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.

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.

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.

Effect of GnRH or hCG administration on Day 4 post insemination on reproductive performance in Merino sheep of North Patagonia.

Different therapeutic strategies have been used with the objective of improve luteal function to reduce embryonic losses. The objective of this work was to study the effect of the administration of GnRH or hCG at Day 4 post fixed time artificial insemination (FTAI) on reproductive efficiency in Merino sheep during the breeding season in North Patagonia. Estrus of multiparous Merino ewes (n = 288) was synchronized by two injections of prostaglandins (PG; 125 µg, Cloprostenol), 14 days apart. Cervical FTAI was performed 53-56 h after the second PG with a dose of fresh semen (100 × 106 spermatozoa) from five Merino rams. In all ewes body condition score (BCS) was determined at FTAI. At 4 days post FTAI ewes were randomly assigned into three experimental groups: GnRH group (4 µg, Buserelin; n = 99), hCG group (300 IU, hCG; n = 92) and Control group (1 ml, saline solution; n = 97). Pregnancy and pregnancy losses were evaluated by ultrasonography on Days 33 and 90 post FTAI. Additionally, embryo crown-rump length (CRL) was measured by ultrasonography (n = 12 single-pregnant ewes by experimental group) at the first ultrasound. Date of birth, litter size and lamb weight were recorded (n = 111 pregnant ewes). Pregnancy rate on Days 33 and 90 post FTAI did not differ among treatment groups (P > 0.05). Pregnancy losses at Day 33 post FTAI were lower in the hCG group compared to the GnRH and Control groups (0, 3, 7.2%, respectively; P < 0.05). Pregnancy losses between Days 33 and 90 after FTAI were negligible (P > 0.05). The embryo CRL at Day 33 post FTAI was not increased by the hormonal treatments (P > 0.05). Moreover, it was lower in GnRH group compared to Control group (P < 0.05). Litter size tended to be greater in the GnRH group compared to the hCG and Control groups (P < 0.1). The birth weight of twin lambs tended to be higher in the GnRH group compared to the Control group (P < 0.1). The birth weight of single lambs was not affected by treatments (P > 0.05). Ram fertility and BCS of ewes at FTAI influenced the effect of hormonal treatments on reproductive parameters. In conclusion, administration of hCG or GnRH at Day 4 post FTAI does not improve pregnancy rate but treatment with hCG reduces pregnancy loss on Day 33 post FTAI. GnRH treatment improves litter size and twin lambs birth weight.

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.

Hormonal therapeutic strategy on the induction of accessory corpora lutea in relation to follicle size and on the increase of progesterone in sheep.

We determined the effect of GnRH or hCG treatment on day 4 post-time artificial insemination (FTAI) on the formation of accessory corpora lutea (acc-CL) and on the concentration of serum progesterone (P4) in sheep. Multiparous adult Merino ewes (n = 36) were synchronized for estrus using double injection of PGF2α agonist (125 µg Cloprostenol) with an interval of 14 days. At 53-56 h after the second PG application, FTAI was performed. On day 4 post FTAI, ewes were either treated with analogue of GnRH (4 µg buserelin; n = 12) or hCG (300 IU, hCG; n = 12) or saline solution (1 ml; Control; n = 12). Two laparoscopic ovarian examinations were performed on days 4 and 10 post FTAI. In the first observation, we determined the number of post ovulation corpora lutea (po-CL) and the site, number and diameter of follicles present in both ovaries. In the second laparoscopy, we observed the number of po-CL and acc-CL. The sizes of the follicles that generated the acc-CL were determined according to the position of the follicles observed in the first laparoscopy. Serum P4 concentration was determined on days 4, 7, 10, 13, 17 and 21 post FTAI by chemiluminescence. A similar follicular population in size and number was observed in the three experimental groups prior to the beginning of treatments (Follicles 2 mm: 6.4 ± 3.7, 3 mm: 3.0 ± 2.3, 4 mm: 1.1 ± 0.5, 5 mm: 1.4 ± 0.8; P Ëƒ 0.05). The formation of 1.0 ± 0.4 and 1.1 ± 0.3 acc-CL was observed in the GnRH and hCG groups, respectively (P Ëƒ 0.05), but was not observed in the Control group (P < 0.05). Follicle sizes from which acc-CL generated were 3, 4 and 5 mm and did not differ between hormonal treatments (P Ëƒ 0.05). The hCG group had higher mean concentrations of P4 on days 7, 10, 13 and 17 post FTAI compared with the GnRH group and the Control group (P < 0.05), while no differences were observed between these two latter groups (P > 0.05). Mean P4 concentrations in ewes treated with hCG showed no differences according to the size of the follicle from which acc-CL were generated (P Ëƒ 0.05). In conclusion, administration of hCG or GnRH on day 4 post FTAI induced the formation of one acc-CL from follicles of 3, 4 or 5 mm, indistinctly. However, serum P4 concentration increased significantly only in the hCG group. The serum P4 concentrations of acc-CL that originated from different follicle sizes did not differ.

