and drug-susceptible (S) laboratory strains of L. salmonis. SSH libraries were subjected to 454 sequencing. Further L. salmonis transcript sequences were available as expressed sequence tags (EST) from GenBank. Contiguous sequences were generated from both SSH and EST sequences and annotated. Transcriptional responses in PT and S salmon lice were investigated using custom 15 K oligonucleotide microarrays designed using the above sequence resources. In the absence of EMB exposure, 359 targets differed in transcript abundance between the two strains, these genes being enriched for functions such as calcium ion binding, chitin metabolism and muscle structure. γ-aminobutyric acid (GABA)-gated chloride channel (GABA-Cl) and neuronal acetylcholine receptor (nAChR) subunits showed significantly lower transcript levels in PT lice compared to S lice. Using RT-qPCR, the decrease in mRNA levels was estimated at ~1.4-fold for GABA-Cl and ~2.8-fold for nAChR. Salmon lice from the PT strain showed few transcriptional responses following acute exposure (1 or 3 h) to 200 μg L-1 of EMB, a drug concentration tolerated by PT lice, but toxic for S lice.
Avermectins are believed to exert their toxicity to invertebrates through interaction with glutamate-gated and GABA-gated chloride channels. Further potential drug targets include other Cys-loop ion channels such as nAChR. The present study demonstrates decreased transcript abundances of GABA-Cl and nAChR subunits in EMB-resistant salmon lice, suggesting their involvement in avermectin toxicity in caligids.
PMCID: PMC3691771  PMID: 23773482
Drug resistance; Sea lice; Avermectin; Ligand-gated chloride channel; Cys-loop receptor
5.  The Effects of Binge Drinking on College Students’ Next-Day Academic Test-Taking Performance and Mood State 
Addiction (Abingdon, England)  2010;105(4):655-665.
To assess the effects of binge drinking on students’ next-day academic test-taking performance.
A placebo-controlled cross-over design with randomly assigned order of conditions. Participants were randomized to either alcoholic beverage (mean =.12 g% breath alcohol concentration [BrAC]) or placebo on the first night and then received the other beverage a week later. The next day, participants were assessed on test-taking, neurocognitive performance and mood state.
193 college students (≥ 21 years) recruited from greater Boston.
The trial was conducted at the General Clinical Research Center at the Boston Medical Center.
The Graduate Record Exams © (GREs) and a quiz on a lecture presented the previous day measured test-taking performance; the Neurobehavioral Evaluation System (NES3) and the Psychomotor Vigilance Test (PVT) measured neurocognitive performance; and, the Profile of Mood States (POMS) measured mood.
Test-taking performance was not affected the morning after alcohol administration, but mood state and attention/reaction time were.
Drinking to a level of .12 g% BrAC does not affect next-day test-taking performance, but does affect some neurocognitive measures and mood state.
PMCID: PMC2859622  PMID: 20403018
binge drinking; academic performance; neurocognitive performance; mood state; students; intoxication
6.  Theranostic Profiling for Actionable Aberrations in Advanced High Risk Osteosarcoma with Aggressive Biology Reveals High Molecular Diversity: The Human Fingerprint Hypothesis 
Oncoscience  2014;1(2):167-179.
The survival of patients with advanced osteosarcoma is poor with limited therapeutic options. There is an urgent need for new targeted therapies based on biomarkers. Recently, theranostic molecular profiling services for cancer patients by CLIA-certified commercial companies as well as in-house profiling in academic medical centers have expanded exponentially. We evaluated molecular profiles of patients with advanced osteosarcoma whose tumor tissue had been analyzed by one of the following methods: 1. 182-gene next-generation exome sequencing (Foundation Medicine, Boston, MA), 2. Immunohistochemistry (IHC)/PCR-based panel (CARIS Target Now, Irving, Tx), 3.Comparative genome hybridization (Oncopath, San Antonio, TX). 4. Single-gene PCR assays, PTEN IHC (MDACC CLIA), 5. UT Houston morphoproteomics (Houston, TX). The most common actionable aberrations occur in the PI3K/PTEN/mTOR pathway. No patterns in genomic alterations beyond the above are readily identifiable, and suggest both high molecular diversity in osteosarcoma and the need for more analyses to define distinct subgroups of osteosarcoma defined by genomic alterations. Based on our preliminary observations we hypothesize that the biology of aggressive and the metastatic phenotype osteosarcoma at the molecular level is similar to human fingerprints, in that no two tumors are identical. Further large scale analyses of osteosarcoma samples are warranted to test this hypothesis.
