Search

Introduction: The influence of pregnancy-related pelvic girdle pain (PPGP) on lumbopelvic muscles has not been comprehensively examined in postpartum individuals. Previous research also presented self-reported activity limitations without objective measures., Methods: Thirty postpartum individuals with PPGP (PPGP group) and 30 age-, parity-, and postpartum duration-matched asymptomatic individuals (healthy group) were recruited. Transabdominal ultrasonography was used to measure muscle thickness or activation changes of the external oblique (EO), internal oblique (IO), transverse abdominals, lumbar multifidus, and pelvic floor muscles (PFMs) during rest and while performing the active straight leg raise (ASLR). Muscle changes were compared separately in the painful and nonpainful sides between the PPGP and health control group. Physical function was assessed using the ASLR fatigue (ASLRF), timed up-and-go, and 6-m walking (6MW) tests., Results: The PPGP group had greater thickening changes in the bilateral IO during ASLR compared with the healthy group (nonpainful side, 16.34 vs 3.52 mm; P = .010; painful side, 18.83 vs 6.60 mm; P = .02) but became thinner in the EO (nonpainful side, -2.19 vs 19.97 mm; P < .001; painful side, -5.97 vs 21.43 mm; P < .001). Thicker IO and EO on the nonpainful side (IO, 6.60 vs 5.78 mm; P = .004; EO, 5.37 vs 4.54 mm; P = .011) and a lower bladder base (indication of PFMs) (91.87 vs 78.61 mm; P = .002) during rest were also observed in the PPGP group. Furthermore, the performance of the ASLRF and 6MW tests was poorer in the PPGP than in the healthy group (ASLRF nonpainful side, 82.36 vs 59.09 sec; P = .01; painful side, 75.73 vs 59.26 sec; P = .04; 6MW, 3.48 vs 3.17 sec; P = .02)., Discussion: Postpartum individuals with PPGP demonstrated altered abdominal muscle recruitment strategies during loading tasks, with objectively impaired physical functions. These findings are critical for developing effective muscle training interventions for PPGP., (© 2024 by the American College of Nurse‐Midwives.)

Background: Perineal trauma and pain can affect the quality of life of women who experience vaginal birth., Aim: To investigate the effect of perineal care and pain management on women's postpartum recovery., Methods: This was a Quasi-experimental study. In Phase 1 women were treated using our old postnatal perineal care management guideline. In Phase 2 an updated guideline was introduced (regular administration of icepacks and analgesia during the first 24-48 h postpartum). During Phase 1, pregnant women planning a vaginal birth completed a baseline questionnaire. Those who sustained perineal trauma completed a survey at 24-48 h, seven days and 12 weeks after birth. In Phase 2 we continued recruiting participants, using the same procedure, and investigated the efficacy of pain relief approaches using the new guideline., Results: In Phase 1, 111 women (Group 1), and Phase 2, 146 women (Group 2) were recruited. No statistically significant differences were found between the two groups in terms of the women's pain catastrophising, their partner's responses to pain behaviours, or birth outcomes. At 24-48 h and seven days postpartum, women in Group 2 were less likely than women in Group 1 to be bothered by back or perineal pain, headache, sleeping difficulties and dizziness (p < 0.05). More women in Group 2 received regular paracetamol and perineal icepacks during their hospital stay, with less use of oxycodone in Group 2 than Group 1., Conclusion: The implementation of the guideline's recommendations was associated with decrease back and perineal pain, headache, sleeping difficulties and dizziness during the first seven days postpartum., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This retrospective cohort study was conducted on 1148 males who presented along with their partners for infertility management at the PIVET Medical Centre between 2013 and 2022 and had a sperm DNA fragmentation (SDF) assay performed by Halosperm, thereafter participating in 1600 assisted reproductive technology (ART) cycles utilising one of three modalities, namely, IVF-Only, ICSI-Only or IVF-ICSI Split cycles. The outcomes from the ART cycles were then analysed as two groups based on SDF levels <15% and ≥15%. The study showed the unadjusted fertilization rates were not different between the groups, neither across the four female age ranges. However, when the fertilization rates were adjusted for the mature oocytes (metaphase-II oocytes), there was a highly significant difference in fertilization rates in favour of the group with SDF levels < 15% where the women were in the younger age grouping of <35 years (78.4% vs. 73.0%; p < 0.0001). Overall, there was no difference in the rates of blastocyst development nor clinical pregnancy rates between the two SDF groups, but there was a significantly higher pregnancy rate for the younger women (<35 years) with the group of SDF level < 15% (44.1% vs. 37.4%; p = 0.04). Similarly, there was no difference in the miscarriage rates overall with respect to SDF groups, and no clear picture could be deciphered among the women's age groups. With respect to cumulative live births, this reflected the pregnancy rates with no overall difference between the two SDF groups, but there was a significantly higher cumulative live birth rate for women <35 years where the SDF level was <15% (38.6% vs. 28.6%; p < 0.01). Among the three modalities, the highest cumulative live birth rate occurred within the group with SDF level < 15%, being highest with the IVF mode, particularly for women aged <40 years (43.0% vs. 37.7% for IVF-ICSI Split and 27.9% for ICSI; p = 0.0002), noting that the IVF case numbers were disproportionately low.

This retrospective cohort study reports on 1291 males who were the partners of women presenting with infertility requiring assisted reproduction and who had sperm DNA fragmentation (SDF) levels measured by the Halosperm test. These men provided clinical and biometric details which included their age, stature, weight, and body mass index (BMI). Of these men, 562 (43.5%) provided detailed historical records of their smoking and alcohol histories. The aim of this study was to determine whether any clinical and biometric parameters, or main lifestyle factors, had any influence on SDF. We found that the only clinical parameter with a direct correlation was that of advancing age (r = 0.064, p = 0.02), but none of the biometric parameters of stature, weight, or BMI showed any significant correlation. In respect to lifestyle, there were significant correlations with smoking history, but not in the way we expected. Our data showed significantly elevated SDF levels among non-smokers ( p = 0.03) compared with smokers. We also found that, among the non-smokers, ex-smokers had higher SDF levels ( p = 0.03). With respect to alcohol, consumers did not show any significant differences in SDF levels. These lifestyle findings did not show any significant relevance with respect to an SDF level of <15% or ≥15%. Furthermore, logistic regression analysis excluded age as a confounder in these lifestyle findings. It is therefore concluded that, apart from age, both clinical and lifestyle aspects have minimal relevance to SDF.

Sperm DNA fragmentation (SDF) levels have been measured in the workup for in vitro fertilization (IVF) at PIVET since 2007, with the Halosperm test having replaced the previous sperm chromatin structure assay (SCSA) since 2013. Of 2624 semen samples analyzed for the Halosperm test, 57 were excluded as the sperm concentration was <5 million/mL, a level too low for accurate testing, leaving 2567 samples for assessment within this study. The SDF rates were categorized in 5 sperm DNA fragmentation indices (DFI), ranging from <5% to levels >30%, and these categories were correlated with the respective semen analysis profiles and two clinical parameters, namely the age of the male and the ejaculatory abstinence period prior to the sample. The results showed a significant correlation with male age (r = 0.088; p < 0.0001), the abstinence period (r = 0.076; p = 0.0001), and the semen volume (r 0.063; p = 0.001), meaning an adversely high SDF was associated with advanced age, prolonged abstinence, and raised semen volume parameters. There was a significant negative correlation with sperm morphology (r = -0.074; p = 0.0001), progressive motility (r = -0.257; p < 0.0001), and semen pH (r = -0.066; p < 0.001), meaning these semen anomalies were associated with high SDF values. With respect to abnormal morphology, sperm tail defects had a positive correlation (r = 0.096; p < 0.0001) while midpiece defects showed a negative correlation (r = -0.057; p = 0.004), meaning that tail defects are most likely to associate with adverse DFI values. With respect to motility patterns, the poorer patterns showed a positive correlation with increased DFI, namely C pattern (r = 0.055; p = 0.005) and D pattern (r = 0.253; p < 0.0001). These results imply that raised DFI reflects poor sperm quality and should be investigated in clinical trials involving IVF and the consideration of intracytoplasmic sperm injection (ICSI).

