GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia.

Gamma aminobutyric acid (GABA) is a critical inhibitory neurotransmitter in the central nervous system that plays a vital role in modulating neuronal excitability. Dysregulation of GABAergic signaling, particularly involving the cotransporters NKCC1 and KCC2, has been implicated in various pathologies, including epilepsy, schizophrenia, autism spectrum disorder, Down syndrome, and ischemia. NKCC1 facilitates chloride influx, whereas KCC2 mediates chloride efflux via potassium gradient. Altered expression and function of these cotransporters have been associated with excitotoxicity, inflammation, and cellular death in ischemic events characterized by reduced cerebral blood flow, leading to compromised tissue metabolism and subsequent cell death. NKCC1 inhibition has emerged as a potential therapeutic approach to attenuate intracellular chloride accumulation and mitigate neuronal damage during ischemic events. Similarly, targeting KCC2, which regulates chloride efflux, holds promise for improving outcomes and reducing neuronal damage under ischemic conditions. This review emphasizes the critical roles of GABA, NKCC1, and KCC2 in ischemic pathologies and their potential as therapeutic targets. Inhibiting or modulating the activity of these cotransporters represents a promising strategy for reducing neuronal damage, preventing excitotoxicity, and improving neurological outcomes following ischemic events. Furthermore, exploring the interactions between natural compounds and NKCC1/KCC2 provides additional avenues for potential therapeutic interventions for ischemic injury.

The characterization of Bordetella pertussis strains isolated in the Central-Western region of Brazil suggests the selection of a specific genetic profile during 2012-2014 outbreaks.

Pertussis is a worldwide acute respiratory disease caused by the bacterium Bordetella pertussis. Despite high vaccine coverage, the bacterium continues to circulate in populations and is still one of the most common vaccine-preventable diseases. In Brazil, pertussis incidence has presented a significant decrease since 1990 but since 2011 a sudden increase in incidence has been observed. Thus, the aim of this study was to perform a molecular epidemiological characterization of B. pertussis strains isolated in the Central-Western region (specifically in Distrito Federal) of Brazil from August 2012 to August 2014. During this period, 92 B. pertussis strains were isolated from the outbreaks. All strains were characterized by serotyping and XbaI pulsed-field gel electrophoresis profiles. From August to December 2012, the most prevalent serotype observed was 1,3 (13/17). During 2013 the prevalence of serotype 1,3 decreased (13/30) and from January 2014 to August 2014 the most prevalent serotype was 1,2 (33/45). Fourteen PFGE profiles were identified. Of these, BP-XbaI0039 prevalence increased from 3/17 in 2012 to 10/30 in 2013, and 35/45 in 2014. These results evidence the selection of a specific genetic profile during this period, suggesting the occurrence of a bacterial genomic profile with high circulation potential.

A multivalent chimeric vaccine composed of Schistosoma mansoni SmTSP-2 and Sm29 was able to induce protection against infection in mice.

Schistosoma mansoni is a blood fluke parasite responsible for schistosomiasis. The best long-term strategy to control schistosomiasis is through immunization combined with drug treatment. In this study, we cloned, expressed and purified SmTSP-2 fused to the N- and C-terminal halves of Sm29 and tested these chimeras as vaccine candidates using an adjuvant approved to be used in humans. The results demonstrated that vaccination with SmTSP-2 fused to N- or C-terminus of Sm29-induced reduction in worm burden and liver pathology when compared to control animals. Additionally, we detected high levels of mouse-specific IgG, IgG1 and IgG2a against both chimeras and significant amounts of IFN-γ and TNF-α and no IL-4. Finally, studies with sera from patients resistant to infection and living in schistosomiasis endemic areas revealed high levels of specific IgG to both chimeras when compared to healthy individuals. In conclusion, SmTSP-2/Sm29 chimeras tested here induced partial protection against infection and might be a potential vaccine candidate.

Cloning and functional expression of the mitochondrial alternative oxidase of Aspergillus fumigatus and its induction by oxidative stress.

Aspergillus fumigatus possesses a branched mitochondrial electron transport chain, with both cyanide-sensitive and -insensitive oxygen-consumption activities. Mitochondrial reactive oxygen species mediate signaling for alternative oxidase (AOX) expression. A 1173 bp-long Afaox gene encoding a 40 kDa protein has been cloned and identified. Recombinant constructs containing the Afaox ORF were transformed into Escherichia coli and Saccharomyces cerevisiae for heterologous expression. In A. fumigatus, AOX activity and mRNA expression were both induced with menadione or paraquat, suggesting an important role of AOX under oxidative stress. Therefore, positive transformants showed a cyanide-resistant and salicylhydroxamic acid-sensitive respiration, whereas in control cells the oxygen uptake was completely inhibited after KCN addition.

