Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD, particularly in the transition from steatosis to NASH. Mitophagy is a mitochondrial quality control mechanism that allows for the selective removal of damaged mitochondria from the cell via the autophagy pathway. While past work demonstrated a negative association between liver fat content and rates of mitophagy, when changes in mitophagy occur during the pathogenesis of NAFLD and whether such changes contribute to the primary endpoints associated with the disease are currently poorly defined. We therefore undertook the studies described here to establish when alterations in mitophagy occur during the pathogenesis of NAFLD, as well as to determine the effects of genetic inhibition of mitophagy via conditional deletion of a key mitophagy regulator, PARKIN, on the development of steatosis, insulin resistance, inflammation and fibrosis. We find that loss of mitophagy occurs early in the pathogenesis of NAFLD and that loss of PARKIN accelerates the onset of key NAFLD disease features. These observations suggest that loss of mitochondrial quality control in response to nutritional stress may contribute to mitochondrial dysfunction and the pathogenesis of NAFLD.

Endoscopic mucosal resection for early esophageal carcinoma is effective and safe but necessitates continued surveillance.

BACKGROUND: Endoscopic mucosal resection (EMR) is used for the treatment of early esophageal cancer (EEC). METHODS: This a retrospective study aimed to study the efficacy, safety, and the recurrence rate of EEC following EMR. RESULTS: Seventy-nine patients who had undergone EMR for early EEC (T1a andT1b lesions) from 2006 to 2015 were included. EMR alone was considered curative in 51 patients who had T1a lesion. Complete remission was achieved in 50 (98%) patients. Mean number of sessions of EMR was 1.14. Cancer recurred locally in 6 (12%) of 50 patients at a median follow-up of 48 (18-72) months. Endoscopic treatment alone achieved complete remission at last follow up in 47 of 50 patients (94%) who had initial EMR with complete remission, or in 47 of all 51 patients (92%) in whom EMR was considered curative for EC. The Kaplan-Meier cancer-free survival following complete remission with EMR was 94.2% at 1 year and 88.4% at 5 years. Patients with complete eradication of Barrett's had lower risk of recurrence of adenocarcinoma (AC) compared with patients who had persistent Barrett's (p = 0.01). EMR alone was not considered curative in 19 patients, 16 with T1b AC and 3 with T1a squamous cell carcinoma (SCC) invading the muscularis mucosa (m3). Two major adverse events were noted: delayed bleeding requiring hospitalization, and perforation that was closed endoscopically. CONCLUSION: EMR is effective and safe for the management of early EC. The risk of cancer recurrence, albeit small, warrants surveillance. Complete eradication of Barrett's should be attempted in all patients after EMR of AC.

Anti-quorum sensing and antibiofilm potential of Alternaria alternata, a foliar endophyte of Carica papaya, evidenced by QS assays and in-silico analysis.

In the present study, secondary metabolites from an endophytic fungus, Alternaria alternata, colonizing Carica papaya, demonstrated antiquorum sensing properties against Pseudomonas aeruginosa. This study reports the antagonistic effects of fungal crude extract of A. alternata against the various quorum sensing (QS) associated virulent factors such as percentage decrease in production of pyocyanin, alginate, chitinase and rhamnolipid; significant decrease in proteases activity such as LasA protease activity, staphylolytic activity, Las B elastase; and a marked decrease in biofilm formation and associated factors such as exopolysaccharide (EPS) production and cell surface hydrophobicity (CSH). Further, motility pattern i.e., swimming and swarming was also found to be inhibited. This down regulation of QS and associated factors are further supported by in-silico analysis of interaction between QS receptor LasR and bioactive molecules viz., sulfurous acid, 2-propyl tridecyl ester and 1,2-benzenedicarboxylic acid, bis(2-methylpropyl) ester present in fungal crude extract, found based on GCMS analysis, sketches the modulating ability of QS expression. This is the first report on an endophytic fungus of C. papaya having a role in QS inhibition against P. aeruginosa and lays a platform to explore further the endophytes for potent therapeutic agents in QS.