Current policy is driving renewed impetus to restore forests to return ecological function, protect species, sequester carbon and secure livelihoods. Here we assess the contribution of tree planting to ecosystem restoration in tropical and sub-tropical Asia; we synthesize evidence on mortality and growth of planted trees at 176 sites and assess structural and biodiversity recovery of co-located actively restored and naturally regenerating forest plots. Mean mortality of planted trees was 18% 1 year after planting, increasing to 44% after 5 years. Mortality varied strongly by site and was typically ca 20% higher in open areas than degraded forest, with height at planting positively affecting survival. Size-standardized growth rates were negatively related to species-level wood density in degraded forest and plantations enrichment settings. Based on community-level data from 11 landscapes, active restoration resulted in faster accumulation of tree basal area and structural properties were closer to old-growth reference sites, relative to natural regeneration, but tree species richness did not differ. High variability in outcomes across sites indicates that planting for restoration is potentially rewarding but risky and context-dependent. Restoration projects must prepare for and manage commonly occurring challenges and align with efforts to protect and reconnect remaining forest areas. The abstract of this article is available in Bahasa Indonesia in the electronic supplementary material. This article is part of the theme issue 'Understanding forest landscape restoration: reinforcing scientific foundations for the UN Decade on Ecosystem Restoration'.

Robotic manipulation refers to how robots intelligently interact with the objects in their surroundings, such as grasping and carrying an object from one place to another. Dexterous manipulating skills enable robots to assist humans in accomplishing various tasks that might be too dangerous or difficult to do. This requires robots to intelligently plan and control the actions of their hands and arms. Object manipulation is a vital skill in several robotic tasks. However, it poses a challenge to robotics. The motivation behind this review paper is to review and analyze the most relevant studies on learning-based object manipulation in clutter. Unlike other reviews, this review paper provides valuable insights into the manipulation of objects using deep reinforcement learning (deep RL) in dense clutter. Various studies are examined by surveying existing literature and investigating various aspects, namely, the intended applications, the techniques applied, the challenges faced by researchers, and the recommendations adopted to overcome these obstacles. In this review, we divide deep RL-based robotic manipulation tasks in cluttered environments into three categories, namely, object removal, assembly and rearrangement, and object retrieval and singulation tasks. We then discuss the challenges and potential prospects of object manipulation in clutter. The findings of this review are intended to assist in establishing important guidelines and directions for academics and researchers in the future.

Objective: Investigate the impact of the COVID-19 pandemic on perinatal outcomes in an Australian high migrant and low COVID-19 prevalent population to identify if COVID-19 driven health service changes and societal influences impact obstetric and perinatal outcomes., Design: Retrospective cohort study with pre COVID-19 period 1 January 2018-31 January 2020, and first year of global COVID-19 period 1 February 2020-31 January 2021. Multivariate logistic regression analysis was conducted adjusting for confounders including age, area-level socioeconomic status, gestation, parity, ethnicity and body mass index., Setting: Obstetric population attending three public hospitals including a major tertiary referral centre in Western Sydney, Australia., Participants: Women who delivered with singleton pregnancies over 20 weeks gestation. Ethnically diverse women, 66% overseas born. There were 34 103 births in the district that met inclusion criteria: before COVID-19 n=23 722, during COVID-19 n=10 381., Main Outcome Measures: Induction of labour, caesarean section delivery, iatrogenic and spontaneous preterm birth, small for gestational age (SGA), composite neonatal adverse outcome and full breastfeeding at hospital discharge., Results: During the first year of COVID-19, there was no change for induction of labour (adjusted OR, aOR 0.97; 95% CI 0.92 to 1.02, p=0.26) and a 25% increase in caesarean section births (aOR 1.25; 95% CI 1.19 to 1.32, p<0.001). During the COVID-19 period, we found no change in iatrogenic preterm births (aOR 0.94; 95% CI 0.80 to 1.09) but a 15% reduction in spontaneous preterm birth (aOR 0.85; 95% CI 0.75 to 0.97, p=0.02) and a 10% reduction in SGA infants at birth (aOR 0.90; 95% CI 0.82 to 0.99, p=0.02). Composite adverse neonatal outcomes were marginally higher (aOR 1.08; 95% CI 1.00 to 1.15, p=0.04) and full breastfeeding rates at hospital discharge reduced by 15% (aOR 0.85; 95% CI 0.80 to 0.90, p<0.001)., Conclusion: Despite a low prevalence of COVID-19, both positive and adverse obstetric outcomes were observed that may be related to changes in service delivery and interaction with healthcare providers. Further research is suggested to understand the drivers for these changes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aims to evaluate the correlation between the results of transcutaneous bilirubin (TcB) levels measured by the 2 transcutaneous bilirubinometers according to the area tested and to compare the TcB measurements and the serum bilirubin (SBR) levels. We screened 78 neonates born at more than 35 weeks of gestation and aged less than 168 hours for jaundice. We used JM-105 and MBJ-20 to measure the TcB at the forehead and the chest. For newborns who had high TcB measurements, we obtained blood samples during the subsequent 30 minutes. There was a strong correlation between the TcB measurements by JM-105 and MBJ-20 and this correlation was stronger when they were used on the sternum. The mean differences between the TcB measurements on the forehead and the sternum and the SBR levels were similar for the JM-105 and the MBJ-20. There was a strong correlation between SBR and the measurements using the 2 devices on the sternum (JM-105: r = 0.805; MBJ-20: r = 0.801), unlike measurements taken on the forehead by each device (r = 0.777 and r = 0.751, respectively). Both devices had high sensitivity and negative predictive values at SBR level of less than 230 μmol/L (<13.4 mg/dL) and high specificity and positive predictive values at SBR level of 230 μmol/L and greater (>13.4mg/dL). Both devices equally overestimated the actual SBR and had more reliable results if used on the sternum., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α 1 -antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α 1 -antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome., Competing Interests: Declaration of interests David Lomas is an inventor on the patent PCT/GB2019/051761 for a small molecule treatment of antitrypsin deficiency. This small molecule has not been used in this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The endothelial glycocalyx (EG) plays a vital role in the physiology and pathophysiology of human microcirculation. Having relevant EG damage model would be important tool for testing new interventions aiming at EG protection and recovery. We describe the first in vivo EG damage model in pig., Objective: To investigate the course of animal EG damage induced by specific enzymes., Material and Methods: Four anesthetized piglets received enzymes: 1g hyaluronidase and 25 IU heparanase I intravenously. Blood and urine samples were collected at baseline and 20/40/60/80/100/120 min for detecting markers of endothelial and EG function. Sublingual microcirculation and EG thickness were assessed by Side-stream Dark Field (SDF) imaging and Perfused Boundary Region (PBR) respectively. EG of the mesentery artery was visualized in fluorescent microscopy., Results: Biochemical marker of EG damage syndecan-1 showed temporary increase with return to baseline and was reflected by PBR values. Albumin levels suggested brief period of capillary leakage (decrease in the serum, increase in the urine) with a trend to normalization. Urine glycosaminoglycans peaked at 120 minutes. Microcirculatory perfusion parameter showed significant alteration. Diffusion parameters were altered with no statistical significance., Conclusion: EG damage induced by specific enzymes was reflected by temporary changes of biochemical makers together with alteration of microcirculation and changes in fluorescent microscopy of EG layer. Our results support to further validate presented model of EG damage on a larger number of animals.

