Thoracoscopic pleural brushing — an innovative method of pleural sampling in diagnostic medical thoracoscopy

Introduction: Pleural biopsy is the commonest mode of obtaining thoracoscopic pleural specimens from suspected pleural lesions. However, this may be associated with a risk of bleeding in certain cases. The decision to perform biopsy could be difficult, especially when the lesions are close to vascular structures and the visceral pleura. So, pleural brushing can be used to get safely thoracoscopic specimens in addition to biopsy samples. Aim: To determine the sensitivity and specificity of thoracoscopic pleural brushing in exudative pleural effusions. Material and methods: This prospective study was done in the Department of Pulmonary Medicine, Sri Manakula Vinayagar Medical College, Pondicherry, India on 80 patients with exudative pleural effusion in whom pleural fluid analysis and closed pleu-ral biopsy results were inconclusive. All these patients were subjected to medical thoracoscopy after getting informed consent. Pleural biopsy and pleural brushings were taken and sent for analysis. Results: Thoracoscopic pleural biopsy was diagnostic in 76 of 80 patients (95%). Thoracoscopic pleural brushing was diagnostic in 74 patients (92.5%). Histopathology revealed malignancy (82.7%), granulomatous inflammation (11.5%) and nonspecific inflam-mation (5.7%). The sensitivity and specificity of pleural brushing were 96% and 75%, respectively. Interestingly, pleural brushing was the only diagnostic modality in one patient that was reported to be adenocarcinoma. Conclusions: Thoracoscopic pleural brushing is an easy, convenient and safe procedure as it can augment the diagnostic yield of thoracoscopy. It is of significant value, especially in sampling pleural lesions close to vessels and the visceral pleura compared to pleural biopsy

Predictors of angiographic restenosis in patients with coronary artery disease who have undergone percutaneous coronary intervention with drug eluting stents

Background: Percutaneous transluminal coronary angioplasty (PTCA) is now widely accepted as a nonsurgical revascularization procedure for selected patients with CAD. In-stent restenosis (ISR) is a frequent complication after PCI which limits its long-term efficacy. Identification of those clinical and angiographic characteristics that may predict the risk of restenosis is extremely important to eliminate restenosis. In this context we conducted this study to assess the profile of patients with drug eluting stents - ISR with an emphasis on demographic characteristics, risk factors, mode of presentation and coronary angiographic characterization.Methods: This study was a Case control study based on the catheterization registry of all patients who have undergone PCI with DES during the period from October 2012 to April 2015. All patients who have undergone PCI with DES and repeat coronary angiogram for evaluation of symptoms and detected to have ISR during same period were taken as case and age matched patients who had previously undergone PCI with DES and repeat coronary angiogram for evaluation of symptoms between 1/10/2012 to 30/4/2015 and detected to have fully patent stents were taken as control.Results: A total of 26 patients were detected to have ISR during the study period as per the study protocol with equal number of age matched controls. The most common presentation of ISR was as chronic stable angina (70%). Binary logistic regression analysis of 6 factors namely diabetes, hypertension, lesion type, stent diameter, stent length and stent overlap found significant in univariate analysis, showed only the lesion type to be statistically significant with p value of 0.023.Conclusions: Patients who have undergone PCI with DES particularly for complex lesions, diabetics with longer stents, lesser diameter stents and overlapping stents need to be meticulously followed up to rule out the possibility of restenosis, as in a small number of patients the presentation could be ACS with comparatively bad prognosis

Indwelling Pleural Catheters

Indwelling pleural catheters (IPC) are now being considered worldwide for patients with recurrent pleural effusions. It is commonly used for patients with malignant pleural effusions (MPE) and can be performed as outpatient based day care procedure. In malignant pleural effusions, indwelling catheters are particularly useful in patients with trapped lung or failed pleurodesis. Patients and care givers are advised to drain at least 3 times a week or in presence of symptoms i.e. dyspnoea. Normal drainage timing may lasts for 15–20 min which subsequently improves their symptoms and quality of life. Complications which are directly related to IPC insertion are extremely rare. IPC’s are being recently used even for benign effusions in case hepatic hydrothorax and in patients with CKD related pleural effusions. Removal of IPC is often not required in most of the patients. It can be performed safely as a day care procedure with consistently lower rates of complications, reduced inpatient stay. They are relatively easy to insert, manage and remove, and provide the ability to empower patients in both the decisions regarding their treatment and the management of their disease itself

