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BACKGROUND: Emergency physicians lack high-quality evidence for many diagnostic and treatment decisions made for patients with suspected or confirmed coronavirus disease 2019 (COVID-19). Our objective is to describe the methods used to collect and ensure the data quality of a multicentre registry of patients presenting to the emergency department with suspected or confirmed COVID-19. METHODS: This methodology study describes a population-based registry that has been enrolling consecutive patients presenting to the emergency department with suspected or confirmed COVID-19 since Mar. 1, 2020. Most data are collected from retrospective chart review. Phone follow-up with patients at 30 days captures the World Health Organization clinical improvement scale and contextual, social and cultural variables. Phone follow-up also captures patient-reported quality of life using the Veterans Rand 12-Item Health Survey at 30 days, 60 days, 6 months and 12 months. Fifty participating emergency departments from 8 provinces in Canada currently enrol patients into the registry. INTERPRETATION: Data from the registry of the Canadian COVID-19 Emergency Department Rapid Response Network will be used to derive and validate clinical decision rules to inform clinical decision-making, describe the natural history of the disease, evaluate COVID-19 diagnostic tests and establish the real-world effectiveness of treatments and vaccines, including in populations that are excluded or underrepresented in clinical trials. This registry has the potential to generate scientific evidence to inform our pandemic response, and to serve as a model for the rapid implementation of population-based data collection protocols for future public health emergencies. TRIAL REGISTRATION: Clinicaltrials.gov, no. NCT04702945.

Background : Perineal hernia is a serious disease characterized by weakening or atrophy and separation of the muscles and fasciae of the perineal musculature, followed by the caudal displacement of pelvic and abdominal organs to the perineum region. Treatment is invariably surgical and several approaches have been proposed, but complication and recurrence rates remain high. This study aimed to evaluate 120 cases of perineal hernia treated at the Veterinary Hospital of Uberaba (HVU) from 2005 to 2020, addressing the clinical and surgical aspects and the postoperative period, seeking to identify the most relevant factors to improve care and treatment of future patients affected by this disease. Materials, Methods & Results : The medical records of dogs with a definitive diagnosis of perineal hernia were collected. The prevalence of perineal hernia was calculated. Data were obtained regarding sex, being castrated or not, age, body mass, race, clinical signs, affected side, possibility of hernia reduction, treatments used, associated pathologies. Of the 120 cases, only 69 underwent surgery at the HVU and from these cases data were obtained regarding hernia content, surgical techniques, surgical wires used, recurrences and postoperative complications. Fisher's exact test was applied to assess the influence of the type of surgical treatment and surgical thread on the occurrence of complications and recurrences. Perineal hernia was the second most frequently observed hernia. Mixed breed, male, non-neutered and geriatric dogs were the most affected. The most frequently observed clinical signs were related to the digestive and urinary tract, consistent with the most commonly found hernia contents (bladder, prostate and rectum). The simple herniorrhaphy technique was the most used and showed a high number of complications. The second most used technique was the elevation of the internal shutter, which proved to be more efficient than the simple technique. Regardless of the technique used, the association of two or more techniques proved to be more efficient to reduce major complications. The use of the vaginal tunic stood out because it proved to be efficient in the treatment of perineal hernias regardless of whether it is associated with simple herniorrhaphy or obturator elevation. The surgical fixations of abdominal organs (Bladder, Ducto deferente and Colon) proved to be effective, since there were no recurrences or major complications associated with their use and the most used threads for herniorrhaphy were polyamide and catgut. Low recurrence rates were found in patients who received synthetic yarns. The most frequent complications were suture dehiscence and serous secretion. Discussion : Perineal hernia is a very important alteration due to difficulties in treatment, high rates of complications and recurrence, in addition to the large number of affected dogs. Several surgical techniques have already been proposed for the treatment of perineal hernia in dogs and are based on the reconstruction of the perineal musculature through sutures, muscle flaps, biological membranes, synthetic mesh and the reduction of pressure on the perineum through the surgical fixation of organs abdominals such as colon, vas deferens and bladder (in the musculature of the abdominal wall). It is concluded that the perineal hernia affects mainly male, non-neutered and geriatric dogs, being rare in females. Regardless of the techniques used, the association of two or more techniques is more efficient to reduce the rate of recurrences and complications. The autogenous vaginal tunic is a good option for muscle strengthening in perineal herniorraphies. The use of synthetic surgical wires leads to better results in the treatment of perineal hernia when compared to biological wires.

Background: Mucopolysaccharidoses (MPS) are a group of rare illnesses caused by deficient activity of enzymes required for degradation of glycosaminoglycans (GAGs). Each type of MPS is caused by mutations in one of the genes that encode the 11 acid hydrolases involved in this degradation process, which are present in the lysosomes. Progressive accumulation of GAGs in the lysosomes result in cellular dysfunction and multisystemic clinical signs, with consequent decrease in quality of life and lifespan of the affected patients. The objective of the present work is to report a case of MPS type I in a dog.Case: A mixed-breed male dog of approximately 2-month-old weighing 2.5 kg was referred to Hospital Veterinário de Uberaba with a distended abdomen. At the clinical examination, the patient exhibited a regular nutritional status, pale mucous membranes, 7% dehydration, an arterial pulse rate of 120 beats per minute, a respiratory rate of 40 breaths per minute, and a heart rate of 120 beats per minute. There were increased abdominal volume and tension, and hepatosplenomegaly. The abdominal percussion exam produced a dull tone. Additional findings included muscular atrophy, increased volume in the metaphyseal areas of the thoracic and pelvic limbs, valgus limb deformity in the thoracic limbs, and instability of the hip joint. Radiographic examination revealed a series of bone alterations such as reduced vertebral bodies, a generalized decrease in radiopacity, thin cortical areas in long bones, narrowing of the pelvic canal, and marked deformation and irregularities in acetabular and epiphyseal (both proximal and distal) areas of the femurs and tibias. Ankylosis of the tibiotarsal and tarsometatarsal joints was also observed. There was also loss of trabecular structure and irregularities on the surfaces of all epiphyses of the bones, epiphyseal lines markedly open, and bones that were shorter and thicker than normal. The suspected diagnoses were pseudoachondroplasia and mucopolysaccharidosis. In view of the clinical and radiographic findings, tests were performed to investigate the clinical suspicion of MPS. Consequently, qualitative and quantitative tests of GAGs in the urine, as well as a blood enzymatic essay, were requested; results confirmed the diagnosis of MPS type I. Intensive treatment allowed the patient to reach adulthood. Whenever new clinical signs emerged, they were treated palliatively. As the disease became more severe, the patient died at the age of 3 years.Discussion: Mucopolysaccharidosis type I is a rare disease that exhibits variable clinical signs and for which there is no specific treatment in dogs; these characteristics hinder diagnosis and treatment of patients as the one described in this report. The major clinical signs observed in this case are in agreement with those reported in the literature, according to which the disease can cause severe alterations such as bone defects, increased volume and deformities in the joints of the limbs, corneal opacity, and enlargement of abdominal organs such as the liver and spleen. In considering diagnostic methods for MPS, the main screening test is quantification of GAGs in the urine. The confirmatory test for MPS consists of analysis of the activity of specific lysosomal enzymes in a blood sample; this test allowed the establishment of a diagnosis in this case. Enzyme replacement therapy, in which a recombinant enzyme is used, have yielded good results in humans and dogs. However, this treatment does not cure the disease – it only attenuates the clinical signs and enables the patient to reach adulthood. Access to enzyme replacement therapy was not possible in the present case. As a conclusion, MPS should be included in the differential diagnosis of developmental diseases in puppies. This highlights the importance of further studies and reports on this disease.

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson’s disease (PD). This mutation results in dopaminergic neurodegeneration via dysregulated protein translation, although how alterations in protein synthesis contributes to neurodegeneration in human neurons is not known. Here we define the translational landscape in LRRK2-mutant dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) via ribosome profiling. We found that mRNAs that have complex secondary structure in the 5’ untranslated region (UTR) are translated more efficiently in G2019S LRRK2 neurons. This leads to the enhanced translation of multiple genes involved in Ca2+ regulation and to increased Ca2+ influx and elevated intracellular Ca2+ levels, a major contributor to PD pathogenesis. This study reveals a link between dysregulated translation control and Ca2+ homeostasis in G2019S LRRK2 human dopamine neurons, which potentially contributes to the progressive and selective dopaminergic neurotoxicity in PD.