The central melanocortin system plays a fundamental role in the control of feeding and body weight. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) also regulate overall glucose homeostasis via insulin-dependent and -independent pathways. Here, we report that a subset of ARC POMC neurons innervate the liver via preganglionic parasympathetic acetylcholine (ACh) neurons in the dorsal motor nucleus of the vagus (DMV). Optogenetic stimulation of this liver-projecting melanocortinergic pathway elevates blood glucose levels that is associated with increased expression of hepatic gluconeogenic enzymes in female and male mice. Pharmacological blockade and knockdown of the melanocortin-4 receptor gene in the DMV abolish this stimulation-induced effect. Activation of melanocortin-4 receptors inhibits DMV cholinergic neurons and optogenetic inhibition of liver-projecting parasympathetic cholinergic fibers increases blood glucose levels. This elevated blood glucose is not due to altered pancreatic hormone release. Interestingly, insulin-induced hypoglycemia increases ARC POMC neuron activity. Hence, this liver-projecting melanocortinergic circuit that we identified may play a critical role in the counterregulatory response to hypoglycemia.

Increasing agricultural irrigation to counteract a soil moisture deficit has resulted in the production of hazardous agricultural wastewater with high turbidity and chemical oxygen demand (COD). An innovative, sustainable, and effective solution is needed to overcome the pollution and water scarcity issues caused by the agricultural anthropogenic processes. This research focused on a sustainable solution that utilized a waste (broken lentil) as natural coagulant for turbidity and COD removal in agricultural wastewater treatment. The efficiency of the lentil extract (LE), grafted lentil extract (LE-g-DMC) and aluminium sulphate (alum) coagulants was optimized through the response surface methodology. Three-level Box-Behnken design was used to statistically visualize the complex interactions of pH, concentration of coagulants and settling time. LE achieved a significant 99.55% and 79.87% removal of turbidity and COD at pH 4, 88.46 mg/L of LE and 6.9 minutes of settling time, whereas LE-g-DMC achieved 99.83% and 80.32% removal of turbidity and COD at pH 6.7, 63.08 mg/L of LE-g-DMC and 5 minutes of settling time. As compared to alum, LE-g-DMC required approximately 30% less concentration. Moreover, LE and LE-g-DMC also required 75% and 65% less settling time as compared to the alum. Both LE and LE-g-DMC produced flocs with excellent settling ability (5.77 mg/L and 4.48 mL/g) and produced a significant less volume of sludge (10.60 mL/L and 8.23 mL/L) as compared with the alum. The economic analysis and assessments have proven the feasibility of both lentil-based coagulants in agricultural wastewater treatment.

Background: Expediting delivery in the second stage of labour often involves a choice between a caesarean section at full dilatation or mid-cavity instrumental delivery. Accumulating evidence suggests that the mode of delivery may influence the risk of preterm birth in the subsequent pregnancy., Aims: To directly compare first birth caesarean section at full dilatation with mid-cavity instrumental delivery for the risk of preterm birth in the subsequent pregnancy (second birth). A further aim was to identify predictive factors associated with these index modes of delivery., Materials and Methods: This is a retrospective cohort study involving three maternity hospitals in western Sydney over the period of 2006-2017. Inclusion criteria were nulliparous women with a singleton term cephalic first birth delivered by caesarean section at full dilatation or mid-cavity instrumental delivery, and whose second birth also occurred under our care. Data were analysed separately for first and second births., Results: There were 425 caesarean section at full dilatation and 874 mid-cavity instrumental cases which met inclusion criteria. The risk of preterm birth in the second birth was 5.7% compared to 3.2%, respectively (risk ratio 1.76; 95% CI 1.04-3.00; P = 0.035). After excluding causes of preterm birth not related to previous mode of delivery, the risk of spontaneous preterm birth was 4.3% compared to 2.0%, respectively (risk ratio 2.18; 1.14-4.19; P = 0.019)., Conclusion: Caesarean section at full dilatation is associated with a significantly higher rate of preterm birth in the subsequent pregnancy compared to a mid-cavity instrumental delivery. This should be considered in second-stage mid-cavity decision-making., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

The importance of graft copolymerization in the field of polymer science is analogous to the importance of alloying in the field of metals. This is attribute to the ability of the grafting method to regulate the properties of polymer 'tailor-made' according to specific needs. This paper described a novel plant-based coagulant, LE-g-DMC that synthesized through grafting of 2-methacryloyloxyethyl trimethyl ammonium chloride (DMC) onto the backbone of the lentil extract. The grafting process was optimized through the response surface methodology (RSM) using three-level Box-Behnken Design (BBD). Under optimum conditions, a promising grafting percentage of 120% was achieved. Besides, characterization study including SEM, zeta potential, TGA, FTIR and EDX were used to confirm the grafting of the DMC monomer chain onto the backbone of lentil extract. The grafted coagulant, LE-g-DMC outperformed lentil extract and alum in turbidity reduction and effective across a wide range of pH from pH 4 to pH 10. Besides, the use of LE-g-DMC as coagulant produced flocs with excellent settling ability (5.09 mL/g) and produced the least amount of sludge. Therefore, from an application and economic point of views, LE-g-DMC was superior to native lentil extract coagulant and commercial chemical coagulant, alum.

Obesity is a neurological disorder that operates by favoring energy storage within adipose depots and increased caloric intake. Most cases of human obesity are acquired without any underlying genetic basis. Here, we suggest that obesity can impair the function of some hypothalamic neurons critical to body weight regulation. Genetic ablation of the retinoblastoma (Rb) gene within pro-opiomelanocortin (POMC) neurons leads to death of the neurons and subsequent obesity. The Rb protein (pRb), a key inhibitor of the cell cycle, can also be inactivated by cyclin dependent kinase (CDK)-mediated phosphorylation. Extensive development led to the production of FDA-approved CDK4/6 inhibitors. Based on our own results, we propose that maintaining or re-instating pRb function using CDK4/6 inhibitors are potentially effective treatments of diet-induced obesity (DIO)., (Copyright © 2019. Published by Elsevier Ltd.)

