BACKGROUND: Ultrabrief stimulation in electroconvulsive therapy (ECT) using a 0.25 or 0.30 ms pulse width markedly reduces the charge required to reach the seizure threshold (ST) and cognitive side effects. It is not known whether further reduction of pulse width to 0.15 ms is advantageous. METHODS: Thirty-seven patients were randomized to ST titration at the first session applying right unilateral (RUL) ECT with either a 0.15 or 0.30 ms pulse width and were titrated again in the second session using the alternative pulse width. All subsequent treatments used the pulse width applied in the second titration session, administering RUL ECT, starting at 6xST. The primary outcome was difference between the pulse widths in ST at the two titration sessions. Exploratory analyses examined differences in seizure duration and postictal time to recover orientation (TRO), averaged across all ECT sessions from the third onwards. Other exploratory analyses examined clinical improvement and retrograde amnesia for autobiographical information and other neuropsychological functions following the ECT course. RESULTS: In the first titration session, ST was significantly lower with the 0.15 ms than 0.30 ms pulse width. ST significantly increased when re-titrating with the 0.30 ms pulse width and significantly decreased when re-titrating with a 0.15 ms pulse width. There were no differences between the pulse width groups in clinical improvement, TRO, or neuropsychological measures. CONCLUSIONS: Ultra-ultrabrief stimulation with a 0.15 ms pulse width is more efficient in seizure induction than a 0.30 ms pulse width. Comprehensive studies should determine whether ultra-ultrabrief stimulation replaces ultrabrief stimulation as a default parameter for ECT.
- MeSH
- Adult MeSH
- Electroconvulsive Therapy * methods adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Seizures therapy MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
Genetic variations in protein expression are implicated in a broad spectrum of common diseases and complex traits but remain less explored compared to mRNA and classical phenotypes. This study systematically analyzed brain proteomes in a rat family using tandem mass tag (TMT)-based quantitative mass spectrometry. We quantified 8,119 proteins across two parental strains (SHR/Olalpcv and BN-Lx/Cub) and 29 HXB/BXH recombinant inbred (RI) strains, identifying 597 proteins with differential expression and 464 proteins linked to cis-acting quantitative trait loci (pQTLs). Proteogenomics identified 95 variant peptides, and sex-specific analyses revealed both shared and distinct cis-pQTLs. We improved the ability to pinpoint candidate genes underlying pQTLs by utilizing the rat pangenome and explored the connections between pQTLs in rats and human disorders. Collectively, this study highlights the value of large proteo-genetic datasets in elucidating protein modulation in the brain and its links to complex central nervous system (CNS) traits.
- Publication type
- Journal Article MeSH
BACKGROUND: The pathophysiology of sepsis-induced acute kidney injury remains elusive. Although mitochondrial dysfunction is often perceived as the main culprit, data from preclinical models yielded conflicting results so far. The aim of this study was to assess the immune-metabolic background of sepsis-associated renal dysfunction using sequential biopsy approach with mitochondria function evaluation in a large clinically relevant porcine models mimicking two different paces and severity of sepsis and couple this approach with traditional parameters of renal physiology. METHODS: In this randomized, open-label study, 15 anaesthetized, mechanically ventilated and instrumented (renal artery flow probe and renal vein catheter) pigs were randomized in two disease severity groups-low severity (LS) sepsis (0.5 g/kg of autologous faeces intraperitoneally) and high severity (HS) sepsis (1 g/kg of autologous faeces intraperitoneally). Sequential cortical biopsies of the left kidney were performed and a pyramid-shaped kidney specimen with cortex, medulla and renal papilla was resected and processed at the end of the experiment. Oxygraphic data and western blot analysis of proteins involved in mitochondrial biogenesis and degradation were obtained. RESULTS: In contrast to increased mitochondrial activity observed in LS sepsis, a significant decrease in the oxidative phosphorylation capacity together with an increase in the respiratory system uncoupling was observed during the first 24 h after sepsis induction in the HS group. Those changes preceded alterations of renal haemodynamics. Furthermore, serum creatinine rose significantly during the first 24 h, indicating that renal dysfunction is not primarily driven by haemodynamic changes. Compared to cortex, renal medulla had significantly lower oxidative phosphorylation capacity and electron-transport system activity. PGC-1-alfa, a marker of mitochondrial biogenesis, was significantly decreased in HS group. CONCLUSIONS: In this experimental model, unique sequential tissue data show that the nature and dynamics of renal mitochondrial responses to sepsis are profoundly determined by the severity of infectious challenge and resulting magnitude of inflammatory insult. High disease severity is associated with early and stepwise progression of mitochondria dysfunction and acute kidney injury, both occurring independently from later renal macro-haemodynamic alterations. Our data may help explain the conflicting results of preclinical studies and suggest that sepsis encompasses a very broad spectrum of sepsis-induced acute kidney injury endotypes.