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson’s disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under non-pathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5’-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention.

Background: Uterine prolapse is an obstetric emergency because the exposed tissue can present edema, devitalization or even gangrene, depending on the evolution time and on the severity of circulatory changes. Haemorrhage due to the rupture of ovarian or uterine vessels can evolve rapidly to hypovolemic shock. More rarely, secondary thromboembolism to the uterine strangulation can be developed, complication that can also lead to death. This study reports the case of a Brazilian Molosser bitch treated by reducing total uterine prolapse, complemented with hysteropexy, in order to prevent recurrence and maintain its reproductive ability. Case: A 5-year-old Brazilian Molosser bitch was attended presenting double firm and tubular mass protruding through the vulva. The patient gave birth to five live pups, the last two of which needed to be pulled. Two days after parturition, she had abdominal contraction when a mass protruded from the vagina. A total uterine prolapse was diagnosed, since both uterine horns were found exposed and inverted, with exposition of the endometrium and the areas of placental implantation, together with the body of the uterus. The tissue was apparently edematous and lightly parched, with the presence of strange bodies, but without signals of circulatory complications or lacerations that could turn a possible reduction and maintenance of the uterus unfeasible. Due to interest of the tutor in preserving the reproductive ability, an internal reduction via ventral medial celiotomy and the fixation of the uterus in the lateral abdominal wall (hysteropexy) was chosen in order to diminish the possibility of relapse in future parturition.Discussion: The definitive treatment of the uterine prolapse can be realized through ovariohysterectomy when the exposed uterine tissue is highly compromised or there is vessel rupture or no reproductive purpose for the female. The amputation of everted tissue through the vulva is also an option, but the risk of intracavitary bleeding during tissue resection must be considered when the uterine and ovarian artery and vein escape to the interior of the abdomen without according hemostasis. In cases which there are no complications of the prolapsed tissue and is desired to maintain the reproductive ability of the female, the internal reduction with hysteropexy is recommended. As the etiology of the uterine prolapse is a condition bound to several factors, in between them multiple pregnancies, relaxation of the uterine ligaments and genetic factors, conditions which can be associated to the cause of the prolapse in the mentioned patient, the hysteropexy was preferred as a complementary technique to uterine preservation and prevention of the prolapse relapse in a possible new parturition. In this case, the reduction of prolapse followed by hysteropexy was preferred, because the female dog was apparently well, without signs of complication of the prolapsed tissue and with satisfactory preoperative evaluation. Adding these to the request of the tutor in maintaining the reproductive ability of the female, since the procedure would not pose as a life risk to it. The absence of severe lacerations and circulatory complications in the prolapsed uterus of the bitch under study and the non-detection of toxemia and septicemia corroborated to the reduction and preservation of the uterus. Even though the uterine prolapse is a rare disease, it is necessary to improve surgical techniques that enable the conservation of the female dog in reproduction. In situations of viability of the prolapsed tissue, the technique of hysteropexy in abdominal wall showed itself effective, concluding that hysteropexy is feasible and efficient as a complementary procedure to the reduction of uterine prolapse, having contributed to avoid relapse and maintaining the reproductive of the subject related in this article.

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson9s disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under nonpathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content in Drosophila studies with both sexes. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high-amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5′-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention. SIGNIFICANCE STATEMENT Parkinson9s disease (PD) prevalence is projected to rise as populations continue to age, yet there are no current therapeutic approaches that delay or stop disease progression. A broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerged. Here, we show that dietary amino acids are important determinants of neurodegeneration in a Drosophila model of LRRK2 PD. Restricting all amino acids effectively suppresses dopaminergic neuron loss and locomotor deficits and is associated with reduced protein synthesis, while moderately high amino acids similarly attenuate these PD-related phenotypes through a stress-responsive induction of 5′-AMP-activated protein kinase and autophagy. These studies suggest that diet plays an important role in the development of PD-related phenotypes linked to LRRK2.

Mutations in LRRK2 (leucine-rich repeat kinase 2) cause Parkinson’s disease through poorly understood mechanisms. Lavoy et al. performed a genome-wide screen to identify genetic modifiers of LRRK2 G2019Sinduced locomotor dysfunction in Drosophila... Disease phenotypes can be highly variable among individuals with the same pathogenic mutation. There is increasing evidence that background genetic variation is a strong driver of disease variability in addition to the influence of environment. To understand the genotype–phenotype relationship that determines the expressivity of a pathogenic mutation, a large number of backgrounds must be studied. This can be efficiently achieved using model organism collections such as the Drosophila Genetic Reference Panel (DGRP). Here, we used the DGRP to assess the variability of locomotor dysfunction in a LRRK2 G2019S Drosophila melanogaster model of Parkinson’s disease (PD). We find substantial variability in the LRRK2 G2019S locomotor phenotype in different DGRP backgrounds. A genome-wide association study for candidate genetic modifiers reveals 177 genes that drive wide phenotypic variation, including 19 top association genes. Genes involved in the outgrowth and regulation of neuronal projections are enriched in these candidate modifiers. RNAi functional testing of the top association and neuronal projection-related genes reveals that pros, pbl, ct, and CG33506 significantly modify age-related dopamine neuron loss and associated locomotor dysfunction in the Drosophila LRRK2 G2019S model. These results demonstrate how natural genetic variation can be used as a powerful tool to identify genes that modify disease-related phenotypes. We report novel candidate modifier genes for LRRK2 G2019S that may be used to interrogate the link between LRRK2, neurite regulation and neuronal degeneration in PD.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of late onset autosomal dominant form of Parkinson disease (PD). Gain of kinase activity due to the substitution of Gly 2019 to Ser (G2019S) is the most common mutation in the kinase domain of LRRK2. Genetic predisposition and environmental toxins contribute to the susceptibility of neurodegeneration in PD. To identify whether the genetic mutations in LRRK2 increase the susceptibility to environmental toxins in PD models, we exposed transgenic mice expressing human G2019S mutant or wild type (WT) LRRK2 to the environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment resulted in a greater loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta (SNpc) in LRRK2 G2019S transgenic mice compared to the LRRK2 WT overexpressing mice. Similarly loss of dopamine levels were greater in the striatum of LRRK2 G2019S mice when compared to the LRRK2 WT mice when both were treated with MPTP. This study suggests a likely interaction between genetic and environmental risk factors in the PD pathogenesis and that the G2019S mutation in LRRK2 increases the susceptibility of dopamine neurons to PD-causing toxins.

Mutations in a number of genes cause rare familial forms of Parkinson's disease and provide profound insight into potential mechanisms governing disease pathogenesis. Recently, a role for translation and metabolism of mRNA has emerged in the development of various neurodegenerative disorders including Parkinson's disease (PD). In PD, preliminary evidence supports a role for aberrant translation in the disease process stemming from mutations in several genes. Translation control is central to maintaining organism homeostasis under variable environmental conditions and deregulation of this may predispose to certain stressors. Hypothetically, deregulated translation may be detrimental to neuronal viability in PD through the misexpression of a subset of transcripts or through the impact of excessive bulk translation on energy consumption and burden on protein homeostatic mechanisms. While compelling preliminary evidence exists to support a role for translation in PD, much more work is required to identify specific mechanisms linking altered translation to the disease process.