Background: One of the first-line options to treat keloid scars is corticosteroid injection after excision of the existing scar. A thorough literature search has shown a lack of research on the injection of corticosteroid injection immediately after the excision of the existing caesarean section keloid scars. Therefore, in the proposed study, we aim to investigate the effect of surgical excision and corticosteroid (triamcinolone acetonide) injection immediately after surgical removal of old caesarean section keloid scars on the recurrence of the scars. This is a protocol for a randomised controlled trial., Methods/design: Pregnant women (n = 150), who attend antenatal clinics at Westmead Hospital in New South Wales, Australia, have a keloid scar from a previous caesarean section, meet the inclusion criteria and sign the consent form, will be randomised to either the control or the intervention group. The control group will receive surgical excision of the keloid scar at the beginning of the procedure during skin incision. The baby will be delivered according to normal procedures, and routine wound closure will be performed in accordance with National Institute for Health and Care Excellence guidelines. The intervention group will receive surgical excision of the keloid scar after the delivery of the baby, and closure of the uterus layers, rectus sheath and the fat layer will be completed as explained above. Then, triamcinolone acetone will be injected sub-dermally at the time of wound closure. Two ampules of triamcinolone acetonide will be administered at a single dose; each ampule contains 10 mg/1 ml active medication. The surgeon will inject one ampule along the entire length of the upper edge of the skin incision and one ampule along the entire length of the lower edge of the skin incision, using a 25 G needle. After the procedure is completed, the surgeon will fill in the post-operation survey. The participants will be followed up post-operation, daily on the ward and then at 6 weeks, 6 months and 12 months post-partum. Main outcomes are (1) keloid formation after caesarean section and (2) changes in the appearance and specification of the keloid scar after the intervention., Discussion: We anticipate that surgical excision and steroid injection will be a safe, lasting and cost-effective treatment in the management of caesarean keloid scars which will be useful for patients unable to undergo cosmetic surgery due to clinical or financial reasons., Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000984291 . Registered on 12 June 2018.

Clinical Question: Do adults with atraumatic shoulder pain for more than 3 months diagnosed as subacromial pain syndrome (SAPS), also labelled as rotator cuff disease, benefit from subacromial decompression surgery? This guideline builds on to two recent high quality trials of shoulder surgery., Current Practice: SAPS is the common diagnosis for shoulder pain with several first line treatment options, including analgesia, exercises, and injections. Surgeons frequently perform arthroscopic subacromial decompression for prolonged symptoms, with guidelines providing conflicting recommendations., Recommendation: The guideline panel makes a strong recommendation against surgery., How This Guideline Was Created: A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines and the GRADE system. The recommendation is based on two linked systematic reviews on ( a ) the benefits and harms of subacromial decompression surgery and ( b ) the minimally important differences for patient reported outcome measures. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of surgery in multilayered evidence summaries and decision aids available in MAGIC (www.magicapp.org) to support shared decisions and adaptation., The Evidence: Surgery did not provide important improvements in pain, function, or quality of life compared with placebo surgery or other options. Frozen shoulder may be more common with surgery., Understanding the Recommendation: The panel concluded that almost all informed patients would choose to avoid surgery because there is no benefit but there are harms and it is burdensome. Subacromial decompression surgery should not be offered to patients with SAPS. However, there is substantial uncertainty in what alternative treatment is best., Competing Interests: Competing interests: All authors have completed the BMJ Rapid Recommendations interest disclosure form and a detailed, contextualised description of all disclosures is reported in appendix 1 on bmj.com. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The effectiveness of continuity of care during the perinatal period is well documented, but implementing continuity of care model to practice requires evaluation., Aim: To evaluate the effect of a caseload midwifery program (CMP) on birth outcomes and rates of perinatal interventions at a metropolitan tertiary hospital in Australia, compared with standard midwifery-led care (SMC)., Methods: This was a retrospective, matched-cohort study. We extracted the data of 1000 nulliparous women from records of 19,001 women who gave birth at the hospital from 2011 to 2014. We used basic statistical tests to compare baseline demographic data, and logistic regression to calculate odds ratios, to evaluate maternal and neonatal outcomes., Results: Adjusted regression analysis for the primary outcome showed that compared with women who received SMC, women who received care through CMP had an increased rate of normal vaginal birth (69% vs. 50%, OR = 1.79, 95%, CI = 1.38-2.32). Assessment of secondary outcomes showed that the women in CMP group had decreased rates of instrumental birth (15% vs. 26%, OR = 0.48, 95% CI = 0.35-0.66), episiotomy (23% vs. 40%, OR = 0.43, 95% CI = 0.33-0.57), epidural analgesia (33% vs. 43%, OR = 0.64, 95% CI = 0.50-0.83) and amniotomy (35% vs. 50%, OR = 0.56, 95% CI = 0.43-0.72). The CMP group also had greater rates of water immersion (54% vs. 22%, OR = 4.18, 95% CI = 3.17-5.5), physiological 3rd stage (7% vs. 1%, OR = 11.71, 95% CI = 3.56-38.43) and 2nd degree tear (34% vs. 24%, OR = 1.60, 95% CI = 1.21-2.11). There were no significant differences between the two groups for rates of other secondary outcomes including Caesarean section, cervical ripening procedures, third- and fourth-degree tears, postpartum haemorrhage and neonatal outcomes., Conclusion: CMP care is associated with increased rate of normal vaginal birth which supports wider implementation of the model. In addition, using routinely collected data and a cohort matching design can be an effective approach to evaluate maternal and neonatal outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In the last decade, considerable advancements have been made to identify the pharmacokinetic/pharmacodynamic (PK/PD) index that defines the antimicrobial activity of polymyxins. Dose-fractionation studies performed in hollow-fiber models found that altering the dosing schedule had little impact on the killing or suppression of resistance emergence, alluding to AUC/MIC as the pharmacodynamic index that best describes polymyxin's activity. For in vivo efficacy, the PK/PD index that was the most predictive of the antibacterial effect of colistin against P. aeruginosa and A. baumannii was ƒAUC/MIC.

