Early Childhood Adversity Predicts Risk of Family Caregiver Suicidal Ideation:Roles of Neuroticism and Self-Compassion.

Background: Despite high rates of family caregiver suicidal ideation (SI), little is known about its relationship with childhood adversity. Those with a history of adverse childhood experiences (ACEs) have been shown to have higher neuroticism, lower self-compassion, and higher rates of late life mental health disorders. Caregiving for a family member with dementia may pose a particular challenge for those with ACEs. Methods: In a secondary analysis of 81 family caregivers of people living with dementia enrolled in clinical trials, we undertook a cross-sectional baseline analysis of the association between childhood adversity, measured with the ACE questionnaire, and self-reported suicidal ideation (SI). We further assessed whether the relationship between ACE and SI was mediated by neuroticism and self-compassion. Results: 18 caregivers self-reported SI (22%). 89% of caregivers with SI reported childhood adversity (ACE > 0), versus 63% of those without SI (p=.04). The relative risk of SI was 3.6x higher in those with childhood adversity than in those without (p=.04), and for those with a specific history childhood abuse, the relative risk of SI was 3.4x higher (p=.005). Neuroticism and self-compassion mediated the relationship between ACE and SI (p<.05), with neuroticism strengthening the association and self-compassion weakening it. Conclusions: The association of SI with history of childhood adversity is high in family caregivers. Whereas elevated neuroticism might be one mechanism linking ACEs and SI, training self-compassion is a promising target for reducing SI. The phenotypic relationship between childhood adversity and SI in family caregivers should be further explored in larger samples, and could represent a new treatment target to improve the efficacy of therapies on caregiver emotional symptoms.

Howler Monkey Die-Off in Southern Mexico.

In May and June 2024, a die-off of Mexican mantled howler monkeys (Alouatta palliata mexicana) occurred in southern Mexico. This commentary documents the event, attributing it to extreme heatwaves, drought, wildfires, and habitat impoverishment. Despite their reported resilience to habitat disturbances, mantled howler monkey mortality rate in some areas reached 31%. Key evidence points to heatstroke as the primary cause of death, exacerbated by limited hydration and reduced dietary diversity in disturbed habitats. Immediate responses included community-led rescues (e.g., hydrating the monkeys), coordination of rescue activities by nongovernmental organizations (NGOs) (e.g., managing donations), involvement of scientists (e.g., monitoring of primate populations), and assistance from government officials (e.g., providing legal support for animal management). This event underscores the urgency of developing action plans to prevent and attend future crises. Among other actions, we highlight (i) establishing primate care infrastructure with medical and rehabilitation centers; (ii) developing protocols and training programs to ensure rapid crisis response; (iii) fostering collaboration among government, NGOs, and academic institutions for effective crisis management; and (iv) developing targeted research on climate change impacts, predictive models, and long-term health monitoring. We emphasize the critical need for coordinated conservation efforts to protect wild primates and maintain natural ecosystem resilience in the face of escalating climate challenges.

Family dementia caregivers with suicidal ideation improve with mentalizing imagery therapy: Results from a pilot study.

Background: Family caregivers of persons living with dementia often experience increased depression and suicidal ideation (SI). However, the feasibility and impact of therapies on caregiver SI has remained largely unexplored. Mentalizing imagery therapy (MIT) helps reduce psychological symptoms through mindfulness and guided imagery. This pilot study examined the feasibility of participation by caregivers with SI in a randomized controlled trial (RCT) of MIT versus a psychosocial support group (SG), and the respective impact of group on SI, depression, and secondary outcomes. Methods: A secondary analysis of data from an RCT of 4-week MIT or SG for caregivers (n = 46) was performed, identifying SI (n = 23) and non-SI (n = 23) cohorts. Group attendance and home practice were compared between cohorts. In the SI cohort (total n = 23, MIT n = 11, SG n = 12), group differences in SI, depression, and secondary outcomes were evaluated post-group and at 4-month follow-up. Results: Attendance in both groups and home practice in MIT were similar between SI and non-SI cohorts. In the SI cohort, MIT evinced greater improvements relative to SG in SI (p=.02) and depression (p=.02) post-group, and other secondary outcomes at follow-up. Limitations: Limitations include small sample size and single-item assessments of SI from validated depression rating scales. Conclusions: Participation in an RCT was feasible for caregivers with SI. MIT resulted in important benefits for SI and depression, while SG showed no acute SI benefit. The role of MIT in improving SI should be confirmed with adequately powered trials, as effective therapies to address caregiver SI are critical.