Disease phenotypes can be highly variable among individuals with the same pathogenic mutation. There is increasing evidence that background genetic variation is a strong driver of disease variability in addition to the influence of environment. To understand the genotype-phenotype relationship that determines the expressivity of a pathogenic mutation, a large number of backgrounds must be studied. This can be efficiently achieved using model organism collections such as the Drosophila Genetic Reference Panel (DGRP). Here, we used the DGRP to assess the variability of locomotor dysfunction in a LRRK2 G2019S Drosophila melanogaster model of Parkinson’s disease. We find substantial variability in the LRRK2 G2019S locomotor phenotype in different DGRP backgrounds. A genome-wide association study for candidate genetic modifiers reveals 177 genes that drive wide phenotypic variation, including 19 top association genes. Genes involved in the outgrowth and regulation of neuronal projections are enriched in these candidate modifiers. RNAi functional testing of the top association and neuronal projection-related genes reveals that pros, pbl, ct and CG33506 significantly modify age-related dopamine neuron loss and associated locomotor dysfunction in the Drosophila LRRK2 G2019S model. These results demonstrate how natural genetic variation can be used as a powerful tool to identify genes that modify disease-related phenotypes. We report novel candidate modifier genes for LRRK2 G2019S that may be used to interrogate the link between LRRK2, neurite regulation and neuronal degeneration in Parkinson’s disease.

The purpose of the present study was to compare two protocols for equine frozen semen programs using either postovulation insemination or fixed-time insemination (FT), evaluating both pregnancy rates and intrauterine fluid (IUF) accumulation after artificial insemination with semen obtained from either highly or poorly fertile stallions. Six ejaculates from two stallions (n = 12) were processed. After thawing, semen samples were evaluated by computerized semen analysis. Fifteen mares (30 cycles) were inseminated with frozen semen from highly fertile stallion A, and 14 mares (28 cycles) were inseminated with frozen semen from poorly fertile stallion B. Ovulations were induced with 1 mg (intramuscular) of deslorelin acetate after the observation of a greater than 35 mm follicle and uterine edema. In postovulation insemination group, mares were inseminated once with 800 × 10(6) total sperm in a maximum 6-hour interval after ovulation. In FT group, mares were inseminated twice with 400 × 10(6) total sperm, 24 and 40 hours after induction. Mares were ultrasonographically examined for IUF accumulation 24 hours and for pregnancy diagnosis 14 days after the last insemination. Although IUF accumulation was more evident in mares inseminated once postovulation, pregnancy rates were similar for both protocols, regardless of the stallion, although a significant effect of the stallion was observed. These results indicated that FTs may be used for both highly and poorly fertile stallions as a practical tool to help spreading the use of frozen semen in equine reproduction programs.

Vitamin D deficiency is a common issue, particularly in obese populations, and is tested by assessing serum 25(OH)D concentrations. This study aimed to identify factors that contribute to the vitamin D status in fifty morbidly obese individuals recruited prior to bariatric surgery. Data collected included serum 25(OH)D concentrations, dietary and supplement intake of vitamin D, sun exposure measures, skin colour via spectrophotometry, and genotype analysis of several single nucleotide polymorphisms in the vitamin D metabolism pathway. Results showed a significant correlation between serum 25(OH)D concentrations and age, and serum 25(OH)D and ITAC score (natural skin colour). Natural skin colour accounted for 13.5% of variation in serum 25(OH)D, with every 10° increase in ITAC score (i.e., lighter skin) leading to a 9 nmol/L decrease in serum 25(OH)D. Multiple linear regression using age, ITAC score, and average UV index in the three months prior to testing, significantly predicted serum 25(OH)D concentrations (R2 = 29.7%). Single nucleotide polymorphisms for all vitamin D genes tested, showed lower serum 25(OH)D for those with the rare genotype compared to the common genotype; this was most pronounced for fok1 and rs4588, where those with the rare genotype were insufficient (

Background Treatment of mild-moderate Alzheimer’s disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores. Methods For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42

During protein translation, cells generate proteins based on the genetic information stored in nucleotides. This is a fundamental, and therefore a very tightly regulated process. Neurons are known to extensively utilize translational regulation to fulfill their functional needs, thereby increasing their susceptibility to translational defects. Recent studies on the molecular mechanisms of familial Parkinson’s disease (PD) suggested that protein translation is one of the major cellular processes implicated in the pathology. In this chapter, we summarize translational defects found in familial PD mutants. Furthermore, we discuss molecular mechanisms involved in the pathology, and also possibilities of targeting the translational machinery for therapeutic intervention in PD.

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. Increasing dietary intake of lutein- and zeaxanthin-rich foods is a potential means of preventing, or at least slowing the progression of AMD. Zeaxanthin levels in tropical super-sweetcorn was increased from 1.1 to 11.9 µg/g FW through conventional breeding and selection, associated with both an increase in the proportion of zeaxanthin relative to other carotenoids, and a general increase in carotenoid synthesis. Increasing zeaxanthin was associated with a colour shift from traditional ‘canary-yellow’ kernels to a golden-orange colour. Kernel colour was most closely correlated (r2=69%) with an increase in beta-arm carotenoid concentration. Consumer analysis revealed that prior to any knowledge of zeaxanthin-related health benefit, consumers would readily purchase both yellow and gold cobs. Once the health benefit was explained, this extended to deep-gold cobs. Colour difference between regular yellow sweetcorn and high-zeaxanthin sweetcorn could potentially be used as a visual means of differentiating high-zeaxanthin sweetcorn in the marketplace.

SummaryMutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson’s disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.

An incompetent vulvar seal leads to reproductive failure, and a surgical intervention might be required. The present paper describes modifications to Pouret's surgery. We suggest the use of a simple interrupted vertical mattress suture, which avoids seroma. Eighteen Brazilian Jumping Horse mares, older than 20 years and barren for 3-5 consecutive years, underwent modified Pouret's surgery. A horizontal skin incision of 3-4 cm was made half way between the anus and upper commissure of the vulva. The submucosal and connective tissue were dissected, and the rectovaginal shelf was split horizontally by sectioning the muscular and ligamentous connections between the anus, vulva, caudal portion of the rectum, and vagina until the vulva was oriented vertically. The wound was changed from a horizontal plane to a vertical plane by placing the suture vertically using approximately eight interrupted U sutures distributed in two layers with polyamide thread. The modified Pouret's surgical technique provided a perfect coaptation of the vulvar lips and a correct perineal position. Those mares that presented with horizontally tipped vulvar lips due to advanced age and stretching of the pelvic tissues by multiple foaling had their vulvas replaced. Also, the surgical procedure was easy to perform. As to fertility, of the 18 initial mares, 14 were inseminated, and all became pregnant. Thus, it was possible to conclude that the anatomical changes performed throughout the surgical procedure predisposed to a better vulvar coaptation, correcting the pneumovagina.

The interaction of soluble β-amyloid (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), with EphB2 receptors is thought to promote depletion of EphB2 receptors from the neuronal cell membrane. Since these receptors are important in maintaining integrity of the N-methyl-D-aspartate (NMDA) receptor—itself important in synaptic plasticity—loss of EphB2 may be a mediator of Aβ-induced neuronal dysfunction. To combat this loss, Shi and colleagues used small interfering peptides (siPs) to block ADDL-EphB2 interactions, rescuing NMDA receptor integrity and memory deficits in a mouse model of Alzheimer’s disease (AD). In cultured rat hippocampal neurons, treatment with ADDLs led to an acute reduction in EphB2 expression and surface localization of the NMDA receptor subunit GluN2B, whereas total GluN2B expression was unaltered. ADDLs interacted with EphB2 through its fibronectin type 3 repeat domain, and two siPs synthesized from the sequence of this domain bound to ADDLs in vitro to competitively inhibit EphB2 binding. One of these siPs, Pep63, prevented the loss of EphB2 and surface expression of GluN2B in hippocampal cultures. The effects of Pep63 were pursued further in vivo via bilateral injection for 5 days into the hippocampus of mice expressing both chimeric mouse/human mutated amyloid precursor protein and mutated human presenilin-1. These mice exhibit age-associated deficits in context- and tone-dependent fear memory along with behavioral impairment in spatial learning and memory that were all rescued by Pep63 treatment. Reductions in EphB2 and active GluN2B protein expression were rescued by Pep63, suggesting that functional NMDA receptors may be preserved in these mice. Progress has been made in developing AD treatments to prevent Aβ neurotoxicity, such as β- or γ-secretase inhibitors and immunotherapy with antibodies that prevent Aβ aggregation. Blocking neurotoxic cascades initiated by Aβ, achieved through the use of siPs in this study, may offer an alternative or complementary approach that renders harmless any toxic oligomers present without depending on altering the levels of ADDLs. The efficacy of long-term treatment with peptide drugs on AD pathology and progression will be an important area of future study. X.-D. Shi et al. , locking the interaction between EphB2 and ADDLs by a small peptide rescues impaired synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease. J. Neurosci. 36 11959–11973 (2016). [[Abstract]][1] [1]: http://www.jneurosci.org/content/36/47/11959.long