Background: Data related to postpartum haemorrhage (PPH) are important clinical parameters which can be applied to all places of birth, and their recording can be missed by busy clinicians providing critical care to women. We compared the accuracy of electronic ObstetriX records to the paper-based medical records of the women who sustained PPH., Methods: In this retrospective cohort study over a period of one month, 363 electronic records were compared to the paper-based medical records. The volume of blood loss for each patient and interventions for PPH were compared across birth unit, operating theatre and postpartum ward. The kappa statistic for agreement between the two types of recording methods was calculated., Results: There was substantial agreement between the ObstetriX records and medical records for the volume of blood loss at birth (kappa = 0.74), but poor agreement between records for the cumulative total volume of blood loss (kappa = 0.18). More women who experienced PPH and delivered in the operating theatre had errors in their ObstetriX records compared to women who had PPH with births in the birth unit (50% vs 16%; n = 73, P = 0.005). Interventions for PPH were found to be poorly recorded in ObstetriX, with 84% (n = 64/76) of women who experienced PPH having none of the interventions they received recorded., Conclusions: The ObstetriX database was not a generally reliable source of data relating to PPH. However, some data were recorded reliably, in particular, the volume of blood loss at birth., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Simultaneous measurement of plant functional traits and the regeneration environment should shed light on the plant-environment interactions and feedbacks as secondary forest regenerates. However, little of such work has been done in the wet tropics, and even fewer studies have examined soil nutrients. We investigated whether plant functional traits and environmental variables explain the varied recovery of secondary forests in Singapore. Our study plots included three primary forest plots and eight approximately 60-year-old secondary forest plots regenerating from intensive agricultural activities. Using 35 seedling quadrats, we asked: Q1) How do environmental variables explain the variation in seedling functional traits observed in primary and secondary forests? Q2) How do seedling traits, adult traits and environmental variables relate and explain variation in species richness and stem density in secondary forests? We found that both light and soil fertility explained the shifts in plants functional traits from poorly recovering secondary forests to primary forests. Poor forest regrowth was correlated with high soil aluminum levels and lower leaf nitrogen concentrations. Low nutrients and high aluminum saturation were also negatively correlated with seedling species richness, but not stem density, in the secondary forests. Forest recovery is probably slowed by positive feedback between slower nutrient returns from slow decaying litter and further recruitment of nutrient conserving species, as indicated by positive correlations among adult leaf CN ratio, litter depth, soil CN ratio and quadrat level CN ratio. Plant functional traits are indicative of the strategies of successful seedlings and do not necessarily relate to overall forest recovery. Hence, while some specialist plant species are able to accrue high nutrients on degraded soils with aluminum toxicity and low nutrients, species richness on these soils was poor. This underscores the need to concurrently measure environmental variables and plant traits when investigating the mechanisms driving changes during forest recovery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Various malignancies are reproducibly cured in mouse models, but most cancer immunotherapies show objective responses in a fraction of treated patients. One reason for this disconnect may be the use of young, lean mice lacking immune-altering comorbidities present in cancer patients. Although many cancer patients are overweight or obese, the effect of obesity on antitumor immunity is understudied in preclinical tumor models. We examined the effect of obesity on two immunotherapeutic models: systemic anti-CTLA-4 mAb and intratumoral delivery of a TRAIL-encoding adenovirus plus CpG. Both therapies were effective in lean mice, but neither provided a survival benefit to diet-induced obese BALB/c mice. Interestingly, tumor-bearing leptin-deficient ( ob/ob ) obese BALB/c mice did respond to treatment. Moreover, reducing systemic leptin with soluble leptin receptor:Fc restored the antitumor response in diet-induced obese mice. These data demonstrate the potential of targeting leptin to improve tumor immunotherapy when immune-modulating comorbidities are present., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1)-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiology, TRPV1 knock-out (KO), and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5) carrying a Cre-dependent channelrhodopsin-2 (ChR2)-enhanced yellow fluorescent protein (eYFP) expression cassette under the control of the two neuronal POMC enhancers (nPEs). Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake.

Pristine habitats have generally been considered to be the most important ecological resource for wildlife conservation, but due to forest degradation caused by human activities, mosaics of secondary forests have become increasingly prominent. We studied three forest types in a mosaic tropical forest consisting of short secondary forest (SS), tall secondary forest (TS) and freshwater swamp forest (SF). These forests differed in stand structure and floristic composition, as well as phenological productivity of fruits, flowers and young leaves. We examined habitat use of long-tailed macaques (Macaca fascicularis) in relation to indices of phenological activity. The macaques used the SS for feeding/foraging more than the TS and the SF. This was because the SS had higher productivity of fruit, which is a preferred food resource for macaques. Stem densities of young leaves in the SS and the TS also influenced habitat use, as they provided more clumped resources. Use of SF was limited, but these forests provided more species-rich resources. Our results showed that M. fascicularis responded to small-scale variability in phenological activity between forest types found in a heterogeneous mosaic forest, with young secondary regrowth forests likely providing the most important food resources. Mosaic landscapes may be important as they can buffer the effects of temporal food resource variability in any given forest type. In our increasingly human-altered landscapes, a better understanding of the role of secondary forest mosaics is crucial to the conservation and management of wildlife habitats and the animals they support.

Background: Point-of-care lactate devices are used worldwide for intrapartum decision making. Current practice is often based on Lactate Pro (Arkray) but its imminent product discontinuation necessitates determination of an optimal replacement device., Aims: To evaluate the performance of Lactate Pro and two other point-of-care devices, Lactate Pro 2 (Arkray) and StatStrip (Nova Biomedical), and to derive scalp lactate cut-offs equivalent to the current intervention trigger of >4.8 mmol/L., Materials and Methods: Paired umbilical cord arterial and venous blood samples from 109 births were tested on the three point-of-care products (two devices each), cross-compared with the reference method blood gas analyser., Results: All brands deviate from the blood gas analyser, with Lactate Pro and StatStrip results consistently lower and Lactate Pro 2 consistently higher. Standard deviation from the blood gas analyser was smallest for StatStrip (0.78 mmol/L, cord artery), and largest for Lactate Pro 2 (1.03 mmol/L, cord artery). Within-brand variation exists and is similar for all brands (mean absolute difference on cord artery 0.23-0.30 mmol/L). Equivalent values to the 4.8 mmol/L intervention threshold based on Lactate Pro are 4.9-5.0 mmol/L for StatStrip and 5.3-5.9 mmol/L for Lactate Pro 2, calculated by receiver-operating characteristic analysis., Conclusions: StatStrip appears superior to Lactate Pro 2 to replace the original Lactate Pro. Using StatStrip, the 4.8 mmol/L intervention threshold equivalent was 4.9-5.0 mmol/L. The variation in accuracy of point-of-care lactate devices may exceed the small increments (eg <4.2 mmol/L vs >4.8 mmol/L) that guide obstetric decisions., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Pancreatic β-cell loss through apoptosis is an important disease mechanism in type 2 diabetes. Apoptosis Repressor with CARD (ARC) is a cell death inhibitor that antagonizes multiple death programs. We previously reported that ARC is abundant in pancreatic β-cells and modulates survival of these cells in vitro. Herein we assessed the importance of endogenous ARC in maintaining islet structure and function in vivo. While generalized loss of ARC did not result in detectable abnormalities, its absence in ob/ob mice, a model of type 2 diabetes, induced a striking pancreatic phenotype: marked β-cell death, loss of β-cell mass, derangements of islet architecture, and impaired glucose-stimulated insulin secretion in vivo. These abnormalities contributed to worsening of hyperglycemia and glucose-intolerance in these mice. Mechanistically, the absence of ARC increased levels of C/EBP homologous protein (CHOP) in wild type isolated islets stimulated with ER stress and in ob/ob isolated islets at baseline. Deletion of CHOP in ob/ob; ARC -/- mice led to reversal of β-cell death and abnormalities in islet architecture. These data indicate that suppression of CHOP by endogenous levels of ARC is critical for β-cell viability and maintenance of normal islet structure in this model of type 2 diabetes.

While various tyrosine kinases have been associated with the pathogenesis of hepatocellular carcinoma (HCC), the identification of a dominant therapeutic target among them remains a challenge. Here, we investigated the role of Tyro3, a relatively uncharacterized member of the TAM (Tyro3, Axl and Mer) receptor family. The present study aimed to profile and identify potential association between Tyro3 expression in HCC and cancer phenotypes. RNAs obtained from 55 HCC patients were quantified for Tyro3 expression in both cancerous tissue and the adjacent normal tissue. Expression profile was correlated with clinical data. These observations were further substantiated with in vitro HCC cell culture investigations.Tyro3 was strongly upregulated (>2-fold elevation) in the tumor tissue of ~42% of the patients. It was shown that higher expression level of Tyro3 was associated with the key tumor marker AFP, and the tumor diameter and liver injury marker ALT. Subsequent cell culture models indicated high expression in various HCC cell lines, in particular Hep3B. Gene silencing of Tyro3 in Hep3B effectively reduced cell proliferation, ERK phosphorylation and cyclin D1 expression, indicating a key in maintaining the proliferative state of these cells. Notably, silencing also suppressed the transcriptional and translational expression of HCC tumor marker AFP. Overall, these data suggest that Tyro3 contributes significantly to tumor growth, aggressiveness and liver dysfunction. Inhibition of Tyro3 and its aberrant signaling in tumors with high expression could present new opportunities for HCC treatment.

