From sensing interactions to controlling the interactions: a novel approach to obtain biological transistors for specific and label-free immunosensing.

Antibody-antigen interactions are shaped by the solution pH level, ionic strength, and electric fields, if present. In biological field-effect transistors (BioFETs), the interactions take place at the sensing area in which the pH level, ionic strength and electric fields are determined by the Poisson-Boltzmann equation and the boundary conditions at the solid-solution interface and the potential applied at the solution electrode. The present study demonstrates how a BioFET solution electrode potential affects the sensing area double layer pH level, ionic strength, and electric fields and in this way shapes the biological interactions at the sensing area. We refer to this as 'active sensing'. To this end, we employed the meta-nano-channel (MNC) BioFET and demonstrate how the solution electrode can determine the antibody-antigen equilibrium constant and allows the control and tuning of the sensing performance in terms of the dynamic range and limit-of-detection. In the current work, we employed this method to demonstrate the specific and label-free sensing of Alpha-Fetoprotein (AFP) molecules from 0.5 µL drops of 1 : 100 diluted serum. AFP was measured during pregnancy as part of the prenatal screening program for fetal anomalies, chromosomal abnormalities, and abnormal placentation. We demonstrate AFP sensing with a limit-of-detection of 10.5 aM and a dynamic range of 6 orders of magnitude in concentration. Extensive control measurements are reported.

Machine learning approaches to optimize small-molecule inhibitors for RNA targeting.

In the era of data science, data-driven algorithms have emerged as powerful platforms that can consolidate bioisosteric rules for preferential modifications on small molecules with a common molecular scaffold. Here we present complementary data-driven algorithms to minimize the search in chemical space for phenylthiazole-containing molecules that bind the RNA hairpin within the ribosomal peptidyl transferase center (PTC) of Mycobacterium tuberculosis. Our results indicate visual, geometrical, and chemical features that enhance the binding to the targeted RNA. Functional validation was conducted after synthesizing 10 small molecules pinpointed computationally. Four of the 10 were found to be potent inhibitors that target hairpin 91 in the ribosomal PTC of M. tuberculosis and, as a result, stop translation.

Evaluation of Serum Levels of Procalcitonin and C-Reactive Protein as Prognostic Indicators in Burns.

Background Burn is a leading cause of fatality in a developing country. C-reactive protein levels (CRP) and procalcitonin (PCT) can be prognostic indicators for the burn patients' mortality. Aim To assess serial levels of serum PCT and serum CRP as prognostic indicators in burns. Patient and Methods In patients admitted with burns, alternate-day serum PCT and CRP were measured from the time of admission until the time of discharge or until survival. The change in trends of CRP and PCT serum levels were studied, and it was then correlated with mortality among these burn patients. Results The first-day value of serum PCT > 1772 pg/mL and serum CRP > 71 mg/mL or any value of serum PCT > 2163 pg/mL and of serum CRP > 90 mg/L indicate a poor prognosis in burns. Conclusions The day-1 values of PCT and CRP were significantly higher in nonsurvivors than survivors in burns. The increasing trends of serum PCT and CRP levels are independent predictors of mortality in burns requiring prompt intervention. Rising PCT and CRP level denote poor prognosis in burns with an increased likelihood of death by 4.5 and 23.6 times, respectively.

Use of Preexpanded Forehead and Neck Skin in Case of Giant Facial Hairy Naevus: Planning and Technique.

A congenital nevi is a pigmented patch which requires complete surgical excision for cosmetic reasons. Here, we report a case of a patient with facial hairy pigmented lesion, occupying the right half of her face since birth, who underwent complete surgical excision and staged reconstruction utilizing, preexpanded forehead and neck skin. We used two rectangular tissue expanders with 150 and 300 cubic cm of volumes inserted in the forehead and the neck, respectively. The length of the expanders selected were equal to 1.2 to 1.5 times the length of their respective lesions, whereas the width of the base of the expanders were approximately similar to the width of their defects. It is concluded with this case report that tissue expansion provides a good cosmetic and anatomical correction to cover large defects, with adjacent skin having similar properties.