EMX2 gene expression predicts liver metastasis and survival in colorectal cancer

Background: The Empty Spiracles Homeobox (EMX-) 2 gene has been associated with regulation of growth and differentiation in neuronal development. While recent studies provide evidence that EMX2 regulates tumorigenesis of various solid tumors, its role in colorectal cancer remains unknown. We aimed to assess the prognostic significance of EMX2 expression in stage III colorectal adenocarcinoma. Methods: Expression levels of EMX2 in human colorectal cancer and adjacent mucosa were assessed by qRT-PCR technology, and results were correlated with clinical and survival data. siRNA-mediated knockdown and adenoviral delivery-mediated overexpression of EMX2 were performed in order to investigate its effects on the migration of colorectal cancer cells in vitro. Results: Compared to corresponding healthy mucosa, colorectal tumor samples had decreased EMX2 expression levels. Furthermore, EMX2 down-regulation in colorectal cancer tissue was associated with distant metastasis (M1) and impaired overall patient survival. In vitro knockdown of EMX2 resulted in increased tumor cell migration. Conversely, overexpression of EMX2 led to an inhibition of tumor cell migration. Conclusions: EMX2 is frequently down-regulated in human colorectal cancer, and down-regulation of EMX2 is a prognostic marker for disease-free and overall survival. EMX2 might thus represent a promising therapeutic target in colorectal cancer

Conceptual Design of Fuel Dumping System in Aircraft

Airlines release the unburned jet fuel into the atmosphere to reduce the weight of aircraft before landing. Sometimes, aircraft reach a weight more than takeoff weight while departing from the airport. Therefore, the pilot follows the ATC comment to dump fuel into the atmosphere to reduce the aircraft\u27s weight to avoid accidents. Due to fuel dumping, an airline faces fuel consumption, loss, and several diseases affect environmental pollutants, and living things. The total fuel consumption of commercial airlines worldwide in 2021 is 57 billion gallons. If jet fuel routinely hit the ground, it would pollute water and land and damage crops and biodiversity. With this, we have worked on the project to rescue fuel dumping into the atmosphere and save living things from various diseases

Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling

Background: Colorectal cancer is the third most common malignancy in humans and novel therapeutic approaches are urgently needed. Autophagy is an evolutionarily highly conserved cellular process by which cells collect unnecessary organelles or misfolded proteins and subsequently degrade them in vesicular structures in order to refuel cells with energy. Dysregulation of the complex autophagy signaling network has been shown to contribute to the onset and progression of cancer in various models. The Bcl-2 family of proteins comprises central regulators of apoptosis signaling and has been linked to processes involved in autophagy. The antiapoptotic members of the Bcl-2 family of proteins have been identified as promising anticancer drug targets and small molecules inhibiting those proteins are in clinical trials. Methods: Flow cytometry and colorimetric assays were used to assess cell growth and cell death. Long term 3D cell culture was used to assess autophagy in a tissue mimicking environment in vitro. RNA interference was applied to modulate autophagy signaling. Immunoblotting and q-RT PCR were used to investigate autophagy signaling. Immunohistochemistry and fluorescence microscopy were used to detect autophagosome formation and autophagy flux. Results: This study demonstrates that autophagy inhibition by obatoclax induces cell death in colorectal cancer (CRC) cells in an autophagy prone environment. Here, we demonstrate that pan-Bcl-2 inhibition by obatoclax causes a striking, late stage inhibition of autophagy in CRC cells. In contrast, ABT-737, a Mcl-1 sparing Bcl-2 inhibitor, failed to interfere with autophagy signaling. Accumulation of p62 as well as Light Chain 3 (LC3) was observed in cells treated with obatoclax. Autophagy inhibition caused by obatoclax is further augmented in stressful conditions such as starvation. Furthermore, our data demonstrate that inhibition of autophagy caused by obatoclax is independent of the essential pro-autophagy proteins Beclin-1, Atg7 and Atg12. Conclusions: The objective of this study was to dissect the contribution of Bcl-2 proteins to autophagy in CRC cells and to explore the potential of Bcl-2 inhibitors for autophagy modulation. Collectively, our data argue for a Beclin-1 independent autophagy inhibition by obatoclax. Based on this study, we recommend the concept of autophagy inhibition as therapeutic strategy for CRC

Cerebellar and basal ganglia structural connections in humans: Effect of aging and relation with memory and learning