Induction treatment for lupus nephritis at a high-complexity hospital in Chile.

INTRODUCTION: Systemic lupus erythematosus (SLE) causes kidney compromise in up to 40% of patients, contributing significantly to morbidity. Lupus nephritis (LN), an early onset manifestation in most patients, is histologically classified into six types, with types III, IV, and V requiring treatment with induction therapies, usually glucocorticoids with mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC). However, up to 60% of patients fail to achieve complete remission, and 27%-66% have subsequent flares. There is scarce literature on the superiority of IVC or MMF in the Latin population. METHODOLOGY: A retrospective cohort study of 72 LN patients at a high-complexity hospital in Chile between 2016 and 2021 was conducted. Demographics, urine studies, creatinine levels, complement levels, antibody profiles, biopsy results, and response to treatment were analysed. RESULTS: The median age of the cohort was 29 years, with women representing 90% of patients. At diagnosis, 87.5% of the patients presented with proteinuria, 55% had haematuria, and 49% had acute kidney injury. The most common LN type was type IV. For induction therapy, half of the patients were treated with IVC, and the other half with MMF. The response to treatment did not differ significantly between the two. DISCUSSION: This is one of the few studies to focus on the Latin American population, specifically Chile. These results are consistent with the current understanding of LN treatment. Despite its limitations, this study provides valuable insights into the treatment effectiveness of IVC and MMF in this population. CONCLUSION: This study did not find significant differences in the clinical response to IVC or MMF at 6 months. Future prospective studies are required to determine the optimal induction therapy for LN, especially in Latin populations.

Can communities be mobilised to build capacity to respond to the COVID-19 pandemic? A qualitative process evaluation.

OBJECTIVES: Government guidance to manage COVID-19 was challenged by low levels of health and digital literacy and lack of information in different languages. 'Covid Confidence' sessions (CC-sessions) were evaluated to assess their effectiveness in counteracting misinformation and provide an alternative source of information about the pandemic. DESIGN: We worked with community anchor organisations to co-ordinate online CC-sessions serving three economically deprived, ethnically mixed, neighbourhoods. We conducted a qualitative, participatory process evaluation, in tandem with the CC-sessions to explore whether a popular opinion leader/local champion model of health promotion could mobilise pandemic responses. Group discussions were supplemented by final interviews to assess changes in community capacity to mobilise. SETTING: Sheffield, England, September 2020 to November 2021. PARTICIPANTS: Community leaders, workers and volunteers representing a variety of local organisations resulted in 314 attendances at CC-sessions. A group of local health experts helped organisations make sense of government information. RESULTS: CC-sessions fostered cross-organisational relationships, which enabled rapid community responses. Community champions successfully adapted information to different groups. Listening, identifying individual concerns and providing practical support enabled people to make informed decisions on managing exposure and getting vaccinated. Some people were unable to comply with self-isolation due to overcrowded housing and the need to work. Communities drew on existing resources and networks. CONCLUSIONS: CC-sessions promoted stronger links between community organisations which reduced mistrust of government information. In future, government efforts to manage pandemics should partner with communities to codesign and implement prevention and control measures.

The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.

Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed. LIFR and its ligand, LIF, have been shown to play a critical role in the progression of multiple solid cancers and therapy resistance. The role of LIF/LIFR in the progression of Type II ECa, on the other hand, is unknown. We investigated the role of LIF/LIFR signaling in Type II ECa and tested the efficacy of EC359, a novel small-molecule LIFR inhibitor, against Type II ECa. The analysis of tumor databases has uncovered a correlation between diminished survival rates and increased expression of leukemia inhibitory factor (LIF), suggesting a potential connection between altered LIF expression and unfavorable overall survival in Type II ECa. The results obtained from cell viability and colony formation assays demonstrated a significant decrease in the growth of Type II ECa LIFR knockdown cells in comparison to vector control cells. Furthermore, in both primary and established Type II ECa cells, pharmacological inhibition of the LIF/LIFR axis with EC359 markedly decreased cell viability, long-term cell survival, and invasion, and promoted apoptosis. Additionally, EC359 treatment reduced the activation of pathways driven by LIF/LIFR, such as AKT, mTOR, and STAT3. Tumor progression was markedly inhibited by EC359 treatment in two different patient-derived xenograft models in vivo and patient-derived organoids ex vivo. Collectively, these results suggest LIFR inhibitor EC359 as a possible new small-molecule therapeutics for the management of Type II ECa.

