Safety and efficacy of tofacitinib for the treatment of patients with juvenile idiopathic arthritis: preliminary results of an open-label, long-term extension study.

OBJECTIVES: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study. METHODS: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0. RESULTS: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48. CONCLUSIONS: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48. TRIAL REGISTRATION NUMBER: NCT01500551.

Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing.

Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.

Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α.

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration.

Two for the Price of One: A Neuroprotective Chaperone Kit within NAD Synthase Protein NMNAT2.

One of the most fascinating properties of the brain is the ability to function smoothly across decades of a lifespan. Neurons are nondividing mature cells specialized in fast electrical and chemical communication at synapses. Often, neurons and synapses operate at high levels of activity through sophisticated arborizations of long axons and dendrites that nevertheless stay healthy throughout years. On the other hand, aging and activity-dependent stress strike onto the protein machineries turning proteins unfolded and prone to form pathological aggregates associated with neurodegeneration. How do neurons protect from those insults and remain healthy for their whole life? Ali and colleagues now present a molecular mechanism by which the enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) acts not only as a NAD synthase involved in axonal maintenance but as a molecular chaperone helping neurons to overcome protein unfolding and protein aggregation.

Hospitalization and death among patients with influenza, Guatemala, 2008-2012.

BACKGROUND: Influenza is a major cause of respiratory illness resulting in 3-5 million severe cases and 291,243-645,832 deaths annually. Substantial health and financial burden may be averted by annual influenza vaccine application, especially for high risk groups. METHODS: We used an active facility-based surveillance platform for acute respiratory diseases in three hospitals in Guatemala, Central America, to estimate the incidence of laboratory-confirmed hospitalized influenza cases and identify risk factors associated with severe disease (defined as admission to the intensive care unit (ICU) or death). We enrolled patients presenting with signs and symptoms of acute respiratory infection (ARI) and obtained naso- and oropharyngeal samples for real-time reverse transcriptase polymerase chain reaction (RT-PCR). We used multivariable logistic regression to identify risk factors for ICU admission or death, adjusted for age and sex. RESULTS: From May 2008 to July 2012, among 6326 hospitalized ARI cases, 446 (7%) were positive for influenza: of those, 362 (81%) had influenza A and 84 (18%) had influenza B. Fifty nine percent of patients were aged ≤ 5 years, and 10% were aged ≥ 65 years. The median length of hospitalization was 5 days (interquartile range: 5). Eighty of 446 (18%) were admitted to the ICU and 28 (6%) died. Among the 28 deaths, 7% were aged ≤ 6 months, 39% 7-60 months, 21% 5-50 years, and 32% ≥ 50 years. Children aged ≤ 6 months comprised 19% of cases and 22% of ICU admissions. Women of child-bearing age comprised 6% of cases (2 admitted to ICU; 1 death). In multivariable analyses, Santa Rosa site (adjusted odds ratio [aOR] = 10, 95% confidence interval [CI] = 2-50), indigenous ethnicity (aOR = 4, 95% CI = 2-13, and radiologically-confirmed pneumonia (aOR = 5, 95% CI = 3-11) were independently associated with severe disease. Adjusted for hospital utilization rate, annual incidence of hospitalized laboratory-confirmed influenza was 24/100,000 overall, 93/100,000 for children aged < 5 years and 50/100,000 for those ≥ 65 years. CONCLUSIONS: Influenza is a major contributor of hospitalization and death due to respiratory diseases in Guatemala. Further application of proven influenza prevention and treatment strategies is warranted.

Different dynamin blockers interfere with distinct phases of synaptic endocytosis during stimulation in motoneurones.

