Patients Comprehension of Pharmaceutical Package Inserts Information in Karachi, Pakistan

Purpose: To investigate the knowledge and attitude of outpatients regarding pharmaceutical package inserts (PPIs) in Karachi, Pakistan.Methods: The study design was cross-sectional and conducted from August to December 2013. A previously validated questionnaire was adopted, modified and revalidated. Outpatients were asked to respond to the questionnaire.Results: A total of 456 patients responded to the questionnaire. The patients (n = 226, 49 %) were found to be keen on reading inserts in their mother language. Among the study population, 24.1 % (n = 110) of respondents faced problem in reading and 29.8 % (n = 136) in understanding inserts. There was general awareness of the essential components of package inserts and 78.3 % (n = 357) of patients opted for further improvement in PPIs of drugs available in Pakistan. Chi square test revealed that educational status of patients was significantly associated with all of the items of the questionnaire (p < 0.05).Conclusion: The current status of PPIs of drugs available in local markets in Pakistan does not satisfy the patients’ criteria and, therefore, needs improvement. The findings of this study provide a direction necessary to overcome problems related to PPIs and hence promote safe and effective use of medicines.Keywords: Patients, Pharmaceutical package inserts, Awareness, Patients, Safe use of medicine

THE STRUCTURAL MODIFICATION CAUSES THE ENHANCEMENT OF ANALGESIC ACTIVITY OF 4-(4′ CHLORO –PHENYL)-4- HYDROXY PIPERIDINE

Objective- The outstanding  position of piperidine analogues  has proven them an important core in the structures of pharmaceutically active molecules, naturally occurring alkaloids, pharmaceuticals and as synthetic intermediates with interesting biological, physical and pharmacological behaviors. The  piperidine ring containing compound like pethidine having strong opiod analgesic activity, more potent than codein and controls the pain of smooth muscle spasm. Because of having similarity in structure the present study was aimed to estimate the analgesic activity of synthesized derivatives of 4-(4′-Chlorophenyl)-4-hydroxy piperidine.Method- The present study was conducted in animal model, mice by using Pethidine as standard drug. For which the Eddy's hot plate method was adopted and analgesia ( mean increase in latency)  was observed.Result- The result showed the more prominent response of substituted compound than the parent one 4-(4′-Chlorophenyl)-4-hydroxy piperidine†and it was studied that alteration in the molecule structure is accountable for  a better analgesic response.Conclusion- The studies proved the positive pharmacological responsiveness of the combination of 4-(4′-Chlorophenyl)-4-hydroxy piperidine with phencyl halides. These synthesized derivatives will establish as potent analgesics.KEY WORDS:AlkaloidsOpiodAnalgesicPiperidin

Evaluation of computer aided detection of tuberculosis on chest radiography among people with diabetes in Karachi Pakistan

Pakistan ranks fifth among high tuberculosis (TB) burden countries and also has seventh highest burden for diabetes mellitus (DM). DM increases the risk of developing TB and contributes to adverse TB treatment outcomes hence screening and integrated management for both diseases in high burden countries is suggested. Computer-Aided Detection for TB (CAD4TB) can potentially be used as triage tool in low resource settings to pre-screen individuals for Xpert MTB/RIF testing. The aim of this study was to evaluate the diagnostic accuracy and performance of CAD4TB software in people with diabetes (PWD) enrolled in a TB screening program in Karachi, Pakistan. A total of 694 individuals with a diagnosis of DM (of whom 31.1% were newly diagnosed) were screened with CAD4TB and simultaneously provided sputum for Xpert MTB/RIF testing. Of the 74 (10.7%) participants who had bacteriologically positive (MTB+) results on Xpert testing, 54 (73%) had a CAD4TB score \u3e70; and 155 (25%) participants who tested MTB-negative had scores \u3e70. The area under the receiver operator curve was 0.78 (95% CI: 0.77-0.80). Our study findings indicate that CAD4TB offers good diagnostic accuracy as a triage test for TB screening among PWD using Xpert MTB/RIF as the reference standard

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The expression and distribution of Wnt and Wnt receptor mRNAs during early sea urchin development.

