The human imperative of stabilizing global climate change at 1.5°C.

Increased concentrations of atmospheric greenhouse gases have led to a global mean surface temperature 1.0°C higher than during the pre-industrial period. We expand on the recent IPCC Special Report on global warming of 1.5°C and review the additional risks associated with higher levels of warming, each having major implications for multiple geographies, climates, and ecosystems. Limiting warming to 1.5°C rather than 2.0°C would be required to maintain substantial proportions of ecosystems and would have clear benefits for human health and economies. These conclusions are relevant for people everywhere, particularly in low- and middle-income countries, where the escalation of climate-related risks may prevent the achievement of the United Nations Sustainable Development Goals.

Ostial left main coronary artery chronic total occlusion presenting as chronic stable angina.

Significant left main coronary artery (LMCA) disease is found in 5-6% of all patients undergoing coronary angiography. It usually presents as acute coronary syndrome and is commonly associated with multi-vessel coronary artery disease (CAD). Complete occlusion of LMCA is a much rarer finding, since these patients usually present as unstable angina, myocardial infarction and cardiogenic shock. We report a case of a young female, who presented with chronic stable angina and had an isolated chronic total occlusion (CTO) of LMCA with no lesions in the other coronary arteries. Aortogram failed to demonstrate the stump of occluded LMCA and demonstrated the filling of the left coronary system from the right coronary artery. Apart from dyslipidemia, she had no other risk factors for CAD. She was extensively evaluated for non-atherosclerotic causes of LMCA CTO including vasculitis. She underwent coronary artery bypass graft successfully without any peri-procedural complications.

Effect of informed consent on patients undergoing gastrointestinal surgery and living donor liver transplantation and on their relatives in a developing country.

BACKGROUND: Informed consent is a systematic process for obtaining permission before conducting a healthcare intervention. In a developing country, gaining informed consent is generally perceived to be a ritual only to comply with legal requirements. The present study examined this by assessing the process of informed consent in patients undergoing gastrointestinal surgery or living donor liver transplantation (LDLT) and their relatives, based on their comprehension and overall satisfaction, in India. METHODS: All patients undergoing any gastrointestinal surgery or LDLT procedure between August 2015 and July 2016 and their relatives were included, and were administered a structured questionnaire 5 days after the procedure. RESULTS: The majority of patients (94·2 per cent) could recall the nature of their disease, the surgery performed (81·6 per cent) and anticipated complications (55·6 per cent). Among their relatives, these proportions were 97·8, 87·3 and 58·5 per cent respectively. Recall was associated with age, occupation and education among both patients and relatives. Patients undergoing LDLT, their donors and their relatives had better recall than those who had other gastrointestinal procedures (P < 0·001). Many patients found the process of informed consent useful and reassuring. CONCLUSION: The details and risks of an operation were understood by most of the patients, especially those undergoing liver transplantation. Patients from developing countries can generally understand 'informed consent', and value it.

Minimizing Hepatic Artery Thrombosis and Establishing Safety of Grafts With Dual Arteries in Living Donor Liver Transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) is a dreaded complication following living donor liver transplantation (LDLT) and can lead to graft failure and biliary complications. We evaluated the results of our arterial anastomotic technique and outcomes in grafts with dual arterial supply. PATIENTS AND METHODS: Between July 2010 and June 2015, 225 patients underwent LDLT. The hepatic artery anastomosis was done using our "W technique". In grafts with a dual arterial supply, two anastomoses were performed unless there was significant pulsatile back-bleeding in the smaller artery after the larger anastomosis. RESULTS: The mean age of the recipients was 43±15.2 years (6 months to 66 years). There were 184 right liver, 30 left liver, 10 left lateral segment, and 1 dual lobe (right liver and left lateral segment) grafts. Twenty-three (10.2%) patients had 2 graft arteries, 10 of which required 2 separate anastomoses, and an interposition saphenous vein conduit was used in one. HAT occurred in 3 (1.3%) patients. The median intensive care unit and postoperative hospital stays were 5 and 14 days, respectively. Post-transplant operative mortality was 12.4%. There was no difference in mortality (8.7% vs 12.4%, P = >.99) and biliary complications (11.9% vs 21.7%, P = .19) between recipients of grafts with single or dual graft arteries, respectively. CONCLUSIONS: A careful surgical "W technique" and intraoperative confirmation of a good arterial flow helps in reducing the incidence of early HAT. The presence of two arteries in the graft was not associated with increased incidence of HAT, mortality, or biliary complications.