Cancer is the leading cause of death in children older than 1 year of age and new drugs are necessary to improve outcomes. Imaging is crucial to the drug development process and assessment of therapeutic response. In adults, tumours are often assessed with CT using size criteria. Unfortunately, techniques established in adults are not necessarily applicable in children due to differing pathophysiology, ability to cooperate and increased susceptibility to ionising radiation. MRI, in particular quantitative MRI, has to date not been fully utilised in children with extracranial neoplasms. The specific challenges of imaging in children, the potential for functional imaging techniques to inform upon and their inclusion in clinical trials are discussed.

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1(-/-) mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1(-/-) mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD(+), and is associated with obesity resistance. Consistent with this, NAD(+) levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences., (© 2015 Bonhoure et al.; Published by Cold Spring Harbor Laboratory Press.)

Although the antidiabetic effects of leptin require intact neuronal melanocortin signaling in rodents with uncontrolled diabetes (uDM), increased melanocortin signaling is not sufficient to mimic leptin's glucose-lowering effects. The current studies were undertaken to clarify the role of melanocortin signaling in leptin's ability to correct metabolic and neuroendocrine disturbances associated with uDM. To accomplish this, bilateral cannulae were implanted in the lateral ventricle of rats with streptozotocin-induced diabetes, and leptin was coinfused with varying doses of the melanocortin 3/4 receptor (MC3/4R) antagonist, SHU9119. An additional cohort of streptozotocin-induced diabetes rats received intracerebroventricular administration of either the MC3/4R agonist, melanotan-II, or its vehicle. Consistent with previous findings, leptin's glucose-lowering effects were blocked by intracerebroventricular SHU9119. In contrast, leptin-mediated suppression of hyperglucagonemia involves both melanocortin dependent and independent mechanisms, and the degree of glucagon inhibition was associated with reduced plasma ketone body levels. Increased central nervous system melanocortin signaling alone fails to mimic leptin's ability to correct any of the metabolic or neuroendocrine disturbances associated with uDM. Moreover, the inability of increased melanocortin signaling to lower diabetic hyperglycemia does not appear to be secondary to release of the endogenous MC3/4R inverse agonist, Agouti-related peptide (AgRP), because AgRP knockout mice did not show increased susceptibility to the antidiabetic effects of increased MC3/4R signaling. Overall, these data suggest that 1) AgRP is not a major driver of diabetic hyperglycemia, 2) mechanisms independent of melanocortin signaling contribute to leptin's antidiabetic effects, and 3) melanocortin receptor blockade dissociates leptin's glucose-lowering effect from its action on other features of uDM, including reversal of hyperglucagonemia and ketosis, suggesting that brain control of ketosis, but not blood glucose levels, is glucagon dependent.

Research indicates that poor sleep quality is linked to and may precede depressive symptomatology in pregnancy, complicating screening for either condition. Pregnancy onset may also contribute to the development of sleep-disordered breathing (SDB). For the first time, the link between SDB and depression was examined in pregnancy. A total of 189 pregnant women completed the Edinburgh Postnatal Depression Scale (EPDS), Pittsburgh Sleep Quality Index (PSQI) for sleep quality and the Berlin Questionnaire for SDB. Women were also asked what they felt was the cause of their symptoms. PSQI-assessed poor sleep quality and self-perceived depression were strongly associated with EPDS scores of probable depression (X (2) 13.39; p < 0.001). Berlin-assessed risk of SDB was also associated with probable depression (X (2) 9.20 p < 0.01), though this was attenuated following multivariate analysis. There was a significant relationship between total PSQI score and the tendency for participants to attribute 'sleep-related causes' to their low mood (X (2) 20.78; p < 0.001). This study confirms the link between PSQI-assessed poor sleep quality and depressive symptoms in pregnancy, suggesting the two questionnaires assess the same or overlapping conditions. Although there was a relationship between probable depression and high risk SDB, the effect was attenuated after accounting for other depression risk factors, including body mass index (BMI).

Background: Management of prelabour rupture of membranes at term (37 weeks gestation or later) (TPROM) remains complicated in the absence of a rapid assay for group B streptococcus (GBS) colonisation., Aims: To evaluate the accuracy and clinical utility of a commercial PCR assay, compared with culture, for detection of GBS colonisation in pregnant women presenting with TPROM., Methods: A prospective study of women presenting with TPROM conducted in a large tertiary hospital (Westmead Hospital, Australia). Five hundred and seventy-four consecutive women with TPROM were enrolled between July 2006 and November 2007. Paired low vaginal and anal swabs were collected from women presenting with TPROM for PCR and culture on GBS selective agar following broth enrichment. Primary outcomes were sensitivity and specificity of PCR compared with GBS selective enrichment culture. Secondary analyses included comparison with a historical but otherwise similar cohort regarding clinical utility, maternal and neonatal outcomes., Results: PCR sensitivity and specificity were 89.0% (95% CI - 82.8-93.6%) and 97.9% (95% CI - 96.0-99.0%), respectively, compared with culture. 72.3% of women were aware of their GBS PCR status within 3 h of presentation. Compared with the historical cohort, PCR reduced the requirement for intrapartum antibiotics by 25.6% (P < 0.001). There were no significant differences in maternal outcomes or combined rates of admissions to neonatal intensive care or special care nursery., Conclusions: Group B streptococcus PCR is an accurate, rapid, safe and practical alternative to culture for detection of GBS colonisation in pregnant women at the time of TPROM. This method has the potential advantage to reduce costs associated with length of hospital stay., (© 2013 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Mice treated with the antidepressant trans-2-phenylcyclopropylamine (2-PCPA) were protected against diet-induced-obesity, and adiposity was reversed in pre-established diet-induced obese mice. Contrary to a recent report that inhibition of lysine-specific demethylase-1 by 2-PCPA results in increased energy expenditure, long-term 2-PCPA treatment had no such effect but its protection against obesity was associated with increased spontaneous locomotor activity, Moreover, pair feeding to assure equal caloric intake in wild type mice as well as in genetic hyperphagic mice (ob/ob) also resulted in weight reduction in 2-PCPA treated mice that correlated with increased activity but no change in energy expenditure. Similarly, short-term intraperitoneal injections of 2-PCPA did not affect food intake but caused a substantial increase in locomotor activity in the light cycle that correlated with increased energy expenditure, whereas activity and energy expenditure were unchanged in the dark cycle. Lastly, 2-PCPA was also effective in reducing obesity in genetic UCP1 null mice. These data suggest that 2-PCPA can reduce obesity by decreasing food intake in the long term while increasing activity in the short-term. However, the protective and weight loss effects of 2-PCPA are independent of UCP1-regulated thermogenesis or basal energy expenditure.