Practical consensus recommendations regarding the use of hormonal therapy in metastatic breast cancer.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors. One of these factors is the levels of hormone receptors (HRs) in the tumor. Cancers with high levels of HRs, called HR-positive, use the hormones estrogen and progesterone to grow and spread. Hormonal therapy is a type of treatment specifically for HR-positive breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of hormonal therapy and the management of HR-positive MBC for the benefit of community oncologists.

Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus.

PURPOSE: The aim of the study was to compare plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between tuberculosis (TB) patients with and without diabetes mellitus (DM). METHODS: Two-hour post-dosing concentrations of RMP, INH and PZA were determined in adult TB patients that were studied with (n = 452) and without DM (n = 1460), treated with a thrice-weekly regimen in India. Drug concentrations were estimated by HPLC. RESULTS: The median (IQR) INH [6.6 (3.9-10.0) and 7.8 (4.6-11.3)] and PZA [31.0 (22.3-38.0) and 34.1 (24.6-42.7)] microgram per milliliter concentrations were significantly lower in diabetic than non-diabetic TB patients (p < 0.001 for both drugs). Blood glucose was negatively correlated with plasma INH (r = -0.09, p < 0.001) and PZA (r = -0.092, p < 0.001). Multiple linear regression analysis showed RMP, INH and PZA concentrations were influenced by age and drug doses, INH and PZA by DM, RMP by alcohol use and PZA by gender and category of ATT. DM reduced INH and PZA concentrations by 0.8 and 3.0 µg/ml, respectively. CONCLUSIONS: TB patients with DM had lower INH and PZA concentrations. Negative correlation between blood glucose and drug concentrations suggests delayed absorption/faster elimination of INH and PZA in the presence of elevated glucose.

Rhinoscleroma with Pharyngolaryngeal Involvement Caused by Klebsiella ozaenae.

Rhinoscleroma is a chronic, slowly progressive granulomatous bacterial infection that is endemic to the tropical world, namely, Central America and Africa. It is occasionally seen in the United States of America (USA). It predominately affects the nasal mucosa but can also involve the rest of the upper respiratory tract. The well-known causative agent for rhinoscleroma is the bacterium Klebsiella rhinoscleromatis, a subspecies of Klebsiella pneumoniae. However, Klebsiella ozaenae can also, albeit very rarely, cause rhinoscleroma. The diagnosis is confirmed by histopathology examination that shows the characteristic Mikulicz cells, considered pathognomonic for this infection. We report a patient with histologically proven rhinoscleroma with pharyngolaryngeal involvement in whom cultures yielded Klebsiella ozaenae. To the best of our knowledge, only two cases of rhinoscleroma due to Klebsiella ozaenae have been reported in the literature to date. Our case illustrates the importance of recognizing this infection in a nonendemic setting such as the USA. A lack of awareness and a delay in the diagnosis of this disease can lead to complications including upper airway obstruction, physical deformity, and, rarely, sepsis. In addition, it must be remembered that the treatment of rhinoscleroma is challenging and requires a prolonged course of antibiotics to achieve a definite cure and avoid relapses.

Electron paramagnetic resonance and photoluminescence investigation on ultraviolet-emitting gadolinium-ion-doped CaAl12O19 phosphors.

The gadolinium doped CaAl12O19 phosphor has been prepared by a low temperature solution combustion method in a short time and characterized using powder X-ray diffraction, energy dispersive analysis of X-ray mapping, electron paramagnetic resonance (EPR) and photoluminescence spectroscopic techniques. EPR and optical analysis of the sample confirm the presence of Gd(3+) in the CaAl12O19 matrix.

Reversible symptoms and clearance of mutant prion protein in an inducible model of a genetic prion disease in Drosophila melanogaster.

