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Background: Tau abnormalities are a central feature of Alzheimer's disease (AD) and the defining feature of non‐AD tauopathies, which include frontotemporal lobar degeneration (FTLD) due to Pick's disease (PiD) or Mapt mutations (FTLD‐tau), as well as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and others. Mapt transcripts undergo alternative splicing to produce 6 distinct isoforms. Exon 2 splicing produces 0, 1 or 2 inserts; exclusion or inclusion of exon 10 results in 3‐repeat (3R) or 4‐repeat (4R) forms, respectively. These forms are differentially present in tauopathies, e.g., 3R in PiD; 4R in almost all FTLD‐tau, PSP, and CBD; and equal 3R/4R in AD. 3R tau is reported to have lower microtubule binding affinity and a higher propensity to form soluble oligomers. Combining structural modeling of tau by AlphaFold 2 (AF2) with biochemical analyses may illuminate the impact of repeat and insert differences. While tau is considered generally disordered, AF2 modeling of 4R tau that we performed predicted a mainly ordered structure for the MTBR from Leu243 to Asp368. Biochemically, we found that the MTBR conformation is altered by some FTD associated mutations and caspase‐3 cleavage. In the present study, we studied the MTBR conformations for the 6 isoforms. Method: We first analyzed FASTA sequences of the tau isoforms by AF2 and aligned them based on the predicted MTBR conformations. We then compared intramolecular distances between selected MTBR residues. Result: Absence of the second repeat in 3R tau causes a dramatic difference in the MTBR conformation compared to 4R tau. Specifically, the inward fold N‐terminus to Pro301 is lost, thereby producing an "open" conformation (Figure, b vs a). The number of inserts does not affect the conformation of 4R tau (Figure, d vs. a) but significantly alters that of 3R tau (Figure, c vs. b). Conclusion: 3R tau's open MTBR conformation may explain its increased propensity to oligomerize and suggests the possibility of additional binding sites that may increase the interactome compared to 4R tau. The absence of the inward fold in 3R tau suggests that this region may be important for microtubule binding. [ABSTRACT FROM AUTHOR]

Background and Objectives Transfusion support for immune-mediated platelet refractoriness ( PR) is clinically challenging, technically laborious and costly. The development of 'Ep HLA/EpVix software' has been used successfully to select kidney donors. Here, we sought to evaluate this new software as a tool for platelet virtual crossmatch (VxM). Materials and Methods This is a prospective study from 2007 to 2014 of PR patients in a tertiary hospital. Platelet components selected by HLAMatchmaker program were crossmatched by Ep HLA/EpVix, anti-human globulin complement-dependent lymphocytotoxicity test ( AHG- CDC), flow cytometry platelet crossmatch ( FCxM) and then compared. Effectiveness of platelet components transfused was evaluated by CCI. Results Ninety-seven crossmatched platelet transfusions for 27 patients were enrolled. Partial matches were analysed for 75 transfusions by the 3 methods, and 22% showed discrepant results among the assays. After further analysis, data showed that all divergent cases could be explained by HPA alloimmunization, prozone effect ( FCxM), low sensitivity of AHG- CDC and possible interference in FCxM/ AHG- CDC assays. Notably, sensitivity and specificity of VxM analysis was excellent (100%). Satisfactory CCI counts were obtained for the majority (22/30) of the transfusions. Conclusion The new Ep HLA/EpVix method showed to be effective, feasible and fast for VxM at no cost and able to minimize labour on donor identification. However, platelet crossmatching may be a necessary step because Ep HLA/EpVix does not formally exclude HPA alloimmunization. [ABSTRACT FROM AUTHOR]