KEY POINTS: Neurotransmitter release requires a tight coupling between synaptic vesicle exocytosis and endocytosis with dynamin being a key protein in that process. We used imaging techniques to examine the time course of endocytosis at mouse motor nerve terminals expressing synaptopHluorin, a genetically encoded reporter of the synaptic vesicle cycle. We separated two sequential phases of endocytosis taking place during the stimulation train: early and late endocytosis. Freshly released synaptic vesicle proteins are preferentially retrieved during the early phase, which is very sensitive to dynasore, an inhibitor of dynamin GTPase activity. Synaptic vesicle proteins pre-existing at the plasma membrane before the stimulation are preferentially retrieved during the late phase, which is very sensitive to myristyl trimethyl ammonium bromide (MitMAB), an inhibitor of the dynamin-phospholipid interaction. ABSTRACT: Synaptic endocytosis is essential at nerve terminals to maintain neurotransmitter release by exocytosis. Here, at the neuromuscular junction of synaptopHluorin (spH) transgenic mice, we have used imaging to study exo- and endocytosis occurring simultaneously during nerve stimulation. We observed two endocytosis components, which occur sequentially during stimulation. The early component of endocytosis apparently internalizes spH molecules freshly exocytosed. This component was sensitive to dynasore, a blocker of dynamin 1 GTPase activity. In contrast, this early component was resistant to myristyl trimethyl ammonium bromide (MiTMAB), a competitive agent that blocks dynamin binding to phospholipid membranes. The late component of endocytosis is likely to internalize spH molecules that pre-exist at the plasma membrane before stimulation starts. This component was blocked by MiTMAB, perhaps by impairing the binding of dynamin or other key endocytic proteins to phospholipid membranes. Our study suggests the co-existence of two sequential synaptic endocytosis steps taking place during stimulation that are susceptible to pharmacological dissection: an initial step, preferentially sensitive to dynasore, that internalizes vesicular components immediately after they are released, and a MiTMAB-sensitive step that internalizes vesicular components pre-existing at the plasma membrane surface. In addition, we report that post-stimulus endocytosis also has several components with different sensitivities to dynasore and MiTMAB.

Demographic and clinical characteristics of deaths associated with influenza A(H1N1) pdm09 in Central America and Dominican Republic 2009-2010.

BACKGROUND: The demographic characteristics of pandemic influenza decedents among middle and low-income tropical countries are poorly understood. We explored the demographics of persons who died with influenza A (H1N1)pdm09 infection during 2009-2010, in seven countries in the American tropics. METHODS: We used hospital-based surveillance to identify laboratory-confirmed influenza deaths in Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama and Dominican Republic. An influenza death was defined as a person who died within two weeks of a severe acute respiratory infection (SARI) defined as sudden onset of fever >38 °C, cough or sore-throat, and shortness of breath, or difficulty breathing requiring hospitalization, and who tested positive for influenza A (H1N1)pdm09 virus by real time polymerase chain reaction. We abstracted the demographic and clinical characteristics of the deceased from their medical records. RESULTS: During May 2009-June 2010, we identified 183 influenza deaths. Their median age was 32 years (IQR 18-46 years). One-hundred and one (55 %) were female of which 20 (20 %) were pregnant and 7 (7 %) were in postpartum. One-hundred and twelve decedents (61 %) had pre-existing medical conditions, (15 % had obesity, 13 % diabetes, 11 % asthma, 8 % metabolic disorders, 5 % chronic obstructive pulmonary disease, and 10 % neurological disorders). 65 % received oseltamivir but only 5 % received it within 48 h of symptoms onset. CONCLUSIONS: The pandemic killed young adults, pregnant women and those with pre-existing medical conditions. Most sought care too late to fully benefit from oseltamivir. We recommend countries review antiviral treatment policies for people at high risk of developing complications.

Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.

Evaluation of heart fatty acid-binding protein as a biomarker for canine leishmaniosis.

BACKGROUND: Myocarditis frequently occurs in canine leishmaniosis (CanL). Heart fatty acid-binding protein (HFABP) is a biomarker of myocardial damage. METHODS: This study aimed to compare HFABP concentration (HFABPc) in healthy dogs and dogs at different stages of CanL and evaluate the correlation of this biomarker with several clinicopathological and echocardiographic variables. Thirty-one dogs diagnosed with CanL and 10 healthy dogs were included. RESULTS: HFABPc was not statistically different (p > 0.05) between groups of dogs at different LeishVet stages of CanL or between groups with high versus low to intermediate serology titres. In 70% of CanL dogs, HFABPc was within the 95% confidence interval limits of the mean of healthy dogs. A moderate negative correlation with globulin (r = -0.519; p = 0.03) and haematocrit (HCT) (r = -0.538; p = 0.02) was observed. No other significant correlation (p > 0.05) was observed with any other variable. LIMITATIONS: Many statistical tests were performed, and therefore, type I error cannot be ruled out. CONCLUSION: HFABPc is not consistently elevated in dogs with CanL and is not associated with the severity of the disease, or most echocardiographic or clinicopathological variables studied. The correlation with globulin and HCT was not strong and not considered clinically significant. HFABPc lacks sufficient predictive capacity in dogs with CanL, discouraging further research or clinical use of this biomarker in this disease.