- Publication type
- Journal Article MeSH
INTRODUCTION: This study investigates the antecedents of perceived teacher work ability, a critical construct for addressing challenges associated with extending working lives and maintaining sustained professional engagement in the teaching profession. Grounded in the job demands-resources (JD-R) model, this cross-sectional study investigates the relationships between job demands (quantitative, cognitive, and emotional), job resources (supervisor support, coworker support, and autonomy), burnout, and work-life conflict in shaping perceived teacher work ability. METHODS: Data were obtained from 841 Czech primary and lower secondary school teachers (86.1% female) with a mean age of 45.9 years (SD = 10.8). The full SEM model was developed and estimated based on the proposed hypotheses. RESULTS: The findings suggest that burnout is the most significant antecedent of perceived teacher work ability, with quantitative and emotional job demands indirectly influencing it through burnout. While supervisor and coworker support directly enhance perceived teacher work ability, autonomy primarily alleviates quantitative and emotional job demands, thereby indirectly mitigating burnout. Work-life conflict partially mediates the relationship between job demands and burnout but does not directly impact perceived teacher work ability. DISCUSSION: These results contribute to a deeper understanding of the interplay between job demands, job resources, and burnout in enhancing teachers' capacity to meet the multifaceted demands of their profession effectively.
- Publication type
- Journal Article MeSH
Impaired awareness of hypoglycemia remains an issue even in the era of modern technologies, as patients with type 1 diabetes (T1DM) face stricter requirements for glycemic targets. The evaluation of hypoglycemia awareness can be accomplished using questionnaires (Clarke and Gold scores) in combination with clinical appearance and sensor data. A 45-year-old man with T1DM was referred to our clinic in July 2019 due to impaired hypoglycemia awareness and repeated severe hypoglycemic episodes resulting in unconsciousness. At that time, he was driving both a car and a motorcycle. Despite good compliance, increased target values and implementation of continuous glucose monitoring (CGM) with alarms, prolonged hypoglycemias were not eliminated. Therefore, the patient was referred for pancreatic islet transplantation, but he decided not to undergo. In May 2021, his driving license was suspended, which eventually led him to accept treatment with a hybrid closed-loop insulin pump (AID). Shortly after initiation, he achieved satisfactory glycemic control, reduced time spent in hypoglycemia, and had no severe hypoglycemic episodes. According to the questionnaires, the hypoglycemia awareness has improved and his driving license was reinstated. This case study highlights the critical importance of identifying impaired awareness of hypoglycemia, its potential social impacts, and the opportunities for using new technologies to reverse this complication.