Participación de pacientes en la guía de práctica clínica de baja visión / Involvement of patients in the clinical practice guideline for low vision / Participação de pacientes na diretriz de prática clínica de visão subnormal

Objetivo: como parte de la elaboración de una guía de práctica clínica (GPC) para el cuidado de personas con baja visión en Colombia, se recomienda incluir la participación de pacientes. El objetivo fue identificar los aspectos de la vida cotidiana que se ven más afectados por la baja visión, los cuales se deben trabajar en un proceso de rehabilitación de la visión y así reconocer las barreras para acceder a ese proceso. Además, se pretende calificar la importancia de los desenlaces para los pacientes y sus cuidadores. Metodología: pacientes con baja visión y sus familiares fueron invitados a participar en un grupo focal que indagó por sus percepciones sobre los aspectos más afectados por la baja visión, los elementos más importantes de los procesos de rehabilitación de la visión y sus barreras más frecuentes. Resultados: se reportaron dificultades en la realización de las actividades instrumentales, como el uso del computador o celular, el uso del transporte público, el manejo del dinero, ir de compras, la movilidad y la orientación. La rehabilitación de la visión exitosa fue definida como aquella que les permite recuperar la independencia y ganar confianza en sí mismos. Las intervenciones de rehabilitación que mejoren las capacidades de orientación y movilidad, que incluyan acompañamiento psicológico para el paciente y la familia y que cuenten con enfoques grupales fueron altamente apreciadas. Las barreras administrativas fueron las más mencionadas. Conclusión: estos resultados apoyaron la toma de decisiones en el desarrollo de las recomendaciones de la GPC para personas con baja visión en Colombia.

Objective: As part of the development of a clinical practice guideline (CPG) for the care of individuals with low vision in Colombia, it is recommended to include patient involvement. The objective was to identify aspects of daily life most affected by low vision, which should be addressed in a vision rehabilitation process, and to recognize barriers to accessing that process. Additionally, the aim was to assess the importance of outcomes for patients and their caregivers. Methodology: Patients with low vision and their family members were invited to participate in a focus group that explored their perceptions regarding the most affected aspects of low vision, the key elements of vision rehabilitation processes, and the most common barriers they face. Results: Difficulties were reported in performing instrumental activities such as computer or cellphone use, using public transportation, handling money, shopping, mobility, and orientation. Successful vision rehabilitation was defined as the ability to recover independence and gain self-confidence. Rehabilitation interventions that improve orientation and mobility skills, include psychological support for patients and their families, and incorporate group approaches were highly valued. Administrative barriers were the most frequently mentioned.

Objetivo: Como parte do desenvolvimento de uma diretriz de prática clínica (CPG) para o atendimento de pessoas com baixa visão na Colômbia, recomenda-se incluir a parti-cipação dos pacientes. O objetivo foi identificar os aspectos do cotidiano mais afetados pela baixa visão, que devem ser trabalhados em um processo de reabilitação da visão e assim reconhecer as barreiras para acessar esse processo. Além disso, pretende-se qualificar a importância dos desfechos para os pacientes e seus cuidadores. Metodologia: os pacientes com baixa visão e seus familiares foram convidados a par-ticipar de um grupo focal que indagou sobre suas percepções sobre os aspectos mais afetados pela baixa visão, os elementos mais importantes dos processos de reabilitação da visão e suas barreiras mais frequentes. Resultados: foram relatadas dificuldades na realização de atividades instrumentais, como uso do computador ou celular, uso de transporte público, administração do dinheiro, compras, locomoção e orientação. A reabilitação visual bem-sucedida foi definida como aquela que lhes permite recuperar a independência e ganhar autoconfiança. Intervenções de reabilitação que melhoram as habilidades de orientação e mobilidade, que incluem apoio psicológico para o paciente e a família e que têm abordagens em grupo foram muito apreciadas. As barreiras administrativas foram as mais mencionadas. Conclusão: estes resultados apoiaram a tomada de decisões no desenvolvimento das recomendações CPG para pessoas com baixa visão na Colômbia.

