Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways.

Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), during early (gestational day (GD) 9-11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes. Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

Barriers to the implementation of new guidelines among pediatric surgeons: online survey.

PURPOSE: To identify barriers that prevent pediatric surgeons from implementing updated practice guidelines. METHODS: An online survey targeting pediatric surgeons was conducted on the StayCurrent MD Application (SCMA) and Pediatric Surgery Education Facebook page (PSE FBP). The survey results for pediatric surgeons of underdeveloped countries (PSUC) and pediatric surgeons of developed countries (PSDC) was compared and analyzed. RESULTS: Based on the number of active members on PSE FBP and SCA, the response rate was 32.3% (174/539), 66.3% of responses were from PSUC. The majority of PSUC (73%) wanted to have convincing guidelines and the plurality of PSDC (46%) wanted to see approval by the American Pediatric Surgical Association (APSA) for implementation of new guidelines. Lack of resources was the number one response (78%) for PSUC not implementing the most up to date guidelines and about 40% of the PSDC responded "concerned about malpractice liability." CONCLUSIONS: PSUC and PSDC identified very different barriers to implementation of new guidelines. It is reassuring that accessibility to treatment is not the primary issue, though resistance to implementation is a resounding concern. Identifying the barriers will highlight areas that need to be addressed, and awareness may help resolve some of the barriers.

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II.

BACKGROUND: A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. OBJECTIVES: To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. METHODS: The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. RESULTS: Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. CONCLUSIONS: The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings.

Skill sets required for the management of military head, face and neck trauma: a multidisciplinary consensus statement.

INTRODUCTION: The evolution of medical practice is resulting in increasing subspecialisation, with head, face and neck (HFN) trauma in a civilian environment usually managed by a combination of surgical specialties working as a team. However, the full combination of HFN specialties commonly available in the NHS may not be available in future UK military-led operations, necessitating the identification of a group of skill sets that could be delivered by one or more deployed surgeons. METHOD: A systematic review was undertaken to identify those surgical procedures performed to treat acute military head, face, neck and eye trauma. A multidisciplinary consensus group was convened following this with military HFN trauma expertise to define those procedures commonly required to conduct deployed, in-theatre HFN surgical combat trauma management. RESULTS: Head, face, neck and eye damage control surgical procedures were identified as comprising surgical cricothyroidotomy, cervico-facial haemorrhage control and decompression of orbital haemorrhage through lateral canthotomy. Acute in-theatre surgical skills required within 24 hours consist of wound debridement, surgical tracheostomy, decompressive craniectomy, intracranial pressure monitor placement, temporary facial fracture stabilisation for airway management or haemorrhage control and primary globe repair. Delayed in-theatre procedures required within 5 days prior to predicted evacuation encompass facial fracture fixation, delayed lateral canthotomy, evisceration, enucleation and eyelid repair. CONCLUSIONS: The identification of those skill sets required for deployment is in keeping with the General Medical Council's current drive towards credentialing consultants, by which a consultant surgeon's capabilities in particular practice areas would be defined. Limited opportunities currently exist for trainees and consultants to gain experience in the management of traumatic head, face, neck and eye injuries seen in a kinetic combat environment. Predeployment training requires that the surgical techniques described in this paper are covered and should form the curriculum of future military-specific surgical fellowships. Relevant continued professional development will be necessary to maintain required clinical competency.

Cerebroplacental ratio in pregnancies complicated by gestational diabetes mellitus.

OBJECTIVE: To assess the relationship between the cerebroplacental ratio (CPR) and intrapartum and perinatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort study of women with a non-anomalous singleton pregnancy diagnosed with GDM who delivered at Mater Mothers' Hospital between 2007 and 2015. CPR was measured in 1089 cases between 34 + 0 and 36 + 6 weeks' gestation. CPR values were compared between groups categorized according to GDM treatment (by diet, oral hypoglycemic agent (OHA) or insulin). The association between CPR and intrapartum and perinatal outcomes was evaluated. RESULTS: No difference in CPR was observed between treatment groups. Fetuses with CPR < 10th centile were significantly more likely to have adverse composite perinatal outcome (odds ratio (OR) = 2.93 (95% CI, 1.95-4.40)), preterm delivery and low birth weight than fetuses with CPR ≥ 10th centile (all P < 0.001). These associations were present regardless of the type of GDM treatment. Fetuses of women with insulin-controlled GDM had poorer neonatal outcomes than did fetuses of women treated with OHA or dietary control alone. The risk of adverse outcome was significantly increased in the insulin-treated group (OR = 1.75 (95% CI, 1.34-2.28); P < 0.001), which also had higher rates of preterm delivery and higher birth weight. CONCLUSION: Regardless of the type of treatment, a low CPR is associated with poorer neonatal outcome in women with GDM. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Autophagy has a key role in the pathophysiology of schizophrenia.

Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.

Pre-Selection Test to Identify High Responder Donor Goats.

The aim of the study was to evaluate the feasibility of pre-selection of high or low responder does prior to the superovulatory protocols. Twenty Saanen does received 800 IU of equine chorionic gonadotropin (eCG) at the end of long-term progestogen treatment. Fourteen days later, a second progestogen protocol associated with a multiple-dose follicle stimulation hormone (FSH) treatment (5 IU/kg of FSH, in six decreasing doses between days 4 to 6 of the protocol) was administered. Transrectal ultrasound was used to assess the follicular status at the beginning of superovulatory treatments, at the oestrous onset and on the seventh day of the oestrous cycle for counting corpora lutea (CL). A significant lower number of CL was obtained in eCG-treated in comparision with FSH-treated does (p < 0.05). A quartic regression was able to explain the relationship between the number of CL in response to both treatments (r(2) =0.50; p < 0.05). Seventy per cent (14 of 20) of does maintained the same ovulatory response (high or low) after treatments. The Kappa (κ = 0.40; p < 0.05) and Spearman (rs = 0.39; p = 0.08) coefficients were able to show a relationship between treatments. Regarding the follicular status, there is a significant relationship between the number of small follicles (r = 0.71; r(2) =0.47; p < 0.01) and total follicles (r = 0.60; p < 0.01) at eCG and first FSH dose with the number of CL. Moreover, it was found a negative relationship between the presence of large follicles and the number of CL in response to eCG treatment (r = -0.44; p < 0.05), but not from FSH (p > 0.05). In conclusion, the screening test with eCG has the potential to identify Saanen does that will better respond to the superovulatory protocol with FSH. In addition, it highlighted the importance of an ultrasound evaluation prior to the beginning of superovulatory treatments with FSH to characterize the follicular status and identify the potential donors of high ovulatory response in MOET programmes in goats.

Prevalence of cervical cancer and associated mortality in Grenada, 2000-2010.

Objective To assess cervical cancer prevalence and associated mortality in Grenada, West Indies during 2000-2010. Methods Records of visits to hospital and clinical facilities were obtained from the histopathology laboratory of the Grenada General Hospital. Records were de-identified and electronically compiled. Cervical cancer prevalence was assessed via cross-sectional analysis of this secondary data. Of a total 12 012 records, 2 527 were selected for analysis using sampling without replacement. Cases were matched to corresponding patient data from death registries, where possible, and used to calculate associated mortality rates. Results The observed prevalence of cervical cancer was 52.4 per 100 000 women (ages 15 and above). The highest rates of cervical cancer occurred in the 35-44 age group, with the second highest among 45-64-year-olds. A total of 65 deaths were attributable to cervical cancer during 2000-2010, more than 50% of which were among women > 65 years old. The observed mortality rate was 16.7 per 100 000, almost twice the rate estimated by WHO for the region. Conclusions This study demonstrates the need for a comprehensive cervical cancer-screening program in Grenada. Results should contribute to informing future studies on how to appropriately generate and execute public health policy for education, screening, prevention, and control of cervical cancer in Grenada.

Different changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and mood disorders.

The growing body of evidence implicating tumor necrosis factor-α (TNFα) in the pathophysiology of psychiatric disorders led us to measure levels of that protein in the cortex of subjects with major depressive disorders (MDD). Having reported an increase (458%) in the levels of the transmembrane (tmTNFα), but not the soluble (sTNFα), form of the protein in Brodmann's area (BA) 46, but not 24, in people with the disorder, we decided to examine additional components of TNFα-related pathways in the same regions in people with MDD and extend our studies to the same cortical regions of people with schizophrenia (Sz) and bipolar disorders (BD). Using postmortem tissue, western blots and quantitative PCR, we have now shown there is a significant increase (305%) in tmTNFα in Brodmann's area 24, but not 46, from subjects with BD, and that levels of the protein were not altered in Sz. Levels of sTNFα were not altered in BD or Sz. In addition, we have shown that levels of TNF receptor 1 (TNFR1) mRNA are increased in BA 24 (53%) and BA 46 (82%) in people with Sz, whereas levels of TNFR2 mRNA was decreased in BA 46 in people with mood disorders (MDD=-51%; BD=-67%). Levels of proteins frequently used as surrogate markers of neuronal, astrocytic and microglia numbers, as well as levels of the pro-inflammatory marker (interleukin 1ß), were not changed in the cortex of people with mood disorders. Our data suggest there are differential changes in TNFα-related markers in the cortex of people with MDD, BD and Sz that may not be related to classical inflammation and may cause changes in different TNFα-related signaling pathways.