Prion diseases are progressive disorders that affect the central nervous system leading to memory loss, personality changes, ataxia and neurodegeneration. In humans, these disorders include Creutzfeldt-Jakob disease, kuru and Gerstmann-Straüssler-Scheinker (GSS) syndrome, the latter being a dominantly inherited prion disease associated with missense mutations in the gene that codes for the prion protein. The exact mechanism by which mutant prion proteins affect the central nervous system and cause neurological disease is not well understood. We have generated an inducible model of GSS disease in Drosophila melanogaster by temporally expressing a misfolded form of the murine prion protein in cholinergic neurons. Flies accumulating this mutant protein develop motor abnormalities which are associated with electrophysiological defects in cholinergic neurons. We find that, upon blocking the expression of the mutant protein, both behavioral and electrophysiological defects can be reversed. This represents the first case of reversibility reported in a model of genetic prion disease. Additionally, we observe that endogenous mechanisms exist within Drosophila that are capable of clearing the accumulated prion protein.

Kikuchi's disease: an uncommon cause of cervical lymphadenopathy.

Kikuchi Fujimoto's disease is a benign self limiting disorder presenting with localised cervical lymphadenopathy, fever, weight loss and night sweats. It is a rare disease with worldwide distribution but commonly reported from Asia. It is diagnosed by excision biopsy of the lymph nodes. Clinical features suggest a viral aetiology though not proven. It is often misdiagnosed as either systemic lupus erythematosus or malignant lymphoma. Better understanding as well as high clinical suspicion would aid in the diagnosis of the disease. Treatment is mainly symptomatic, with non-steroidal analgesics and antipyretics. Corticosteroids are rarely indicated. Although patients show a spontaneous recovery in 1-4 months, a follow-up of several years would be required to study the development of SLE in these patients.

IAPs on the move: role of inhibitors of apoptosis proteins in cell migration.

Inhibitors of Apoptosis Proteins (IAPs) are a class of highly conserved proteins predominantly known for the regulation of caspases and immune signaling. However, recent evidence suggests a crucial role for these molecules in the regulation of tumor cell shape and migration by controlling MAPK, NF-κB and Rho GTPases. IAPs directly control Rho GTPases, thus regulating cell shape and migration. For instance, XIAP and cIAP1 function as the direct E3 ubiquitin ligases of Rac1 and target it for proteasomal degradation. IAPs are differentially expressed in tumor cells and have been targeted by several cancer therapeutic drugs that are currently in clinical trials. Here, we summarize the current knowledge on the role of IAPs in the regulation of cell migration and discuss the possible implications of these observations in regulating tumor cell metastases.

Protein losing enteropathy in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic immunologic disorder that may affect multiple organ systems and present with myriad of clinical features. Gastro-intestinal (GI) manifestations are oral ulcers, dysphagia and abdominal pain caused by autoimmune peritonitis/intestinal vasculitis. Hypoalbuminaemia due to GI loss is uncommon. Protein losing enteropathy (PLE) is a group of clinical entities where there is loss of protein through GI tract. PLE due to SLE is rare but it can be the initial manifestation. Patients usually present with pedal oedema mimicking nephrotic syndrome clinically. It is diagnosed by excluding other causes of hypoalbuminaemia. Radio nucleotide labelled albumin scan is useful in confirming albumin loss through GI tract. Often there is a good response to corticosteroids and immunosuppressive drugs. Here we present two SLE patients whose presenting manifestation was protein losing enteropathy and both improved with corticosteroids.

Hypokalaemic paralysis and normocalcaemic tetany--a rare presentation of Sjogren's syndrome.

38 year old woman was admitted with acute onset of quadriplegia. Biochemical investigation revealed severe hypokalaemia with hyperchloraemic metabolic acidosis, alkaline urine, and positive urinary anion gap which are the hallmark of distal tubular acidosis. In addition she also had hypophosphataemia, normoglycaemic glycosuria, aminoaciduria, and hyperphosphaturia suggestive of proximal tubular dysfunction. Further evaluation confirmed the diagnosis of Sjogren's syndrome. Interestingly our patient also had carpopedal spasm despite normal calcium and magnesium level. Quadriplegia and carpopedal spasm improved with correction of hypokalaemia and acidosis. Proximal tubular abnormalities (except albuminuria) were normalised at the time of discharge. Distal tubular acidosis is a well known renal manifestation of Sjogren's syndrome. But this type of transient proximal tubular dysfunction with distal tubular acidosis in Sjogren's syndrome is very rare and hypokalaemic tetany also deserves mention.