BackgroundThe aim of this study was to evaluate the effect of topical fibrin glue applied externally to all anastomoses after a pancreaticoduodenectomy (PD) on drain lipase levels, anastomotic leaks, complication rates and length of hospital stay.MethodsA standardized non‐pylorus preserving PD was performed with or without fibrin glue applied to each anastomosis.ResultsFifty‐seven patients were randomized: 32 with and 25 without TISSEEL. There were no statistical differences in each group with respect to drain lipase levels (high 40% versus 43%, P = 0.794), complications including gastric or biliary leaks (24% versus 28%, P = 1.00), wound infection (16% versus 9%, P = 0.28) and a Clavien score of 3 or more (16% versus 25%, P = 0.757) or hospital stay (12 versus 17 days, P = 0.777). Most patients with elevated drain lipase levels had an unaltered clinical course not predictive of adverse outcomes. However, the operative finding of a soft pancreas (27 out of 57 patients) was associated with post‐operative complications (P = 0.002). There were no peri‐operative deaths.Conclusions1Fibrin glue application to all anastomoses does not alter drain lipase levels.2Drain lipase levels are not a significant surrogate marker for clinically significant anastomotic leaks or complications.3Fibrin glue application did not reduce the incidence of an anastomotic leak or complications.

Gaucher disease (GD) is a lysosomal storage disorder caused by deficiencies in glucocerebrosidase, which functions in glycolipid metabolism to break down glucocerebroside. Mutations in GBA1 , the gene encoding glucocerebrosidase, are the most common genetic risk factor for Parkinson’s disease (PD

In 2013, the Food and Drug Administration approved dimethyl fumarate (DMF) for the treatment of multiple sclerosis under the trade name Tecfidera. The neuroprotective action of DMF is thought to involve activation of the Nrf2 pathway leading to enhanced antioxidant function and antiinflammatory

The iron chelator desferrioxamine (DFO) has received attention recently as a potential therapeutic for diseases such as Parkinson’s and Alzheimer’s, in which iron accumulation in the brain is thought to be pathogenic. As DFO may cause widespread iron depletion when administered systemically, intranasal application is an attractive route for focused delivery of DFO to the brain via the olfactory neurons. New evidence from Guo et al. supports intranasal DFO delivery as an effective approach to block neurodegeneration in a mouse model of Parkinson’s disease (PD). Intranasal treatment with DFO every other day for a period of 4 weeks attenuated the disease-related loss of dopaminergic neurons in the substantia nigra of mice induced by a chemical called MPTP and characterized by accumulation of iron in nigral and striatal neurons. Such iron accumulation may be due to up-regulation of a metal transporter and the transferrin receptor. DFO alleviated iron uptake into neurons in these regions and also limited metal transporter and transferrin receptor expression following induction of neurodegeneration with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mechanistically, DFO may promote neuronal recovery from MPTP-related toxicity through the stabilization and activation of hypoxia-inducible factor–1α (HIF-1α) and, in turn, up-regulation of HIF-1α–responsive genes. Decreased stress-responsive JNK activation and a decreased ratio of proapoptotic Bax to antiapoptotic Bcl2 were also observed following DFO treatment, which might contribute to its neuroprotective effects. DFO also ameliorated locomotor deficits caused by MPTP and associated with dopamine neuron degeneration. As the MPTP animal model recapitulates the elevated iron concentrations seen in the substantia nigra of PD patients, it is a useful preclinical model for assessing intranasal delivery of iron chelators such as DFO. The study suggests that restoring iron homeostasis in the brain can prevent neurodegeneration in these mice. Yet, more work is needed to determine whether iron accumulation plays a primary role in the loss of dopamine neurons in PD patients, since this will ultimately determine the therapeutic potential of DFO, regardless of how it is administered. C. Guo et al ., Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice. Exp. Neurol. 10.1016/j.expneurol.2016.03.016 (2016). [[Abstract]][1] [1]: http://www.sciencedirect.com/science/article/pii/S0014488616300590

BackgroundLittle has been published regarding presenting symptoms, investigations and outcomes for patients with pancreatic cancer in Australia. Data from a series of patients undergoing attempted resection in Queensland, Australia, are presented with the aim of assisting development of consistent strategies in disease management.

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T18:56:38Z No. of bitstreams: 1 S0102-09352012000500004.pdf: 556723 bytes, checksum: 34ba8578ed766aceed7c751736bb6dac (MD5) Made available in DSpace on 2013-08-22T18:56:38Z (GMT). No. of bitstreams: 1 S0102-09352012000500004.pdf: 556723 bytes, checksum: 34ba8578ed766aceed7c751736bb6dac (MD5) Previous issue date: 2012-10-01 Made available in DSpace on 2013-09-30T19:50:47Z (GMT). No. of bitstreams: 2 S0102-09352012000500004.pdf: 556723 bytes, checksum: 34ba8578ed766aceed7c751736bb6dac (MD5) S0102-09352012000500004.pdf.txt: 34890 bytes, checksum: 2f977a37f8ea5d8ab5005ca2bf2c33e1 (MD5) Previous issue date: 2012-10-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T13:39:25Z No. of bitstreams: 2 S0102-09352012000500004.pdf: 556723 bytes, checksum: 34ba8578ed766aceed7c751736bb6dac (MD5) S0102-09352012000500004.pdf.txt: 34890 bytes, checksum: 2f977a37f8ea5d8ab5005ca2bf2c33e1 (MD5) Made available in DSpace on 2014-05-20T13:39:25Z (GMT). No. of bitstreams: 2 S0102-09352012000500004.pdf: 556723 bytes, checksum: 34ba8578ed766aceed7c751736bb6dac (MD5) S0102-09352012000500004.pdf.txt: 34890 bytes, checksum: 2f977a37f8ea5d8ab5005ca2bf2c33e1 (MD5) Previous issue date: 2012-10-01 Analisou-se a piometra de 31 cadelas, de raças e idades variadas, sendo 25 cadelas com piometra de cérvice aberta e seis de cérvice fechada. Após ovariossalpingo-histerectomia, foram coletados fragmentos da cérvice e do útero para a avaliação imunoistoquímica. Foram analisados os receptores de estrógenos α e β, progesterona e colágenos I e III. Foram realizadas imunomarcações em diferentes regiões da cérvice, como o epitélio glandular, o epitélio luminal e o estroma glandular, assim como em diferentes regiões do útero, como o epitélio glandular e o estroma glandular. As imunomarcações de colágenos I e III foram realizadas nas regiões glandular e muscular da cérvice e do útero. Concentrações de receptores de progesterona foram maiores em cadelas com piometra fechada. The pyometra in 31 bitches of different breeds and ages, 25 with pyometra cervix open and 6 closed cervix was analyzed. After the ovariohysterectomy procedure, samples were collected from the cervix and uterus to evaluate immunohistochemistry. For immunohistochemical evaluation estrogen receptors α and β, progesterone and collagen I and III were analyzed. Immunostainings were performed in different regions of the cervix such as glandular epithelium, luminal epithelium and glandular stroma, as well as in different regions of the uterus, such as glandular epithelium and glandular stroma. The immunostainings for collagen I and III were performed in muscular and glandular regions of the cervix and uterus. The concentration the progesterone receptors were elevated in bitches from the closed pyometra. UNESP Faculdade de Medicina Veterinária e Zootecnia UNESP Faculdade de Medicina Veterinária e Zootecnia

Genetic studies have provided valuable insight into the pathological mechanisms underlying Parkinson's disease (PD). The elucidation of genetic components to what was once largely considered a nongenetic disease has given rise to a multitude of cell and animal models enabling the dissection of molecular pathways involved in disease etiology. Here, we review advances obtained from models of dominant mutations in α-synuclein and LRRK2 as well as recessive PINK1, parkin and DJ-1 mutations. Recent genome-wide association studies have implicated genetic variability at two of these loci, α-synuclein and LRRK2, as significant risk factors for developing sporadic PD. This, coupled with the established role of mitochondrial impairment in both familial and sporadic PD, highlights the likelihood of common mechanisms fundamental to the etiology of both.