Contemporary management of maxillofacial ballistic trauma.

Ballistic maxillofacial trauma in the UK is fortunately relatively rare, and generally involves low velocity handguns and shotguns. Civilian terrorist events have, however, shown that all maxillofacial surgeons need to understand how to treat injuries from improvised explosive devices. Maxillofacial surgeons in the UK have also been responsible for the management of soldiers evacuated from Iraq and Afghanistan, and in this review we describe the newer types of treatment that have evolved from these conflicts, particularly that of damage-control maxillofacial surgery.

Optimising ballistic facial coverage from military fragmenting munitions: a consensus statement.

VIRTUS is the first United Kingdom (UK) military personal armour system to provide components that are capable of protecting the whole face from low velocity ballistic projectiles. Protection is modular, using a helmet worn with ballistic eyewear, a visor, and a mandibular guard. When all four components are worn together the face is completely covered, but the heat, discomfort, and weight may not be optimal in all types of combat. We organized a Delphi consensus group analysis with 29 military consultant surgeons from the UK, United States, Canada, Australia, and New Zealand to identify a potential hierarchy of functional facial units in order of importance that require protection. We identified the causes of those facial injuries that are hardest to reconstruct, and the most effective combinations of facial protection. Protection is required from both penetrating projectiles and burns. There was strong consensus that blunt injury to the facial skeleton was currently not a military priority. Functional units that should be prioritised are eyes and eyelids, followed consecutively by the nose, lips, and ears. Twenty-nine respondents felt that the visor was more important than the mandibular guard if only one piece was to be worn. Essential cover of the brain and eyes is achieved from all directions using a combination of helmet and visor. Nasal cover currently requires the mandibular guard unless the visor can be modified to cover it as well. Any such prototype would need extensive ergonomics and assessment of integration, as any changes would have to be acceptable to the people who wear them in the long term.

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.

Prevalence of cervical cancer and associated mortality in Grenada, 2000-2010 / Prevalencia del cáncer cervicouterino y mortalidad asociada en Granada, 2000-2010

ABSTRACT 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.

RESUMEN Objetivo Evaluar la prevalencia del cáncer cervicouterino y la mortalidad asociada en Granada, Antillas Menores, entre el 2000 y el 2010. Métodos Se obtuvieron los registros de las visitas al hospital y a consultorios clínicos a partir del laboratorio de histopatología del Hospital General de Granada. Se borraron los datos personales de los registros y se los compiló electrónicamente. La prevalencia de cáncer cervicouterino se evaluó por medio del análisis transversal de estos datos secundarios. De un total de 12 012 registros, fueron seleccionados para el análisis 2 527 mediante un método de muestreo sin reemplazo. Los casos se compararon con los datos correspondientes de pacientes en los registros de defunciones, cuando fue posible, y se usaron para calcular las tasas de mortalidad asociadas. Resultados La prevalencia observada de cáncer cervicouterino fue 52,4 por 100 000 mujeres (de 15 años o más). Las tasas más elevadas de cáncer cervicouterino se observaron en el grupo de edad de 35 a 44 años, seguido por el grupo de 45 a 64 años. Del 2000 al 2010, 65 defunciones fueron atribuibles al cáncer cervicouterino, más del 50% en mujeres mayores de 65 años. La tasa de mortalidad observada fue 16,7 por 100 000, casi el doble de la calculada por la Organización Mundial de la Salud para la región. Conclusiones Este estudio indica la necesidad de establecer un programa integral de detección del cáncer cervicouterino en Granada. Los resultados deben servir como base para estudios futuros sobre cómo generar y ejecutar apropiadamente políticas de salud pública para la educación en la materia, la detección, la prevención y el control del cáncer cervicouterino en Granada.

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.

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.

Management of maxillofacial wounds sustained by British service personnel in Afghanistan.