"Herbal remedy is natural and safe"--truth or myth?

Neem oil is often used externally as a traditional medicine in India. Its ingestion, even in small doses produces toxic effects like severe metabolic acidosis, seizures, renal failure and encephalopathy. Management is supportive and prognosis is generally good but fatalities may occur. Herein we report an unusual case of neem oil toxicity in a previously normal adult.

An uncommon presentation of a rare disease - high-degree AV block with takotsubo cardiomyopathy.

Takotsubo cardiomyopathy is a type of non-ischemic cardiomyopathy in which there is sudden temporary left ventricular dysfunction. High-degree AV block and takotsubo cardiomyopathy have been reported together rarely in medical literature. Here we discuss a case of takotsubo cardiomyopathy presenting with complete heart block. A 72-year-old female presented with retrosternal chest pain. Electrocardiogram showed complete heart block without any significant ST-T changes. Echocardiogram revealed regional wall motion abnormality not consistent with coronary artery disease and was suggestive of apical ballooning. Coronary angiogram showed no significant coronary artery lesion. LV angiogram showed apical ballooning and LV systolic dysfunction. Patient underwent temporary pacemaker implantation. Since the complete heart block did not revert even after 18 days, she underwent a permanent pacemaker implantation.

Atrial flutter and pericarditis--a rare complication of right lobe amoebic liver abscess.

A 38 year old gentleman presented with fever and right hypochondrial pain. On further evaluation he was detected to have an amoebic liver abscess (ALA) in the right lobe of the liver. The abscess yielded anchovy sauce pus on percutaneous drainage. Following the percutaneous drainage the patient developed tachycardia. Electrocardiogram revealed atrial flutter with rapid ventricular rate and ST elevation in all leads suggestive of pericarditis. The atrial flutter was reverted to sinus rhythm by cardioversion. The patient then had an uncomplicated convalescence. Amoebic pericarditis, though rare, is a serious complication of amoebic liver abscess. Pericardial complications are usually seen with left lobe liver abscess due to its proximity. Both pericarditis and cardiac arrhythmias due to amoebic liver abscess especially from right lobe are very rare.

Disseminated infection with Strongyloides stercoralis in a diabetic patient.

A 58-year-old male diabetic who was operated for carcinoma larynx 4 years back was admitted with exertional dyspnoea and bilateral leg swelling for the past 2 years. Over the last 2 months, there was a progressive worsening of symptoms. Echocardiography done 2 years back showed pericardial effusion. Echo done during the current admission also showed pericardial effusion with preserved left ventricular function; cytological examination of the pericardial fluid showed larvae of Strongyloides stercoralis. He was treated with antinematodal drugs. A follow-up echo done at discharge showed no pericardial effusion and the patient was completely asymptomatic. To our knowledge, this is the first reported case of Strongyloides pericardial effusion in a diabetic patient.

Regulation of de novo-initiated RNA synthesis in hepatitis C virus RNA-dependent RNA polymerase by intermolecular interactions.

The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has been proposed to change conformations in association with RNA synthesis and to interact with cellular proteins. In vitro, the RdRp can initiate de novo from the ends of single-stranded RNA or extend a primed RNA template. The interactions between the Delta1 loop and thumb domain in NS5B are required for de novo initiation, although it is unclear whether these interactions are within an NS5B monomer or are part of a higher-order NS5B oligomeric complex. This work seeks to address how polymerase conformation and/or oligomerization affects de novo initiation. We have shown that an increasing enzyme concentration increases de novo initiation by the genotype 1b and 2a RdRps while primer extension reactions are not affected or inhibited under similar conditions. Initiation-defective mutants of the HCV polymerase can increase de novo initiation by the wild-type (WT) polymerase. GTP was also found to stimulate de novo initiation. Our results support a model in which the de novo initiation-competent conformation of the RdRp is stimulated by oligomeric contacts between individual subunits. Using electron microscopy and single-molecule reconstruction, we attempted to visualize the low-resolution conformations of a dimer of a de novo initiation-competent HCV RdRp.