The protein beta-catenin plays a critically important role in establishing axial polarity during early animal development. In many organisms, beta-catenin is degraded preferentially on one side of the cleavage stage embryo. On the opposite side of the embryo, beta-catenin is stabilized and accumulates in the nucleus, where it functions in concert with members of the LEF/TCF family to activate the transcription of diverse target genes. Genes that are activated by beta-catenin play an essential role in the specification of endomesoderm and in the establishment of key signaling centers in the early embryo. In several organisms, the asymmetric distribution of maternal components of the canonical Wnt pathway has been shown to be responsible for the polarized stabilization of beta-catenin. In this study, we identified all Wnt and Wnt receptor mRNAs that are present in unfertilized sea urchin eggs and early embryos and analyzed their distributions along the primary (AV) axis. Our findings indicate that the asymmetric distribution of a maternal Wnt or Wnt receptor mRNA is unlikely to be a primary determinant of the polarized stabilization of beta-catenin along the AV axis. This contrasts sharply with findings in other organisms and points to remarkable evolutionary flexibility in the molecular mechanisms that underlie this otherwise very highly conserved patterning process.</p

The genomic regulatory control of skeletal morphogenesis in the sea urchin.

<p>A central challenge of developmental and evolutionary biology is to understand how anatomy is encoded in the genome. Elucidating the genetic mechanisms that control the development of specific anatomical features will require the analysis of model morphogenetic processes and an integration of biological information at genomic, cellular and tissue levels. The formation of the endoskeleton of the sea urchin embryo is a powerful experimental system for developing such an integrated view of the genomic regulatory control of morphogenesis. The dynamic cellular behaviors that underlie skeletogenesis are well understood and a complex transcriptional gene regulatory network (GRN) that underlies the specification of embryonic skeletogenic cells (primary mesenchyme cells, PMCs) has recently been elucidated. Here, we link the PMC specification GRN to genes that directly control skeletal morphogenesis. We identify new gene products that play a proximate role in skeletal morphogenesis and uncover transcriptional regulatory inputs into many of these genes. Our work extends the importance of the PMC GRN as a model developmental GRN and establishes a unique picture of the genomic regulatory control of a major morphogenetic process. Furthermore, because echinoderms exhibit diverse programs of skeletal development, the newly expanded sea urchin skeletogenic GRN will provide a foundation for comparative studies that explore the relationship between GRN evolution and morphological evolution.</p

Genome-wide analysis of the skeletogenic gene regulatory network of sea urchins.

A central challenge of developmental and evolutionary biology is to understand the transformation of genetic information into morphology. Elucidating the connections between genes and anatomy will require model morphogenetic processes that are amenable to detailed analysis of cell/tissue behaviors and to systems-level approaches to gene regulation. The formation of the calcified endoskeleton of the sea urchin embryo is a valuable experimental system for developing such an integrated view of the genomic regulatory control of morphogenesis. A transcriptional gene regulatory network (GRN) that underlies the specification of skeletogenic cells (primary mesenchyme cells, or PMCs) has recently been elucidated. In this study, we carried out a genome-wide analysis of mRNAs encoded by effector genes in the network and uncovered transcriptional inputs into many of these genes. We used RNA-seq to identify >400 transcripts differentially expressed by PMCs during gastrulation, when these cells undergo a striking sequence of behaviors that drives skeletal morphogenesis. Our analysis expanded by almost an order of magnitude the number of known (and candidate) downstream effectors that directly mediate skeletal morphogenesis. We carried out genome-wide analysis of (1) functional targets of Ets1 and Alx1, two pivotal, early transcription factors in the PMC GRN, and (2) functional targets of MAPK signaling, a pathway that plays an essential role in PMC specification. These studies identified transcriptional inputs into >200 PMC effector genes. Our work establishes a framework for understanding the genomic regulatory control of a major morphogenetic process and has important implications for reconstructing the evolution of biomineralization in metazoans.</p

CREB mediates the insulinotropic and anti-apoptotic effects of GLP-1 signaling in adult mouse β-cells

Objective: Glucagon-like peptide-1 (GLP-1) plays a major role in pancreatic β-cell function and survival by increasing cytoplasmic cAMP levels, which are thought to affect transcription through activation of the basic leucine zipper (bZIP) transcription factor CREB. Here, we test CREB function in the adult β-cell through inducible gene deletion. Methods: We employed cell type-specific and inducible gene ablation to determine CREB function in pancreatic β-cells in mice. Results: By ablating CREB acutely in mature β-cells in tamoxifen-treated CrebloxP/loxP;Pdx1-CreERT2 mice, we show that CREB has little impact on β-cell turnover, in contrast to what had been postulated previously. Rather, CREB is required for GLP-1 to elicit its full effects on stimulating glucose-induced insulin secretion and protection from cytokine-induced apoptosis. Mechanistically, we find that CREB regulates expression of the pro-apoptotic gene p21 (Cdkn1a) in β-cells, thus demonstrating that CREB is essential to mediating this critical aspect of GLP-1 receptor signaling. Conclusions: In sum, our studies using conditional gene deletion put into question current notions about the importance of CREB in regulating β-cell function and mass. However, we reveal an important role for CREB in the β-cell response to GLP-1 receptor signaling, further validating CREB as a therapeutic target for diabetes