Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence.

PhoP-PhoR, one of the 12 two-component systems (TCSs) that empower M. tuberculosis to sense and adapt to diverse environmental conditions, remains essential for virulence, and therefore, represents a major target to develop novel anti-TB therapies. Although both PhoP and PhoR have been structurally characterized, the signal(s) that this TCS responds to remains unknown. Here, we show that PhoR is a sensor of acidic pH/high salt conditions, which subsequently activate PhoP via phosphorylation. In keeping with this, transcriptomic data uncover that acidic pH- inducible expression of PhoP regulon is significantly inhibited in a PhoR-deleted M. tuberculosis. Strikingly, a set of PhoP regulon genes displayed a low pH-dependent activation even in the absence of PhoR, suggesting the presence of non-canonical mechanism(s) of PhoP activation. Using genome-wide interaction-based screening coupled with phosphorylation assays, we identify a non-canonical mechanism of PhoP phosphorylation by the sensor kinase PrrB. To investigate how level of P~PhoP is regulated, we discovered that in addition to its kinase activity PhoR functions as a phosphatase of P~PhoP. Our subsequent results identify the motif/residues responsible for kinase/phosphatase dual functioning of PhoR. Collectively, these results uncover that contrasting kinase and phosphatase functions of PhoR determine the homeostatic mechanism of regulation of intra-mycobacterial P~PhoP which controls the final output of the PhoP regulon. Together, these results connect PhoR to pH-dependent activation of PhoP with downstream functioning of the regulator. Thus, PhoR plays a central role in mycobacterial adaptation to low pH conditions within the host macrophage phagosome, and a PhoR-deleted M. tuberculosis remains significantly attenuated in macrophages and animal models.

Impact of pretransplant minimal residual disease in patients with multiple myeloma and a very good partial response or better receiving autologous hematopoietic stem cell transplantation.

BACKGROUND: The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. METHODS: Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. RESULTS: A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p = .025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p < .001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6 months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2 months (95% confidence interval [CI], 0.3-80.5) versus 80.1 months (95% CI, 0.5-80.1), respectively (p < .001). There was no significant difference in overall survival between the two groups (p = .41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p < .001). The impact of pretransplant MRD status was retained in most of the examined subgroups. CONCLUSIONS: In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.

Molecular docking studies on α-amylase inhibitory peptides from milk of different farm animals.

Milk-derived peptides have emerged as a popular mean to manage various lifestyle disorders such as diabetes. Fermentation is being explored as one of the faster and efficient way of producing peptides with antidiabetic potential. Therefore, in this study, an attempt was made to comparatively investigate the pancreatic α-amylase (PAA) inhibitory properties of peptides derived from milk of different farm animals through probiotic fermentation. Peptide's identification was carried out using liquid chromatography-quadrupole time-of-flight mass spectrometry and inhibition mechanisms were characterized by molecular docking. Results obtained showed a PAA-IC50 value (the amount of protein equivalent needed to inhibit 50% of enzymes) between 2.39 and 36.1 µg protein equivalent for different fermented samples. Overall, Pediococcus pentosaceus MF000957-derived fermented milk from all animals indicated higher PAA inhibition than other probiotic derived fermented milk (PAA-IC50 values of 6.01, 3.53, 15.6, and 10.8 µg protein equivalent for bovine, camel, goat, and sheep fermented milk). Further, molecular docking analysis indicated that camel milk-derived peptide IMEQQQTEDEQQDK and goat milk-derived peptide DQHQKAMKPWTQPK were the most potent PAA inhibitory peptides. Overall, the study concluded that fermentation derived peptides may prove useful in for managing diabetes via inhibition of carbohydrate digesting enzyme PAA.

Alocasia odora-mediated synthesis of silver nanoparticles, their cytotoxicity, and virucidal potential.