The aim of the current study was to monitor the early pregnancy development in buffalo heifers and establish biometric threshold of different gestational vesicle and embryo/fetal parts from the day 15 following fertilization to day 70. Serial daily ultrasonographic examinations were carried out on eleven pregnant buffalo-heifers, during which the gestational vesicle diameter, amniotic vesicle diameter, crown-rump length, trunk diameter and biparietal diameter were measured and embryo/fetal sex characteristics were determined. The gestational vesicle, embryo and its heartbeats were assessed, respectively, by gestational days (d) 20.55 ± 2.34; 25.18 ± 1.91 and 25.27 ± 3.58 of pregnancy. The liquid column in non-pregnant horn and amniotic vesicle were detected, respectively, by d 31.0 ± 3.83 and 31.64 ± 2.34 of pregnancy. Subsequently were sequentially detected the neural tube (d 33.0 ± 3.51), umbilical cord (d 0.25 ± 2.76), early limbs, (d 41.67 ± 4.85), embryos proper movement (d 46.25 ± 2.36), vertebral column (d 47.33 ± 4.9), genital tubercle (d 47.2 ± 3), fetal bones (d 56.56 ± 1.67), brain (d 57.5 ± 1.2), urinary bladder (d 57.88 ± 3.08), stomach cavities (d 59.17 ± 4.36), brain ventricles (d 61.09 ± 2.34), end of migration of genital tubercle in males (d 58.4 ± 2.2) and in females (d 60.4 ± 4.2), skull acoustic shadow (d 59.66 ± 3.13), vertebra acoustic shadow (d 62.14 ± 3.13), ribs acoustic shadow (d 64 ± 2.65), limb bones acoustic shadow (d 65 ± 1.58) and liver (d 66.63 ± 3.54). High regression and correlation coefficients were found between different studied parameters and gestational age, where the highest were found for the crown-rump length and biparietal diameter. In conclusion, the overall data indicated the feasibility and value of ultrasonographic embryo, fetal and vesicle characteristics and embryo/fetometry in buffaloes for the evaluation of fetal development and estimation of gestational age during the first 70th pregnancy days.

Aims: This study investigated a possible association between violence and the use of drugs, particularly methamphetamine and alcohol. Methods: Cross-sectional, baseline data were derived from the At-Risk Youth Study, a prospective cohort of street-involved youth in Vancouver, Canada. Subjects were asked whether they had suffered or perpetrated violence in the 6 months prior to the interview. Results: In total, 478 youth were enrolled, with a median age of 22 years (interquartile range = 20.0–23.9); 230 (48%) reported having been victims of violence, while 165 (34.5%) reported having perpetrated violence. Daily methamphetamine use was not associated with either outcome. In a multivariate analysis, daily alcohol consumption was significantly associated with being a victim (adjusted odds ratio = 2.10) and a perpetrator (adjusted odds ratio = 2.02) of violence. A history of abuse, failing a grade, and dealing drugs were also independently associated with violence, while having a regular partner was protective. Conclusion: Contrary to popular media reports that methamphetamine causes violence, we found no association. The association of alcohol with violence, though, has implications for screening and intervention programs.

Objective: The authors report the recurrence pattern of oesophageal cancer after minimally invasive esophagectomy (MIE), comparing it to the recurrence pattern after open surgery and identify prognostic factors of recurrence. Summary Background Data: In efforts to improve long term survival for oesophageal cancer increasingly radical surgery has been reported, however recurrent disease remains a problem. Opinion is divided as to the adequacy of resection possible using minimally invasive techniques with concerns there would be an increase incidence of locoregional recurrence. Methods: A total of 222 patients who underwent esophagectomy at The Princess Alexandra Hospital without any neoadjuvant or adjuvant therapy were identified. Within this group 166 underwent (MIE) and 66 an open transthoracic esophagectomy (TTE). Patients were followed up for the detection of any symptomatic recurrence over a median period of 50 months. Results: Recurrence developed in 134/222 (60%). The pattern of recurrence in MIE was 4%, 8% and 46% for local, regional and distant recurrence respectively. The pattern of recurrence for TTE was 7%, 20% and 55% for local, regional and distant recurrence respectively. Operative approach was not a prognostic factor for any type of recurrence. Independent prognostic factors associated with local recurrence were positive margins and number of positive nodes. Factors associated with regional recurrence were positive margins and T stage. Distant recurrence was associated with distant recurrence was T stage, differentiation, tumor length >6 cm and number of positive nodes. Conclusion: Recurrence is not associated with operative approach. MIE can be performed with comparable recurrence patterns to open radical surgery.

Chemoradiotherapy (CRT) as a definitive treatment for esophageal cancer, is being used with increasing frequency and as a result, surgeons will be required to assess more patients who have residual or recurrent local malignancy. This article aimed to assess outcomes after esophagectomy following definitive CRT (dCRT) and compare any difference between them and patients who had preoperative neoadjuvant CRT (nCRT) using a similar regimen of chemotherapy. From a prospective database the details of patients who had a resection following nCRT and dCRT were analyzed. The main therapeutic difference between the groups was the dose of radiotherapy (35 vs 60 Gy) and the timing of the resection following completion of the CRT (median 4 vs 28 weeks). Fourteen patients had an esophagectomy following a dCRT and 53 had one following a nCRT. Preoperatively, the dCRT group had worse respiratory function and more ECG abnormalities. Preoperative tumor length, pathological TNM staging and R0 resection rates were the same in both groups. Post resection, the dCRT group had greater morbidity than the nCRT group, spending longer in the intensive care unit (median 48 vs 24 h), more days in hospital (median 31 vs 13) and having more severe respiratory complications (37%vs 6%). The operative mortality was higher in the dCRT group (7%vs 0%). The three-year survival was 24% after dCRT. Patients selected for salvage esophagectomy following dCRT are a major challenge in postoperative care. However, some patients survive for a reasonable period of time, making resection a worthwhile option.

The totally extraperitoneal (TEP) approach for surgical repair of inguinal hernias has emerged as a popular technique. We conducted a prospective randomised trial to compare patient comfort scores using different mesh types and fixation using this technique. Over a 14 month period, 146 patients underwent 232 TEP inguinal hernia repairs. We compared the comfort scores of patients who underwent these procedures using different types of mesh and fixation. A non-absorbable 15 × 10 cm anatomical mesh fixed with absorbable tacks (Control group) was compared with either a non-absorbable 15 × 10 cm folding slit mesh with absorbable tacks (Group 2), a partially-absorbable 15 × 10 cm mesh with absorbable tacks (Group 3) or a non-absorbable 15 × 10 cm anatomical mesh fixed with 2 ml fibrin sealant (Group 4). Outcomes were compared at 1, 2, 4 and 12 weeks using the Carolina Comfort Scale (CCS) scores. At 1, 2, 4 and 12 weeks, the median global CCS scores were low for all treatment groups. Statistically significant differences were seen only for median CCS scores and subscores with the use of partially-absorbable mesh with absorbable tacks (Group 3) at weeks 2 and 4. However, these were no longer significant at week 12. In this study, the TEP inguinal hernia repair with minimal fixation results in low CCS scores. There were no statistical differences in CCS scores when comparing types of mesh, configuration of the mesh or fixation methods.