Melanocyte stimulating hormone (MSH) derived from the pro-hormone pro-opiomelanocortin (POMC) has potent effects on metabolism and feeding that lead to reduced body weight in the long-term. To determine the individual roles of POMC derived peptides and their sites of action, we created a method for the delivery of single MSH peptides using lentiviral vectors and studied the long-term anti-obesity effects of hypothalamic α-MSH overexpression in mice. An α-MSH lentivirus (LVi-α-MSH-EGFP) vector carrying the N'-terminal part of POMC and the α-MSH sequence was generated and shown to produce bioactive peptide in an in vitro melanin synthesis assay. Stereotaxis was used to deliver the LVi-α-MSH-EGFP or control LVi-EGFP vector to the arcuate nucleus (ARC) of the hypothalamus of male C57Bl/6N mice fed on a high-fat diet. The effects of 6-week-treatment on body weight, food intake, glucose tolerance and organ weights were determined. Additionally, a 14-day pairfeeding study was conducted to assess whether the weight decreasing effect of the LVi-α-MSH-EGFP treatment is dependent on decreased food intake. The 6-week LVi-α-MSH-EGFP treatment reduced weight gain (8.4 ± 0.4 g versus 12.3 ± 0.6 g; P < 0.05), which was statistically significant starting from 1 week after the injections. The weight of mesenteric fat was decreased and glucose tolerance was improved compared to LVi-EGFP treated mice. Food intake was decreased during the first week in the LVi-α-MSH-EGFP treated mice but subsequently increased to the level of LVi-EGFP treated mice. The LVi-EGFP injected control mice gained more weight even when pairfed to the level of food intake by LVi-α-MSH-EGFP treated mice. We demonstrate that gene transfer of α-MSH, a single peptide product of POMC, into the ARC of the hypothalamus, reduces obesity and improves glucose tolerance, and that factors other than decreased food intake also influence the weight decreasing effects of α-MSH overexpression in the ARC. Furthermore, viral MSH vectors delivered stereotaxically provide a novel tool for further exploration of chronic site-specific effects of POMC peptides., (© 2013 British Society for Neuroendocrinology.)

Deficient leptin signaling causes infertility via reduced activity of GnRH neurons, causing a hypogonadal state in both rodents and humans. Because GnRH neurons do not express leptin receptors, leptin's effect on GnRH neurons must be indirect. Neurons within the hypothalamic arcuate nucleus that coexpress AGRP and NPY are considered to be important intermediate neurons involved in leptin regulation of GnRH neurons. Previously, we reported that the absence of AGRP and haploinsufficiency of MC4R in leptin receptor mutant (Lepr(db/db)) females result in restoration of fertility and lactation despite the persistence of obesity and insulin resistance. The overarching hypothesis in the present study is that the absence or reduction of leptin's inhibition of AGRP/NPY neurons leads to suppression of GnRH release in cases of leptin signaling deficiency. Since TAC2 (NKB)-TAC3R signaling plays a role in puberty maturation and is modulated by metabolic status, the other aim of this study is to test whether TAC2/NKB neurons in ARC regulated by melanocortinergic signals herein affect leptin's action on puberty and reproduction. Our data showed that AGRP deficiency in Lepr(db/db) females restores normal timing of vaginal opening and estrous cycling, although uterine weight gain and mammary gland development are morphologically delayed. Nonetheless, Agrp(-/-) Lepr(db/db) females are fertile and sustain adequate nutrition of pups with lactation to weaning age. AGRP deficiency results in advanced vaginal opening in wild-type female mice. The postpubertal increase in hypothalamic TAC2 mRNA was not observed in Lepr(db/db) females, whereas AGRP deficiency restored it in Lepr(db/db) females. Additionally, MC4R activation with MTII induced FOS expression in TAC2 neurons, supporting the concept of melanocortinergic regulation of TAC2 neurons. These studies suggest that AGRP imposes an inhibitory effect on puberty and that TAC2 neurons may transmit melanocortinergic inhibition of GnRH neurons.

We previously mapped a locus on BALB/c chromosome 2 associated with protection from leptin-deficiency-induced obesity. Here, we generated the corresponding congenic mouse strain by introgression of a segment of C57BL/6J chromosome 2 to the BALB/c background to confirm the genotype-phenotype associations. We found that the BALB/c alleles decreased fat mass expansion by limiting adipocyte hyperplasia and adipocyte hypertrophy. This was concomitant to an increase in adipocyte triglyceride lipase (ATGL)-mediated triglyceride breakdown and prolongation of ATGL half-life in adipose tissue. In addition, BALB/c alleles on chromosome 2 exerted a cell-autonomous role in restraining the adipogenic potential of preadipocytes. Within a 9.8-Mb critical interval, we identified a nonsynonymous coding single nucleotide polymorphism in the gene coding for the ubiquitin-conjugating enzyme E2L6 (Ube2l6, also known as Ubch8) and showed that the BALB/c allele of Ube2l6 is a hypomorph leading to the lack of UBE2L6 protein expression. Ube2l6 knockdown in 3T3-L1 adipocytes repressed adipogenesis. Thus, altered adipogenic potential caused by Ube2l6 knockdown is likely critically involved in BALB/c obesity resistance by inhibiting adipogenesis and reducing adipocyte numbers. Overall, we have identified a loss-of-function mutation in Ube2l6 that contributes to the chromosome 2 obesity quantitative trait locus.

Background: Lactate measurements have become increasingly preferred over pH analysis in the evaluation of fetal acidaemia in labour. In a busy labour ward, often the umbilical cord may be sampled late and as a result yield unreliable lactate values., Aim: To investigate the agreement of hand-held device Lactate Pro with a reference method blood gas analyser and evaluate the stability of umbilical cord lactate values over time., Methods: Prospective study carried out at elective caesarean section. Sixteen umbilical cords were double clamped immediately after delivery with paired arterial and venous blood samples collected by an independent researcher, at varying time intervals, and processed by two Lactate Pro devices and a reference method blood gas analyser., Results: A significant difference of -0.41 to 0.10 mmol/L was found when different groups of Lactate Pro devices were compared with blood gas analyser at lactate values up to 5.70 mmol/L, with average lactate value of 2.45 mmol/L. Over time, there is progressive rise in lactate samples obtained from the umbilical cord., Conclusion: Lactate Pro devices have a significant difference, but when used in clinical practice on cord blood after delivery, this is unlikely to be meaningful. In intrapartum fetal surveillance, a systematic overestimation might lead to unnecessary intervention. It is possible to retrospectively predict the likely level of lactate at birth in delayed cord samples., (© 2013 The Authors ANZJOG © 2013 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Previous studies have demonstrated that leptin and its receptors (LepRb) in the central nervous system play an important role in regulating depression- and anxiety-related behaviours. However, the physiological functions of LepRb in specific brain regions for mediating different emotional behaviours remain to be defined. In this study, we examined the behavioural effects of LepRb ablation in the adult hippocampus using a series of behavioural paradigms for assessing depression- and anxiety-related behaviours. Targeted deletion of LepRb was achieved using the Cre/loxP site-specific recombination system through bilateral stereotaxic delivery of an adeno-associated virus expressing Cre-recombinase (AAV-Cre) into the dentate gyrus of adult mice homozygous for a floxed leptin receptor allele. AAV-Cre-mediated deletion of the floxed region of LepRb was detected 2 wk after injection. In accordance with this, leptin-stimulated phosphorylation of Akt was attenuated in the hippocampus of AAV-Cre injected mice. Mice injected with AAV-Cre displayed normal locomotor activity and anxiety-like behaviour, as determined in the elevated plus-maze, light-dark box and open field tests, but showed increased depression-like behaviours in the tail suspension, saccharin preference and learned helplessness tests. Taken together, these data suggest that deletion of LepRb in the adult hippocampus is sufficient to induce depression-like behaviours. Our results support the view that leptin signalling in the hippocampus may be essential for positive mood states and active coping to stress.