The frequency of Neospora spp., Leptospira spp. and Brucella abortus infections in adult cattle was determined in herds of the State of Pará, Brazil, which is an important region for cattle production located in the Amazon region. A total of 3466 adult female cattle from 176 herds were tested, leading to a frequency of seropositive animals of 14.7%, 3.7% and 65.5% and a herd positivity of 87.4%, 41.3% and 98.8% for infections caused by Neospora spp., B. abortus and Leptospira spp., respectively. The five most frequently diagnosed serologic responses to Leptospira spp. were those against serovars hardjo, wolfii, grippotyphosa, hebdomadis and shermani. The following associations were found: practice of artificial insemination, large farm size, large herd size, large number of dogs and high number of total abortions per year with the presence of antibodies against serovar hardjo; positive results to serovar grippotyphosa with the presence of dogs; inappropriate disposal of aborted foetuses with positivity to serovar hebdomadis. Serovar grippotyphosa was also associated with number of episodes of abortions. Neospora spp. positive herds were associated with episodes of abortion and B. abortus infection with the disposal of dead animals and aborted foetuses on pastures and with the use of artificial insemination. In conclusion, the high frequency of brucellosis, leptospirosis and neosporosis in the region may be a consequence of social, natural and raising conditions as: (i) climate conditions that favour the survival and spread of pathogens in the environment; (ii) farms located in regions bordering forest areas; (iii) farms in areas of difficult access to the veterinary service; (iv) extensive beef herds raised at pastures with different age and productive groups inter-mingled; and (v) minimal concerns regarding hygiene practices and disease prevention measures. [ABSTRACT FROM AUTHOR]

Background Asthma is a highly prevalent chronic inflammatory disease characterised by reversible airflow obstruction and hyperreactivity and inflammation of the airways. Factors that cause and/or trigger asthma attacks include host-related factors (genetic predisposition, obesity and sex) and environmental factors (allergens, infections, occupational sensitisation, smoking status, pollution and diet). Objective To describe the epidemiology of asthma exacerbations (AEs) in the Basque Country and to explore its relationship with potentially associated environmental variables. We studied a total of 31 579 emergency department (ED) visits and 28 189 hospitalisations due to asthma. We describe the trends, incidence, seasonality and the influence of age and sex, as well as of exposure to NO2, CO, PM, O3, and pollen, temperature, relative humidity and flu status. We calculated the Pearson0s R correlation coefficient for the study variables. Results The incidence was 486 and 88.9 cases per 100 000 people for ED visits and hospitalisations, respectively. Slightly over half (53.5%) of the ED cases were male, while females represented 62.6% of the hospital admissions. Hospitalisations are tending to decrease in children and increase in over 64-year-olds. Peaks in cases occur at the beginning of autumn in children and in winter in adults. AEs were correlated positively with exposure to NO2, CO and to the influenza virus and negatively with temperature and exposure to O3. These relationships vary, however, with age and season. Conclusions and Clinical Relevance Rates of hospitalisation for AEs and trends in these rates over time are different in adults and children with the patterns varying by sex, season and environmental conditions. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the prevalence and to identify the risk factors associated with Leptospira spp. infection in technified pig farms in the state of Alagoas, Brazil. To compose sample for the prevalence study, 342 pigs were used (312 sows and 30 boars) proceeding from seven swine farms distributed in five districts of the state of Alagoas, Brazil. The infection's serological diagnosis was performed by microscopic agglutination test. The risk factors analysis was performed using research questionnaires consisting of objective questions related to the breeder, the general characteristics of the property, and the productive, reproductive and sanitary management. Prevalence of 16.1% (55/342) of pigs seropositive was obtained. The associated risk factors were not performing quarantine ( P = 0.003, OR = 5.43, CI = 1.79-16.41) and the use of artificial insemination ( P = 0.023, OR = 3.38, CI = 1.18-9.66). A significant association of sow infection with the increased number of stillborn and mummified foetuses was found, as well as with the increased frequency of oestrus recurrence and the increased weaning-to-oestrus interval of seropositive sows. One might state that Leptospira spp. infection is disseminated in technified pig farms in the State of Alagoas, favouring reproductive failures and the impairment of zootechnical performance in these properties. The risk factors identified in this study are facilitators in the infecting agent dissemination and should be adjusted to control the disease in the herds studied. [ABSTRACT FROM AUTHOR]