Imaging during percutaneous coronary intervention for optimizing outcomes.

Angiography is the current gold standard for imaging during percutaneous coronary interventions but has significant limitations. Catheter-based intravascular imaging techniques such as intravascular ultrasound and the more recent optical coherence tomography have the potential to overcome these limitations and thus optimize clinical outcomes. In this update, we discussed the current applications of the available imaging techniques, existing evidence, continuing unmet needs, and potential areas for further research.

Fluid and Medication Considerations in the Traumatized Patient.

This article reviews fluid therapy and medications in pediatric trauma. For resuscitation in the setting of hemorrhagic shock, isotonic crystalloid solution is the first-line agent of choice. Colloid solutions offer no additional benefit, introduce possible increased risks and cost more than crystalloids. Blood products, starting with pRBCs, should be introduced after 20-40 ml/kg of crystalloid has been administered if there is ongoing need for volume replacement. The use of a massive transfusion protocol of 1:1:1 (if >30 kg) or 30:20:20 (if <30 kg) of pRBCs:FFP:platelets is suggested after an initial 30 ml/kg of pRBcs has been administered. Cryoprecipitate should be given for documented low fibrinogen or ongoing bleeding after administration of 1 round of all 3 blood components. For patients at risk of massive hemorrhage, early administration of tranexamic acid with an initial loading dose of 15 mg/kg (maximum 1 g) is recommended. Choice of medication for intubation of the patient with Traumatic Brain Injury (TBI) may best be guided by physiology: in the TBI patient with a high mean arterial pressure, premedication with lidocaine, fentanyl and use of etomidate may be most appropriate, whereas in the hemodynamically compromised patient, use of ketamine alone may be considered. If needed, norepinephrine has been recommended as a temporizing agent for vasopressor support in the setting of fluid-refractory shock. Although controversial, in the setting of significant spinal cord injury, the potential benefits of administering 24-48 hours of steroids (initial 30 mg/kg of methylprednisolone within 8 hours of injury) may outweigh the risks especially in previously healthy pediatric patients.

Repression of caspase-3 and RNA-binding protein HuR cleavage by cyclooxygenase-2 promotes drug resistance in oral squamous cell carcinoma.

A well-studied RNA-binding protein Hu Antigen-R (HuR), controls post-transcriptional gene regulation and undergoes stress-activated caspase-3 dependent cleavage in cancer cells. The cleavage products of HuR are known to promote cell death; however, the underlying molecular mechanisms facilitating caspase-3 activation and HuR cleavage remains unknown. Here, we show that HuR cleavage associated with active caspase-3 in oral cancer cells treated with ionizing radiation and chemotherapeutic drug, paclitaxel. We determined that oral cancer cells overexpressing cyclooxygenase-2 (COX-2) limited the cleavage of caspase-3 and HuR, which reduced the rate of cell death in paclitaxel resistant oral cancer cells. Specific inhibition of COX-2 by celecoxib, promoted apoptosis through activation of caspase-3 and cleavage of HuR in paclitaxel-resistant oral cancer cells, both in vitro and in vivo. In addition, oral cancer cells overexpressing cellular HuR increased the half-life of COX-2 mRNA, promoted COX-2 protein expression and exhibited enhanced tumor growth in vivo in comparison with cells expressing a cleavable form of HuR. Finally, our ribonucleoprotein immunoprecipitation and sequencing (RIP-seq) analyses of HuR in oral cancer cells treated with ionizing radiation (IR), determined that HuR cleavage product-1 (HuR-CP1) bound and promoted the expression of mRNAs encoding proteins involved in apoptosis. Our results indicated that, cellular non-cleavable HuR controls COX-2 mRNA expression and enzymatic activity. In addition, overexpressed COX-2 protein repressed the cleavage of caspase-3 and HuR to promote drug resistance and tumor growth. Altogether, our observations support the use of the COX-2 inhibitor celecoxib, in combination with paclitaxel, for the management of paclitaxel resistant oral cancer cells.

Antisperm antibodies in repeat-breeding cows: Frequency, detection and validation of threshold levels employing sperm immobilization, sperm agglutination and immunoperoxidase assay.