Objective: Prospectively evaluate whether for patients having laparoscopic cholecystectomy with failed trans-cystic duct clearance of bile duct (BD) stones they should have laparoscopic choledochotomy or postoperative endoscopic retrograde cholangiography (ERCP). Summary Background Data: Clinical management of BD stones found at laparoscopic cholecystectomy in the last decade has focused on pre-cholecystectomy detection with ERCP clearance in those with suspected stones. This clinical algorithm successfully clears the stones in most patients, but no stones are found in 20% to 60% of patients and rare unpredictably severe ERCP morbidity can result in this group. Our initial experience of 300 consecutive patients with fluoroscopic cholangiography and intraoperative clearance demonstrated that, for the pattern of stone disease we see, 66% of patients' BD stones can be cleared via the cystic duct with dramatic reduction in morbidity compared to the 33% requiring choledoehotomy or ERCP. Given the limitations of the preoperative approach to BD stone clearance, this trial was designed to explore the limitations, for patients failing laparoscopic trans-cystic clearance, of laparoscopic choledochotomy or postoperative ERCP. Methods: Across 7 metropolitan hospitals after failed trans-cystic duct clearance, patients were intraoperatively randomized to have either laparoscopic choledochotomy or postoperative ERCP. Exclusion criteria were: ERCP prior to referral for cholecystectomy, severe cholangitis or pancreatitis requiring immediate ERCP drainage, common BD diameter of less than 7 mm diameter, or if bilio-enteric drainage was required in addition to stone clearance. Drain decompression of the cleared BD was used in the presence of cholangitis, an edematous ampulla due to instrumentation or stone impaction and technical difficulties from local inflammation and fibrosis. The ERCP occurred prior to discharge from hospital. Mechanical and extracorporeal shockwave lithotripsy was available. Sphincter balloon dilation as an alternative to sphincterotomy to allow stone extraction was not used. Major endpoints for the trial were operative time, morbidity, retained stone rate, reoperation rate, and hospital stay. Results: From June 1998 to February 2003, 372 patients with BD stones had successful trans-cystic duct clearance of stones in 286, leaving 86 patients randomized into the trial. Total operative time was 10.9 minutes longer in the choledochotomy group (158.8 minutes), with slightly shorter hospital stay 6.4 days versus 7.7 days. Bile leak occurred in 14.6% of those having choledochotomy with similar rates of pancreatitis (7.3% versus 8.8%), retained stones (2.4% versus 4.4%), reoperation (7.3% versus 6.6%), and overall morbidity (17% versus 13%). Conclusions: These data suggest that the majority of secondary BD stones can be diagnosed at the time of cholecystectomy and cleared trans-cystically, with those failing having either choledochotomy or postoperative ERCP. However, because of the small trial size, a significant chance exists that small differences in outcome may exist. We would avoid choledochotomy in ducts less than 7 mm measured at the time of operative cholangiogram and severely inflamed friable tissues leading to a difficult dissection. We would advocate choledochotomy as a good choice for patients after Billroth II gastrectomy, failed ERCP access, or where long delays would occur for patient transfer to other locations for the ERCP.

Two new studies report on the potential of a number of antioxidants and a cholesterol-lowering drug to prevent neurodegeneration in a Drosophila genetic model of parkinsonism. This research shines a spotlight on the power of invertebrate models as an in vivo screening tool.

A common cause of Parkinson disease are missense mutations in the leucine-rich repeat kinase 2 (LRRK2) catalytic Roc-COR domain, leading to a decrease in GTPase activity; and its kinase domain, leading to an increase in kinase activity and subsequent LRRK2 toxicity. Targeting LRRK2 with selective, brain-permeable kinase inhibitors is a promising approach to reduce toxicity, and thus is a major goal of clinical development. Understanding the specific signaling cascades triggered by LRRK2 mutations will be key to this aim. This article is part of a special issue on Parkinson disease.

Purpose A subset of patients with oesophageal cancer will have a complete response to neoadjuvant therapy. These patients have a greatly improved survival over nonresponders. By selecting only those who have a response to neoadjuvant therapy for surgery we could potentially improve overall survival as well as rationalizing the management of nonresponders. We have assessed the accuracy of oesophagogastroscopy in this setting. Methodology A prospective data base of 804 patients undergoing oesophageal resection for carcinoma was reviewed. 100 patients had undergone endoscopic assessment of response to neoadjuvant therapy prior to surgery. The endoscopic assessment of response to neoadjuvant therapies was compared with the pathological assessment of response. Kaplan-Meier estimates of survival were used for each level of response and the log rank test used to compare results. Results Oesophagogastroscopy has an accuracy of 52%, sensitivity of 65.2% and specificity of 50% for prediction of complete pathological response. Overall 3-year survival was 35.7 ± 6.0%. 3-year survival was improved in those with a pathologically confirmed complete response ( n = 23; 62.4 ± 12.9%). Those with microscopic residual disease also had an improved 3-year survival ( n = 33; 46.3 ± 12.2%) compared with patients with large volume residual disease ( n = 44; 16.3 ± 6.6%), however, oesophagogastroscopy failed to identify this subset. Conclusion Oesophagogastroscopy may be considered a useful tool in the assessment of tumour response to neoadjuvant therapies, however, its poor accuracy means it would not be appropriate to exclude patients from further therapeutic intervention on the basis of this assessment alone.

Background: Laparoscopic repair of ventral incisional hernias was first reported in 1993. Since then, there have been sporadic case reports and small series published about this procedure, but it has not been widely adopted. Newer types of composite prosthetic mesh may reduce the potential problem of bowel adhesion. Methods: Thirty cases of laparoscopic ventral incisional hernia repairs (carried out by two surgeons or their senior registrars) have been retrospectively reviewed and reported in this article. The data were obtained from patient records and subsequent phone surveys. Results: Thirty patients between 29 and 82 years (mean: 58 years) underwent this procedure. There were 14 men and 16 women. The average weight of the patients was 81 kg. The hernias were up to 6 or 7 cm in diameter. Mesh was used in 28 cases (polypropylene in 25 cases, expanded polytetrafluoroethylene in two cases and composite mesh in one case). Most meshes were laid intraperitoneally and fixed into position with laparoscopic spiral tacks. Twenty-nine cases were completed laparoscopically. One operation (3.3%) was converted to an open procedure because of severe bowel adherence to the hernia sac. The mean operating time was 52 min for laparoscopic ventral incisional hernia repairs only. All but two patients tolerated an oral diet within 24 h. The postoperative hospital stay ranged from 0 to 11 days, with 17 patients (57%) staying overnight and eight patients (27%) staying another day. Over 80% of the patients returned to house duties within a week. There was no mortality, and minor complications occurred in four patients (14%). One patient had a small bowel obstruction treated successfully by repeat laparoscopy with division of fibrinous adhesions to polypropylene mesh on day four. Follow up ranged from 1 to 69 months (mean: 12 months). One patient did not attend follow-up appointments. There were three cases of hernia recurrence (10%). Conclusion: The results suggest that laparoscopic repair of ventral incisional hernias is a safe, effective and technically feasible operation for small- to medium-sized hernias allowing shorter hospital stay, early recovery and resumption of normal activities. However, recurrence rates are comparable to open mesh hernioplasty especially for larger hernias.

Mutations in the catalytic Roc-COR and kinase domains of leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD). LRRK2 mutations cause PD with age-related penetrance and clinical features identical to late-onset sporadic PD. Biochemical studies support an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc-COR mutations, respectively. Strong evidence exists that LRRK2 toxicity is kinase dependent leading to extensive efforts to identify selective and brain-permeable LRRK2 kinase inhibitors for clinical development. Cell and animal models of PD indicate that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. Although some of these biological functions are affected consistently by most disease-linked mutations, others are not and it remains currently unclear how mutations that produce variable effects on LRRK2 biochemistry and function all commonly result in the degeneration and death of dopamine neurons. LRRK2 is typically present in Lewy bodies and its toxicity in mammalian models appears to be dependent on the presence of α-synuclein, which is elevated in human iPS-derived dopamine neurons from patients harboring LRRK2 mutations. Here, we summarize biochemical and functional studies of LRRK2 and its mutations and focus on aberrant vesicular trafficking and protein synthesis as two leading mechanisms underlying LRRK2-linked disease.