Virtual mentalizing imagery therapy for Spanish language Latino family dementia caregivers: A feasibility and acceptability study.

Spanish speaking family caregivers of people living with dementia have limited supportive resources in Spanish. There are few validated, culturally acceptable virtual interventions for reducing these caregivers' psychological distress. We investigated the feasibility of a Spanish language adaptation of a virtual Mentalizing Imagery Therapy (MIT) program, which provides guided imagery and mindfulness training to reduce depression, increase mentalizing, and promote well-being. 12 Spanish-speaking family dementia caregivers received a 4-week virtual MIT program. Follow-up was obtained post group and at 4 months post baseline assessment. Feasibility, acceptability, and satisfaction with MIT were assessed. The primary psychological outcome was depressive symptoms; secondary outcomes included caregiver burden, dispositional mindfulness, perceived stress, well-being, interpersonal support, and neurological quality of life. Statistical analysis was performed with mixed linear models. Caregivers were 52 ± 8 (mean ± SD) years of age. 60% had a high school education or less. Participation in weekly group meetings was 100%. Home practice was performed on average 4 ± 1 times per week [range 2-5]. Satisfaction with MIT reached 19 ± 2 of a possible 20 points. Reduction in depression from baseline was observed by week three (p = 0.01) and maintained at 4 month follow-up (p = 0.05). There were significant improvements in mindfulness post-group, and in caregiver burden and well-being at 4 months. MIT was successfully adapted for Latino Spanish language family dementia caregivers within a virtual group environment. MIT is feasible and acceptable and may help reduce depressive symptoms and improve subjective well-being. Larger, randomized controlled trials of MIT should determine durability of effects and validate efficacy in this population.

Experiencia de la pandemia por SARS-CoV-2 en un centro hospitalario de alta complejidad en Chile / Epidemiological profile of patients with COVID-19 admitted to a tertiary care public hospital

BACKGROUND The knowledge about the epidemiological profile of patients admitted to the hospital for severe COVID infection, allows an adequate health care planning and resource allocation. AIM: To describe the epidemiology of patients with COVID-19 admitted to a public hospital between March 2020 and July 2021. Material and Methods: Demographic variables, comorbidities, ventilatory support requirements, and hospital resources were recorded from clinical records and hospital databases of diagnosis related groups. The primary outcomes were overall mortality and need of ventilatory support. RESULTS: In the study period, 4,474 patients (56% males) were hospitalized with a diagnosis of COVID-19. Overall mortality was 25.8% and in-hospital mortality was 18%. Invasive and non-invasive ventilatory support was required in 1349 (30.2%) and 2060 (46%) patients, respectively. The most common comorbidities in admitted patients were diabetes mellitus (29.2%), chronic kidney disease (11.1%), and chronic liver disease (10.4%). The readmission rate was 3.2%. CONCLUSIONS: Mortality associated with COVID-19 in this hospital was similar to the rates reported abroad. Local risk predictors for this infection should be identified.

Early Intraluminal Frozen Elephant Trunk Stent Graft Thrombosis After Aortic Arch Surgery.