The lipid-lowering agent pravastatin and the antidepressant paroxetine are among the most widely prescribed drugs in the world. Unexpected interactions between them could have important public health implications. We mined the US Food and Drug Administration's (FDA's) Adverse Event Reporting System (AERS) for side-effect profiles involving glucose homeostasis and found a surprisingly strong signal for comedication with pravastatin and paroxetine. We retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received comedication with these two drugs, using data in electronic medical record (EMR) systems of three geographically distinct sites. We assessed the mean random blood glucose levels before and after treatment with the drugs. We found that pravastatin and paroxetine, when administered together, had a synergistic effect on blood glucose. The average increase was 19 mg/dl (1.0 mmol/l) overall, and in those with diabetes it was 48 mg/dl (2.7 mmol/l). In contrast, neither drug administered singly was associated with such changes in glucose levels. An increase in glucose levels is not a general effect of combined therapy with selective serotonin reuptake inhibitors (SSRIs) and statins. [ABSTRACT FROM AUTHOR]

We report a new and efficient methodology of labelling red blood cells, in order to investigate the expression of anti-A antigen, employing luminescent semiconductor nanocrystals. Highly luminescent and stable core-shell cadmium sulphide/cadmium hydroxide [CdS/CdS(OH)2] colloidal particles were obtained in the nanometre size range. The surface of these particles was characterized by using a monoclonal anti-A antibody via a one-step glutaraldehyde cross-linking procedure, followed by conjugation of the particles to red cells of blood groups A+, and O+. Laser scanning confocal microscopy images indicated that after conjugation for 30 min, A+ and erythrocytes presented different patterns of dual bright emission whereas the O+ group cells showed no emission. We suggest that this labelling procedure may be applied as a quantitative tool to investigate the distribution and expression of alloantigen in red blood cells. [ABSTRACT FROM AUTHOR]

Polymorphisms of platelet membrane glycoproteins such as human platelet antigen (HPA)-1b, HPA-2b, the -5T/C Kozak sequence and C807T have been described as risk factors for vascular disease. Vaso-occlusion episodes are a common feature of sickle cell anaemia (SCA), leading to complications such as stroke, acute chest syndrome, avascular head femur necrosis and priapism. Complex interactions are involved in vaso-occlusion, and activated platelets may play an important role. These data raised the question of whether platelet polymorphisms could be implicated in occlusive vascular complications (OVC) of SCA.In this study, 97 patients with SCA were analysed in two groups: 34 patients presenting with OVC (SCA-VC) and 63 without these complications (SCA-N). The distribution of the HPA-1, -2 and -5 systems, as well as C807T dimorphism and -5T/C Kozak sequence alleles, was evaluated using DNA-based methods.Patients of the SCA-VC group showed a higher frequency of the HPA-5b allele (0·324) compared with those of the SCA-N group (0·111) (χ2 = 13·19,P = 0·0002). None of the other polymorphisms, isolated or associated as haplotypes, demonstrated any correlation with the development of OVC in these patients.The findings of this study suggest that the HPA-5b allele is a genetic risk factor for the development of OVC in patients with SCA. This allele could be explored as a target for the development of new therapeutic approaches. [ABSTRACT FROM AUTHOR]

AbstractThe human platelet antigen (HPA) systems are related to immune platelet disorders as well as to the development of occlusive vascular disease. Several distinct biallelic HPA systems are known, and a heterogeneous distribution of HPA alleles has been described among distinct ethnic groups. In this study we genotyped 320 carefully selected individuals from three distinct ethnic groups in Brazil (Caucasians, Blacks and Amazonian Indians) for the HPA-1, -2, -3, -4 and -5 systems. A similar prevalence for all HPA alleles was found in Brazilians of Caucasian and Black descent. These data contrast with those reported for similar ethnic groups in other countries. Among the Amazonian Indians, no b allele of the HPA-1, -4 and -5 systems was identified. The data presented here could be useful in the diagnosis of alloimmune platelet disease, in genetic counselling and in the development of screening programmes for HPA-related diseases. [ABSTRACT FROM AUTHOR]

The preparation and identification of four types of SO-sulfonated products of 1-alkenes are described.C and, to a lesser extent,H nuclear magnetic resonance spectra are used to ascertain the structures of 2-alkenesulfonic acids, β-sultones (as 2-methoxyalkanesulfonic acids), γ- and δ-sultones. The mass spectra of some methyl 2-methoxyalkanesulfonates and 4-alkyl-δ-sultones are also studied. Sufficiently volatile mixtures are separated by gas liquid chromatography after methylation of the sulfonic groups. [ABSTRACT FROM AUTHOR]