Proteomic research on new urinary biomarkers of renal disease in canine leishmaniosis: Survival and monitoring response to treatment.

The objective of our study was to search for survival biomarkers (SB) and treatment response monitoring biomarkers (TRMB) in the urinary proteome of dogs with renal disease secondary to canine leishmaniosis (CanL), using UHPLC-MS/MS. The proteomic data are available via ProteomeXchange with identifier PXD042578. Initially, a group of 12 dogs was evaluated and divided into survivors (SG; n = 6) and nonsurvivors (NSG; n = 6). A total of 972 proteins were obtained from the evaluated samples. Then, bioinformatic analysis reduced them to 6 proteins like potential SB increased in the NSG, specifically, Haemoglobin subunit Alpha 1, Complement Factor I, Complement C5, Fibrinogen beta chain (fragment), Peptidase S1 domain-containing protein, and Fibrinogen gamma chain. Afterwards, SG was used to search for TRMB, studying their urine at 0, 30, and 90 days, and 9 proteins that decreased after treatment were obtained: Apolipoprotein E, Cathepsin B, Cystatin B, Cystatin-C-like, Lysozyme, Monocyte differentiation CD14, Pancreatitis-associated precursor protein, Profilin, and Protein FAM3C. Finally, enrichment analysis provided information about the biological mechanisms in which these proteins are involved. In conclusion, this study provides 15 new candidate urinary biomarkers and an improved understanding of the pathogenesis of kidney disease in CanL.

Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease.

In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice). We have found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-α, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats.

Estimated incidence of influenza-virus-associated severe pneumonia in children in El Salvador, 2008-2010.

OBJECTIVE: To estimate the incidence of influenza-virus-associated severe pneumonia among Salvadorian children aged < 5 years. METHODS: Data on children aged < 5 years admitted with severe pneumonia to a sentinel hospital in the western region were collected weekly. Nasal and oropharyngeal swab specimens were collected from a convenience sample of case patients for respiratory virus testing. A health-care utilization survey was conducted in the hospital catchment area to determine the proportion of residents who sought care at the hospital. The incidence of influenza-virus-associated severe pneumonia among all Salvadorian children aged < 5 years was estimated from surveillance and census data, with adjustment for health-care utilization. Influenza virus strains were characterized by the United States Centers for Disease Control and Prevention to determine their correspondence with northern and southern hemisphere influenza vaccine formulations. FINDINGS: Physicians identified 2554 cases of severe pneumonia. Samples from 608 cases were tested for respiratory viruses and 37 (6%) were positive for influenza virus. The estimated incidence of influenza-virus-associated severe pneumonia was 3.2 cases per 1000 person-years (95% confidence interval, CI: 2.8-3.7) overall, 1.5 cases per 1000 person-years (95% CI: 1.0-2.0) during 2008, 7.6 cases per 1000 person-years (95% CI: 6.5-8.9) during 2009 and 0.6 cases per 1000 person-years (95% CI: 0.3-1.0) during 2010. Northern and southern hemisphere vaccine formulations matched influenza virus strains isolated during 2008 and 2010. CONCLUSION: Influenza-virus-associated severe pneumonia occurred frequently among young Salvadorian children during 2008-2010. Antigens in northern and southern hemisphere influenza vaccine formulations corresponded to circulating strains.

Effects of Competitive ELISA-Positive Results of Piroplasmosis on the Performance of Endurance Horses.

Endurance is an increasingly popular equestrian sport. However, in southern Europe, there is a high prevalence of horses that are asymptomatic carriers of equine piroplasmosis (EP), a tick-borne disease that could affect their performance. This study aimed to evaluate the impact and influence of EP on the performance of endurance horses. Blood samples were collected from 40 horses in Extremadura, Spain, before and after a race, in different national elite horse endurance competitions. Hematological and biochemical parameters and EP seroprevalence were analysed by competitive enzyme-linked immunosorbent assay. The global seroprevalence of EP was 70%, with 27 horses testing positive for Theileria equi (67.5%) and three (7.5%) for Babesia caballi, with two of these horses (5%) positive for both. Approximately 82.5% of the horses (33 of 40) completed the competition, with no influence on performance or position achieved in those with subclinical parasitosis. There were also no significant differences in hematological or biochemical values between seropositive and seronegative horses. The data suggest that horses without clinical signs of EP can participate without performance impairment in competitions of up to 80 km. Although it is recommended that longer distance competitions should be further evaluated, this is the first step for decision-making by organizers and participants in this sport.