BACKGROUND: Partial intraluminal thrombosis of the frozen elephant trunk (FET) stent graft is a poorly described but not infrequent complication after aortic arch surgery. This study aims to describe and analyze the occurrence of early FET stent graft thrombosis. METHODS: Retrospective single-center analysis including patients who underwent aortic arch replacement with FET technique between 2006 and 2020. Stent graft thrombosis was diagnosed through computed tomography scan. Several computed tomography scan parameters and clinical variables were analyzed as predictors of this event. RESULTS: A total of 125 patients were included for analysis. Among these, 21 (16.8%) patients developed early postoperative FET stent graft thrombosis. Mean volumetric size of the aorta was 12.2 ± 2.0 mL in patients with FET stent graft thrombosis and 10.1 ± 2.8 mL in patients without thrombosis (P < .01). Thrombosis occurred more frequently among patients requiring thoracic endovascular aortic repair completion (15 of 21 [71.4%] patients) than in patients with completely excluded aneurysms (6 of 21 [28.6%] patients) (P = .01). Mean stent-to-aneurysm diameter ratio was 0.8 ± 0.2 among patients with thrombosis and 1.0 ± 0.2 among patients without thrombosis (P < .01). Thrombosis was more frequently observed among patients with conservative management of postoperative bleeding (P = .04). Patients with early FET thrombosis had a nonsignificantly higher in-hospital all-cause mortality than patients without thrombosis (19.0% vs 8.7%; P = .3). CONCLUSIONS: Early postoperative intraluminal thrombosis is a frequent complication post FET surgery. Smaller stent graft sizes, larger or partially covered aneurysms, and major bleeding are associated with early thrombosis. Slight FET oversizing, prompt thoracic endovascular aortic repair completion, and early reintervention for major bleeding may prevent early thrombosis.

Psychometric Properties of Scales for Assessing the Vision-related Quality of Life of People with Low Vision: A Systematic Review.

OBJECTIVE: To synthesize information on the psychometric properties of scales used to assess vision-related quality of life in people with low vision. METHODS: A systematic review was conducted. The Cochrane Library, Embase, PubMed, Bireme and Epistemonikos databases were consulted in July 2020. Eligibility assessment of abstracts and full texts was performed independently by two investigators.A standardized template was used for data extraction regarding study design, scale and version, clinical condition of participants, and psychometric properties measured, using database-specific controlled vocabulary terms for low vision and keywords for vision-related quality of life and validity. Data was synthesized considering two approaches for scales validations, Classical Test Theory and Rasch Analysis. RESULTS: A total of 53 articles were included in our analysis. In total, 40 studies evaluated the NEI VFQ scale, four evaluated the IVI scale, two evaluated the VA LV VFQ instrument and seven validated the LVQOL scale. This review found that the VRQoL NEI VFQ, IVI, LVQOL and VA LV VFQ-48 scales have adequate psychometric properties, with good internal consistency, when assessed using the CTT approach. The NEI VFQ scale also showed adequate test-retest reliability and adequate construct and content validity. The NEI VFQ and LVQOL scales showed inadequate items and multidimensionality when Rasch analysis was used. The IVI scale showed potential for assessing change in HRQoL after providing interventions to patients with low vision. CONCLUSIONS: Many questionnaires exist to measure vision-related quality of life in people with low vision, but the psychometric properties of the questionnaires are variable.

[Epidemiological profile of patients with COVID-19 admitted to a tertiary care public hospital]. / Experiencia de la pandemia por SARS-CoV-2 en un centro hospitalario de alta complejidad en Chile.

BACKGROUND: The knowledge about the epidemiological profile of patients admitted to the hospital for severe COVID infection, allows an adequate health care planning and resource allocation. AIM: To describe the epidemiology of patients with COVID-19 admitted to a public hospital between March 2020 and July 2021. MATERIAL AND METHODS: Demographic variables, comorbidities, ventilatory support requirements, and hospital resources were recorded from clinical records and hospital databases of diagnosis related groups. The primary outcomes were overall mortality and need of ventilatory support. RESULTS: In the study period, 4,474 patients (56% males) were hospitalized with a diagnosis of COVID-19. Overall mortality was 25.8% and in-hospital mortality was 18%. Invasive and non-invasive ventilatory support was required in 1349 (30.2%) and 2060 (46%) patients, respectively. The most common comorbidities in admitted patients were diabetes mellitus (29.2%), chronic kidney disease (11.1%), and chronic liver disease (10.4%). The readmission rate was 3.2%. CONCLUSIONS: Mortality associated with COVID-19 in this hospital was similar to the rates reported abroad. Local risk predictors for this infection should be identified.

Deficiency of ataxia-telangiectasia mutated kinase attenuates Western-type diet-induced cardiac dysfunction in female mice.

