Epigenetics in the Pathogenesis of Esophageal Adenocarcinoma

Epigenetic influences, such as DNA methylation, histone acetylation, and up‐regulation/down‐regulation of genes by microRNAs, change the genetic makeup of an individual without affecting DNA base‐pair sequences. Indeed, epigenetic changes play an integral role in the progression from normal esophageal mucosa to Barrett''s esophagus to esophageal adenocarcinoma via dysplasia–metaplasia–neoplasia sequence. Many genes involved in esophageal adenocarcinoma display hypermethylation, leading to their down‐regulation. The classes of these genes include cell cycle control, DNA and growth factor repair, tumor suppressors, antimetastasis, Wnt‐related genes, and proapoptotic genes. Histone acetylation in the pathophysiology of esophageal diseases has not been thoroughly investigated, and its critical role in the development of esophageal adenocarcinoma is less defined. Many microRNAs have been associated with the development of Barrett''s esophagus and esophageal adenocarcinoma. Here, we critically addressed the specific steps most closely influenced by microRNAs in the progression from Barrett''s esophagus to esophageal adenocarcinoma. However, microRNAs can target up to hundreds of genes, making it difficult to correlate directly with a given phenotype of the disease. Esophageal adenocarcinoma progressing from premalignant condition of Barrett''s esophagus carries an extremely poor prognosis. Risk stratification for patients based on their epigenetic profiles may be useful in providing more targeted and directed treatment to patients.     

National Trends and Outcomes in Dialysis-Requiring Acute Kidney Injury in Heart Failure: 2002–2013

Background

Dialysis-requiring acute kidney injury (D-AKI) is a serious complication in hospitalized heart failure (HF) patients. However, data on national trends are lacking after 2002.

Variations in the branching pattern of posterior division of mandibular nerve: a case report

Purpose

Abnormal communications among the branches of mandibular nerve especially the posterior division are significant due to various procedures undertaken in this region. These variations are worth reporting as they pose serious implications in several interventions in this region, and may even lead to false diagnosis.

Methods

During routine dissection, the mandibular nerve and its branches were dissected in the infratemporal fossa. The branches from the posterior division of the mandibular nerve namely the inferior alveolar and auriculotemporal nerves were carefully dissected, and their abnormal branching pattern was noted.

Results

There was a communicating branch between left inferior alveolar and auriculotemporal nerve. There was also a variant recurrent branch from the left inferior alveolar nerve that supplied the lateral pterygoid muscle.

Conclusions

Such variant branches and communications between the branches of mandibular nerve as seen in this case have an embryological basis and are clinically important in this region especially for dental surgeries and anesthesia.     

Fractional exhaled nitric oxide in children with acute exacerbation of asthma

Objective

To determine whether fractional exhaled nitric oxide (FENO) has a utility as a diagnostic or predictive maker in acute exacerbations of asthma in children.

Design

Analysis of data collected in a pediatric asthma cohort.

Setting

Pediatric Chest Clinic of a tertiary care hospital

Methods

A cohort of children with asthma was followed up every 3 months in addition to any acute exacerbation visits. Pulmonary function tests (PFT) and FENO were obtained at all visits. We compared the FENO values during acute exacerbations with those at baseline and those during the follow up.

Results

243 asthmatic children were enrolled from August 2009 to December 2011 [mean (SD) follow up — 434 (227) days]. FENO during acute exacerbations was not different from FENO during follow up; however, FENO was significantly higher than personal best FENO during follow up (P < 0.0001). FENO during acute exacerbation did not correlate with the severity of acute exacerbation (P=0.29). The receiver operating characteristics curve for FENO as a marker for acute exacerbation had an area under the curve of 0.59. Cut-off of 20 ppb had a poor sensitivity (44%) and specificity (68.7%) for acute exacerbation.

Conclusions

FENO levels during acute exacerbation increase from their personal best levels. However, no particular cut off could be identified that could help in either diagnosing acute exacerbation or predicting its severity.     