PMCID: PMC4128257  PMID: 25126591
Osteosarcoma; Targeted therapy; Sarcoma; Bone tumors; Next generation sequencing; CLIA; biomarker
7.  Theranostic profiling for actionable aberrations in advanced high risk osteosarcoma with aggressive biology reveals high molecular diversity: the human fingerprint hypothesis 
Oncoscience  2014;1(2):167-179.
The survival of patients with advanced osteosarcoma is poor with limited therapeutic options. There is an urgent need for new targeted therapies based on biomarkers. Recently, theranostic molecular profiling services for cancer patients by CLIA-certified commercial companies as well as in-house profiling in academic medical centers have expanded exponentially. We evaluated molecular profiles of patients with advanced osteosarcoma whose tumor tissue had been analyzed by one of the following methods: 1. 182-gene next-generation exome sequencing (Foundation Medicine, Boston, MA), 2. Immunohistochemistry (IHC)/PCR-based panel (CARIS Target Now, Irving, Tx), 3. Comparative genome hybridization (Oncopath, San Antonio, TX). 4. Single-gene PCR assays, PTEN IHC (MDACC CLIA), 5. UT Houston morphoproteomics (Houston, TX). The most common actionable aberrations occur in the PI3K/PTEN/ mTOR pathway. No patterns in genomic alterations beyond the above are readily identifiable, and suggest both high molecular diversity in osteosarcoma and the need for more analyses to define distinct subgroups of osteosarcoma defined by genomic alterations. Based on our preliminary observations we hypothesize that the biology of aggressive and the metastatic phenotype osteosarcoma at the molecular level is similar to human fingerprints, in that no two tumors are identical. Further large scale analyses of osteosarcoma samples are warranted to test this hypothesis.
PMCID: PMC4128257  PMID: 25126591
Osteosarcoma; Targeted therapy; Sarcoma; Bone tumors; Next generation sequencing; CLIA; biomarker
8.  Detection of Mycoplasma pneumoniae in Spiked Clinical Samples by Nucleic Acid Sequence-Based Amplification 
Journal of Clinical Microbiology  2002;40(4):1339-1345.
Isothermal nucleic acid sequence-based amplification (NASBA) was applied to the detection of Mycoplasma pneumoniae. M. pneumoniae RNA prepared from a plasmid construct was used to assess the sensitivity of the assay, and an internal control for the detection of inhibitors was constructed. The sensitivity of the NASBA assay was 10 molecules of wild-type M. pneumoniae RNA generated in vitro and 5 color-changing units (CCU) of M. pneumoniae. An appropriate specimen preparation procedure was developed: after protease treatment of the respiratory specimens, guanidine thiocyanate lysis solution (4.7 M guanidine thiocyanate [Sigma-Aldrich NV], 46 mM Tris-HCl [Merck, Darmstadt, Germany], 20 mM EDTA [Sigma-Aldrich NV], 1.2% [wt/vol] Triton X-100 [Sigma-Aldrich NV], pH 6.2.) was added. With spiked throats, nasopharyngeal aspirates, bronchoalveolar lavage specimens, and sputum specimens, the sensitivity of the NASBA assay in the presence of the internal control was 2 × 104 molecules of in vitro-generated RNA or 5 CCU of M. pneumoniae. The sensitivity of the NASBA assay was comparable to that of a PCR targeted to the P1 adhesin gene. Fifteen clinical specimens positive for M. pneumoniae by PCR were also positive by NASBA. These results indicate that the sensitivity of detection of M. pneumoniae in spiked respiratory samples by NASBA is high. Together with the use of the internal control, the assay merits evaluation as a diagnostic tool.
PMCID: PMC140351  PMID: 11923354
9.  Bioequivalence of two formulations of montelukast sodium 4 mg oral granules in healthy adults 
Montelukast is an effective and well-tolerated treatment for the prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction and symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. The aim of the study was to compare bioavailability, and characterise the pharmacokinetic profile and safety of Sandoz generic montelukast 4 mg oral granules relative to Singulair® mini (Merck, Sharp & Dohme). An open-label, randomised, single-dose, two-treatment, two-period, two-sequence, two-way crossover bioequivalence study was conducted in healthy male volunteers aged 18–55 years, under fasting conditions. The duration of the clinical part of the trial was ≈ 11 days. Montelukast levels in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters calculated from the drug concentration–time profile using a non-compartmental model. A total of 40 subjects completed both study periods. The ratio test/reference of geometric least squares means was calculated for both formulations of montelukast for the In-transformed pharmacokinetic parameters; the 90% confidence intervals (CIs) were within the pre-defined limits of 80.00–125.00%: 92.2% (90% CI: 87.42–97.30%) for Cmax, 98.1% (90% CI: 94.49–101.81%) for AUC0–t and 97.6% (90% CI: 94.14–101.27%) for AUC0–∞. Two study subjects each reported one mild adverse event: dyspepsia (possibly related to study medication) and throat pain (not considered related to study medication). Sandoz montelukast 4 mg oral granules are bioequivalent to Singulair® 4 mg mini oral granules, with a similar safety profile. This suggests that these two preparations can be considered interchangeable in clinical practice.