The effects of long-term administration of sub-convulsive doses of aldrin, an organochlorinated pesticide, on seizure susceptibility of rats were studied. Results show that treatment with the pesticide made the rats more susceptible to sound-induced seizures; an increment in post-seizure depression time after maximal electroschock administration was also observed in aldrin-treated animals. Aldrin administration displaced the control dose-response curves constructed for amphetamine and pentylenetetrazol to the left and right, respectively; no differences were detected between control and aldrin-treated rats for strychnine, picrotoxin or 3-mercaptopropionic acid. The results, discussed in the light of the effects of aldrin on biogenic amines or on the electrophysiology of neurones suggested an involvement of both noradrenergic and alteration excitability of the CNS with the observed increments on seizure susceptibility. [ABSTRACT FROM AUTHOR]

Summary. Haemolysis caused by passive ABO antibodies is a rare transfusional complication. We report a case of severe haemolytic reaction in a 38-year-old man (blood group A) with lymphoma who had received one red blood cell (RBC) unit group O. After transfusion of 270 mL, the patient experienced fever, dyspnoea, chills and back pain. On the following morning he was icteric and pale. Haptoglobin was inferior to 5.8 mg dL-1 , haemoglobin was not increased and lactate dehydrogenase was elevated. Haemolysis was evident on observation of the patient's post-transfusion samples. The recipient's red cells developed a positive direct antiglobulin test and Lui elution showed anti-A coated the cells. Fresh donor serum had an anti-A titre of 1024, which was not reduced by treating the serum with dithiothreitol. Donor isoagglutinin screening has been determined by microplate automated analyser and showed titre higher than 100. Physicians should be aware of the risk of haemolysis associated with ABO-passive antibodies. There is generally no agreement justifying the isoagglutinin investigation prior to transfusion. However, automated quantitative isoagglutinin determination could be part of the modern donor testing process, mainly in blood banks where identical ABO group units (platelets or phenotyped RBCs) are not available owing to limited supply. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study on the frequency of platelet antigen Cab's polymorphism among Brazilians which shows the absence of Cab allele among Brazilian respondents.

In the present work, we addressed the relationship between parental leave policies and social norms. Using a pre-registered, cross-national approach, we examined the relationship between parental leave policies and the perception of social norms for the gender division of childcare. In this study, 19,259 students (11,924 women) from 48 countries indicated the degree to which they believe childcare is (descriptive norm) and should be (prescriptive norm) equally divided among mothers and fathers. Policies were primarily operationalized as the existence of parental leave options in the respective country. The descriptive and prescriptive norms of equal division of childcare were stronger when parental leave was available in a country - also when controlling for potential confounding variables. Moreover, analyses of time since policy change suggested that policy change may initially affect prescriptive norms and then descriptive norms at a later point. However, due to the cross-sectional nature of the data, drawing causal inferences is difficult., (© 2024 British Psychological Society.)

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) affects cross-talk between the individual cell types of the neurovascular unit, which then contributes to disruption of the blood-brain barrier (BBB) and the development of neurological dysfunctions. Although the toxicity of HIV-1 on neurons, astrocytes and brain endothelial cells has been widely studied, there are no reports addressing the influence of HIV-1 on pericytes. Therefore, the purpose of this study was to evaluate whether or not pericytes can be infected with HIV-1 and how such an infection affects the barrier function of brain endothelial cells. Our results indicate that human brain pericytes express the major HIV-1 receptor CD4 and co-receptors CXCR4 and CCR5. We also determined that HIV-1 can replicate, although at a low level, in human brain pericytes as detected by HIV-1 p24 ELISA. Pericytes were susceptible to infection with both the X4-tropic NL4-3 and R5-tropic JR-CSF HIV-1 strains. Moreover, HIV-1 infection of pericytes resulted in compromised integrity of an in vitro model of the BBB. These findings indicate that human brain pericytes can be infected with HIV-1 and suggest that infected pericytes are involved in the progression of HIV-1-induced CNS damage., (© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Organochalcogens are extensively produced and employed by industry and agriculture, and the risk of occupational and environmental toxicity to them has been poorly understood. Here, we investigated the acute effect of a new organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on biochemical and hematological parameters in male Wistar rats. The animals were treated with a single intraperitoneal injection of the organochalcogen at doses of 125, 250 or 500 µg·kg(-1). After 60 min, the animals were sacrificed by decapitation, and the trunk blood was collected for determination of glucose, triglycerides, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase, lactate dehydrogenase, urea, creatinine, C-reactive protein, red blood cells, hematocrit, hemoglobin and white blood cells (WBC). Our results showed a reduction in cholesterol levels in all treated groups, an increase in ALT activity at doses of 250 and 500 µg·kg(-1), a decrease of hemoglobin and an increase in WBC in animals that received 250 and 500 µg·kg(-1) of the organoselenium. In addition, we observed an increase in neutrophil counts at 125 µg·kg(-1) dose and a decrease at 500 µg·kg(-1) dose. We also verified an increase in lymphocyte counts at the dose of 500 µg·kg(-1). Thus, the present study shows that the acute treatment with this new organochalcogen causes biochemical changes and hematological disorders in male rats., (Copyright © 2012 John Wiley & Sons, Ltd.)