Lifestyle Modification for Metabolic Syndrome: A Systematic Review

Background

All 5 components of metabolic syndrome have been shown to improve with lifestyle and diet modification. New strategies for achieving adherence to meaningful lifestyle change are needed to optimize atherosclerotic cardiovascular risk reduction. We performed a systematic literature review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework (PRISMA), investigating optimal methods for achieving lifestyle change in metabolic syndrome.

Methods

We submitted standardized search terms to the PubMed Central, CINAHL, Web of Science, and Ovid databases. Within those results, we selected randomized controlled trials (RCTs) presenting unique methods of achieving lifestyle change in patients with one or more components of the metabolic syndrome. Data extraction using the population, intervention, comparator, outcome, and risk of bias framework (PICO) was used to compare the following endpoints: prevalence of metabolic syndrome, prevalence of individual metabolic syndrome components, mean number of metabolic syndrome components, and amount of weight loss achieved.

Results

Twenty-eight RCTs (6372 patients) were included. Eight RCTs demonstrated improvement in metabolic syndrome risk factors after 1 year. Team-based, interactive approaches with high-frequency contact with patients who are motivated made the largest and most lasting impact. Technology was found to be a useful tool in achieving lifestyle change, but ineffective when compared with personal contact.

Conclusion

Patient motivation leading to improved lifestyle adherence is a key factor in achieving reduction in metabolic syndrome components. These elements can be enhanced via frequent encounters with the health care system. Use of technologies such as mobile and Internet-based communication can increase the effectiveness of lifestyle change in metabolic syndrome, but should not replace personal contact as the cornerstone of therapy. Our ability to derive quantitative conclusions is limited by inconsistent outcome measures across studies, low power and homogeneity of individual studies, largely motivated study populations, short follow-up periods, loss to follow-up, and lack of or incomplete blinding.     

Vectorial capacity and genetic diversity of Anopheles annularis (Diptera: Culicidae) mosquitoes in Odisha,India from 2009 to 2011

Anopheles annularis is one of the major vectors of malaria in Odisha, India. The present study was undertaken to determine the vectorial capacity and assess the genetic diversity of An. annularis collected from different endemic regions of Odisha. Mosquitoes were collected from thirteen endemic districts using standard entomological collection methods from 2009 to 2011. Sibling species of An. annularis were identified by PCR-RFLP and sequencing of D3 region of 28S ribosomal DNA (rDNA) region. Plasmodium falciparum (Pf) sporozoite rate and human blood fed percentage (HBF) were estimated by multiplex PCR using Pf and human specific primers. Genetic diversity of An. annularis was estimated by ISSR markers. Out of 1647 An. annularis collected, 1353 (82.15%) were collected by mechanical aspirators and 294 (17.85%) by light trap. 49 (2.97%) were positive for human blood and 18 (1.09%) were positive for Pf sporozoite. PCR-RFLP and sequencing analyses detected only An annularis A in the study areas. Overall genetic differentiation among An. annularis populations was moderate (F_ST = 0.048) and showed significant correlation between genetic distance and geographic distance (r = 0.882; P < 0.05). Angul population proved to be genetically unique and was highly divergent F_ST > 0.110) from other populations, suggesting low gene flow between them. The study indicated that only An. annularis A was found in Odisha with potential vectorial capacity that can play a major role in malaria transmission. ISSR markers proved to be useful molecular tools to evaluate genetic variability in An. annularis populations.     

Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.The subthalamic nucleus (STN) has long been a structure of interest for researchers and clinicians alike. There is ample evidence that high-frequency stimulation of the STN improves symptoms such as tremor, rigidity, and slowness of movement, so called bradykinesia, in patients with Parkinson disease (see ref. 1 for review), but the mechanism through which this is achieved is still unknown. Some studies suggest that electrical stimulation causes a hyperexcitation of this structure (2), whereas others find evidence that the opposite is true (3–5). Other possible interpretations include the activation of the zona incerta, a neighboring white-matter structure (6) or of fibers coming from the motor cortex (7). Bilateral lesions of the STN improve locomotion (8), a result that is consistent with the inactivation hypothesis. However, previous studies have also found cognitive side effects when using high-frequency stimulation of the STN (9), findings supported by lesion studies in experimental animals, which led to abnormalities in operant tasks involving attention and impulsivity (10, 11). The projections of the STN to other regions help explain the multiple roles of this structure: It sends projections to other targets in the basal ganglia, such as the internal segment of the globus pallidus [also termed the entopeduncular nucleus (EP) in rodents] and the substantia nigra pars reticulata (SNr) (12, 13). The STN is also part of a circuit that includes the prefrontal cortex and the nucleus accumbens (14). It is currently unknown, however, whether these different roles reflect a heterogeneous population of cells, characterized by distinct gene expression. If that is the case, it would allow direct control over each cell population, facilitating the investigation of their respective roles. In rodents, the STN is believed to be composed solely of glutamatergic neurons, characterized by expression of the subtype 2 Vesicular glutamate transporter (Vglut2), whereas the other two subtypes (Vglut1 and Vglut3) have not been detected (15, 16). Selective targeted deletion of Vglut2 expression in this nucleus would therefore provide a specific loss-of-function model that would bypass a common problem presented by traditional lesions with pharmacological agents, which have patterns of diffusion that likely affect surrounding structures (17). It is known, however, that Vglut2 is expressed in many other parts of the brain (18), and a complete knockout in the mouse is not viable (19, 20). There is also evidence that the promoter driving expression of the Paired-like homeodomain 2 (Pitx2) gene is strong in the mouse STN (21) but is also not specific to this structure and a full knockout of Pitx2 expression results in premature death (22). To achieve the desired level of specificity, using a conditional knockout technique previously used to eliminate glutamatergic transmission in other cell types (23), we crossed Pitx2-Cre and Vglut2-lox mice, producing Vglut2^{f/f;Pitx2-Cre} conditional knockout (cKO) mice in which Vglut2 expression in the STN was strongly reduced in comparison with expression levels in littermate control mice. To understand the physiological contribution of the selected subpopulation of STN cells, we characterized these cKO mice with regard to anatomical, electrophysiological, and molecular properties, as well as their performance in a range of behavioral tasks.     

Thyroid status two decades after salt iodization: country-wide data in school children from India

Objective Country‐wide evaluation of thyroid disorders in school children following two decades of universal salt iodization (USI) has not been carried out till date. This study was planned with aim to assess thyroid status of school children two decades after the launch of USI programme. Design Population survey. Patients We collected data from 25 schools in 19 cities across five different geographical zones of India. Those children who were evaluated for anthropometry, and goitre status by palpation formed ‘total population’. Children who consented to give blood samples were defined as ‘study population’. Measurements Serum free T3, free T4, TSH, anti‐TPO antibody and thyroid ultrasound. Results A total of 38 961 children aged 5–15 years formed total population. Goitre rate was 15·5% while thyroid hypoechogenicity was found in 4404 (11·3%) children. In the study population (13 790 children), 2258 (16·4%) had goitre, 505 (3·7%) had positive anti‐TPO antibody titres, 1001 (7·3%) had hypothyroidism (TSH > 5·2 μIU/ml) and 41 (0·3%) had thyrotoxicosis (TSH < 0·1 μIU/ml). Among goitrous children, 203 (9·0%) had anti‐TPO positivity, 365 (16·1%) had hypoechogenicity of thyroid and either of these were present in 488 (21·6%) children. Conclusions Endemic goitre in school children persisted nationwide, despite more than two decades of USI programme. Thyroid autoimmunity only partially explains the increase in goitre prevalence.