Antisperm antibodies have been found in repeat-breeding(RB) cows, and those causing agglutination and/or immobilization of sperm are considered to be closely related to unexplained infertility. However, a standard protocol for identifying antisperm antibodies (ASA) in cattle is not validated. Therefore, an investigation was undertaken to evaluate sperm immobilization (SIT), sperm agglutination (SAT) and immunoperoxidase (IPT)assays for detection of ASA in serum and their respective threshold levels for confirmation. Animals (heifers, normally breeding, repeat-breeding and pregnant animals) that were free from IBR, brucellosis and uterine infections (screened by clinical examination) were included in the study. Sperm agglutinating, sperm immobilizing and antisperm antibodies evaluated by respective assay were significantly higher (p < .05) in RB cows compared to other groups. The SIT assay was able to identify 61% of RB caused by ASA, more than those employing SAT and IPT. Furthermore, a dilution rate of 1:5 and 1:80 (confirms 59.0 and 57.0% RB+ve)were sufficient to diagnose ASA by SAT and IPT, respectively. Results indicate the presence of __12.6% clumped spermatozoa and __ 2.6%(cut-off value) peroxidase-positive spermatozoa at 1:5 and 1:80 dilutions diagnosed with SAT and IPT, respectively, may be considered as repeaters arising out of ASA. Furthermore, study also showed the presence of lower incidence of ASA positivity in other groups of animals (heifer

Evaluating a murine model of endometritis using uterine isolates of Escherichia coli from postpartum buffalo.

Ascending infection of the uterus with Gram-negative bacteria is responsible for postpartum endometritis in cattle and buffalo and can adversely affect fertility. Development of a laboratory animal model for bovine endometritis would facilitate the understanding of the pathogenesis as it is difficult to conduct controlled experimentation in the native host. In the present study, 30 virgin Swiss Albino mice (5-8 weeks old) were used to evaluate the pathogenic potential of Escherichia coli, isolated from the normally calved postpartum buffalo to induce endometritis. Mice in the diestrus phase of the estrous cycle were randomly allotted to one of the following four intravaginal inoculation (100 µL) treatments: EG (experimental group)-1: sterile normal saline; EG-2, -3 and -4: E. coli@ 1.5 × 104, 105 and 106 CFU/ml, respectively. The animals were then scarified 36 h post-inoculation to study gross and microscopical lesions. Gross changes were confined to EG-4. Acute endometritis was recorded in 50% of the EG-3 and 66.7% of the EG-4. The rate of acute endometritis development was significantly higher in EG-4 (P<0.05) as compared to the other groups. The present study demonstrated that the animal model for bubaline endometritis can be developed in mice by intravaginal inoculation of E.coli@ 1.5 × 106 CFU/ml at diestrus. Ease of intravaginal inoculation, apparent absence of systemic involvement and high infective rate are the advantages of the model over other studies.

High traffic congestion in right atrium.

A 62-year lady presented with limb swelling and heart failure due to leads induced venous fibrosis and severe tricuspid stenosis, 33 years after pacemaker implantation. After undergoing surgical removal of all leads and tricuspid valve replacement under cardiopulmonary bypass, she regained a normal functional status and tricuspid and right ventricular functions.

Communicating to Influence Drug Development and Regulatory Decisions: A Tutorial.

Pharmacometricians require three skills to be influential: technical, business (e.g., drug development), and soft skills (e.g., communication). Effective communication is required to translate technical and often complicated quantitative findings to interdisciplinary team members in order to influence drug development or regulatory decisions. In this tutorial, we highlight important aspects related to communicating pharmacometric analysis to influence decisions.

Supplementation of Slow-Release Melatonin Improves Recovery of Ovarian Cyclicity and Conception in Summer Anoestrous Buffaloes (Bubalus bubalis).