IntroductionThe cerebellum and basal ganglia were initially considered anatomically distinct regions, each connected via thalamic relays which project to the same cerebral cortical targets, such as the motor cortex. In the last two decades, transneuronal viral transport studies in non-human primates showed bidirectional connections between the cerebellum and basal ganglia at the subcortical level, without involving the cerebral cortical motor areas. These findings have significant implications for our understanding of neurodevelopmental and neurodegenerative diseases. While these subcortical connections were established in smaller studies on humans, their evolution with natural aging is less understood.MethodsIn this study, we validated and expanded the previous findings of the structural connectivity within the cerebellum-basal ganglia subcortical network, in a larger dataset of 64 subjects, across different age ranges. Tractography and fixel-based analysis were performed on the 3 T diffusion-weighted dataset using Mrtrix3 software, considering fiber density and cross-section as indicators of axonal integrity. Tractography of the well-established cerebello-thalamo-cortical tract was conducted as a control. We tested the relationship between the structural white matter integrity of these connections with aging and with the performance in different domains of Addenbrooke’s Cognitive Examination.ResultsTractography analysis isolated connections from the dentate nucleus to the contralateral putamen via the thalamus, and reciprocal tracts from the subthalamic nucleus to the contralateral cerebellar cortex via the pontine nuclei. Control tracts of cerebello-thalamo-cortical tracts were also isolated, including associative cerebello-prefrontal tracts. A negative linear relationship was found between the fiber density of both the ascending and descending cerebellum-basal ganglia tracts and age. Considering the cognitive assessments, the fiber density values of cerebello-thalamo-putaminal tracts correlated with the registration/learning domain scores. In addition, the fiber density values of cerebello-frontal and subthalamo-cerebellar (Crus II) tracts correlated with the cognitive assessment scores from the memory domain.ConclusionWe validated the structural connectivity within the cerebellum-basal ganglia reciprocal network, in a larger dataset of human subjects, across wider age range. The structural features of the subcortical cerebello-basal ganglia tracts in human subjects display age-related neurodegeneration. Individual morphological variability of cerebellar tracts to the striatum and prefrontal cortex was associated with different cognitive functions, suggesting a functional contribution of cerebellar tracts to cognitive decline with aging. This study offers new perspectives to consider the functional role of these pathways in motor learning and the pathophysiology of movement disorders involving the cerebellum and striatum

Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling

Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease (IBD), a condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition of oxygen-sensing prolyl hydroxylases (PHD), which confer oxygen-sensitivity upon the hypoxia inducible factor (HIF) pathway, has recently been shown to have therapeutic potential in colitis, although the mechanisms involved remain unclear. Here, we investigated the impact of hydroxylase inhibition on inflammation-driven fibrosis in a murine colitis model. Mice exposed to dextran sodium sulfate followed by period of recovery developed intestinal fibrosis characterized by alterations in the pattern of collagen deposition and infiltration of activated fibroblasts. Treatment with the hydroxylase inhibitor dimethyloxalylglycine (DMOG) ameliorated fibrosis. TGF-β1 is a key regulator of fibrosis which acts through the activation of fibroblasts. Hydroxylase inhibition reduced TGF-β1-induced expression of fibrotic markers in cultured fibroblasts suggesting a direct role for hydroxylases in TGF-β1 signalling. This was at least in part due to inhibition of non-canonical activation of extracellular signal-regulated kinase (ERK) signalling. In summary, pharmacologic hydroxylase inhibition ameliorates intestinal fibrosis, through suppression of TGF-β1-dependent ERK activation in fibroblasts. We hypothesize that in addition to previously reported immunosupressive effects, hydroxylase inhibitors independently suppress pro-fibrotic pathway

Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990-2019, for 204 countries and territories: the Global Burden of Diseases Study 2019

Background: The sustainable development goals (SDGs) aim to end HIV/AIDS as a public health threat by 2030. Understanding the current state of the HIV epidemic and its change over time is essential to this effort. This study assesses the current sex-specific HIV burden in 204 countries and territories and measures progress in the control of the epidemic. Methods: To estimate age-specific and sex-specific trends in 48 of 204 countries, we extended the Estimation and Projection Package Age-Sex Model to also implement the spectrum paediatric model. We used this model in cases where age and sex specific HIV-seroprevalence surveys and antenatal care-clinic sentinel surveillance data were available. For the remaining 156 of 204 locations, we developed a cohort-incidence bias adjustment to derive incidence as a function of cause-of-death data from vital registration systems. The incidence was input to a custom Spectrum model. To assess progress, we measured the percentage change in incident cases and deaths between 2010 and 2019 (threshold >75% decline), the ratio of incident cases to number of people living with HIV (incidence-to-prevalence ratio threshold <0·03), and the ratio of incident cases to deaths (incidence-to-mortality ratio threshold <1·0). Findings: In 2019, there were 36·8 million (95% uncertainty interval [UI] 35·1–38·9) people living with HIV worldwide. There were 0·84 males (95% UI 0·78–0·91) per female living with HIV in 2019, 0·99 male infections (0·91–1·10) for every female infection, and 1·02 male deaths (0·95–1·10) per female death. Global progress in incident cases and deaths between 2010 and 2019 was driven by sub-Saharan Africa (with a 28·52% decrease in incident cases, 95% UI 19·58–35·43, and a 39·66% decrease in deaths, 36·49–42·36). Elsewhere, the incidence remained stable or increased, whereas deaths generally decreased. In 2019, the global incidence-to-prevalence ratio was 0·05 (95% UI 0·05–0·06) and the global incidence-to-mortality ratio was 1·94 (1·76–2·12). No regions met suggested thresholds for progress. Interpretation: Sub-Saharan Africa had both the highest HIV burden and the greatest progress between 1990 and 2019. The number of incident cases and deaths in males and females approached parity in 2019, although there remained more females with HIV than males with HIV. Globally, the HIV epidemic is far from the UNAIDS benchmarks on progress metrics. Funding: The Bill & Melinda Gates Foundation, the National Institute of Mental Health of the US National Institutes of Health (NIH), and the National Institute on Aging of the NIH

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.