Made available in DSpace on 2015-02-02T12:39:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-06-01Bitstream added on 2015-02-02T13:07:49Z : No. of bitstreams: 1 S0100-736X2014000600013.pdf: 634896 bytes, checksum: 4503892aa65aaf09df2c8ab02d1ff332 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) A viabilidade e maturidade fetais podem ser estimadas através da avaliação dos fluídos fetais em muitas espécies, no entanto a composição bioquímica do líquido amniótico durante a gestação ainda não está bem definida para a espécie equina. O objetivo deste estudo foi estabelecer e comparar o perfil bioquímico do liquido amniótico em diferentes momentos da gestação e no momento do parto para um melhor entendimento da fisiologia da gestação de equinos. Foram avaliados valores encontrados para pH, osmolaridade, glicose, uréia, creatinina, gamma-GT, sódio, potássio, cloretos e proteína total no liquido amniótico colhido de 122 éguas comparando-se os resultados encontrados entre as colheitas em terço inicial (TI), médio (TM) e final (TF) da gestação e no momento do parto (MP). As amostras colhidas nos períodos gestacionais foram realizadas em frigoríficos abatedouros. As idades gestacionais (IG), em dias, foram definidas através de fórmula de regressão sugerida por Naves et al. (2008), utilizando-se a mensuração crânio-caudal dos fetos. Devido a presença de graus variados de assimetria e desvios de um padrão Gaussiano de distribuição, o teste de Kruskal-Wallis foi usado para comparar a mediana de cada variável-resposta entre os grupos de estudo. Quando houve evidência significante de que pelo menos uma das medianas era diferente das outras, o teste de Wilcoxon foi usado para realizar comparações múltiplas entre os grupos. O método de Bonferroni foi usado para ajustar o valor-P resultante das comparações múltiplas. A análise estatística foi realizada com o procedimento PROC NPAR1WAY e significância estatística foi definida como p

Background: The treatment of common bile duct stones discovered at routine intraoperative cholangiography includes postoperative endoscopic retrograde cholangiography or intraoperative laparoscopic common bile duct exploration. Given the equivalence of short-term outcome data for these two techniques, the choice of one over the other may be influenced by long-term follow-up data. We aimed to establish the long-term outcomes following laparoscopic common bile duct exploration and compare this with endoscopic retrograde cholangiography. Methods: One hundred and fifty consecutive patients underwent laparoscopic common bile duct exploration between March 1998 and March 2006 carried out by a single surgeon. All were prospectively studied for 1 month followed by a late-term phone questionnaire ascertaining the prevalence of adverse symptoms. Patients presented with a standardized series of questions, with reports of symptoms corroborated by review of medical records. Results: In 150 patients, operations included laparoscopic transcystic exploration (135), choledochotomy (10) and choledochoduodenostomy (2). At long-term follow up (mean 63 months), 116 (77.3%) patients were traceable, with 24 (20.7%) reporting an episode of pain and 18 (15.5%) had more than a single episode of pain. There was no long-term evidence of cholangitis, stricture or pancreatitis identified in any patient. Conclusion: Laparoscopic bile duct exploration appears not to increase the incidence of long-term adverse sequelae beyond the reported prevalence of postcholecystectomy symptoms. There was no incidence of bile duct stricture, cholangitis or pancreatitis. It is a safe procedure, which obviates the need and expense of preoperative or postoperative endoscopic retrograde cholangiography in most instances.

The incidence of gastric cancer is decreasing in Australia, yet it remains a common cause of cancer-related mortality. Surgical resection remains the cornerstone of curative treatment. High-volume specialized units have reported superior perioperative and oncological outcomes. The role of D2 lymphadenectomy has been controversial as a result of concerns over increased morbidity. Our aim is to report the perioperative and oncological outcomes of curative gastric resection from a specialist Australian upper GI unit.Data from a prospectively maintained database were reviewed for all patients undergoing curative resection for gastric adenocarcinoma from a single unit during a 12-year period. Perioperative and long-term outcomes were compiled.There were 255 curative gastric resections during 12 years. An R0 resection was performed in 96 % with a perioperative mortality rate of 1.6 %. A D2 dissection was performed in 85 % of cases in the past 6 years, with no increase in perioperative morbidity or mortality detected. The 5-year overall survival was 53 %.Our results demonstrate that both short- and long-term outcomes of surgical resection in gastric cancer patients, comparable to international high-volume centers, can be achieved in an Australian upper GI unit. A D2 lymph node dissection can be performed safely without any increase in perioperative risk in a specialist unit that has the necessary training but also the perioperative support structures to manage these complex patients.

The authors report the recurrence pattern of esophageal cancer after thoracoscopic-assisted esophagectomy (TAE), comparing it to the recurrence pattern after open surgery and identify prognostic factors for recurrence.To improve long-term survival for esophageal cancer radical surgery has been proposed increasingly, however, recurrent disease remains a problem. Opinion is divided as to the adequacy of resection possible using minimally invasive techniques with concerns that there may be an increased incidence in locoregional recurrence.A total of 221 patients who underwent esophagectomy at the Princess Alexandra Hospital without any neoadjuvant or adjuvant therapy were identified from a prospective database. Patients were followed up for the detection of symptomatic recurrence for a median of 59 months.Within this group 165 patients underwent TAE and 56 an open transthoracic esophagectomy (TTE). The 5-year overall recurrence rate was 133/221 (60%). The 5-year rates of symptomatic first recurrence following TAE was 4%, 9%, and 47% for local, regional, and distant recurrence, respectively. The 5-year rates of symptomatic first recurrence following TTE was 5%, 18%, and 55% for local, regional, and distant recurrence, respectively. Operative approach was not a prognostic factor for any type of recurrence. Independent prognostic factors associated with locoregional recurrence were positive margins and number of positive nodes. Distant recurrence was associated with T stage, differentiation, tumor length6 cm, and number of positive nodes.Distant recurrence remains a significant problem in esophageal cancer. TAE achieved adequate locoregional control and compared favorably with open TTE.

Until recently, genetics was thought to play a minor role in the development of Parkinson’s disease (PD). Over the last decade, a number of genes that definitively cause PD have been identified, which has led to the generation of disease models based on pathogenic gene variants that recapitulate many features of the disease. These genetic studies have provided novel insight into potential mechanisms underlying the aetiology of PD. This chapter will provide a profile of the genes conclusively linked to PD and will outline the mechanisms of PD pathogenesis implicated by genetic studies. Mitochondrial dysfunction, oxidative stress and impaired ubiquitin–proteasome system function are disease mechanisms that are particularly well supported by genetic studies and are therefore the focus of this chapter.