The role of melatonin as a protective neurohormone against restoring cyclicity in summer anoestrous animals in photoperiod species has gained wider acceptance. This study was designed to uncover the evidence the slow-release melatonin (MLT) has on initiation of ovarian cyclicity and conception rate (CR) in summer anoestrous buffaloes. Thus, buffaloes diagnosed as summer anoestrous (absence of overt signs of oestrus, concurrent rectal examination and radioimmunoassay for serum progesterone at 10 days interval) were grouped as untreated (Group I, sterilized corn oil, n = 8) and treated (Group II, single subcutaneous injection of MLT @18 mg/50 kg bwt in sterilized corn oil, n = 20). Animals treated and detected in oestrus were artificially inseminated (AI) followed by division into Group III (second dose of MLT on 5th day post-AI, n = 8) and Group IV (no melatonin administration, n = 10). Blood samples were collected at 4 days interval for estimation of serum MLT, progesterone and oestrogen using radioimmunoassay kit. Mean oestrous induction rate (OIR), oestrous induction interval (OII), interoestrous interval (IOI) and CR were estimated. Compared to control, concentration of melatonin was significantly (p < 0.05) higher in treated group ranging from 14.34 ± 1.72 to 412.31 ± 14.47 pg/ml whereas other two hormones did not show any concentration difference. Melatonin-administered buffaloes showed significantly (p < 0.05) higher (90%) OIR with OII of 18.06 ± 1.57 days. Results showed improvement in conception rate in buffaloes administered with post-insemination melatonin. It can be concluded from the study that slow-release melatonin supplementation restored cyclicity in summer anoestrous animals resulting in improvement in conception rate in buffaloes.

IL-12 conditioning improves retrovirally mediated transduction efficiency of CD8+ T cells.

The ability to genetically modify T cells is a critical component to many immunotherapeutic strategies and research studies. However, the success of these approaches is often limited by transduction efficiency. As retroviral vectors require cell division for integration, transduction efficiency is dependent on the appropriate activation and culture conditions for T cells. Naive CD8(+) T cells, which are quiescent, must be first activated to induce cell division to allow genetic modification. To optimize this process, we activated mouse T cells with a panel of different cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-12, IL-15 and IL-23, known to act on T cells. After activation, cytokines were removed, and activated T cells were retrovirally transduced. We found that IL-12 preconditioning of mouse T cells greatly enhanced transduction efficiency, while preserving function and expansion potential. We also observed a similar transduction-enhancing effect of IL-12 preconditioning on human T cells. These findings provide a simple method to improve the transduction efficiencies of CD8(+) T cells.

Prospective study to develop surface landmarks for blind axillary vein puncture for permanent pacemaker and defibrillator lead implantation and compare it to available contrast venography guided technique.

OBJECTIVE: To develop surface landmarks for blind axillary vein puncture for pacemaker lead implantation. METHODS AND RESULTS: Patients for routine coronary angiography were counseled for participating in our study. 20 patients who gave consent were taken up for axillary venogram after proper positioning at the time of coronary angiogram. The venograms of these 20 patients, were reviewed and the landmarks were used to develop a blind axillary puncture technique. Success rate of 100% was achieved with surface landmark guided axillary vein puncture. The implantation time while using surface landmark guided axillary puncture was not significantly longer than when venography based approach was used. Another interesting observation made from the study was that increasing BMI had a positive correlation with the time taken for venous access, the fluoroscopic time and the volume of contrast used, all the associations being statistically significant. Thus, the surface landmark guided technique is more safe and expeditious in non obese patients and probably in pediatric patients as well. Moreover, the new surface landmark guided approach is a significant safety step in terms of reducing the unwanted and avoidable radiation exposure to the hands. CONCLUSION: The results of this study demonstrate that placement of endocardial permanent pacemaker and ICD leads via the developed surface landmarks is effective and safe and is devoid of the harmful effects of radiation and contrast exposure.

Sustained delivery of exogenous melatonin influences biomarkers of oxidative stress and total antioxidant capacity in summer-stressed anestrous water buffalo (Bubalus bubalis).

High ambient temperature during summer in tropical and subtropical countries predisposes water buffaloes (Bubalus bubalis) to develop oxidative stress having antigonadotropic and antisteroidogenic actions. Melatonin is a regulator of seasonal reproduction in photoperiodic species and highly effective antioxidant and free radical scavenger. Therefore, a study was designed to evaluate the effect of sustained-release melatonin on biomarkers of oxidative stress i.e., the serum malondialdehyde (MDA) and nitric oxide (NO), and the total antioxidant capacity (TAC). For the study, postpartum buffaloes diagnosed as summer anestrus (absence of overt signs of estrus, concurrent rectal examination, and RIA for serum progesterone) were grouped as treated (single subcutaneous injection of melatonin at 18 mg/50 kg body weight dissolved in sterilized corn oil as vehicle, n = 20) and untreated (subcutaneous sterilized corn oil, n = 8). Blood sampling for estimation of serum TAC and MDA (mmol/L) and NO (µmol/L) was carried out at 4 days of interval from 8 days before treatment till 28 days after treatment or for the ensuing entire cycle length. Results showed serum TAC concentration was higher in the treatment group with a significant (P < 0.05) increasing trend, whereas MDA and NO revealed a significant (P < 0.05) decline. Serum MDA and NO were higher in control compared with those of treatment group. Moreover, buffaloes in the treatment group showed 90% estrus induction with 18.06 ± 1.57 days mean interval from treatment to the onset of estrus. These results report that melatonin has a protective effect by elevating antioxidant status and reducing oxidative stress resulting in the induction of cyclicity in summer-stressed anestrous buffaloes.

Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing.

The Pim protein kinases contribute to transformation by enhancing the activity of oncogenic Myc and Ras, which drives significant metabolic changes during tumorigenesis. In this report, we demonstrate that mouse embryo fibroblasts (MEFs) lacking all three isoforms of Pim protein kinases, triple knockout (TKO), cannot tolerate the expression of activated K-Ras (K-Ras(G12V)) and undergo cell death. Transduction of K-Ras(G12V) into these cells markedly increased the level of cellular reactive oxygen species (ROS). The addition of N-acetyl cysteine attenuated ROS production and reversed the cytotoxic effects of K-Ras(G12V) in the TKO MEFs. The altered cellular redox state caused by the loss of Pim occurred as a result of lower levels of metabolic intermediates in the glycolytic and pentose phosphate pathways as well as abnormal mitochondrial oxidative phosphorylation. TKO MEFs exhibit reduced levels of superoxide dismutase (Sod), glutathione peroxidase 4 (Gpx4) and peroxiredoxin 3 (Prdx3) that render them susceptible to killing by K-Ras(G12V)-mediated ROS production. In contrast, the transduction of c-Myc into TKO cells can overcome the lack of Pim protein kinases by regulating cellular metabolism and Sod2. In the absence of the Pim kinases, c-Myc transduction permitted K-Ras(G12V)-induced cell growth by decreasing Ras-induced cellular ROS levels. These results demonstrate that the Pim protein kinases have an important role in regulating cellular redox, metabolism and K-Ras-stimulated cell growth.

A prospective double blind study comparing the effects of oxytocin and human chorionic gonadotrophin as trigger for ovulation.

This study was undertaken to compare the effect of oxytocin and human chorionic gonadotrophin (hCG) on ovulation and conception. A total of 100 women with anovulatory infertility were allocated into two equal groups to take clomiphene citrate plus hCG or clomiphene citrate plus oxytocin. The size and number of follicles by transvaginal sonography determined the administration of hCG or oxytocin. The serum progesterone concentration was measured to provide evidence for ovulation. The ovulation and pregnancy rate of the two groups were compared. There was no significant difference between the groups with respect to mean number of follicles, mean follicular size and rate of ovulation in three cycles. The rate of pregnancy was higher in the oxytocin group compared with the hCG group (12% vs 4%) but it failed to reach statistical difference (p = 0.140). Mild pain was the only side-effect observed in the two groups. Oxytocin was found to be a viable alternative to hCG for triggering ovulation in infertile patients.

Post-radiation atypical vascular lesion/angiosarcoma arising in the larynx.

Atypical vascular lesions (AVL) and angiosarcomas (AS) are lesions known to arise after radiation therapy. These lesions can show overlap in both their gross and histologic pictures, and distinction between the two can be extremely challenging at times. They are known most commonly to arise in the breast region after radiation therapy. We present the first unique case of post-radiation AVL/AS arising in the larynx of a 51 year old woman, occurring 8 years after she received radiation for tonsillar squamous cell carcinoma.

Management of bleeding in extrahepatic portal venous obstruction.

Extrahepatic portal venous obstruction, although rare in the western world, is a common cause of major and life threatening upper gastrointestinal bleeding among the poor in developing countries. Patients have large spleens and stunted growth. The diagnosis is easily confirmed by Doppler ultrasonography. Endoscopy sclerotherapy is the best option for the control of acute variceal bleeding. For secondary prophylaxis of bleeding, the choice lies between repeated sclerotherapy and a portosystemic shunt. We believe that due consideration should be given to performing a splenectomy and a lienorenal shunt. Performed by experienced surgeons, it carries a low operative mortality of 1%, a rebleeding rate of about 10%, removes the large spleen, reverses hypersplenism, and is not followed by portosystemic encephalopathy. Most importantly, it is a onetime procedure particularly suited to those who have little access to blood transfusion and sophisticated medical facilities.