Silver nanoparticles (AgNPs) have various applications in the biomedical field and are considered excellent microbicidal agents. Moreover, biological synthesis of AgNPs using medicinal plants further improves the medicinal applicability of these plants. In this study, the aqueous extract of Alocasia odora rhizome (RE) and Alocasia odora stem (SE) were used to synthesize stem aqueous extract-AgNPs (SNP) and rhizome aqueous extract-AgNPs (RNP). Furthermore, RNP and SNP were evaluated for their virucidal potential. The synthesis of SNP and RNP was monitored using a UV spectrophotometer by observing their surface plasmon resonance peak. In addition, scanning electron microscopy (SEM) gave further insight into their morphology and particle size, whereas energy-dispersive X-ray spectroscopy (EDX) confirmed the presence of silver ions. Interestingly, Fourier-transform infrared spectroscopy (FTIR) analysis of AgNPs revealed that phytomolecules acted as capping and stabilizing agents for SNP and RNP. The in vitro cytotoxicity of SNP and RNP was further analyzed using MTT assay on the U87-MG human glioblastoma cancer cell line and SNP found to be the most cytotoxic (43.40 µg/ml) among all. Besides that, SNP has also found to show the maximum cytopathic effects (CPE) against dengue virus type 2 (DENV-2) on Huh-7 cell line. As a result of the observations, it can be concluded that they can become a promising antiviral drug candidate and thus merit further testing. KEY POINTS: • AgNPs were successfully synthesized through Alocasia odora aqueous extract. • AgNPs were more cytotoxic on the U87-MG cell line than the extract alone. • AgNPs have shown significant reduction in the dengue viral infection than the extract alone.

Association between risk factors and migraine in Pakistani females.

BACKGROUND: Migraine is a typical cripple issue of the brain identified with cerebral pain which is an indication of numerous health conditions. About 18% of women (27 million) and 6% of men (10 million) are afflicted by migraine in the United States. Based on a case-control study, to explore the different risk factors, causing migraine in females and examine the association between risk factors and migraine. METHODS: A sample of 1055 individuals were selected in different areas of Lahore from September 2019 to March 2020. The information was obtained by using the direct interview method and questionnaire method. Descriptive analysis, bivariate analysis and binary logistic regression analysis were carried out in data analysis. RESULTS: Among 1055 individuals 740 cases and 315 controls were included. In a binary logistic regression model, physical activities, stress, summer season, menstruation and morning were the risk factors that cause migraine and these were found to be positively significant with the odds ratios and 95% confidence interval of odds ratios (1.399; 1.122-1.746), (1.510; 1.187-1.922), (1.595; 1.374-1.851), (1.513; 1.247-1.836) and (1.309; 1.028-1.665) respectively. Nausea, isolation and back head pain were caused by migraine and these were found positively significant with the odds ratios and 95% confidence interval of odds ratios(1.290; 1.122-1.484), (1.882; 1.617-2.190) and (1.285; 1.123-1.471) respectively. CONCLUSIONS: Stress, physical Activities and Menstruation increase the risk of migraine but weight loss, Breakfast, lunch, thirst, injury and Second trimester during pregnancy reduce the risk of migraine.

Dermatological aspects of ticks in Australia: An update.

Ticks are ectoparasites that cause dermatologic reactions directly by their bites and indirectly as vectors of bacterial, protozoal and viral diseases. Consequences vary from minor local reactions to significant systemic sequelae and are therefore of clinical relevance to dermatologists. In this article, Australian ticks of medical importance are reviewed through the lens of dermatology.

Molecular Connectivity between Extracytoplasmic Sigma Factors and PhoP Accounts for Coupled Mycobacterial Stress Response.

Mycobacterium tuberculosis encounters numerous stress conditions within the host, but how it is able to mount a coupled stress response remains unknown. Growing evidence suggests that under acidic pH, M. tuberculosis modulates redox homeostasis. In an attempt to dissect the mechanistic details of responses to multiple stress conditions, here we studied the significance of connectivity of extracytoplasmic sigma factors with PhoP. We show that PhoP impacts the mycothiol redox state, and the H37Rv ΔphoP deletion mutant strain displays a significantly higher susceptibility to redox stress than the wild-type bacilli. To probe how the two regulators PhoP and redox-active sigma factor SigH contribute to redox homeostasis, we show that SigH controls expression of redox-active thioredoxin genes, a major mycobacterial antioxidant system, and under redox stress, SigH, but not PhoP, is recruited at the target promoters. Consistent with these results, interaction between PhoP and SigH fails to impact redox-dependent gene expression. This is in striking contrast to our previous results showing PhoP-dependent SigE recruitment within acid-inducible mycobacterial promoters to maintain pH homeostasis. Our subsequent results demonstrate reduced PhoP-SigH interaction in the presence of diamide and enhanced PhoP-SigE interaction under low pH. These contrasting results uncover the underlying mechanism of the mycobacterial adaptive program, coupling low pH with maintenance of redox homeostasis. IMPORTANCE M. tuberculosis encounters reductive stress under acidic pH. To investigate the mechanism of coupled stress response, we show that PhoP plays a major role in mycobacterial redox stress response. We observed a strong correlation of phoP-dependent redox-active expression of thioredoxin genes, a major mycobacterial antioxidant system. Further probing of functioning of regulators revealed that while PhoP controls pH homeostasis via its interaction with SigE, direct recruitment of SigH, but not PhoP-SigH interaction, controls expression of thioredoxin genes. These strikingly contrasting results showing enhanced PhoP-SigE interaction under acidic pH and reduced PhoP-SigH interaction under redox conditions uncover the underlying novel mechanism of the mycobacterial adaptive program, coupling low pH with maintenance of redox homeostasis.