Synthesis and Antimalarial Activity of 4-Methylaminoquinoline Compounds against Drug-Resistant Parasite.

A series of novel 4-aminoquinoline analogues bearing a methyl group at 4-aminoquinoline moiety were synthesized via a new and robust synthetic route comprising in situ tert-butoxycarbonyl (Boc) deprotection-methylation cascade resulting in the corresponding N-methylated secondary amine using Red-Al and an efficient microwave-assisted strategy for the fusion of N-methylated secondary amine with 4-chloroquinoline nucleus to access the series of novel 4-N-methylaminoquinoline analogues. The new series of compounds were evaluated for their antimalarial activity in in vitro and in vivo models. Among 21 tested compounds, 9a-i have shown a half-maximal inhibitory concentration (IC50) value less than 0.5 µM (i.e., <500 nM) against both chloroquine-sensitive strain 3D7 and chloroquine-resistant strain K1 of Plasmodium falciparum with acceptable cytotoxicity. Based on the in vitro antimalarial activity, selected compounds were screened for their in vivo antimalarial activity against Plasmodium yoelii nigeriensis (a multidrug-resistant) parasite in Swiss mice. Most of the compounds have shown significant inhibition on day 4 post infection at the oral dose of 100 mg/kg. Compound 9a has shown 100% parasite inhibition on day 4, and out of five treated mice, two were cured till the end of the experiment. The present study suggests that 4-methylamino substitution is well tolerated for the antiplasmodial activity with reduced toxicity and therefore will be highly useful for the discovery of a new antimalarial agent against drug-resistant malaria.

Pyrrolidine ring puckering and prolyl amide bond configurations of 2-methyl-allo-hydroxyproline-based dipeptides.

An expeditious method for the synthesis of homo and heterochiral dipeptides containing l-alanine and d/l 2-methyl allo-hydroxyl prolines was developed using direct aminolysis of bicyclic lactones derived from d/l alanine. The impact of C-2 methylation and its spatial orientation on the pyrrolidine ring puckering and prolyl amide bond configuration was ascertained by solution NMR studies. The present studies reveal that C-2 methylation causes the prolyl amide bond to exist exclusively in the trans geometry in both homo- and heterochiral dipeptides. However, the spatial orientation of the C-2 methyl group and its i + 2 position in appropriately capped model dipeptides may nucleate into a turn like structure.

High-Flow Vascular Malformation of Ear: A Case Report.

Vascular anomalies are categorized into vascular tumours or vascular malformations on the basis of clinical features and histopathology. The literature regarding high flow arteriovenous malformations of the auricle is rare. A case of a patient clinically diagnosed with an arteriovenous malformation of the external ear and was managed with preoperative embolization, surgical excision and reconstruction of ear with split thickness skin graft, is presented. The pathogenesis, clinical presentation, diagnostic work up, radiological intervention and management options regarding arteriovenous malformations are discussed. Total cure is an illusion and rarely achieved in high flow high grade vascular malformation with nearly 98% recurrence reported in 5 years. Patient followed for next 3 months with no evidence of recurrence.

Feto-maternal Outcomes in Pregnancies Complicated by Thermal Burns.