Which behavioral and psychological symptoms of dementia are the most problematic? Variability by prevalence, intensity, distress ratings, and associations with caregiver depressive symptoms.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) impact well-being for persons with dementia (PWD) and caregivers. Identifying the most problematic symptoms is vital in targeting interventions and allocating resources. The current study highlights inconsistencies in the "most problematic" symptoms when identified via prevalence, intensity, caregiver distress, or associations with caregiver depressive symptoms. METHODS: Caregivers (N = 177) were mostly female (77%) and spouses of PWD (73%), with average age of 66.7 years (SD = 16.1). They reported BPSD frequency and distress via the Revised Memory and Behavior Problem Checklist (RMBPC) and Neuropsychiatric Inventory (NPI), and their own depressive symptoms via the Geriatric Depression Scale (GDS). BPSD were ranked by prevalence, average frequency, and average distress ratings. RMBPC subscales were correlated with GDS, and discriminant function analyses used NPI symptoms to discriminate between caregivers' normal (range 0-9) or elevated (10+) GDS. RESULTS: Most prevalent NPI symptoms were Apathy, Depression, and Agitation. Most intense (frequency × severity) were Appetite, Motor behaviors, and Apathy, and most distressing were Delusions, Agitation, and Irritability. For RMBPC, Memory was most frequent but least distressing, whereas Disruptive was least frequent but most distressing. RMBPC frequency and distress subscales were significantly associated with caregiver GDS. Discriminant function analyses were statistically significant (Lambda = 0.822; χ(2) (12) = 30.62; p = 0.002. Canonical correlation = 0.442); NPI symptoms correctly classified caregivers GDS status 72% of the time. CONCLUSIONS: Symptoms revealed as "most problematic" varied by measurement criterion. Common or frequent symptoms are not necessarily the most distressing or most predictive of caregiver depression.

Operative treatment of paediatric penetrating head injuries in southern Afghanistan.

The operative management and early post-operative outcome of 16 consecutive cases of paediatric penetrating head injury treated by a single surgeon at a military trauma centre in Southern Afghanistan are retrospectively analysed. The majority of cases of injury were caused by fragments from exploding munitions. The aim of neurosurgical intervention in penetrating head injury is the prevention of wound infection and treatment or prevention of a critical rise in intracranial pressure. In 14 cases in this study, these aims were fulfilled without resort to brain resection, although a delayed cranioplasty procedure was required in 6 patients. Despite the ongoing conflict, families, local communities and coalition forces transport teams combine to make the latter a viable option in Southern Afghanistan, with an excellent short-term outcome.

Effects of season and superovulatory treatment on embryo yields in fine-wool Merinos maintained under field conditions.

The aim of the study was to assess the effects of superovulatory treatment (multiple FSH-dose vs single-shot FSH treatment) and seasonality on embryo yields in fine-wool Merino ewes. Treatment based on multiple FSH-dose consisted of 200 mg of FSH (Folltropin(®)) administered in seven decreasing doses. Single-shot treatment consisted of a single dose of 70 mg of FSH + eCG. In ewes treated with multiple FSH doses, number of recovered embryos was higher (6.0 ± 0.5 vs 3.5 ± 1.0), while non-fertilization rate was lower (12.8 ± 3.9 vs 40.3 ± 9.5) during the breeding season when compared to the non-breeding season (p < 0.05); although similar values of recovered Grades 1-2 embryos were observed between seasons. During the breeding season, proportion of responding ewes (98.1 vs 57.1%), ovulation rate (13.9 ± 0.8 vs 3.2 ± 1.2), recovered structures (7.9 ± 0.6 vs 1.7 ± 0.7), total recovered embryos (6.0 ± 0.5 vs 1.2 ± 0.6) and good-quality embryos (5.1 ± 0.5 vs 0.9 ± 0.6) were higher for the multiple FSH-dose treatment than for the single-shot protocol. In a similar way, in the non-breeding season, ovulation rate (11.3 ± 1.8 vs 6.0 ± 1.1) and recovered structures (6.6 ± 1.2 vs 2.7 ± 0.6) were higher for the multiple FSH injections protocol than those for the single-shot treatment, resulting in higher recovered Grades 1-2 embryos (3.2 ± 0.9 vs 1.4 ± 0.5). Current results indicate that seasonal anestrus affected embryo yields when applying multiple FSH-dose superovulatory treatment in Merino ewes, by decreasing the number of recovered embryos although the number of recovered good-quality embryos was not affected. During both seasons, multiple FSH injections produced higher ovarian response and number of viable embryos than the single-shot treatment.