Atypical Conjunctival Lesion as the Initial Presentation of Granulomatosis With Polyangiitis in an Adolescent Male.

PURPOSE: The purpose of this study was to report the first case of a conjunctival granulomatous lesion as the presenting sign of granulomatous polyangiitis (GPA) in a pediatric patient. METHODS: This study is a case report. RESULTS: A 14-year-old Hispanic boy presented with a conjunctival lesion on the inferior bulbar conjunctiva of the right eye associated with diffuse conjunctival injection. The mass progressively grew and became painful over the course of 6 weeks. No retinal or orbital abnormalities were noted on examination. The lesion was excised, and histopathological analysis was consistent with granulomatous inflammation. The lesion recurred after 15 months, and a second excisional biopsy was performed. The lesion again slowly recurred, and on presentation to our clinic, an elevated lesion in the inferior limbal/bulbar conjunctiva of the right eye was noted from 4 to 8 o'clock with accompanying forniceal shortening. Five months after the second excision, the patient developed flu-like symptoms with polyarthralgia. A full diagnostic workup revealed multiple pulmonary nodules on chest imaging, proteinuria on urinalysis, and a positive c-antineutrophil cytoplasmic antibody on serological studies. Based on these findings, the patient underwent a kidney biopsy which showed pauci-immune crescentic glomerulonephritis, consistent with a diagnosis of GPA. The patient achieved disease remission with rituximab. Despite treatment, the conjunctival lesion did not regress and remained unchanged in size for 3 years with periodic episodes of inflammation. CONCLUSIONS: This is the first documented case of a conjunctival mass as the initial presenting feature of pediatric GPA. The presence of granulomatous inflammation on histopathology and recurrences after excision should raise suspicion for GPA in children and adults.

Urinary proteome of dogs with renal disease secondary to leishmaniosis.

Canine leishmaniosis is frequently associated with the development of renal disease. Its pathogenesis is complex and not fully understood. For this reason, this study aimed to describe the urinary proteome, and identify possible new biomarkers in dogs with kidney disease secondary to leishmaniosis. Urine samples were collected from 20 dogs, 5 from healthy dogs, and 15 from stages Leishvet III and IV. Urine samples were analyzed by UHPLC-MS/MS. The data are available via ProteomeXchange with identifier PXD029165. A total of 951 proteins were obtained. After bioinformatic analysis, 93 urinary proteins were altered in the study group. Enrichment analysis performed on these proteins showed an overrepresentation of the complement activation pathway, among others. Finally, 12 discriminant variables were found in dogs with renal disease secondary to leishmaniosis, highlighting C4a anaphylatoxin, apolipoprotein A-I, haptoglobin, leucine-rich alpha-2-glycoprotein 1, and beta-2-microglobulin. This study is the first to describe the urinary proteomics of dogs with renal disease caused by leishmaniosis, and it provides new possible biomarkers for the diagnosis and monitoring of this disease.

Cysteine string protein-alpha prevents activity-dependent degeneration in GABAergic synapses.

The continuous release of neurotransmitter could be seen to place a persistent burden on presynaptic proteins, one that could compromise nerve terminal function. This supposition and the molecular mechanisms that might protect highly active synapses merit investigation. In hippocampal cultures from knock-out mice lacking the presynaptic cochaperone cysteine string protein-alpha (CSP-alpha), we observe progressive degeneration of highly active synaptotagmin 2 (Syt2)-expressing GABAergic synapses, but surprisingly not of glutamatergic terminals. In CSP-alpha knock-out mice, synaptic degeneration of basket cell terminals occurs in vivo in the presence of normal glutamatergic synapses onto dentate gyrus granule cells. Consistent with this, in hippocampal cultures from these mice, the frequency of miniature IPSCs, caused by spontaneous GABA release, progressively declines, whereas the frequency of miniature excitatory AMPA receptor-mediated currents (mEPSCs), caused by spontaneous release of glutamate, is normal. However, the mEPSC amplitude progressively decreases. Remarkably, long-term block of glutamatergic transmission in cultures lacking CSP-alpha substantially rescues Syt2-expressing GABAergic synapses from neurodegeneration. These findings demonstrate that elevated neural activity increases synapse vulnerability and that CSP-alpha is essential to maintain presynaptic function under a physiologically high-activity regimen.