BACKGROUND: Burns in pregnancy can be a potentially life-threatening condition for both mother and baby. Human physiology is altered during pregnancy and burns add further stress leading to diminished maternal reserves. Very few studies have been reported for management of such patients. MATERIALS AND METHODS: This was a prospective based study carried out in Department of Burns and Plastic Surgery in collaboration with Department of Obstetrics and Gynaecology and Department of Pediatrics for a period of 20 months from December 2011 to July 2013. Pregnant women with thermal injuries more than 15% TBSA were included in the study. Patients with coexisting obstetrics complications and burns other than thermal were excluded. RESULTS: Out of 3397 female patients of burns admitted, 1382 patients were in reproductive groups, 1116 were married and 67 were pregnant; these were enrolled. Maternal and fetal outcome is inversely linked with the TBSA of the mother (p < 0.001). In TBSA group 15-30%, there was no maternal and fetal mortality, but in TBSA >30-50% maternal mortality was 44%, and in 50-70% maternal mortality was 83% and no mother survived in >70%. In TBSA 30-50%, fetal mortality was 72%. Only one baby survived in 50-70% TBSA group and one in >70% TBSA group after intensive care in NICU for prematurity. Fetal survival was also dependent on gestational age, and there are better outcomes in late trimesters. CONCLUSION: Maternal and fetal outcome are directly related to TBSA of mother, and best care can be offered to such patients with a multidisciplinary team-based approach.

Intraoperative partial pressure of oxygen measurement to predict flap survival.

INTRODUCTION: Flap monitoring using partial pressure of oxygen (pO2) is a proven modality. Instruments needed are expensive and are not readily available to a clinician. Here, pO2 of flap has been determined using readily available and cheap methods, and a cut-off value is calculated which helps in predicting flap outcome. METHODS AND RESULTS: Total 235 points on 84 skin flaps were studied. Capillary blood was collected from flap and fingertip using 1-ml syringes after at least 30 min of flap inset, and pO2 analysed using blood gas analyser. Fall/change of pO2 (difference of mean of pO2 [diff-pO2]) was also calculated by subtracting the flap pO2 from the finger pO2. Flap was monitored clinically in post-operative period and divided into two groups depending on its survival with Group 1 - dead points and Group 2 - alive points. pO2 and diff-pO2 amongst both the groups were compared and found to be statistically different (P = 0.0001). Cut-off value calculated for pO2 was found to be <86.3 mmHg with a sensitivity of 100% and specificity of 89.05%. The difference of >68.503 mmHg of flap pO2 compared from finger pO2 was calculated as a cut-off with sensitivity of 94.12 and specificity of 79.60%. CONCLUSIONS: Flap areas having intra-operative pO2 value <86.3 mmHG have higher chances (60.71%) of getting necrosis later. Similarly, if diff-pO2 compared to fingertip is >68.5 mmHg, chances of those points getting necrosed in post-operative period are high.

A prospective analysis of risk factors for pediatric burn mortality at a tertiary burn center in North India.

BACKGROUND: None of the available mortality predicting models in pediatric burns precisely predicts outcomes in every population. Mortality rates as well as their risk factors vary with regions and among different centers within the regions. The aim of this study was to identify socio-demographic and clinical risk factors for mortality in pediatric burns in an effort to decrease the mortality in these patients. METHODS: A prospective analytical study was conducted in patients up to the age of 18 years admitted for burn injuries in a tertiary care burn center in India from January to December 2014. Clinical and demographic data was collected through questionnaire-interview and patient follow-up during their stay in the hospital. Univariate and multivariate firth logistic regression was used to identify various risk factors for mortality in pediatric burns. RESULTS: A total of 475 patients were admitted during the study period. Overall mortality was 31.3% (n = 149) in this study. Mean age of the patients who died was 8.68 years. Of the 149 deaths, 74 were males and 75 were females (male to female ratio = 0.98). Mean total body surface area (TBSA) involved of the patients who expired was 62%. Inhalational injury was seen in 15.5% (n = 74) of pediatric burn admissions. Mortality was significantly higher (74.3%) in patients with inhalation injury. Mortality was highest in patients with isolates of Acinetobacter + Klebsiella (58.3%), followed by Pseudomonas + Klebsiella (53.3%), Acinetobacter (31.5%), and Pseudomonas (26.3%) (p < 0.0005). Factors found to be significant on univariate firth analysis were older age, female gender, suicidal burns, higher TBSA, presence of inhalation injury, increased depth of burn, and positive microbial cultures. On multivariate analysis, higher TBSA was identified as an independent risk factor for mortality. The adjusted odds ratios for TBSA involvement was 21.706 (25.1-50%), 136.195 (50.1-75%), and 1019.436 (75.1-100%), respectively. CONCLUSION: TBSA is the most important factor predicting mortality in pediatric burns. The higher the TBSA, the higher is the risk of mortality. Other significant risk factors for mortality are female gender, deeper burns, positive wound cultures, and inhalation injury. Risk of mortality was significantly lower in children who belonged to urban areas, nuclear family, who sustained burn injury in the last quarter of the year, and who stayed in the hospital for longer period.

