Association between preeclampsia and prostasin polymorphism in Pakistani females

Objectives:To investigate the relationship between a prostasin gene variations and the development of preeclampsia in a Pakistani female population.Methods:This was a case-control study carried out at University of Karachi, Karachi, Pakistan between May 2018 and 2019. A single nucleotide polymorphism (SNP) at rs12597511 locus was examined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses in 76 preeclamptic and 74 normotensive expecting mothers.Results:We observed significantly increased risk of preeclampsia associated with the CC genotype of rs12597511 polymorphism as compared to TT (p<0.001, OR=8.08, 95% CI:1.28-31.19) and TT/TC (p<0.001, OR=14.66 and 95% CI: 3.31-65.07) genotypes carriers. Calculation of the allelic distribution revealed a higher frequency of the T allele (82%) among controls; however, the C allele was more prevalent in the preeclamptic group (36%) significantly.Conclusion:The significantly higher C allele frequency in the prostasin gene at the rs12597511 locus in the preeclamptic group indicates that the distribution of the C allele of the prostasin gene is a potential risk factor contributing to the development of preeclampsia.     

Current concepts in combination antibiotic therapy for critically ill patients

Widespread emergence of multidrug resistant (MDR) bacterial pathogens is a problem of global dimension. MDR infections are difficult to treat and frequently associated with high mortality. More than one antibiotic is commonly used to treat such infections, but scientific evidence does not favor use of combination therapy in most cases. However, there are certain subgroups where combination therapy may be beneficial, e.g. sepsis due to carbapenem-resistant Enterobacteriaceae (CRE), bacteremic pneumococcal pneumonia, and patients with multiple organ failure. Well-designed prospective studies are needed to clearly define the role of combination therapy in these subgroups.     

Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features.     

Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice

Interferon‐induced transmembrane protein 3 (IFITM3) ?plays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long‐lasting neuronal impairments in mice following polyriboinosinic‐polyribocytidylic acid (polyI:C, a synthetic double‐stranded RNA)‐induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C‐treated astrocytes (polyI:C‐ACM), neurite development was impaired. These polyI:C‐ACM‐induced neurodevelopmental abnormalities were alleviated by ifitm3^?/? astrocyte‐conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C‐treated wild‐type mice, but such neuronal impairments were not observed in ifitm3^?/? mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non‐cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes. GLIA 2013     

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX-2

Prostanoids generated by COX-2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX-2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX-2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX-2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (DeltaU) or ExoU and ExoT (DeltaUT). COX-2(-/-) mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX-2 products such as prostaglandin E(2) on the function of phagocytic cells. Our studies indicate that prostaglandin E(2) may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E(2) suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor(-/-) mice compared to the wild-type controls. Thus it is possible that inhibition of COX-2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.     

A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin

OBJECTIVE: Glyburide is the most widely used sulfonylurea but has unique pharmacodynamic properties that may increase harm. We hypothesized that glyburide causes more hypoglycemia and cardiovascular events than other secretagogues or insulin. RESEARCH DESIGN AND METHODS: Data sources were Medline, Embase, Cochrane, and three other web-based clinical trial registers (1966-2005). Parallel, randomized, controlled trials in people with type 2 diabetes comparing glyburide monotherapy with monotherapy using secretagogues or insulin were selected. Outcomes were hypoglycemia, glycemic control, cardiovascular events, body weight, and death. Titles and abstracts of 1,806 publications were reviewed in duplicate and 21 relevant articles identified. Data on patient characteristics, interventions, outcomes, and validity were extracted in duplicate using predefined criteria. RESULTS: Glyburide was associated with a 52% greater risk of experiencing at least one episode of hypoglycemia compared with other secretagogues (relative risk 1.52 [95% CI 1.21-1.92]) and with 83% greater risk compared with other sulfonylureas (1.83 [1.35-2.49]). Glyburide was not associated with an increased risk of cardiovascular events (0.84 [0.56-1.26]), death (0.87 [0.70-1.07]), or end-of-trial weight (weighted mean difference 1.69 kg [95% CI -0.41 to 3.80]) compared with other secretagogues. Limitations included suboptimal reporting of original trials. Loss to follow-up exceeded 20% in some studies, and major hypoglycemia was infrequently reported. CONCLUSIONS: Glyburide caused more hypoglycemia than other secretagogues and other sulfonylureas. Glyburide was not associated with an increased risk of cardiovascular events, death, or weight gain.     

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

Compared with other breast cancer subtypes, patients with triple‐negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This—in return—has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti‐PD‐L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key—practice changing—clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.     

Unexpected complication of arteriovenous fistula of the left common carotid to internal jugular vein following central venous catheterization

Incidence of inadvertent arterial puncture secondary to central venous catheter insertion is not common with an arterial puncture rate of<1%.This is due to the advancements and wide availability of ultrasound to guide its insertion.Formation of arteriovenous fistula after arterial puncture is an unexpected complication.Till date,only five cases(including this case)of acquired arteriovenous fistula formation has been described due to inadvertent common carotid puncture.The present case is a 26-year-old man sustained traumatic brain injuries,chest injuries and multiple bony fractures.During resuscitative phase,attempts at left central venous catheter via left internal jugular vein under ultrasound guidance resulted in inadvertent puncture into the left common carotid artery.Surgical neck exploration revealed that the catheter had punctured through the left internal jugular vein into the common carotid artery with formation of arteriovenous fistula.The catheter was removed successfully and common carotid artery was repaired.Postoperatively,the patient recovered and clinic visits revealed no neurological deficits.From our literature review,the safest method for removal is via endovascular and open surgical removal.The pull/push technique(direct removal with compression)is not recommended due to the high risk for stroke,bleeding and hematoma formation.