Chronic consumption of Western-type diet (WD) induces cardiac structural and functional abnormalities. Previously, we have shown that WD consumption in male ATM (ataxia-telangiectasia mutated kinase) deficient mice associates with accelerated body weight (BW) gain, cardiac systolic dysfunction with increased preload, and exacerbation of hypertrophy, apoptosis, and inflammation. This study investigated the role of ATM deficiency in WD-induced changes in functional and biochemical parameters of the heart in female mice. Six-week-old wild-type (WT) and ATM heterozygous knockout (hKO) female mice were placed on WD or NC (normal chow) for 14 weeks. BW gain, fat accumulation, and cardiac functional and biochemical parameters were measured 14 weeks post-WD. WD-induced subcutaneous and total fat contents normalized to body weight were higher in WT-WD versus hKO-WD. Heart function measured using echocardiography revealed decreased percent fractional shortening and ejection fraction, and increased LV end systolic diameter and volume in WT-WD versus WT-NC. These functional parameters remained unchanged in hKO-WD versus hKO-NC. Myocardial fibrosis, myocyte hypertrophy, and apoptosis were higher in WT-WD versus WT-NC. However, apoptosis was significantly lower and hypertrophy was significantly higher in hKO-WD versus WT-WD. MMP-9 and Bax expression, and Akt activation were higher in WT-WD versus WT-NC. PARP-1 (full-length) expression and mTOR activation were lower in WT-WD versus hKO-WD. Thus, ATM deficiency in female mice attenuates fat weight gain, preserves heart function, and associates with decreased cardiac cell apoptosis in response to WD.

Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity.

A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.

Biochemical and Kinetic Characterization of the Glucose-6-Phosphate Dehydrogenase from Helicobacter pylori Strain 29CaP.

Helicobacter pylori (H. pylori) has been proposed as the foremost risk factor for the development of gastric cancer. We found that H. pylori express the enzyme glucose-6-phosphate dehydrogenase (HpG6PD), which participates in glucose metabolism via the pentose phosphate pathway. Thus, we hypothesized that if the biochemical and physicochemical characteristics of HpG6PD contrast with the host G6PD (human G6PD, HsG6PD), HpG6PD becomes a potential target for novel drugs against H. pylori. In this work, we characterized the biochemical properties of the HpG6PD from the H.pylori strain 29CaP and expressed the active recombinant protein, to analyze its steady-state kinetics, thermostability, and biophysical aspects. In addition, we analyzed the HpG6PD in silico structural properties to compare them with those of the HsG6PD. The optimal pH for enzyme activity was 7.5, with a T1/2 of 46.6 °C, at an optimum stability temperature of 37 °C. The apparent Km values calculated for G6P and NADP+ were 75.0 and 12.8 µM, respectively. G6P does not protect HpG6PD from trypsin digestion, but NADP+ does protect the enzyme from trypsin and guanidine hydrochloride (Gdn-HCl). The biochemical characterization of HpG6PD contributes to knowledge regarding H. pylori metabolism and opens up the possibility of using this enzyme as a potential target for specific and efficient treatment against this pathogen; structural alignment indicates that the three-dimensional (3D) homodimer model of the G6PD protein from H. pylori is different from the 3D G6PD of Homo sapiens.

Off-pump coronary artery bypass grafting is safe and effective in patients with severe left ventricular dysfunction.

OBJECTIVES: Severe left ventricular dysfunction (LVD) is associated with increased risk following coronary artery bypass grafting (CABG). Due to a dearth of reports on the choice of CABG technique in patients with LVD, this study aims to compare the outcomes of off-pump CABG (OPCAB) and conventional CABG (ONCAB) in such patients. METHODS: Retrospective single-centre propensity-matched analysis comparing early- and long-term outcomes of OPCAB and ONCAB in patients with severe LVD. Primary outcome was long-term all-cause mortality. RESULTS: Between 2002 and 2014, a total of 1161 consecutive patients with severe LVD underwent isolated CABG [442 patients underwent OPCAB and 719 ONCAB (430 matched pairs)]. Incomplete revascularization was observed more frequently among OPCAB than ONCAB patients (35.3% vs 21.6%; P < 0.01). The overall 30-day mortality was 5% and was comparable between the matched groups [OR 0.64 (0.34-1.22); P = 0.18]. OPCAB patients had shorter median hospital stay (11 vs 12 days; P = 0.02) and lower packed red blood cell transfusion rates [2.7 (2.21-3.19) vs 4.4 (3.56-5.24); P < 0.01]. Estimated adjusted survival was 86.0% vs 85.8%, 69.1% vs 65.5% and 59.9% vs 49.1% at 1, 5 and 10 years for OPCAB and ONCAB patients, respectively (P = 0.99). Long-term risk of mortality was similar between groups [hazard ratio (HR) 0.94 (0.66-1.32); P = 0.7]. Incomplete revascularization was weakly associated with increased risk of long-term all-cause mortality [HR 1.33 (0.99-1.77); P = 0.05]. CONCLUSIONS: OPCAB is safe and effective in patients with severe LVD. Although incomplete revascularization is more commonly observed in patients undergoing OPCAB, it is not associated with increased late mortality.