Stereoselective Synthesis of (R)-3-Methylthalidomide by Piperidin-2-one Ring Assembly Approach.

A simple and stereoselective synthesis of 3-methylthalidomide, a configurationally stable thalidomide analog, is presented. Herein we describe the synthesis of (R)-3-methylthalidomide starting from (S)-alanine by piperidin-2-one ring assembly approach in high yield and enantiomeric purity without using a chiral auxiliary or reagent. Starting from (R)-alanine, the corresponding (S)-3-methylthalidomide can be prepared using the same methodology.

A qualitative study of the background and in-hospital medicolegal response to female burn injuries in India.

BACKGROUND: Most burns happen in low- and middle-income countries. In India, deaths related to burns are more common in women than in men and occur against a complex background in which the cause - accidental or non-accidental, suicidal or homicidal - is often unclear. Our study aimed to understand the antecedents to burns and the problem of ascribing cause, the sequence of medicolegal events after a woman was admitted to hospital, and potential opportunities for improvement. METHODS: We conducted semi-structured interviews with 33 women admitted to two major burns units, their families, and 26 key informant doctors, nurses, and police officers. We used framework analysis to examine the context in which burns occurred and the sequence of medicolegal action after admission to hospital. RESULTS: Interviewees described accidents, attempted suicide, and attempted homicide. Distinguishing between these was difficult because the underlying combination of poverty and cultural precedent was common to all and action was contingent on potentially conflicting narratives. Space constraint, problems with cooking equipment, and inflammable clothing increased the risk of accidental burns, but coexisted with household conflict, gender-based violence, and alcohol use. Most burns were initially ascribed to accidents. Clinicians adhered to medicolegal procedures, the police carried out their investigative requirements relatively rapidly, but both groups felt vulnerable in the face of the legal process. Women's understandable reticence to describe burns as non-accidental, the contested nature of statements, their perceived history of changeability, the limited quality and validity of forensic evidence, and the requirement for resilience on the part of clients underlay a general pessimism. CONCLUSIONS: The similarities between accident and intention cluster so tightly as to make them challenging to distinguish, especially given women's understandable reticence to describe burns as non-accidental. The contested status of forensic evidence and a reliance on testimony means that only a minority of cases lead to conviction. The emphasis should be on improving documentation, communication between service providers, and public understanding of the risks of burns.

The social construction of 'dowry deaths'.

The classification of cause of death is real in its consequences: for the reputation of the deceased, for her family, for those who may be implicated, and for epidemiological and social research and policies and practices that may follow from it. The study reported here refers specifically to the processes involved in classifying deaths of women from burns in India. In particular, it examines the determination of 'dowry death', a class used in India, but not in other jurisdictions. Classification of death is situated within a framework of special legal provisions intended to protect vulnerable women from dowry-related violence and abuse. The findings are based on 33 case studies tracked in hospital in real time, and interviews with 14 physicians and 14 police officers with experience of dealing with burns cases. The formal class into which any given death is allocated is shown to result from motivated accounting processes representing the interests and resources available to the doctors, victims, victim families, the victim's husband and his family, and ultimately, the police. These processes may lead to biases in research and to injustice in the treatment of victims and alleged offenders. Suggestions are made for methods of ameliorating the risks.