Cannabinoid and endocannabinoid system: a promising therapeutic intervention for multiple sclerosis.

Multiple sclerosis (MS) is a chronic and complex neurodegenerative disease, distinguished by the presence of lesions in the central nervous system (CNS) due to exacerbated immunological responses that inflict oligodendrocytes and the myelin sheath of axons. In recent years, studies have focused on targeted therapeutics for MS that emphasize the role of G protein-coupled receptors (GPCRs), specifically cannabinoids receptors. Clinical studies have suggested the therapeutic potential of cannabinoids derived from Cannabis sativa in relieving pain, tremors and spasticity. Cannabinoids also appear to prevent exaggerated immune responses in CNS due to compromised blood-brain barrier. Both, endocannabinoid system (ECS) modulators and cannabinoid ligands actively promote oligodendrocyte survival by regulating signaling, migration and myelination of nerve cells. The cannabinoid receptors 1 (CB1) and 2 (CB2) of ECS are the main ones in focus for therapeutic intervention of MS. Various CB1/CB2 receptors agonists have been experimentally studied which showed anti-inflammatory properties and are considered to be effective as potential therapeutics for MS. In this review, we focused on the exacerbated immune attack on nerve cells and the role of the cannabinoids and its interaction with the ECS in CNS during MS pathology.

Manual loop in laparoscopic appendectomy: A retrospective cohort study and literature review.

OBJECTIVES: To determine the incidence of complications [Surgical site infection (SSI), intra-abdominal abscess (IAA), stump leak] related to stump ligation with manual loop of sliding extracorporeal suture knot in laparoscopic appendectomy. METHODS: This cohort study was conducted on patients who underwent laparoscopic appendectomy from June 2014 to November 2020 performed by the same surgeon with almost similar technique. Stump was ligated with manual loops, applied by the surgeon or trainee or both (one by surgeon and other by trainee). SSI and IAA were classified according to Centers for Disease Control and Prevention (CDC) criteria. RESULTS: Total 120 patients were included with median (Interquartile range, IQR) age of 24 (19-35) years and male predominance i.e. 81 (67.5%). Median (IQR) for the duration of symptoms, time from presentation to surgery and duration of surgery was 2(1-4) days, 10 (4-15) hours and 60 (44-70) minutes, respectively. SSI was documented in 9(7.5%) patients, managed by wound hygiene and antibiotics. IAA was observed in one(0.8%) patient who required readmission for antibiotics and radiology guided drain placement. No stump leak was observed. CONCLUSIONS: Manual endo-loop is a safe, reliable and cost effective technique for stump ligation in LA, and can safely be incorporated into teaching of surgical trainees.

A prospective randomized trial to compare the effectiveness of zero calorie carbonated drink and water as a solvent in sodium phosphate for colonoscopy.

Objectives: To compare the effectiveness of zero-calorie soft drink and plain water as a solvent for sodium phosphate in terms of good palatability and better patient tolerance. METHODS: The randomised controlled trial was conducted from May to December 2019 at the Dowites Operation Theatre Endoscopy Suite, Surgical Unit 3, Civil Hospital Karachi, and comprised patients aged >18 years of either gender undergoing colonoscopy for screening and non-emergency/non-urgent colorectal diseases. The patients were randomised into group A, which was assigned to take sodium phosphate in water, and group B, which was assigned to take sodium phosphate in zero-calorie soft drink. Bowel preparation was assessed by the consultant during endoscopy. Outcome variables, such as bowel cleanliness, palatability, tolerance of solution, adverse effects, and willingness to repeat the preparation, were evaluated in both groups. Data was analysed using SPSS 21. RESULTS: Of the 162 patients, there were 81(50%) in each of the two groups. There were 124(76.5%) males and the overall mean age was 43±8.66 years. The palatability score was significant (p=0.01) for group B compared to group A. Due to better palatability and tolerance, 64(79%) patients in group B took the preparation in <6 hours. CONCLUSIONS: Use of zero-calorie soft drink was found to be a better option for colonoscopic preparation compared to plain water. RCT Registration: Clinical trial unit (www.clinicaltrials.gov), NCT04316858.

