Elucidating Signal Transduction Modulatory Drug Target Network of Colon Cancer: A Network Biology Approach

Latest evaluation and validation of cancer drugs and their targets has demonstrated the lack and inadequate development of new and better drugs, based on available protocols. Even though the specificity of drug targets is a great challenge in the pharmaco-proteomics field of cancer biology, for eradicating such hurdles and paving the way for the drugs of future, a novel step has been envisaged here to study the relation between drug target network and the corresponding drug network using the advanced concepts of proteomics and network biology. The literature mining was done for the collection of receptors and the ligands. About 1000 natural compounds were collected and out of those 300 molecules showed anti-cancer activity against colon cancer. Ligand Vs multiple receptor docking was done using the software Quantum 3.3.0; the results were further used for the designing of a well connected Protein Ligand Interaction (PLI) network of colon cancer. The obtained network is then extrapolated to sort out the receptors expressed in the specific cancer type. The network is then statistically analyzed and represented by the graphical interpretation, in order to ascertain the hub nodes and their locally parsed neighbours. Based on the best docking scores, the graphs obtained from the docking analysis are statistically validated with the help of VisANT. In the network three hub nodes Neutrophil cytosol factor 2, UV excision repair protein RAD23 homolog A, & Receptor-type tyrosine-protein phosphatase eta were identified, which showed the highest interaction with the ligands. Butyrate and Farnesol showed highest interaction as ligands. Multiple Sequence Alignment was done of the binding site sequence of the drug targets to find out the evolutionary closeness of the binding sites. The phylogenetic tree was also constructed to further validate the observation. Further in-vitro and in-vivo studies needs to be done to analyse the receptor specificity and anti tumor activity of these compounds in Colon cancer

Variable Chaplygin Gas: Constraints from CMBR and SNe Ia

We constrain the parameters of the variable Chaplygin gas model, using the location of peaks of the CMBR spectrum and SNe Ia ``gold '' data set. Equation of state of the model is $P=-A(a)/\rho$, where $A(a)=A_0 a^{-n}$ is a positive function of the cosmological scale factor $a$, $A_0$ and $n$ being constants. The variable Chaplygin gas interpolates from dust-dominated era to quintessence dominated era. The model is found to be compatible with current type Ia Supernovae data and location of first peak if the values of $\Omega_m$ and $n$ lie in the interval $[0.017,~0.117]$ and $[-1.3,~2.6]$ respectively.Comment: 9 pages,4 figure

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

De Novo Histoid Leprosy in an Elderly: A Case Report and Review of the Literature

Histoid leprosy, an uncommon variant of lepromatous leprosy, develops usually as relapse in lepromatous patients who are on dapsone monotherapy, but uncommonly arises de novo. This rare form of the disease, with unique clinical and histopathological features, may pose a diagnostic challenge even to astute clinicians. We report the case that occurred de novo in an elderly who presented with small to large lesions all over the body. A fresh focus on histoid leprosy is the primary objective of this paper, especially in the context of the postglobal leprosy elimination era

Renal sympathetic denervation: A promising therapy for resistant hypertension

Despite rapid strides in pharmacotherapy for hypertension over last few decades, resistant hypertension continues to be prevalent. Activation of the sympathetic nervous system is an important etiological factor in the pathogenesis of hypertension and renal sympathetic nervous system is one of its pivotal arm. Thus, renal sympathetic system was the target of therapy for hypertension in the initial period, in the form of sympathectomy. The major adverse events associated with this procedure and the emergence of potent blood pressure (BP) lowering medications led to disrepute of this procedure. Of late, novel techniques targeting the sympathetic nervous system have emerged. Among them and the most promising one is catheter-based radiofrequency ablation of renal nerves-Renal sympathetic denervation (RSD). Clinical trials of renal denervation therapy have shown consistent and durable reduction of systolic as well as diastolic BP persisting up to 3 years. Beyond BP control, renal denervation also exerts favorable effects on glucose metabolism, heart failure, and sleep apnea. As many as five different catheter-based renal denervation systems are now approved for treating resistant hypertension, the maximum clinical experience being with Medtronic′s symplicity system. The European Society of Cardiology guidelines for hypertension 2013 now recommend catheter-based renal denervation for management of drug-resistant hypertension. In this review, we briefly discuss the role of sympathetic nervous system in the pathogenesis of hypertension, the present status, and future perspectives of RSD in the treatment of resistant hypertension

Penile cutaneous horn-a rare case

Penile cutaneous horn is a horn like hyper-keratotic lesion over penis which is an unusual site and a rare case. We report a case of cutaneous horn of penis in age of 20 years which is also a rare presentation in this age group

Right aortic arch with isolation of the left innominate artery in a case of double chamber right ventricle and ventricular septal defect

Herein, we report an unusual case of right aortic arch with isolation of the left innominate artery in a case of double chamber right ventricle with ventricular septal defect. The blood supply to the innominate artery was by a collateral arising from the descending aorta. The embryological development of this anomaly can be explained by the hypothetical double aortic arch model proposed by Edwards with interruption of the arch at two levels

A prospective randomized study for comparison of onset time of intubation and intubating conditions using rocuronium with priming and without priming

Background: Rocuronium, a non-depolarizing neuromuscular blocking agent, with priming, can be used as an alternative to succinylcholine for rapid sequence intubation because it produces rapid onset of intubation with comparable intubating conditions. We aimed to compare the onset time of intubation and intubating conditions using rocuronium with priming and without priming. Methods: Sixty adult patients of either sex, aged 18-60 years, ASA grade I and II, scheduled for various elective surgeries under general anaesthesia were randomly allocated into two groups (30 patients in each group). Group P received 0.06 mg/kg of rocuronium as priming dose and Group C received normal saline as placebo before induction. The patients in both groups received fentanyl 1.5 µg/kg and induced with propofol 2.5 mg/kg. The intubating dose of rocuronium 0.54 mg/kg for Group P and 0.6 mg/kg for Group C were given after 3 min of priming. The time interval between the intubating dose and the loss of T1 of TOF stimuli was considered as the onset time of intubation and Cooper’s scoring system was used to compare the intubating conditions. Results: The onset time of intubation was significantly shorter (P &lt;0.05) in group P (54.87 ± 3.75 sec) than group C (94.37 ± 3.52 sec). Intubating conditions were found to be excellent in both the groups with no any adverse effects. Conclusion: Rocuronium (0.6 mg/kg) with priming provides rapid onset time of intubation (&lt;60 sec) along with excellent intubating conditions without any adverse effects which may be particularly useful for rapid sequence intubation and where succinylcholine is contraindicated