Lessons learned in oral and maxillofacial surgery from British military deployments in Afghanistan.

This article describes the combined lessons learned from two deployments of a cadre of British Oral and Maxillofacial surgeons to Kandahar between July 2006 to April 2007, and September 2008 to April 2009.

Five months of surgery in the multinational field hospital in Afghanistan with an emphasis on oral and maxillofacial injuries.

The aim of this review was to assess the workload of theatres in the role 3 Multinational Field Hospital in Kandahar, Afghanistan and to identify what period of day most emergency admissions arrived. During the period 05 August 2006 to 21 December 2006, 288 operations were performed on 259 patients and comprised 393 individually quantifiable procedures. 98% of these operations were to treat acute injuries. Oral and Maxillofacial surgeons were involved in 24% of operations. 63% of procedures done at these operations involved upper or lower limbs, 19% the head and neck and 18% involved the torso. An analysis of emergency admissions in November 2006 showed that most occurred between 18.00 and midnight. Although theatre timetabling made provision for this, whenever possible, elective surgery was scheduled for the following morning when emergency injury admissions were at their lowest.

Developing a craniomaxillofacial and cervical equipment module for surgeons in the austere environment: a systematic review.

The treatment of craniomaxillofacial and cervical wounds in a disaster relief setting is done by clinicians from local medical treatment facilities, non-governmental organisations (NGO), or the military. Although each group and individual surgeon will need specific equipment, this will be restricted by weight, portability and interoperability. We systematically reviewed scientific and commercial publications according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The papers we identified described the portable equipment that is required to treat patients who need damage-control surgery (decompressive craniectomy, temporary stabilisation, and internal and external fixation of the facial bones) for craniomaxillofacial and cervical injuries in austere or military settings. Austere settings are those in which there is an inherent lack of infrastructure, such as facilities, roads, and power. A total of 35 papers or scientific articles recommended the equipment that is needed to manage these injuries, but we could find no module that was specifically designed for use in these environments. Multiple modules are currently required to provide comprehensive surgical care and many of the items in the existing maxillofacial and neurosurgical kits are rarely used, which increases the cost of initial procurement and resupply. Duplications in equipment between modules also increase the size, weight, and financial cost. We suggest the equipment that is required to make up a rationalised, lightweight, and compact module that can be used for all craniomaxillofacial and cervical operations in austere settings.

Addition of eCG to a 14 d prostaglandin treatment regimen in sheep FTAI programs.

In the present study, there was evaluation of the alternative of adding eCG as part of a long-interval prostaglandin-F2α (PG) treatment on the reproductive efficiency of Merino sheep during the breeding season. A total of 210 ewes and 182 ewe lambs were randomly assigned to three experimental groups to induce the timing of estrus among ewes in a: Long-interval PG, group being synchronized using two doses of PG 14 days apart; Long-interval PG + eCG group being synchronized using the same treatment regimen as Group PG with the addition of 200 IU eCG to the regimen, administered concomitantly with the second PG administration; and MAP + eCG group being synchronized with intravaginal progestin sponges for 14 days plus 200 IU eCG, administered at the time of sponge removal. The percentage pregnancy rate in ewes of the MAP + eCG group was greater than the ewes of the Long-interval PG and Long-interval PG + eCG groups (76.4 % compared with 52.0 % and 62.5 %, respectively; P < 0.05). The prolificacy rate was greater in the ewes of the Long-interval PG+eCG group compared with the other groups (114 % compared with 100 % and 103 %, respectively; P < 0.05). When considering the fecundity rate, ewes of the Long-interval PG+eCG and MAP+eCG groups had greater values than ewes of the Long-interval PG group (71.2 % and 78.8 % compared with 52.0 %, respectively; P < 0.05). The Long-interval PG+eCG is an alternative to the conventional progestin sponge plus eCG treatment regimen with there being a greater fecundity rate when this regimen is used compared with the Long-term PG and similar to MAP-eCG treatment regimens.

Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory.

Over 20 years of accumulated evidence has shown that the major female sex hormone 17ß-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clinical use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1) cross the blood-brain barrier, 2) rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3) activate neural estrogen response element (ERE)-dependent gene transcription. Using liquid chromatography-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute intraperitoneal injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clinical applicability.

Anthropologists bet on their latest data in las vegas.

Anthropologists need luck on their side when they search for key fossils or study monkeys in the wild, but their work can still hit the jackpot. That was clear at the 61 st annual meeting of the American Association of Physical Anthropology, which brought more than 800 anthropologists to Las Vegas in early April. Among the reports was one on new fossils of early hominids in Ethiopia and another on extinct giant sloth lemurs in Madagascar.