PMCID: PMC4172315  PMID: 25250173
Montelukast; Bioequivalence; Asthma; 4 mg oral granules; Sandoz; Singulair® mini; Rhinitis
10.  Pharmacokinetics of recombinant human growth hormone administered by™ 2, a new needle-free device, compared with subcutaneous administration using a conventional syringe and needle 
Growth hormone (GH) is used to treat growth hormone deficiency (GHD, adult and paediatric), short bowel syndrome in patients on a specialized diet, HIV-associated wasting and, in children, growth failure due to a number of disorders including Turner's syndrome and chronic renal failure, and in children born small for gestational age. Different brands and generic forms of recombinant human growth hormone (r-hGH) are approved for varying indications in different countries. New ways of administering GH are required because the use of a needle and syringe or a device where a patient still has to insert the needle manually into the skin on a daily basis can lead to low adherence and sub-optimal treatment outcomes. The objective of this study was to assess the relative bioavailability of r-hGH (Saizen®, Merck Serono) administered by a new needle-free device,™ 2, and a standard needle and syringe.
The study was performed with 38 healthy volunteers who underwent pituitary somatotrope cell down-regulation using somatostatin, according to a randomized, two-period, two-sequence crossover design. Following subcutaneous administration of r-hGH using™ 2 or needle and syringe, pharmacokinetic parameters were analysed by non-compartmental methods. Bioequivalence was assessed based on log-transformed AUC and Cmax values.
The 90% confidence intervals for test/reference mean ratio of the plasma pharmacokinetic variables Cmax and AUC0-inf were 103.7–118.3 and 97.1–110.0, respectively, which is within the accepted bioequivalence range of 80–125%. r-hGH administered by™ 2 is, therefore, bioequivalent to administration by needle and syringe with respect to the rate and extent of GH exposure. Treatment using™ 2 was found to be well tolerated. With™ 2 the tmax was less (3.0 hours) than for needle and syringe delivery (4.5 hours), p = 0.002 (Friedman test), although this is unlikely to have any clinical implications.
These results demonstrate that™ 2 delivers subcutaneous r-hGH exposure that is bioequivalent to the conventional mode of injection. The new device has the additional advantage of being needle-free, and should help to increase patient adherence and achieve good therapeutic outcomes from r-hGH treatment.
PMCID: PMC2093927  PMID: 17922895
11.  A randomised prospective comparison of the Flamingo Wallstent and Ultraflex stent for palliation of dysphagia associated with lower third oesophageal carcinoma 
Gut  2003;52(7):922-926.
Background: Covered metallic oesophageal stents offer effective palliation of malignant oesophageal strictures. However, first generation devices were associated with a high rate of migration, particularly when used in the lower oesophagus.
Aim: To compare the rate of complications and palliative effect of two newer covered metallic oesophageal stents.
Patients and methods: We performed a prospective randomised study using two of these newer stent designs in the treatment of malignant lower third oesophageal tumours. Fifty three patients with dysphagia due to inoperable oesophageal carcinoma involving the lower third of the oesophagus were randomly selected to receive either a Flamingo covered Wallstent (Boston Scientific Inc., Watertown, Massachusetts, USA) or an Ultraflex covered stent (Boston Scientific Inc.). Dysphagia was scored on a five point scale, recorded before stent insertion, the day after, and at least one month later at follow up. Technical success, early and late complications (perforation, migration, severe gastro-oesophageal reflux, haematemesis, and reobstruction due to tumour overgrowth) were also recorded.
Results: In both stent groups, a significant improvement in dysphagia score was seen both the next day post stenting and at late follow up (p<0.05). No significant difference was seen in the improvement in dysphagia between the two groups (p>0.1). The frequency of complications encountered in the two groups was similar. Three patients in the Ultraflex group required two stents at primary stenting.
Conclusion: The two types of stent are equally effective in the palliation of dysphagia associated with lower third oesophageal malignancy and the complication rates associated with their use are comparable.