Forecasting the daily deaths caused by COVID-19 using ARIMA model.

Coronavirus disease (COVID-19) pandemic has recently become a global health crisis. On the basis of this study the data reported from ten different countries on confirmed daily deaths caused by COVID-19. By fitting the linear regression models based on the data from ten countries to find the relationship between the new cases and deaths reported daily. We also used the autoregressive integrated moving average model (ARIMA) to predict the potential number of daily deaths caused by COVID-19 in these countries in the next 3 Months. The R2 value obtained for Iran (0.24) implies that 24% of daily deaths correspond to the daily cases. The R2of Pakistan 0.662 which indicates that 66.2% of daily deaths are explained by our predictor variable. In Turkey 70.2% of daily deaths are explained by daily cases and India recorded the highest number of deaths while UAE had the lowest number of deaths. Our results suggest that the pandemic is under control in China, UAE and Australia. Pakistan, Iran, Germany and Italy however, showed an upward trend in the spread of the disease, which may correlate with a high increase in death rate as the data indicated.

The circulatory small non-coding RNA landscape in community-acquired pneumonia on intensive care unit admission.

Community-acquired pneumonia (CAP) is a major cause of sepsis. Despite several clinical trials targeting components of the inflammatory response, no specific treatment other than antimicrobial therapy has been approved. This argued for a deeper understanding of sepsis immunopathology, in particular factors that can modulate the host response. Small non-coding RNA, for example, micro (mi)RNA, have been established as important modifiers of cellular phenotypes. Notably, miRNAs are not exclusive to the intracellular milieu but have also been detected extracellular in the circulation with functional consequences. Here, we sought to determine shifts in circulatory small RNA levels of critically ill patients with CAP-associated sepsis and to determine the influence of clinical severity and causal pathogens on small RNA levels. Blood plasma was collected from 13 critically ill patients with sepsis caused by CAP on intensive care unit admission and from 5 non-infectious control participants. Plasma small RNA-sequencing identified significantly altered levels of primarily mature miRNAs in CAP relative to controls. Pathways analysis of high or low abundance miRNA identified various over-represented cellular biological pathways. Analysis of small RNA levels against common clinical severity and inflammatory parameters indices showed direct and indirect correlations. Additionally, variance of plasma small RNA levels in CAP patients may be explained, at least in part, by differences in causal pathogens. Small nuclear RNA levels were specifically altered in CAP due to Influenza infection in contrast to Streptococcus pneumoniae infection. Pathway analysis of plasma miRNA signatures unique to Influenza or Streptococcus pneumoniae infections showed enrichment for specific proteoglycan, cell cycle, and immunometabolic pathways.

Factors influencing exclusive breastfeeding duration in Pakistan: a population-based cross-sectional study.

BACKGROUND: Breastfeeding has the most profound impact on infant health and wellness, and also have significant implications for the mother. The duration of the breastfeeding determines the infant's protection from malnutrition and other common infectious diseases; consequently, the World Health Organization (WHO) recommends exclusive breastfeeding (EBF) six months, followed by gradual weaning and breastfeeding until the baby is two years old. In Pakistan, the practice of breastfeeding is heavily dependent upon certain demographic, economic, social, and biological factors, which ultimately impact the quality of care provided to the infant and their health. The aim of this paper, therefore, is to measure the impact of these factors on the exclusive breastfeeding duration in Pakistan. METHODS: The data for the study has been collected from Pakistan Demographic and Health Survey (PDHS) for the year 2017-18. Binary logistic regression model and survival analysis are used to determine the relationship between the independent and dependent variables. RESULTS: We use a binary logistic regression to estimate the effect of each factor on the duration of EBF. The binary logistic regression finds significant relationships between region, maternal education, wealth index, size of a child, watching television, delivery by cesarean, and maternal age and EBF. We then use log-likelihood, AIC, BIC criteria to determine if a parametric or non-parametric model would provide a better fit; based on these results we fit an Inverse Gaussian (Weibull) distribution for the survival analysis. These results show that there are more significant factors associated with EBF duration in parametric survival analysis than in the binary logistic regression results. Thus, the survival analysis is a better method for predicting the relationship between the duration of EBF and its factors. Furthermore, logically EBF is designated to be done for six months which would not be properly gauged with a binary response variable. CONCLUSIONS: The results of this study provide proof that exclusive breastfeeding is a common practice among women in Pakistan, and to improve the quality of post-natal care, health policy in the country needs to focus on the existing demographic and social factors which are found significant in this study.