A PMR1-like calcium ATPase of Aspergillus fumigatus: cloning, identification and functional expression in S. cerevisiae.

The understanding of the controlling factors of calcium homeostasis in Aspergillus fumigatus is very poor, although this ion is involved in several important events of these particular cells. We have cloned, identified and expressed for functional complementation a PMR1-like Ca(2+)-ATPase gene from A. fumigatus. The Afpmr1 gene encodes a protein of 1061 deduced amino acids, containing all the conserved subdomains found in other P-type ATPases: the phosphatase region, phosphorylation site, FITC labelling site, ATP binding domain; E(386), N871, D875 amino acid residues for calcium ion interaction and Q880, a residue that alters ion selectivity in PMR1. The expressed AfPMR1 in S. cerevisiae K616 strain functionally complemented the deficient growth in EGTA (5-20 mM)- and MnCl2 (4 mM)-containing medium. These results demonstrate the first evidence of a Ca(2+)-ATPase in A. fumigatus and strongly suggest a role for this enzyme in calcium and manganese homeostasis.

[The implantation of VDD pacemakers with a single electrode--a comparative study. The experience of the last 5 years]. / Implantação de pacemakers VDD com um único eléctrodo--estudo comparativo. Experiência dos últimos cinco anos.

OBJECTIVE: To compare the epidemiological characteristics and immediate results of all first single lead VDD pacemaker (PM) implantations with those of an equal number of dual chamber DDD PM, implanted during a 5-year period in a tertiary-care hospital. POPULATION AND METHODS: A total of 41 patients (pts) (25 males, mean age of 69.0 +/- 11.8 years) underwent a VDD PM implantation, from 30-11-92 to 15-9-97. This group was compared with an equal number of patients (28 males, mean age of 69.9 +/- 7.31 years) with a DDD PM implanted in the same period, selected by a criterion of immediate temporal proximity of procedure. For each patient we collected the clinical and electrocardiographic (ECG) indications for PM implantation, parameters of atrial (AS) and ventricular (VS) sensing and ventricular pacing (VP), X-ray exposure time (XRT) and complications. RESULTS: In the VDD group, 46.3% of the patients had syncope, 51.2% had complete AV block on the ECG, and 14.6% were PM-dependent. Analyzed procedure-related parameters were as follows: P-wave amplitude: 2.1 +/- 0.6 V; AS threshold: 1.2 +/- 0.7 V; R-wave amplitude: 9.1 +/- 3.3 V; VS threshold: 7.0 +/- 2.0 V; VP thresholds: 0.68 +/- 0.24 mA, 0.43 +/- 0.12 V (for a spike duration of 0.5 ms); ventricular impedance: 644.9 +/- 132.0 ohm; XRT; 7' 43" +/- 8' 23". There were two minor complications, for an incidence of 4.9% (one local hematoma and a vagal reaction). In the DDD group the clinical and ECG characteristics were similar, but there was a 22.0% prevalence of sinus-node dysfunction, VS 0% in the VDD group). The P-wave amplitude and AS threshold were significantly (p < 0.005) better (2.8 +/- 0.9 V and 2.8 +/- 0.9 V respectively). The other parameters were similar to those of the VDD group. CONCLUSIONS: The immediate results of VDD PM implantation are good and comparable with those of DDD PM, although with worse acute AS parameters.

[Acute myocardial infarct in infants]. / Enfarte agudo do miocárdio na criança.

A retrospective study was made of 6 children, with nonsurgical-related acute myocardial infarction (AMI), between January 1987 and December 1994. The ratio for gender was 1 and mean age at AMI was 49 days, 4 cases being associated with congenital heart disease (Fallot's tetralogy, truncus arteriosus and DiGeorge syndrome, one case each, and anomalous origin of left coronary artery, 2 cases). Kawasaki disease and coronary embolisation from thrombosis of the renal vein occurred in the other 2 cases respectively. All developed congestive cardiac failure and cardiomegaly. In the ECG pathologic q waves with more than 35 msec occurred in all, and QT prolongation occurred in 3. Five children (83%) all with AMI in the anterior and lateral wall of the left ventricle died, death being related with cardiac mechanical failure and not with arrhythmias.