- Publication type
- Journal Article MeSH
- Case Reports MeSH
BACKGROUND: The Swedish Family-Cancer Database (FCD) is the largest source of data on familial cancer in the world, including practically complete family structures and individual cancer diagnoses from the high-quality cancer registry. We present a novel application of FCD by analyzing age-specific familial risks and interpreting them through likely causes, such as germline pathogenic variants and/or environmental exposures. MAIN BODY: The basic assumption for this approach is that a discrete familial clustering in a narrow age-interval is not random but may provide causal clues. For this analysis we selected reasonably common cancers to meaningfully scrutinize familial risk through adulthood in which cancers are diagnosed, that included colorectal (CRC) and endometrial cancers, prostate and kidney cancers and breast and lung cancers. The interpretation is based on the literature. The highest familial relative risks for CRC and endometrial cancers were found at ages 40-44 years, matching the peak impact of mismatch repair gene mutations. However endometrial cancer showed also a small early onset component which could not be explained. Age-related familial risks for breast, prostate and kidney cancers also matched data from large-scale sequencing; these included the early onset component in kidney cancer which was likely due to VHL mutations. Age distribution of familial lung cancer was unique in showing a wide peak extending from middle to old ages, which would be consistent with a combination of direct genetic effects and indirect influence on inheritance of smoking dependence. CONCLUSIONS: The present review of age-specific familial risks and age-of-onset data from the literature may allow an interpretation that the familial and germline landscapes are reasonably harmonious for relatively early onset cancers but at higher ages no discrete peaks can be found which may implicate attenuated impact of high-risk genes and polygenic influence.
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND: Preventing type 2 diabetes during humanitarian crises is under-researched. In Venezuela, a third of adults have prediabetes amid a prolonged crisis. AIM: This study assessed the effectiveness of an intensive weight reduction strategy aimed at achieving a 7% weight loss in Venezuelan individuals with elevated risk of type 2 diabetes. METHODS: A six-month pilot randomized clinical trial was conducted at a Community Health Center. Participants were assigned to the Diabetes Prevention Program (DPP) or a low-calorie liquid diet followed by DPP (LD-DPP). The LD-DPP group underwent a two-month liquid diet, followed by food reintroduction and DPP content. The DPP group received a transculturally adapted Group Lifestyle Balance curriculum through 16 group sessions. Both Intention to Treat and Per-Protocol analyses with Inverse Probability Weighting were conducted. RESULTS: Of 127 adults (64 LD-DPP, 63 DPP), 70 (55.1%) completed the intervention. In the ITT analysis, 32.9% achieved the 7% weight loss goal, significantly higher in the LD-DPP arm (54.8%) compared to DPP (15.4%). CONCLUSION: Initiating the DPP with intensive low-calorie restriction led to greater weight loss and improved chances of meeting weight loss goals during a humanitarian crisis.
- MeSH
- Diabetes Mellitus, Type 2 * prevention & control diet therapy epidemiology MeSH
- Adult MeSH
- Weight Loss * physiology MeSH
- Caloric Restriction * methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Obesity prevention & control diet therapy MeSH
- Pilot Projects MeSH
- Prediabetic State diet therapy therapy MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Pragmatic Clinical Trial MeSH
- Randomized Controlled Trial MeSH
- Geographicals
- Venezuela MeSH