PMCID: PMC1773700  PMID: 12801944
oesophageal carcinoma; metallic stents; dysphagia; palliation
12.  Safety and Tolerability of Sitagliptin in Type 2 Diabetes: Pooled Analysis of 25 Clinical Studies 
Diabetes Therapy  2013;4(1):119-145.
In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the sitagliptin clinical development program continues, additional studies with sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of sitagliptin by examining pooled data from 25 double-blind clinical studies.
The present analysis included data from 14,611 patients in 25 studies with T2DM who received either sitagliptin 100 mg/day (n = 7,726; sitagliptin group) or a comparator agent (n = 6,885; non-exposed group). These studies represent all randomized, double-blind trials conducted by Merck that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years, and for which results were available as of December 2011. These studies assessed sitagliptin, versus comparator agents, taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or metformin + pioglitazone or rosiglitazone). Patient-level data from each study were used to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events (AEs).
Overall incidence rates of AEs and drug-related AEs were higher in the non-exposed group compared with the sitagliptin group. Incidence rates of specific AEs were generally similar between the two groups, except for higher incidence rates of hypoglycemia related to the greater use of a sulfonylurea and diarrhea related to the greater use of metformin in the non-exposed group, and of constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events, malignancy, or pancreatitis.
In this updated pooled safety analysis of data from 14,611 patients with T2DM, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.
PMCID: PMC3687098  PMID: 23700194
Adverse events; Dipeptidyl peptidase-4 inhibitor; Safety; Sitagliptin; Tolerability; Type 2 diabetes
13.  S28 peptidases: lessons from a seemingly 'dysfunctional' family of two 
BMC Biology  2010;8:87.
A recent paper in BMC Structural Biology reports the crystal structure of human prolylcarboxypeptidase (PRCP), one of the two members of the S28 peptidase family. Comparison of the substrate-binding site of PRCP with that of its family partner, dipeptidyl dipeptidase 7 (DPP7), helps to explain the different enzymatic activities of these structurally similar proteins, and also reveals a novel apparent charge-relay system in PRCP involving the active-site catalytic histidine.
See research article:
The S28 serine peptidase family is something of an enzymatic odd couple. While showing low sequence similarity to all proteins except each other, the two known family members appear to be at odds functionally; one, prolylcarboxypeptidase (PRCP), is a carboxypeptidase that cleaves single hydrophobic residues from the carboxyl termini of proteins that end with a Pro-X motif (where X is any hydrophobic amino acid), while the other, human dipeptidyl peptidase (DPP7), is an aminopeptidase that cleaves amino-terminal X-Pro dipeptides. The structural basis of this orthogonal specificity would undoubtedly be interesting, and a recent report in BMC Structural Biology from the Merck Global Structural Biology group (Soisson et al. [1]) has now met that expectation. In addition they reveal a new wrinkle to the iconic catalytic triad common to most serine hydrolases.
The practical pharmaceutical interest in both these enzymes as potential drug targets is at present speculative. PRCP can inactivate a number of peptide hormones, such as angiotensin II, III and prekallikrein, implicating a role for the enzyme in hypertension, tissue proliferation and smooth-muscle growth. These properties suggest that this enzyme may well be a useful target for hypertension and anti-inflammatory therapy [2]. Another (non-S28 family) dipeptidyl dipeptidase (DPP4) is a major drug target in type 2 diabetes, and Merck has already developed a successful inhibitor of DPP4, the anti-hyperglycemic drug sitagliptin, for the treatment of type 2 diabetes. The DPP enzymes are rich in biological functions and other drug targets emerging from the group are possible [3].
PMCID: PMC2893137  PMID: 20598110
14.  Bicyclic 1-Hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-Containing HIV-1 Integrase Inhibitors Having High Antiviral Potency against Cells Harboring Raltegravir-Resistant Integrase Mutants 
Journal of Medicinal Chemistry  2014;57(4):1573-1582.
Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for the treatment of HIV-1 infections. Merck’s Raltegravir (RAL) (October 2007) and Gilead’s Elvitegravir (EVG) (August 2012), which act as IN strand transfer inhibitors (INSTIs), were the first anti-IN drugs to be approved by the FDA. However, the virus develops resistance to both RAL and EVG, and there is extensive cross-resistance to these two drugs. New “2nd-generation” INSTIs are needed that will have greater efficacy against RAL- and EVG-resistant strains of IN. The FDA has recently approved the first second generation INSTI, GSK’s Dolutegravir (DTG) (August 2013). Our current article describes the design, synthesis, and evaluation of a series of 1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, 1,4-dihydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides. This resulted in the identification of noncytotoxic inhibitors that exhibited single digit nanomolar EC50 values against HIV-1 vectors harboring wild-type IN in cell-based assays. Importantly, some of these new inhibitors retain greater antiviral efficacy compared to that of RAL when tested against a panel of IN mutants that included Y143R, N155H, G140S/Q148H, G118R, and E138K/Q148K.