Factors affecting delay in diagnosis of colorectal cancer: A cross-sectional study from a tertiary care hospital of Karachi, Pakistan.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing in our region. There is no specific CRC control programme or national cancer registry in Pakistan. Previously, no data have been published on presentation delay and diagnosis delay of CRC in our region. This study is conducted to determine the factors affecting delay in presentation and diagnosis and to provide baseline information to launch a CRC control programme. The primary objective is to determine factors causing delay in diagnosis of CRC. The secondary objective is to evaluate the relationship between tumour site and stage of CRC with presenting symptoms and symptom duration. METHODS: This project is a prospective cross-sectional study on 113 biopsy-proven CRC patients admitted to the surgical ward of Civil Hospital Karachi. RESULTS: The total number of participants was 113. Presentation delay was observed in 83.2% of patients. The main reasons for a reported delay in the presentation were lack of patients' knowledge that these symptoms may be cancer (60.4%), the wrong diagnosis by the primary physician (34.6%) or the patient did not want to visit the doctor (0.04%). Most tumours (95%) originated from the sigmoid and rectum; 44.2% and 38.9% of the patients were diagnosed at Stages 3 and 4, respectively. CONCLUSIONS: This study revealed that CRC patients in Pakistan are facing delays in presentation and diagnosis. This is the reason behind diagnosis at the advanced stage with a poor prognosis. On the basis of this study findings, CRC control programme should be introduced to detect CRC at an early stage.

Monitoring of three-phase variations in the mortality of COVID-19 pandemic using control charts: where does Pakistan stand?

BACKGROUND: At the end of December 2019, the world in general and Wuhan, the industrial hub of China, in particular, experienced the COVID-19 pandemic. Massive increment of cases and deaths occurred in China and 209 countries in Europe, America, Australia, Asia and Pakistan. Pakistan was first hit by COVID-19 when a case was reported in Karachi on 26 February 2020. Several methods were presented to model the death rate due to the COVID-19 pandemic and to forecast the pinnacle of reported deaths. Still, these methods were not used in identifying the first day when Pakistan enters or exits the early exponential growth phase. OBJECTIVE: The present study intends to monitor variations in deaths and identify the growth phases such as pre-growth, growth, and post-growth phases in Pakistan due to the COVID-19 pandemic. METHODS: New approaches are needed that display the death patterns and signal an alarming situation so that corrective actions can be taken before the condition worsens. To meet this purpose, secondary data on daily reported deaths due to the COVID-19 pandemic have been considered, and the $c$ and exponentially weighted moving average (EWMA) control charts are used To meet this purpose, secondary data on daily reported deaths in Pakistan due to the COVID-19 pandemic have been considered. The $ c$ and exponentially weighted moving average (EWMA) control charts have been used for monitoring variations. RESULTS: The chart shows that Pakistan switches from the pre-growth to the growth phase on 31 March 2020. The EWMA chart demonstrates that Pakistan remains in the growth phase from 31 March 2020 to 17 August 2020, with some indications signaling a decrease in deaths. It is found that Pakistan moved to a post-growth phase for a brief period from 27 July 2020 to 28 July 2020. Pakistan switches to re-growth phase with an alarm on 31/7/2020, right after the short-term post-growth phase. The number of deaths starts decreasing in August in that Pakistan may approach the post-growth phase shortly. CONCLUSION: This amalgamation of control charts illustrates a systematic implementation of the charts for government leaders and forefront medical teams to facilitate the rapid detection of daily reported deaths due to COVID-19. Besides government and public health officials, it is also the public's responsibility to follow the enforced standard operating procedures as a temporary remedy of this pandemic in ensuring public safety while awaiting a suitable vaccine to be discovered.

Late-onset eccrine syringofibroadenoma of the feet in a patient with hypohidrotic ectodermal dysplasia.

A 56-year-old woman with hypohidrotic ectodermal dysplasia presented with a 10-year history of persisting wart-like skin lesions on her feet. Biopsy revealed changes of eccrine syringofibroadenoma. These lesions are rare, with only nine case reports describing an association with ectodermal dysplasia of hidrotic type (Clouston and Schopf's syndrome). To our knowledge, this is the first case of eccrine syringofibroadenoma developing in the hypohidrotic/anhidrotic subtype of ectodermal dysplasia.