Accumulation of misfolded α-synuclein (α-Syn) leads to the formation of Lewy bodies and is a major hallmark of Parkinson's disease (PD). The accumulation of α-Syn involves several post-translational modifications. Recently, though, glycation of α-Syn (advanced glycation end products) and activation of the receptor for advanced glycation end products (RAGE) have been linked to neuroinflammation, which leads to oxidative stress and accumulation of α-Syn. The present study aims to detect the effect of glycated α-Syn (gly-α-Syn)-induced synucleinopathy and loss of dopaminergic (DAergic) neurons in the development of PD. We isolated, purified, and prepared glycated recombinant human α-Syn using d-ribose. Gly-α-Syn was characterized by SDS-PAGE, intact mass analysis, and bottom-up peptide sequence through LC-HRMS/MS. The aggregation propensity of gly-α-Syn has been verified by morphological and shape analysis through Bio-AFM. The gly-α-Syn (2 μg/μL) was injected stereotaxically in the substantia nigra (SN) of ICR mice (3-4 months) and compared with the normal α-Syn, d ribose, and Tris-HCl/artificial CSF groups. 56 days postsurgery (DPS), an immunohistochemical examination was conducted to investigate gly-α-Syn-induced α-Syn accumulation, neuroinflammation, and neurodegeneration. The glycation of α-Syn led to the expression of transglutaminase 2 (TGM2), an enzyme that cross-linked with AGEs and may have caused the accumulation of α-Syn. Significant RAGE activation was also observed in gly-α-Syn, which might have induced glial cell activation, resulting in oxidative stress and, ultimately, apoptosis of dopaminergic neurons. It is important to note that TGM2, phosphorylated α-Syn, RAGE expression, and glial cell activation were only found in the gly-α-Syn group and not in the other groups. This suggests that gly-α-Syn plays a major role in synucleinopathy, neuroinflammation, and neurodegeneration. Overall, the present study demonstrated glycation of α-Syn as one of the important age-associated post-translational modifications that are involved in the degeneration of dopaminergic neurons, at least in a subset of the diabetic patients susceptible to developing PD.
- MeSH
- alpha-Synuclein * metabolism MeSH
- Dopaminergic Neurons * metabolism pathology drug effects MeSH
- Glycosylation MeSH
- Humans MeSH
- Mice, Inbred ICR MeSH
- Mice MeSH
- Neuroglia * metabolism pathology drug effects MeSH
- Oxidative Stress MeSH
- Parkinson Disease * metabolism pathology MeSH
- Glycation End Products, Advanced metabolism MeSH
- Receptor for Advanced Glycation End Products metabolism MeSH
- Substantia Nigra metabolism pathology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Ticks are important vectors of various microorganisms, including bacteria. In this study, we examined Hyalomma aegyptium ticks collected from 240 spur-thighed tortoises Testudo graeca at 42 localities in the Mediterranean and Middle East and analysed them for the presence of bacteria of the genera Anaplasma, Borrelia, Coxiella, and Rickettsia. Altogether, 576 out of 928 analysed ticks (62.1%) were positive for at least one of the tested bacteria. The highest prevalence in individual ticks was found for Borrelia turcica (43.6%), followed by Rickettsia (12.3%) and Anaplasma (6.1%). No sample was positive for Coxiella burnetii. Among Rickettsia, we detected two species, Rickettsia africae and Rickettsia aeschlimannii, and also other unspecified Rickettsia. Anaplasma (100% identity with A. phagocytophilum) was detected at 15 (35%) out of 42 studied localities, any of Rickettsia at 28 (67%), and B. turcica at 32 (76%) localities. The geographic distribution of the studied microorganisms varied, with none of them detected in Syria, and only Rickettsia spp. detected in Morocco. Sequence analysis revealed substantial genetic variability in all detected agents, with the most variable (36 new haplotypes) being glpQ gene used as a marker for B. turcica. We also analysed the prevalence of various co-infections among studied ticks, with the mean number of co-infected ticks per tortoise increased with the number of ticks per tortoise. However, the frequencies of co-infected ticks do not indicate the presence of antagonistic or synergistic facilitative interactions between the agents. According to our data, we could expect that the eco-epidemiological importance of H. aegyptium does not stem from their tortoise hosts but rather from the low host specificity of its larvae and nymphs, feeding on a wider spectrum of reptilian, avian, and mammalian hosts.
- MeSH
- Anaplasma * isolation & purification MeSH
- Borrelia isolation & purification MeSH
- Coxiella isolation & purification genetics MeSH
- Tick Infestations veterinary epidemiology parasitology MeSH
- Ixodidae * microbiology growth & development MeSH
- Rickettsia * isolation & purification MeSH
- Turtles * microbiology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Middle East MeSH
- Mediterranean Region MeSH