PMCID: PMC3983366  PMID: 24471816
15.  Are Drug Companies Living Up to Their Human Rights Responsibilities? The Merck Perspective 
PLoS Medicine  2010;7(9):e1000343.
As one viewpoint of three in the PLoS Medicine Debate on whether drug companies are living up to their human rights responsibilities, Geralyn Ritter, Vice President of Global Health Policy and Corporate Social Responsibility at Merck & Co., argues that that multiple stakeholders could do more to help States deliver the right to health.
Background to the debate
The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The “Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines” include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.
PMCID: PMC2946952  PMID: 20927355
16.  Does administration of non-steroidal anti-inflammatory drug determine morphological changes in adrenal cortex: ultrastructural studies 
Protoplasma  2010;246(1-4):109-118.
Rofecoxib (Vioxx© made by Merck Sharp & Dohme, the USA) is a non-steroidal anti-inflammatory drug which belongs to the group of selective inhibitors of cyclooxygenasis-2, i.e., coxibs. Rofecoxib was first registered in the USA, in May 1999. Since then the drug was received by millions of patients. Drugs of this group were expected to exhibit increased therapeutic action. Additionally, there were expectations concerning possibilities of their application, at least as auxiliary drugs, in neoplastic therpy due to intensifying of apoptosis. In connection with the withdrawal of Vioxx© (rofecoxib) from pharmaceutical market, attempts were made to conduct electron-microscopic evaluation of cortical part of the adrenal gland in preparations obtained from animals under influence of the drug. Every morning animals from the experimental group (15 rats) received rofecoxib (suspension in physiological saline)—non-steroidal anti-inflammatory drug (Vioxx©, Merck Sharp and Dohme, the USA), through an intragastric tube in the dose of 1.25 mg during 8 weeks. In the evaluated material, there was found a greater number of secretory vacuoles and large, containing cholesterol and other lipids as well as generated glucocorticoids, lipid drops in cytoplasm containing prominent endoplasmic reticulum. There were also found cells with cytoplasm of smaller density—especially in apical and basal parts of cells. Mitochondria occasionally demonstrated features of delicate swelling. The observed changes, which occurred on cellular level with application of large doses of the drug, result from mobilization of adaptation mechanisms of the organism.
PMCID: PMC2947012  PMID: 20721677
Adrenal cortex; Zona fasciculata; Ultrastructure; Coxibs; Vioxx©
17.  Validation and characterization of DNA microarray gene expression data distribution and associated moments 
BMC Bioinformatics  2010;11:576.
The data from DNA microarrays are increasingly being used in order to understand effects of different conditions, exposures or diseases on the modulation of the expression of various genes in a biological system. This knowledge is then further used in order to generate molecular mechanistic hypotheses for an organism when it is exposed to different conditions. Several different methods have been proposed to analyze these data under different distributional assumptions on gene expression. However, the empirical validation of these assumptions is lacking.
Best fit hypotheses tests, moment-ratio diagrams and relationships between the different moments of the distribution of the gene expression was used to characterize the observed distributions. The data are obtained from the publicly available gene expression database, Gene Expression Omnibus (GEO) to characterize the empirical distributions of gene expressions obtained under varying experimental situations each of which providing relatively large number of samples for hypothesis testing. All data were obtained from either of two microarray platforms - the commercial Affymetrix mouse 430.2 platform and a non-commercial Rosetta/Merck one. The data from each platform were preprocessed in the same manner.
The null hypotheses for goodness of fit for all considered univariate theoretical probability distributions (including the Normal distribution) are rejected for more than 50% of probe sets on the Affymetrix microarray platform at a 95% confidence level, suggesting that under the tested conditions a priori assumption of any of these distributions across all probe sets is not valid. The pattern of null hypotheses rejection was different for the data from Rosetta/Merck platform with only around 20% of the probe sets failing the logistic distribution goodness-of-fit test. We find that there are statistically significant (at 95% confidence level based on the F-test for the fitted linear model) relationships between the mean and the logarithm of the coefficient of variation of the distributions of the logarithm of gene expressions. An additional novel statistically significant quadratic relationship between the skewness and kurtosis is identified. Data from both microarray platforms fail to identify with any one of the chosen theoretical probability distributions from an analysis of the l-moment ratio diagram.
