Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

Peroxisomal footprint in the pathogenesis of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a form of fatty liver disease where benign hepatic steatosis leads to chronic inflammation in the steatotic liver of a patient without any history of alcohol abuse. Mechanisms underlying the progression of hepatic steatosis to NASH have long been investigated. This review outlines the potential role of peroxisomal dysfunctions in exacerbating the disease in NASH. Loss of peroxisomes as well as impaired peroxisomal functions have been demonstrated to occur in inflammatory conditions including NASH. Because peroxisomes and mitochondria co-operatively perform many metabolic functions including O2 and lipid metabolisms, a compromised peroxisomal biogenesis and function can potentially contribute to defective lipid and reactive oxygen species metabolism which in turn can lead the progression of disease in NASH. Impaired peroxisomal biogenesis and function may be due to the decreased expression of peroxisomal proliferator-activated receptor-α (PPAR-α), the major transcription factor of peroxisomal biogenesis. Recent studies indicate that the reduced expression of PPAR-α in NASH is correlated with the activation of the toll-like receptor-4 pathway (TLR-4). Further investigations are required to establish the mechanistic connection between the TLR-4 pathway and PPAR-α-dependent impaired biogenesis/function of peroxisomes in NASH.

Extranodal lymphoma of the tongue, a very rare entity-report of two cases with literature review.

BACKGROUND: Lymphomas are malignant neoplasms of the lymphocyte cell lines affecting the lymph nodes, spleen and other nonhemopoietic tissues. Of the extranodal lymphomas found in the head and neck region, 3-5% of malignant lymphomas arise in the oral and paraoral region, mainly from Waldeyer's ring. The involvement of the base of the tongue is extremely rare. SUMMARISED CASE: Case 1: 64 year old female who presented initially with an enlarged occipital lymph node which gradually became generalized cervical lymphadenopathy with initial histology confirmed reactive lymphoid hyperplasia. Biopsy of left postero-lateral tongue lesion eventually showed high grade T cell lymphoma. Case 2: 85 year old male presented with history of dysphagia for one year who was found to have a lesion extending from his base of tongue into the nasopharynx. Histology showed a diffuse B cell lymphoma. DISCUSSION: Both patients were noted to have lesion of the tongue, but tongue lesions are noted in the literature to be extremely rare. When tongue lymphomas do occur, most are of B-cell origin; the diffuse large-cell variety is the most common. Extranodal lymphomas of the T cell phenotype tend more to be sinonasal in origin than of the tongue, with T cell lymphomas of the tongue being even rarer than B cell lymphomas. CONCLUSION: With regards to tumours arising in the tongue, squamous cell carcinomas are still classified as the most common. Lymphomas however, should still be kept in consideration as a differential diagnosis with regards to lesions arising from this site.

Mechanical Circulatory Support in the Treatment of Advanced Heart Failure.

According to the Centers for Disease Control, heart failure (HF) remains a pervasive condition with high morbidity and mortality, affecting 5.8 million people in the United States and 23 million worldwide. For patients with refractory end-stage HF, heart transplantation is the "gold standard" for definitive treatment. However, the demand for heart transplantation has consistently exceeded the availability of donor hearts, with approximately 2331 orthotopic heart transplantations performed in the United States in 2015 despite an estimated 100 000 to 250 000 patients with New York Heart Association class IIIB or IV symptoms that are refractory to medical treatment, making such patients potential transplant candidates. As such, the need for mechanical circulatory support (MCS) to treat patients with end-stage HF has become paramount. In this review, we focus on the history, advancements, and current use of durable MCS device therapy in the treatment of advanced heart failure.

The effectiveness of conservative management for retropharyngeal abscesses greater than 2 cm.

OBJECTIVES: Conservative management for retropharyngeal abscesses <2 cm is now a first line option. It is unclear if conservative management can be used to manage larger abscesses without increased morbidity and mortality. STUDY DESIGN: A prospective case series was performed from 2012 to 2015 by the Otolaryngology department of the San Fernando General Hospital involving pediatric patients who presented with retropharyngeal abscesses. All patients were initially treated with antibiotics alone. METHODS: Patients with clinical features and CT scan confirmation of a retropharyngeal abscess were included in the study. Those who improved clinically and biochemically within 48 h continued to be treated conservatively and those who deteriorated had surgical intervention. RESULTS: Sixteen patients fulfilled the inclusion criteria. Most patients were Afro Trinidadian males between the ages of two and five who were also found to be iron deficient. Drooling was a sensitive predictor for the presence of an abscess but did not indicate the need for drainage. Hoarseness was the clinical feature that prompted surgical intervention. Sixty three percent of patients had an abscess >2 cm of which 90% improved within 48 h. One patient required surgical drainage with no increase in morbidity or mortality. CONCLUSION: Conservative management of retropharyngeal abscesses >2 cm can be offered to patients during the first 48 h. If the patient demonstrates clinical and biochemical improvement, antibiotics alone can be continued. If the patient deteriorates, surgical drainage can be subsequently performed with no increase in morbidity and mortality.

A simple diagnostic index comprising epithelial membrane antigen and fibronectin for hepatocellular carcinoma.