Association of myocardial parasitic load with cardiac biomarkers and other selected variables in 10 dogs with advanced Canine Leishmaniasis.

BACKGROUND: The association between myocardial parasitic load (MPL) and cardiac biomarkers in Canine Leishmaniasis (CanL) has not been studied. METHODS: Dogs with advanced CanL were prospectively recruited and were included if they were euthanised. Prior to euthanasia these variables were assessed: hematocrit, globulin, creatinine, N-terminal-pro brain natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI), blood pressure, urine protein/creatinine ratio and echocardiographic parameters. A left ventricular (LV) sample was taken for histopathology and MPL evaluation by quantitative PCR. Correlation of MPL with all variables was analysed. Dogs with lower and higher histopathology scores were compared. RESULTS: Ten dogs were included. NT-proBNP was 6946 pmol/ (interquartile range [IQR] 3751-9268 pmol/L) and cTnI 4.56 ng/mL (IQR 0.46-13.1 ng/mL). In all dogs, echocardiography showed an increase in LV thickening, and histopathology revealed moderate to severe lympho-plasmocytic myocarditis and/or myocardial cell degeneration. MPL was 215.53 parasites/gram (IQR 21.2-1372.63 parasites/gram). A strong correlation (p < 0.001; R = 0.90; R2 0.81) with cTnI was observed but correlation with any of the other variables or differences between the two histopathological scores, were not detected. CONCLUSIONS: MPL in dogs with advanced CanL shows variable but generally high levels. A strong association between MPL and cTnI was observed, which encourages the exploration of cTnI as a marker in CanL.

Presynaptic dysfunction in Huntington's disease.

HD (Huntington's disease) is produced by the expression of mutant forms of the protein htt (huntingtin) containing a pathologically expanded poly-glutamine repeat. For unknown reasons, in HD patients and HD mouse models, neurons from the striatum and cerebral cortex degenerate and lead to motor dysfunction and dementia. Synaptic transmission in those neurons becomes progressively altered during the course of the disease. However, the relationship between synaptic dysfunction and neurodegeneration in HD is not yet clear. Are there early specific functional synaptic changes preceding symptoms and neurodegeneration? What is the role of those changes in neuronal damage? Recent experiments in a Drosophila model of HD have showed that abnormally increased neurotransmitter release might be a leading cause of neurodegeneration. In the present review, we summarize recently described synaptic alterations in HD animal models and discuss potential underlying molecular mechanisms.

Comparison of N-terminal proB-type natriuretic peptide levels at different stages of visceral leishmaniosis and in patients with chronic kidney disease.

N-terminal proB-type natriuretic peptide (NT-proBNP) may be a useful marker in canine leishmaniosis (CanL). The aim was to compare NT-proBNP in dogs at different LeishVet stages of CanL and with idiopathic chronic kidney disease (CKD). Dogs diagnosed with CanL or CKD and a group of healthy dogs were included (group A, five normal dogs; group B, six dogs LeishVet 1-2; group C, 13 dogs LeishVet 3-4; group D, six dogs with CKD). NT-proBNP was higher (P<0.001) in group C (7.616 pmol/l, interquartile range (IQR) 3537-10,000 pmol/l) than in group A (293 pmol/l, IQR 257-373), group B (388.5 pmol/l, IQR 324-793) and group D (740 pmol/l, IQR 557-962 pmol/l). International Renal Interest Society (IRIS) kidney stage was not different between groups C and D or between groups A and B, but was different within all the rest of the group comparisons (P<0.001). In group C all dogs had echocardiographic increase in left ventricular mass index. NT-proBNP had negative correlation with haematocrit (P<0.001, r=0.749) and positive correlation with systemic blood pressure (P<0.001, r=0.728). NT-proBNP is consistently elevated in dogs with advanced CanL and is strongly correlated with the degree of systemic hypertension and anaemia. Moreover, dogs with advanced CanL exhibit increase in left ventricular mass. NT-proBNP may however be a less desirable cardiac marker as unlike cardiac troponin I it is often not elevated at earlier stages of CanL.