PMCID: PMC3002903  PMID: 21092329
18.  Cation Concentration Variability of Four Distinct Mueller-Hinton Agar Brands Influences Polymyxin B Susceptibility Results 
Journal of Clinical Microbiology  2012;50(7):2414-2418.
Polymyxins have been the only alternative therapeutic option for the treatment of serious infections caused by multidrug-resistant Acinetobacter baumannii or Pseudomonas aeruginosa isolates. For this reason, it is of crucial importance that susceptibility tests provide accurate results when testing these drug-pathogen combinations. In this study, the effect of cation concentration variability found on different commercial brands of Mueller-Hinton agar (MHA) for testing polymyxin B susceptibility was evaluated. The polymyxin B susceptibilities determined using Etest and disk diffusion were compared to those determined by the CLSI reference broth microdilution method. In general, the polymyxin B MIC values were higher when determined by Etest than when determined by broth microdilution against both A. baumannii and P. aeruginosa isolates. A high very major error rate (10%) was observed, as well as a trend toward lower MICs, compared to those determined by broth microdilution when the Merck MHA was tested by Etest. Poor essential agreement rates (10 to 70%) were observed for P. aeruginosa when all MHA brands were tested by Etest. Although an excellent categorical agreement rate (100%) was seen between the disk diffusion and broth microdilution methods for P. aeruginosa, larger zones of inhibition were shown obtained using the Merck MHA. The high cation concentration variability found for the MHA brands tested correlated to the low accuracy, and discrepancies in the polymyxin B MICs were determined by Etest method, particularly for P. aeruginosa isolates.
PMCID: PMC3405622  PMID: 22553247
19.  Adaptation of a previously validated vaccination report card for use in adult vaccine clinical trials to align with the 2007 FDA Toxicity Grading Scale Guidance 
Human Vaccines & Immunotherapeutics  2012;8(9):1208-1212.
The Adult/Adolescent Vaccination Report Card (VRC) was developed and validated by Merck in 1998 for use in vaccine clinical trials to collect information from trial subjects on complaints for both local and systemic events after vaccination. This short report describes the revision to the original validated VRC in order to align with the guidelines outlined in the 2007 FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Since the VRC elicits trial subjects' self-reports of any adverse experiences (AE) occurring post vaccination, it was important that subsequent modifications of the VRC retained the original user-friendly characteristics while gathering the appropriate information to align with the FDA Guidance. A convenience sample of 15 participants (71% females, 87% white and mean (SD) age 45 (13) years was recruited to obtain feedback in order to revise the Adult/Adolescent VRC. Based on the feedback received, the following were slightly revised: ruler for the measurements of local systemic reactions, severity ratings, and general instructions. The revised VRC is currently being used in Merck vaccine clinical trials.
PMCID: PMC3579899  PMID: 22906942
vaccine report card; patient reported outcomes; vaccine safety; vaccination complaints; adverse event collection; injection site reaction
20.  Workplace Safety and Health Improvements Through a Labor/Management Training and Collaboration 
Seven hundred thirty-nine workers at Merck's Stonewall plant in Elkton, Virginia, have a safer and healthier workplace because four of them were enthusiastic about health and safety training they received from the union's training center in Cincinnati, Ohio. What emerged was not only that all 739 plant employees received OSHA 10-hour General Industry training, but that it was delivered by “OSHA-authorized” members of the International Chemical Workers Union Council who worked at the plant. Merck created a new fulltime position in its Learning and Development Department and hired one of the four workers who had received the initial training. Strong plant leadership promoted discussions both during the training, in evaluation, and in newly energized joint labor-management meetings following the training. These discussions identified safety and health issues needing attention. Then, in a new spirit of trust and collaboration, major improvements occurred.
PMCID: PMC4149977  PMID: 24704812
training; labor-management collaboration; safety and health
21.  A comparative study on iMed© and European database for multiple sclerosis to propose a common language of multiple sclerosis data elements 
Establishing and developing minimum data set (MDS), controlled vocabularies, taxonomies and classification systems are requirements of health information system in every society.
The aim of this study was to propose an integrated multiple sclerosis (MS) data set by comparing European database for multiple sclerosis (EDMUS Coordinating Center Lyon, France) and iMed© software's (iMed, Merck Serono SA - Geneva). EDMUS is being developed at the EDMUS coordinating centers in Lyon, France and iMed© is owned and distributed by Merck Serono in Geneva, Switzerland.
Settings and Designs:
Retrieval of data of MDS performed through scholars responsible in related agencies and clinics.