UK service personnel sustaining maxillofacial wounds in Afghanistan are stabilised in a field hospital prior to evacuation for definitive treatment at the Royal Centre for Defence Medicine (RCDM). Descriptive injury data were gathered from the Joint Theatre Trauma Registry (JTTR) between 1 January 2008 and 31 December 2009 and matched to hospital clinical records. The mean Abbreviated Injury Severity (AIS) scores in service personnel sustaining maxillofacial wounds alone were compared with those with injuries to all body areas. Maxillofacial wounds were present in 21% of British servicemen sustaining battle injuries, but 30% of all evacuations despite the similar mean AIS of each group. This probably reflects the complex care these injuries often require that is not possible in the field. In the field hospital, maxillofacial wounds were predominantly debrided and definitive repair was deferred until evacuated to RCDM. AIS codes are an excellent predictor of mortality from face and eye wounds but they reflect morbidity poorly. The authors propose that instead of a single AIS code, each military face and eye injury should be ascribed a second separate Occulo-Facial Functional and Aesthetic (OFFA) outcome score that more accurately predicts the aesthetic and functional parameters of these wounds.

Oral and maxillofacial surgical contribution to 21 months of operating theatre activity in Kandahar Field Hospital: 1 February 2007-31 October 2008.

Our aim was to assess oral and maxillofacial operating theatre activity at the NATO Multinational Medical Unit at Kandahar Airfield (MMU KAF). We made a retrospective analysis of the theatre logbook of the MMU KAF between 1 February 2007 and 31 October 2008. During that period, 1778 operations were done for 1639 patients. A total of 563 local civilians (34% of all patients) were operated on. Oral and maxillofacial surgeons were involved in 322/1778 (18%), general surgeons in 943/1778 (53%), and orthopaedic surgeons in 716/1778 (40%) of operations. Neurosurgeons were present only between March and October 2008, resulting in them being involved in 73/789 procedures (9%). Debridement and closure of wounds were the most common procedures in all specialties. A total of 247 operations on the face, neck, and scalp made up 16% of the total operations for trauma (n=1556), but most for coalition service personnel (n=69, 24%). Only 28 operations (10%) on coalition service personnel were done on the torso. This could be accounted for by the increased numbers of blast injuries and the effectiveness of modern body armour among coalition forces. Brain injuries were also more common among this group of patients than among the other groups, showing that helmets have only a limited effect in protecting against the effects of blast injury. Of all procedures, 163 operations (9%) were done for children. Training of general surgeons is becoming more specialised, which may result in greater dependence on larger teams of subspecialists (including oral and maxillofacial surgeons) in future conflicts.

Use of a custom designed external fixator system to treat ballistic injuries to the mandible.

The authors describe a custom designed mandibular external fixator II system that can be used to treat complex, comminuted fractures. The system is adjustable and lightweight, quick, robust, simple to apply, and allows mouth opening during healing, It is well suited to use in the modern war surgery environment. The authors present a case of successful treatment of a ballistic fracture of the mandible using this device.

Mandibular fractures in British military personnel secondary to blast trauma sustained in Iraq and Afghanistan.

Blast trauma is the primary cause of maxillofacial injury sustained by British service personnel on deployment, and the mandible is the maxillofacial structure most likely to be injured in combat, but there are few reports about the effect of blast trauma on it. The Joint Theatre Trauma Registry identified all mandibular fractures sustained by British servicemen secondary to blast injury between 1 January 2004 and 30 September 2009. These were matched to corresponding hospital notes from the Royal Centre for Defence Medicine (RCDM) for those evacuated servicemen and autopsy records for those who died of wounds. Seventy-four mandibular fractures were identified in 60 servicemen. Twenty-two soldiers were evacuated to the RCDM and the remaining 38 died from wounds. Fractures of the symphysis (39/106, 37%) and body (31/106, 29%) were more common than those of the angle (26/106, 25%) and condyle (10/106, 9%). This pattern of injury differs from that of civilian blunt trauma where the condyle is the site that is injured most often. Those fractures thought to result from the blast wave itself usually caused simple localised fractures, whereas those fractures thought to result from fragments of the blast caused comminution that affected several areas of the mandible. The pattern of fractures in personnel injured while they were inside a vehicle resembled that traditionally seen in blunt trauma, which supports the requirement for mandatory wearing of seat-belts in the rear of vehicles whenever tactically viable. All mandibular fractures in servicemen injured while in the turret of a vehicle had evidence of foreign bodies or radio-opaque fragments as a result of their exposed position. Many of these injuries could therefore be potentially prevented by the adoption of facial protection.

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.