Application of Cp2TiCl-Promoted Radical-Induced Cyclization: An Expeditious Access to [a]-Annelated Indoles.

An efficient and novel route for assembling pyrrolo/piperido[1,2-a]indoles is portrayed involving a radical-mediated reductive epoxide opening reaction of N-tethered epoxy-indoles that trigger facile intramolecular cyclization followed by an oxidative quenching step. Capitalizing on the operational simplicity of the method involving just two steps and use of an efficient C-C bond-forming reaction, this radical-based protocol enables the modular assembly of an important class of N-fused indole derivatives with versatile functional and structural diversity.

The circular RNA landscape in specific peripheral blood mononuclear cells of critically ill patients with sepsis.

BACKGROUND: Dysregulation of the host immune response is a pathognomonic feature of sepsis. Abnormal physiological conditions are understood to shift efficient linear splicing of protein-coding RNA towards non-canonical splicing, characterized by the accumulation of non-coding circularized (circ)RNA. CircRNAs remain unexplored in specific peripheral blood mononuclear cells (PBMCs) during sepsis. We here sought to identify and characterize circRNA expression in specific PBMCs of patients with sepsis due to community-acquired pneumonia (CAP) relative to healthy subjects. METHODS: The study comprised a discovery cohort of six critically ill patients diagnosed with sepsis due to community-acquired pneumonia and four (age, gender matched) healthy subjects. PBMCs were isolated, and fluorescence-activated cell sorting was used to purify CD14+ monocytes, CD4+, CD8+ T cells, and CD19+ B cells for RNA sequencing. CD14+ monocytes from independent six healthy volunteers were purified, and total RNA was treated with or without RNase R. RESULTS: RNA sequencing of sorted CD14+ monocytes, CD4+, CD8+ T cells, and CD19+ B cells from CAP patients and healthy subjects identified various circRNAs with predominantly cell-specific expression patterns. CircRNAs were expressed to a larger extent in monocytes than in CD4+, CD8+ T cells, or B cells. Cells from CAP patients produced significantly higher levels of circRNA as compared to healthy subjects. Considering adjusted p values, circVCAN (chr5:83519349-83522309) and circCHD2 (chr15:93000512-93014909) levels in monocytes were significantly altered in sepsis. Functional inference per cell-type uncovered pathways mainly attuned to cell proliferation and cytokine production. In addition, our data does not support a role for these circRNAs in microRNA sequestration. Quantitative PCR analysis in purified monocytes from an independent group of healthy volunteers confirmed the existence of circVCAN and circCHD2. CONCLUSIONS: We provide a benchmark map of circRNA expression dynamics in specific immune cell subsets of sepsis patients secondary to CAP. CircRNAs were more abundant in immune cells of sepsis patients relative to healthy subjects. Further studies evaluating circRNA expression in larger cohorts of sepsis patients are warranted.

Socioeconomic and demographic factors determining the underweight prevalence among children under-five in Punjab.

BACKGROUND: Underweight prevalence continues to be major public health challenge worldwide, particularly in developing countries like Pakistan. This study is focused on socio-economic and demographic aspects of underweight prevalence among children under-five in Punjab. METHODS: In this study, several socioeconomic and demographic factors are considered using MICS-4 data-set. Only those variables which are usually described in the nutritional studies of children were picked. Covariates include: the age of children, sex of the children, age of mother, total number of children born to women, family wealth index quintile, source of drinking water, type of sanitation, place of residence, parents' education and occupation. All Categorical variables are effect coded. The child's age and the mother's age are assumed to be nonlinear, geographical region is spatial effect, while other variables are parametric in nature. Since, the response is binary, covariate comprises linear terms, nonlinear effects of continues covariates and geographic effects, so we have use Geo-additive models (based on Fully Bayesian approach) with binomial family under logit link. Statistical analysis is performed on Statistical package R using Bayes X and R2 Bayes X Libraries. RESULTS: Underweight status of children was found to be positively associated with number of under-five children in household, total number of children ever born to women and age of mother when the child was born. Whereas, it negatively associated with place of residence, parent's education and family wealth index quintile. On the regional effect, the Southern Punjab has higher prevalence of underweight compared to Central and Northern Punjab. CONCLUSION: Similarity of our results with several other studies demonstrate that the Geo-additive models are an ideal substitute of other statistical models to analyze the underweight prevalence among children. Moreover, our findings suggest the Punjab Government, to introduce target-oriented programs such as poverty reduction and enhancement of education and health facilities for poor population and disadvantaged regions, especially Southern Punjab.