Materials and Methods:
This research was an applied. The study was comparative-exploratory. In this study, data elements in iMed© and EDMUS software's were compared. Data collecting tool was data raw form.
Statistical Analysis Used:
Results analyzing was carried out in a descriptive-comparative method. MS data elements were proposed in three general categories: administrative; clinical; and socio-economic. In this study, a MS data set was suggested by studying data elements of EDMUS and iMed© softwares.
The MS data set includes administrative, clinical and socio-economic data elements that collect information of MS patients during the treatment course. iMed©, EDMUS and other available databases are suitable patterns for determining and recognizing MS key data elements.
Developing MS data set in this study and studying other available MS information systems result in establishing standardized MS data set. By establishing this data set, it will be possible to present MS MDS internationally. MS MDS is the main base of establishing MS information systems at different levels.
PMCID: PMC4275612  PMID: 25540780
Data element; data set; database; information system; minimum data set; multiple sclerosis
22.  Enhancing the quality of international orthopedic medical mission trips using the blue distinction criteria for knee and hip replacement centers 
Several organizations seek to address the growing burden of arthritis in developing countries by providing total joint replacements (TJR) to patients with advanced arthritis who otherwise would not have access to these procedures. Because these mission trips operate in resource poor environments, some of the features typically associated with high quality care may be difficult to implement. In the U.S., many hospitals that perform TJRs use the Blue Cross/Shield’s Blue Distinction criteria as benchmarks of high quality care. Although these criteria were designed for use in the U.S., we applied them to Operation Walk (Op-Walk) Boston’s medical mission trip to the Dominican Republic. Evaluating the program using these criteria illustrated that the program provides high quality care and, more importantly, helped the program to find areas of improvement.
We used the Blue Distinction criteria to determine if Op-Walk Boston achieves Blue Distinction. Each criterion was grouped according to the four categories included in the Blue Distinction criteria— “general and administrative”, “structure”, “process”, or “outcomes and volume”. Full points were given for criteria that the program replicates entirely and zero points were given for criteria that are not replicated entirely. Of the non-replicated criteria, Op-Walk Boston’s clinical and administrative teams were asked if they compensate for failure to meet the criterion, and they were also asked to identify barriers that prevent them from meeting the criterion.
Out of 100 possible points, the program received 71, exceeding the 60-point threshold needed to qualify as a Blue Distinction center. The program met five out of eight “required” criteria and 11 out of 19 “informational” criteria. It scored 14/27 in the “general” category, 30/36 in the “structure” category, 17/20 in the “process” category, and 10/17 in the “outcomes and volume” category.
Op-Walk Boston qualified for Blue Distinction. Our analysis highlights areas of programmatic improvement and identifies targets for future quality improvement initiatives. Additionally, we note that many criteria can only be met by hospitals operating in the U.S. Future work should therefore focus on creating criteria that are applicable to TJR mission trips in the context of developing countries.
PMCID: PMC3850934  PMID: 24060381
Total joint replacement; International medical mission; Dominican; Arthroplasty; Program evaluation
23.  A Comparison of Acute Hemorrhagic Stroke Outcomes in two Populations: The Crete-Boston Study 
While corticosteroid use in Acute Hemorrhagic Stroke (AHS) is not widely adopted, management with intravenous dexamethasone (IVDxM) has been standard of care at the University Hospital of Heraklion, Crete (UH-Crete) with observed outcomes superior to those reported in literature. To explore this further, we conducted a retrospective, multivariable-adjusted two-center study.
We studied 391 AHS cases admitted to UH-Crete between 1/1997 and 7/2010 and compared them with 510 AHS cases admitted to Massachusetts General Hospital, Boston from 1/2003 to 9/2009. Of the Cretan cases, 340 received a tapering scheme of IVDxM, starting with 16–32 mg/day, while the Boston patients were managed without steroids.
The two cohorts had comparable demographics and stroke severity on admission, although anticoagulation was more frequent in Boston. The in-hospital mortality was significantly lower on Crete (23.8%, n=340) than in Boston (38.0 %, n=510; p<0.001) as was the 30-day mortality (Crete: 25.4%, n=307; Boston: 39.4%, n=510; p<0.001). Exclusion of patients on anticoagulants showed even greater differences (30-day mortality: Crete 20.8%; n=259; Boston 37.0%; n=359; p<0.001). The improved survival on Crete was observed three days after initiation of IVDxM and was pronounced for deep-seated hemorrhages. After adjusting for AHS volume/location, GCS, hypertension, diabetes mellitus, smoking, coronary artery disease and statin, antiplatelet and anticoagulant use, IVDxM treatment was associated with better functional outcomes and significantly lower risk of death at 30-days (odds ratio 0.357; 95% C.I. 0.174–0.732).