In a systematic review of randomized controlled trials on tuberculosis treatment, Dick Menzies and colleagues find shorter courses of rifampin to be associated with poorer treatment outcomes., Background Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes. Methods and Findings PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1–2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy. Conclusions TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy. Please see later in the article for the Editors' Summary, Editors' Summary Background Tuberculosis—a contagious infection, usually of the lungs—kills nearly two million people annually. It is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with tuberculosis cough. Most people infected with M. tuberculosis do not become ill—their immune system contains the infection. However, the bacteria remain dormant within the body and can cause tuberculosis years later if immunity declines because of, for example, infection with HIV (the virus that causes AIDS). The symptoms of tuberculosis include a persistent cough, weight loss and night sweats. The disease can usually be cured by taking several powerful antibiotics regularly for several months although drug-resistant tuberculosis is increasingly widespread. The standardized drug regimen recommended by the World Health Organization (WHO) for previously uninfected patients consists of an initial treatment phase, in which rifampin, isoniazid, ethambutol, and pyrazinamide are taken daily or thrice weekly for 2 months, and a continuation phase, in which two antibiotics are taken for a further 4–6 months. Why Was This Study Done? Resistance to rifampicin, which can develop if this drug is not taken regularly, is associated with poor treatment outcomes, particularly in patients infected with isoniazid-resistant M. tuberculosis. WHO recommends, therefore, that health-care workers watch patients take all their doses of rifampicin (“directly observed therapy”). Treatment regimens for tuberculosis that use rifampicin only during the initial phase and/or give rifampicin several times a week (intermittently) rather than daily would make direct observation of treatment much easier but are such regimens effective? In this study (which, together with two similar studies, was commissioned by WHO to provide the evidence needed for a revision of their treatment guidelines), the researchers undertook a systematic review (a search using specific criteria to identify relevant research studies, which are then appraised and analyzed according to an explicit protocol) and a meta-analysis (a statistical approach that pools the results of several studies) of published trials of various rifampicin-containing regimens for the treatment of tuberculosis in previously untreated patients. What Did the Researchers Do and Find? The researchers identified 57 randomized controlled trials (studies in which groups of patients are randomly assigned to different interventions) that reported the treatment failure and/or relapse rates (determined by seeing whether M. tuberculosis could be grown from sputum brought up from the lungs by coughing, so-called bacteriologically confirmed tuberculosis) associated with various rifampicin-containing treatment regimens. In their statistical analysis of the results of these trials (which involved more than 21,000 previously untreated patients), the researchers found that regimens that used rifampicin during only the first 1–2 months of treatment had higher rates of failure, relapse, and acquired drug resistance than regimens that used rifampicin for 6 months. Indeed, relapse rates decreased with the duration of rifampicin treatment up to 8 months of treatment. Furthermore, outcomes were particularly bad with regimens that included rifampicin during only the first 1–2 months of treatment if there was initial resistance to isoniazid and/or streptomycin (another antibiotic). Outcomes were similar, however, in regimens in which rifampicin was given daily throughout treatment, daily during the initial phase then twice or thrice weekly, or thrice weekly throughout treatment; insufficient evidence was available to evaluate the efficacy of regimens in which rifampicin was given twice weekly throughout treatment. What Do These Findings Mean? These findings suggest that tuberculosis treatment regimens for previously untreated patients who use rifampicin during only the first two months of treatment should be phased out and replaced by regimens that use rifampicin for 6 months, particularly in settings where there is likely to be resistance to isoniazid and/or streptomycin. This recommendation will be made in the planned 2009 revision of the WHO tuberculosis treatment guidelines. In addition, these findings suggest that giving rifampicin thrice weekly is as effective as giving it daily during the initial phase or throughout treatment. Importantly, these findings also indicate that more trials are needed to investigate other dosing schedules, to determine the optimal duration of treatment, and to determine the best way to manage patients infected with isoniazid-resistant bacteria. Finally, since very few of the trials identified in the systematic review included HIV-positive participants, trials designed to test drug regimens in people infected with both HIV and M. tuberculosis are urgently needed to reduce global deaths from tuberculosis. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000146. The results of another WHO-commissioned study into the treatment of tuberculosis are presented in a separate PLoS Medicine Research Article by Menzies et al. (Menzies D, Benedetti A, Paydar A, Royce S, Pai M, et al. (2009) Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis. PLoS Med 6(9): e1000150. doi:10.1371/journal.pmed.1000150) The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis The US Centers for Disease Control and Prevention provide several facts sheets and other information resources about tuberculosis The American Thoracic Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America have published guidelines on TB treatment The 2003 (2004 revision) WHO guidelines for national programs for the treatment of tuberculosis are available; WHO also provides information on efforts to reduce the global burden of tuberculosis (in several languages) and its 2009 annual report on global control of tuberculosis describes the current situation (key points are available in several languages) The WHO publishes guidelines on TB treatment

Preoperative staging for esophageal adenocarcinoma is suboptimal for predicting outcomes when compared with pathological data. The aim of this study was to assess if the quantitative values obtained by preoperative 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are independent prognostic indicators for survival in patients with resectable adenocarcinoma of the esophagus undergoing surgical treatment without neoadjuvant therapy. Patients were identified from a prospective database, survival analyses were undertaken using log rank and Cox method. The median follow-up was 44 months (range 18-61 months). Between November 2002 and November 2005, 45 consecutive patients underwent FDG-PET followed by surgery. The median age was 72 years (range 38-82 years). On univariate analysis of overall survival and disease-free survival, preoperative FDG-PET maximum standardized uptake value (SUV(max); P= 0.008 and P= 0.015, respectively) and postoperative pathological stage (P= 0.001 and P= 0.001, respectively) as well as postoperative histological grade (P= 0.001 and P= 0.001, respectively) were significantly associated with outcome. Multivariate analysis demonstrated that only the postoperative pathological variables were independent predictors of outcome (Wald 11.81, P= 0.001). Preoperative FDG-PET SUV(max) is associated with outcome after esophageal adenocarcinoma resection but remains less accurate than postoperative variables. A high FDG-PET SUV(max) could be used to identify a high-risk population who would benefit most from neoadjuvant therapies.

The most common techniques for the treatment of common bile duct (CBD) stones have been outlined in detail in the preceding four chapters. In this chapter we evaluate the published evidence for these techniques and provide conclusions with clinical validity for practicing physicians. We have summarised these findings with the use of a flow diagram (Fig. 27.1) for quick reference to help guide evidence-and expertise-based management.

Laparoscopic and open techniques are both recognized treatment options for ventral hernias. We conducted a prospective randomized trial of both methods, to assess hernia recurrence, postoperative recovery and complications. Fifty-eight patients with ventral hernias were enrolled into the trial between August 2003 and December 2005. Of these, 31 underwent laparoscopic repair and 27 underwent open repair. Clinical parameters were documented on all patients during a median follow-up period of 27.5 months. The demographics of the two groups were similar. There was one recurrence in each of the laparoscopic and open groups. There was an equivalent rate of operative time, length of stay, postoperative pain scores, return to normal activities, wound infection and seroma formation between the two groups. Laparoscopic and open ventral hernia repair are comparable and offer low recurrence rates.

Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was -56.8% (SD 29) and in the non-responders -27.8% (SD 32.1) (P = 0.035). The mean percentage change in TLR was -49.1% (SD 44.8) in the responders and in the non-responders -27.3% (SD 31.3) (P = 0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3-6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear.

Background and aims. Laparoscopic distal pancreatectomy (LDP) is a safe alternative to conventional open distal pancreatectomy, with advantages that include smaller incisions, less pain, and shorter postoperative recovery. Despite these apparent advantages, however, uptake of the procedure has been slow, with only a handful of series published. Material and methods. All LDPs performed in Brisbane, Australia, over a 10-year period (May 1996 to June 2006) were retrospectively reviewed. Results. Forty-six consecutive LDPs were performed. A variety of lesions were resected, including nine cancers. Twelve patients were converted for oncological (6) or technical reasons (6). The spleen was retained in 14/29 patients, either by main splenic vessel preservation (9) or solely supported by the short gastric vessels (5), resulting in inferior pole infarction in 2 patients. Overall morbidity was 39%, including 15% pancreatic fistula. All fistulas resolved after a median of 6 weeks without re-operation. A non-significant trend toward fewer fistulas with stapled rather than sutured stump closure was observed (13% vs 19%; p=0.43). Median operative duration and hospital stay were 157min and 7days, respectively. There was no mortality. Conclusion. LDP is a safe alternative to conventional resection for a wide range of lesions. As with open resection, pancreatic fistula is the dominant morbidity, but is generally indolent. While spleen preservation is often possible, care must be taken to avoid infarction of the inferior pole if the Warshaw technique is utilized.

Manganese superoxide dismutase (MnSOD or SOD2) is a key mitochondrial enzymatic antioxidant. Arguably the most striking phenotype associated with complete loss of SOD2 in flies and mice is shortened life span. To further explore the role of SOD2 in protecting animals from aging and age-associated pathology, we generated a unique collection of Drosophila mutants that progressively reduce SOD2 expression and function. Mitochondrial aconitase activity was substantially reduced in the Sod2 mutants, suggesting that SOD2 normally ensures the functional capacity of mitochondria. Flies with severe reductions in SOD2 expression exhibited accelerated senescence of olfactory behavior as well as precocious neurodegeneration and DNA strand breakage in neurons. Furthermore, life span was progressively shortened and age-dependent mortality was increased in conjunction with reduced SOD2 expression, while initial mortality and developmental viability were unaffected. Interestingly, life span and age-dependent mortality varied exponentially with SOD2 activity, indicating that there might normally be a surplus of this enzyme for protecting animals from premature death. Our data support a model in which disruption of the protective effects of SOD2 on mitochondria manifests as profound changes in behavioral and demographic aging as well as exacerbated age-related pathology in the nervous system.