UNLABELLED: Background and rationale for the study. Continuing search for suitable tumor-markers is of clinical value in managing patients with various malignancies. These markers may be presented as intracellular substances in tissues or may be released into the circulation and appear in serum. Therefore, this work is concerned with identification and quantitative determination of epithelial membrane antigen (EMA) and fibronectin and estimating their performances as surrogate markers for identifying hepatocellular carcinoma (HCC). RESULTS: A total of 627 individuals constituted this study [fibrosis (F1-F3) = 217; cirrhosis = 191; HCC = 219]. Western-blot was used for identifying EMA and fibronectin in sera. As a result, a single immunoreactive band was shown at 130-kDa and 90-kDa corresponding to EMA and fibronectin, respectively. They were quantified using ELISA providing values in HCC higher than fibrosis or cirrhosis with a significant difference (P < 0.0001). For identifying HCC, EMA showed 0.82 area under receiver-operating characteristic curve (AUC) with sensitivity = 70% and specificity = 78% while fibronectin yielded AUC = 0.70 with sensitivity = 67% and specificity = 82%. FEBA-Test comprising fibronectin and EMA together with total-bilirubin and AFP was constructed yielding AUC = 0.92 for identifying HCC from cirrhosis with sensitivity = 89% and specificity = 85%. FEBA-Test was then tested for differentiating HCC from fibrosis showing AUC = 0.97 with sensitivity = 90% and specificity = 89%. FEBA-Test enabled the correct identification of HCC patients with CLIP 0-1 and size ≤ 3 cm with AUC = 0.80 and AUC = 0.84, respectively, indicating its ability in identifying early HCC. CONCLUSIONS: A four-marker index may improve the early detection of HCC with a high degree of accuracy.

Cardiovascular risk and events in 17 low-,middle-, and high-income countries

BACKGROUNDMore than 80% of deaths from cardiovascular disease are estimated to occur inlow-income and middle-income countries, but the reasons are unknown.METHODSWe enrolled 156,424 persons from 628 urban and rural communities in 17 countries(3 high-income, 10 middle-income, and 4 low-income countries) and assessedtheir cardiovascular risk using the INTERHEART Risk Score, a validated score forquantifying risk-factor burden without the use of laboratory testing (with higherscores indicating greater risk-factor burden). Participants were followed for incidentcardiovascular disease and death for a mean of 4.1 years.RESULTSThe mean INTERHEART Risk Score was highest in high-income countries, intermediatein middle-income countries, and lowest in low-income countries (P<0.001).However, the rates of major cardiovascular events (death from cardiovascularcauses, myocardial infarction, stroke, or heart failure) were lower in high-incomecountries than in middle- and low-income countries (3.99 events per 1000 personyearsvs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Casefatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3%in high-, middle-, and low-income countries, respectively; P = 0.01). Urban communitieshad a higher risk-factor burden than rural communities but lower ratesof cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) andcase fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medicationsand revascularization procedures was significantly more common in high-incomecountries than in middle- or low-income countries (P<0.001).CONCLUSIONSAlthough the risk-factor burden was lowest in low-income countries, the rates ofmajor cardiovascular disease and death were substantially higher in low-incomecountries than in high-income countries. The high burden of risk factors in highincome...

Relation of percentage of body fat and maximal aerobic capacity to risk factors for atherosclerosis and diabetes in black and white seven- to eleven-year-old children.

OBJECTIVE: To determine whether body fatness, aerobic capacity, and fat distribution are associated with levels of cardiovascular risk factors in children. METHODS: Subjects (N = 57) were 7 to 11 years of age; their percentage of body fat ranged from 10% to 58%. The percentage of fat was measured with dual-energy x-ray absorptiometry, maximal aerobic capacity was measured on a treadmill, fat distribution was expressed as the waist/hip circumference ratio, and blood pressures were measured with an automated monitor. Measurements of several lipoproteins and apoproteins were combined into one atherogenic index. RESULTS: The percentage of fat was related to the atherogenic index (p = 0.38; p > 0.01) and insulin level (p = 0.78; p > 0.001). Aerobic capacity was inversely related to the atherogenic index (p = -0.27; p > 0.05) and insulin level (p = -0.72; p > 0.001). The waist/hip ratio was not related to the risk factors, and blood pressures were not related to fatness or aerobic capacity. In multiple regression analyses, only fatness explained significant independent proportions of the variance in the atherogenic index and insulin level. After control for fatness, the black children had higher insulin levels (p > 0.05). CONCLUSION: At early ages (7- to 11-year-old children), fatness was related to risk factors for cardiovascular disease and diabetes.

Oral therapy in children with cholera: a comparison of sucrose and glucose electrolyte solutions.

We performed a double-blind trial comparing sucrose electrolyte oral solution with glucose electrolyte oral solution in children less than 5 years of age with severe cholera-like diarrhea. Of 111 patients studied (102 with bacteriologically confirmed cholera), 55 received sucrose solution and 56 received glucose solution. The success rates, as defined by the absence of the need to give unscheduled intravenous therapy, were similar in the two groups (73% and 77% in the sucrose and glucose groups, respectively). There was no difference in purging rates between the two groups. The primary determinant of success for oral fluid regardless of the sugar was the purging rate. Sucrose malabsorption was responsible for oral therapy failure in one child. This study demonstrates that sucrose is an effective alternative to glucose in the oral therapy solution, but either must be used in conjunction with intravenous solution when treating severe dehydrating diarrhea.

PIP: This study compared, in children with cholera-like severe diarrhea, an oral glucose-electrolyte solution with an oral sucrose-electrolyte solution in equimolar amounts (WHO formula) in a double-blind manner. Of 111 patients, 55 were given sucrose and 56 glucose solutions. An absence of the need to use unscheduled intravenous therapy defined the success rate, which was similar in both groups: 73 and 77%, respectively, in the sucrose and glucose groups. Purgation rates also showed no difference between groups. The main determinant of success for oral fluid regardless of the sugar used was the purging rate. 1 failure of therapy in the sucrose group was attributed to sucrose malabsorption. It is concluded that sucrose is an effective alternative to glucose for oral rehydration therapy, but if the diarrhea has caused severe dehydration before the start of treatment, intravenous supplementation must also be used.