This study suggests that IVDxM improves outcome in AHS and supports a randomized clinical trial using this approach.
PMCID: PMC3226858  PMID: 22020030
ICH; Dexamethasone; stroke management
24.  Evaluation of a recombinant human gelatin as a substitute for a hydrolyzed porcine gelatin in a refrigerator-stable Oka/Merck live varicella vaccine 
The labile nature of live, attenuated varicella-zoster virus (Oka/Merck) requires robust stabilization during virus bulk preparation and vaccine manufacturing in order to preserve potency through storage and administration. One stabilizing ingredient used in a varicella-zoster virus (VZV) vaccine is hydrolyzed porcine gelatin which represents the major protein/peptide-based excipient in the vaccine formulation.
In this comparative study, a recombinant human gelatin fragment (8.5 kD) was assessed as a potential replacement for hydrolyzed porcine gelatin in an experimental live, attenuated VZV (Oka/Merck) vaccine. VZV (Oka/Merck) was harvested in two formulations prepared with either a hydrolyzed porcine gelatin or a recombinant human gelatin. Moreover, the viral stability in the experimental VZV (Oka/Merck) vaccines was evaluated under accelerated and real-time conditions in a comparative study.
Results and discussion
The stabilizing effect of recombinant human gelatin on VZV (Oka/Merck) potency change during vaccine lyophilization was similar to the experimental vaccine containing porcine-derived gelatin. Vaccine viral potency changes were comparable in stabilized VZV (Oka/Merck) formulations containing either hydrolyzed porcine gelatin or recombinant human gelatin. No statistically significant difference in potency stability was observed between the vaccine formulations stored at any of the temperatures tested.
The recombinant human gelatin demonstrated similar ability to stabilize the live attenuated VZV (Oka/Merck) in an experimental, refrigerator-stable varicella vaccine when compared to the vaccine preparation formulated with hydrolyzed porcine gelatin used in currently marketed varicella vaccine.
PMCID: PMC1808055  PMID: 17319952
25.  The Hospital for the Ruptured and Crippled Eugene H. Pool, Fourth Surgeon-in-Chief 1933–1935 Followed by Philip D. Wilson, Fifth Surgeon-in-Chief 1935 
HSS Journal  2008;4(2):97-106.
In 1933, for the second time in the history of the Hospital for the Ruptured and Crippled (R & C), a general surgeon, Eugene Hillhouse Pool, MD, was appointed Surgeon-in-Chief by the Board of Managers of the New York Society for the Relief of the Ruptured and Crippled. R & C (whose name was changed to the Hospital for Special Surgery in 1940), then the oldest orthopaedic hospital in the country, was losing ground as the leading orthopaedic center in the nation. The R & C Board charged Dr. Pool with the task of recruiting the nation’s best orthopaedic surgeon to become the next Surgeon-in-Chief. Phillip D. Wilson, MD, from the Massachusetts General Hospital in Boston and the Harvard Medical School was selected and agreed to accept this challenge. He joined the staff of the Hospital for the Ruptured and Crippled in the spring of 1934 as Director of Surgery and replaced Dr. Pool as Surgeon-in-Chief the next year. It was the time of the Great Depression, which added a heavy financial toll to the daily operations of the hospital. With a clear and courageous vision, Dr. Wilson reorganized the hospital, its staff responsibilities, professional education and care of patients. He established orthopaedic fellowships to support young orthopaedic surgeons interested in conducting research and assisted them with the initiation of their new practices. Recognizing that the treatment of crippling conditions and hernia were becoming separate specialties, one of his first decisions was to restructure the Hernia Department to become the General Surgery Department. His World War I experiences in Europe helped develop his expertise in the fields of fractures, war trauma and amputations, providing a broad foundation in musculoskeletal diseases that was to be beneficial to him in his future role as the leader of R & C.
PMCID: PMC2553161  PMID: 18815851
Eugene H. Pool; Virgil P. Gibney; William Bradley Coley; Hospital for the Ruptured and Crippled (R & C); New York Hospital; Hospital for Special Surgery (HSS); Philip D. Wilson; Franklin D. Roosevelt; Fiorella H. LaGuardia; Robert Moses; Robert B. Osgood; Memorial Hospital; Philip D. Wilson, Jr; Bradley L. Coley; Bradley L. Coley, Jr; Helen Coley Nauts; Fenwick Beekman

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