Hemophilia B is a genetic disease of the coagulation system that affects one in 30,000 males worldwide. Recombinant human Factor IX (rhFIX) has been used for hemophilia B treatment, but the amount of active protein generated by these systems is inefficient, resulting in a high-cost production of rhFIX. In this study, we developed an alternative for rhFIX production. We used a retrovirus system to obtain two recombinant cell lines. We first tested rhFIX production in the human embryonic kidney 293 cells (293). Next, we tested a hepatic cell line (HepG2) because FIX is primarily expressed in the liver. Our results reveal that intracellular rhFIX expression was more efficient in HepG2/rhFIX (46%) than in 293/rhFIX (21%). The activated partial thromboplastin time test showed that HepG2/rhFIX expressed biologically active rhFIX 1.5 times higher than 293/rhFIX (P = 0.016). Recovery of rhFIX from the HepG2 by reversed-phase chromatography was straightforward. We found that rhFIX has a pharmacokinetic profile similar to that of FIX purified from human plasma when tested in hemophilic B model. HepG2/rhFIX cell line produced the highest levels of rhFIX, representing an efficient in vitro expression system. This work opens up the possibility of significantly reducing the costs of rhFIX production, with implications for expanding hemophilia B treatment in developing countries., (Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.)

Platelet membrane glycoprotein (GP) Ibalpha is a critical component of platelet adhesion complex to subendothelium structures following tissue injury or pathological surfaces, such as atherosclerotic plaques. Polymorphisms of the GPIbalpha gene have been associated with a high risk for occlusive vascular disease, and its distribution varies considerably among distinct populations. These polymorphisms comprise the human platelet antigen (HPA)-2 system, the -5C/T dimorphism of the Kozak sequence, and the variable number of tandem 39-bp repeats (VNTR). Here we report the prevalence of the GPIbalpha gene polymorphisms among Brazilians, a highly ethnically diverse population. We analyzed 492 subjects of European, African, or Indigenous origin. It was possible to determine ten distinct haplotypes. The most common ( reverse similar 40%) haplotype was the Kozak-TT/HPA-2aa/VNTR-CC for both Caucasian and African descent. However, among Indigenous, Kozak-TT/HPA-2aa/VNTR-CC and Kozak-TC/HPA-2aa/VNTR-CC were equally present. Although a strong linkage disequilibrium between VNTR and HPA-2 polymorphism had also been observed, here we determined incomplete linkage disequilibrium in 10% of subjects from all ethnic groups. VNTR-E, a rare variant lacking the 39-bp repeat, was identified in two unrelated subjects, and functional platelet studies revealed no abnormalities. The VNTR-A allele, the largest variant containing four copies of the repeats, was not identified in this population. However, homozygosity for the VNTR-A allele (Kozak-TT/HPA-2aa/VNTR-AA) was determined in two distinct species of nonhuman primates. These results suggest a greater complex evolutionary mechanism in the macroglycoprotein region of the GPIbalpha gene and may be useful in the design of gene-disease association studies for vascular disease., (Copyright 2004 Wiley-Liss, Inc.)