Type 2 diabetes involves insulin resistance and β-cell failure leading to inadequate insulin secretion. An important component of β-cell failure is cell loss by apoptosis. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of apoptosis that is expressed in cardiac and skeletal myocytes and neurons. ARC possesses the unusual property of antagonizing both the extrinsic (death receptor) and intrinsic (mitochondria/endoplasmic reticulum [ER]) cell death pathways. Here we report that ARC protein is abundant in cells of the endocrine pancreas, including >99.5% of mouse and 73% of human β-cells. Using genetic gain- and loss-of-function approaches, our data demonstrate that ARC inhibits β-cell apoptosis elicited by multiple inducers of cell death, including ER stressors tunicamycin, thapsigargin, and physiological concentrations of palmitate. Unexpectedly, ARC diminishes the ER stress response, acting distal to protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein 1α, to suppress C/EBP homologous protein (CHOP) induction. Depletion of ARC in isolated islets augments palmitate-induced apoptosis, which is dramatically rescued by deletion of CHOP. These data demonstrate that ARC is a previously unrecognized inhibitor of apoptosis in β-cells and that its protective effects are mediated through suppression of the ER stress response pathway.

This study used two mouse models with genetic manipulation of the melanocortin system to investigate prolactin regulation. Mice with overexpression of the melanocortin receptor (MC-R) agonist, α-melanocyte-stimulating hormone (Tg-MSH) or deletion of the MC-R antagonist agouti-related protein (AgRP KO) were studied. Male Tg-MSH mice had lower blood prolactin levels at baseline (2.9±0.3 vs. 4.7±0.7ng/ml) and after restraint stress (68±6.5 vs. 117±22ng/ml) vs. WT (p<0.05); however, pituitary prolactin content was not different. Blood prolactin was also decreased in male AgRP KO mice at baseline (4.2±0.5 vs. 7.6±1.3ng/ml) and after stress (60±4.5 vs. 86.1±5.7ng/ml) vs. WT (p<0.001). Pituitary prolactin content was lower in male AgRP KO mice (4.3±0.3 vs. 6.7±0.5μg/pituitary, p<0.001) vs. WT. No differences in blood or pituitary prolactin levels were observed in female AgRP KO mice vs. WT. Hypothalamic dopamine activity was assessed as the potential mechanism responsible for changes in prolactin levels. Hypothalamic tyrosine hydroxylase mRNA was measured in both genetic models vs. WT mice and hypothalamic dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) content were measured in male AgRP KO and WT mice but neither were significantly different. However, these results do not preclude changes in dopamine activity as dopamine turnover was not directly investigated. This is the first study to show that baseline and stress-induced prolactin release and pituitary prolactin content are reduced in mice with genetic alterations of the melanocortin system and suggests that changes in hypothalamic melanocortin activity may be reflected in measurements of serum prolactin levels., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of melanocortin signaling in female db/db mice through ablation of agouti-related peptide, or heterozygosity of melanocortin 4 receptor, restores the timing of pubertal onset, fertility, and lactation. Additionally, melanocortin 4 receptor activation increases action potential firing and induces c-Fos expression in GnRH neurons, providing further evidence that melanocortin signaling influences GnRH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of GnRH neuron activity, initiation of puberty and fertility.

Leptin, a polypeptide hormone produced mainly by adipocytes, has diverse effects in both the brain and peripheral organs, including suppression of feeding. Other than mediating leptin transport across the blood-brain barrier, the role of the endothelial leptin receptor remains unclear. We recently generated a mutant mouse strain lacking endothelial leptin receptor signaling, and showed that there is an increased uptake of leptin by brain parenchyma after its delivery by in situ brain perfusion. Here, we tested the hypothesis that endothelial leptin receptor mutation confers partial resistance to diet-induced obesity. These ELKO mice had similar body weight and percent fat as their wild-type littermates when fed with rodent chow, but blood concentrations of leptin were significantly elevated. In response to a high-fat diet, wild-type mice had a greater gain of body weight and fat than ELKO mice. As shown by metabolic chamber measurement, the ELKO mice had higher oxygen consumption, carbon dioxide production, and heat dissipation, although food intake was similar to that of the wild-type mice and locomotor activity was even reduced. This indicates that the partial resistance to diet-induced obesity was mediated by higher metabolic activity in the ELKO mice. Since neuronal leptin receptor knockout mice show obesity and diabetes, the results suggest that endothelial leptin signaling shows opposite effects from that of neuronal leptin signaling, with a facilitatory role in diet-induced obesity.

Brown adipose tissue (BAT) and white adipose tissue (WAT) and adipocytes are targets of Trypanosoma cruzi infection. Adipose tissue obtained from CD-1 mice 15 days after infection, an early stage of infection revealed a high parasite load. There was a significant increase in macrophages in infected adipose tissue and a reduction in lipid accumulation, adipocyte size, and fat mass and increased expression of lipolytic enzymes. Infection increased levels of Toll-like receptor (TLR) 4 and TLR9 and in the expression of components of the mitogen-activated protein kinase pathway. Protein and messenger RNA (mRNA) levels of peroxisome proliferator-activated receptor γ were increased in WAT, whereas protein and mRNA levels of adiponectin were significantly reduced in BAT and WAT. The mRNA levels of cytokines, chemokines, and their receptors were increased. Nuclear Factor Kappa B levels were increased in BAT, whereas Iκκ-γ levels increased in WAT. Adipose tissue is an early target of T. cruzi infection.

The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates NMDA-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the GluN2B subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestations of depression.

Gastric fluid is a source of gastric cancer biomarkers. However, very little is known about the normal gastric fluid proteome and its biological variations. In this study, we performed a comprehensive analysis of the human gastric fluid proteome using samples obtained from individuals with benign gastric conditions. Gastric fluid proteins were prefractionated using ultracentrifuge filters (3 kDa cutoff) and analyzed by two-dimensional gel electrophoresis (2-DE) and multidimensional LC-MS/MS. Our 2-DE analysis of 170 gastric fluid samples revealed distinct protein profiles for acidic and neutral samples, highlighting pH effects on protein composition. By 2D LC-MS/MS analysis of pooled samples, we identified 284 and 347 proteins in acidic and neutral samples respectively (FDR ≤1%), of which 265 proteins (72.4%) overlapped. However, unlike neutral samples, most proteins in acidic samples were identified from peptides in the filtrate (i.e., <3 kDa). Consistent with this finding, immunoblot analysis of six potential gastric cancer biomarkers rarely detected full-length proteins in acidic samples. These findings have important implications for biomarker studies because a majority of gastric cancer patients have neutral gastric fluid compared to noncancer controls. Consequently, sample stratification, choice of proteomic approaches, and validation strategy can profoundly affect the interpretation of biomarker findings. These observations should help to refine gastric fluid biomarker studies.