Preputial flap as an adjunct to groin flap for the coverage of electrical burns in the hand.

High voltage electrical contact to hand result in injuries at multiple levels that may require more than a single flap for effective coverage. We present here a simple technique to utilise preputial flap as an adjunct to groin flap in cases where simultaneous coverage was required at more than one site in hands. In the past two years, 15 patients with unilateral involvement of hands due to electrical contact injury underwent this procedure. In addition to a comfortable position of the hand, stable and purposeful coverage at the wrist and various areas of hands was achieved in all the patients and none had flap failure. Minor complications related to penile erection were encountered that resulted in partial wound dehiscence that was managed with resuturing, pain relief and temporary suppression of erection. In our opinion, preputial flap is a good addition in our armamentarium to be used alongside groin flap for effective coverage of more than a single site requiring flap cover in electric injuries of the hand.

Epidemiological and clinico-mycological profile of fungal wound infection from largest burn centre in Asia.

The current study was conducted to know the incidence, predisposing factors, spectrum, clinical profile and antifungal susceptibility (AFS) of fungal wound infection (FWI) in burn patients. Of a total of 71 patients, 20 (28.2%) emerged with the diagnosis of FWI. Fungal pathogens in this study were Candida tropicalis (14%), Candida parapsilosis (5.6%), Aspergillus niger (2.8%) and one each of Candida albicans (1.4%), Candida glabrata (1.4%), Syncephalestrum (1.4%) and Fusarium solani (1.4%). All patients with mould infections expired before the mycological culture results could be conveyed to clinicians. Of the yeasts isolated in the study, one each of C. tropicalis and C. albicans showed cross-resistance to azoles. All the moulds were susceptible to amphotericin B. This study depicted that fungal invasion is associated with a high mortality, burn size 30-60% and high incidence of inhalational injury. Fungal invasion was detected on an average of 14 days after injury. Association of use of four classes of drugs - aminoglycosides, imipenem, vancomycin and third generation cephalosporins and use of total parenteral nutrition was observed. Expedient laboratory diagnosis of FWI and appropriate systemic antifungal therapy guided by AFS may improve outcome for severely injured burn victims.

Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors.

Based on rational drug design approach, a series of novel thiazolidin-4-ones bearing different aryl/heteroaryl moieties at position C-2 and N-3 are synthesized and evaluated as potent inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme (HIV-1 RT). An in vitro HIV-1 RT assay showed that the compounds 4, 5, 6, 8, 12, 13, 14 and 17 have shown high inhibition of reverse transcriptase (75.41, 95.50, 98.07, 91.24, 85.27, 77.59, 84.11 & 76.49% inhibition) enzyme activity. Further, cell based assay showed that compounds 4, 5, 8 &12 are identified as the best compounds of the series (EC(50) ranged from 0.09 to 0.8 µg/ml and 0.12 to 1.06 µg/ml) against HIV-1 III(B) and HIV-1 ADA5 strains, respectively. Moreover, the compounds which were active against HIV-1 III(B) and HIV-1 ADA5 were also found to be active against primary isolates (EC(50) ranged from 0.10 to 1.55 µg/ml against HIV-1 UG070 and 0.07 to 1.1 µg/ml against HIV-1 VB59), respectively. Structure-activity relationship (SAR) studies demonstrated the importance of the lipophilic bulky substituent pattern on compact heteroaryl ring at N-3, replacement of C4' at C-2 phenyl by trivalent bioisosteric nitrogen and dihalo groups at C-2 aryl/heteroaryl of thiazolidin-4-ones is crucial for anti-HIV-1 activity. Molecular modeling of compounds 4, 5, 8 and 12 in complex with HIV-1 RT demonstrate that there is good correlation of results obtained from SAR studies. Therefore the compounds 4, 5, 8 and 12 may be considered as good candidates for further optimization of anti-HIV-1 activity.