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors.

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC50 = 310, 465, 340, 204 and 304 µM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP+ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP+ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme's active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.

Characterizing the Fused TvG6PD::6PGL Protein from the Protozoan Trichomonas vaginalis, and Effects of the NADP+ Molecule on Enzyme Stability.

This report describes a functional and structural analysis of fused glucose-6-phosphate dehydrogenase dehydrogenase-phosphogluconolactonase protein from the protozoan Trichomonas vaginalis (T. vaginalis). The glucose-6-phosphate dehydrogenase (g6pd) gene from T. vaginalis was isolated by PCR and the sequence of the product showed that is fused with 6pgl gene. The fused Tvg6pd::6pgl gene was cloned and overexpressed in a heterologous system. The recombinant protein was purified by affinity chromatography, and the oligomeric state of the TvG6PD::6PGL protein was found as tetramer, with an optimal pH of 8.0. The kinetic parameters for the G6PD domain were determined using glucose-6-phosphate (G6P) and nicotinamide adenine dinucleotide phosphate (NADP+) as substrates. Biochemical assays as the effects of temperature, susceptibility to trypsin digestion, and analysis of hydrochloride of guanidine on protein stability in the presence or absence of NADP+ were performed. These results revealed that the protein becomes more stable in the presence of the NADP+. In addition, we determined the dissociation constant for the binding (Kd) of NADP+ in the protein and suggests the possible structural site in the fused TvG6PD::6PGL protein. Finally, computational modeling studies were performed to obtain an approximation of the structure of TvG6PD::6PGL. The generated model showed differences with the GlG6PD::6PGL protein (even more so with human G6PD) despite both being fused.

Effects of Single and Double Mutants in Human Glucose-6-Phosphate Dehydrogenase Variants Present in the Mexican Population: Biochemical and Structural Analysis.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most frequent human enzymopathy, affecting over 400 million people globally. Worldwide, 217 mutations have been reported at the genetic level, and only 19 have been found in Mexico. The objective of this work was to contribute to the knowledge of the function and structure of three single natural variants (G6PD A+, G6PD San Luis Potosi, and G6PD Guadalajara) and a double mutant (G6PD Mount Sinai), each localized in a different region of the three-dimensional (3D) structure. In the functional characterization of the mutants, we observed a decrease in specific activity, protein expression and purification, catalytic efficiency, and substrate affinity in comparison with wild-type (WT) G6PD. Moreover, the analysis of the effect of all mutations on the structural stability showed that its presence increases denaturation and lability with temperature and it is more sensible to trypsin digestion protease and guanidine hydrochloride compared with WT G6PD. This could be explained by accelerated degradation of the variant enzymes due to reduced stability of the protein, as is shown in patients with G6PD deficiency.

Burst-Like Subcutaneous Electrical Stimulation Induces BDNF-Mediated, Cyclotraxin B-Sensitive Central Sensitization in Rat Spinal Cord.

Intrathecal administration of brain derived neurotrophic factor (BDNF) induces long-term potentiation (LTP) and generates long-lasting central sensitization in spinal cord thus mimicking chronic pain, but the relevance of these observations to chronic pain mechanisms is uncertain. Since C-fiber activation by a high-frequency subcutaneous electrical stimulation (SES) protocol causes spinal release of BDNF and induces spinal cord LTP, we propose that application of such protocol would be a sufficient condition for generating long-lasting BDNF-mediated central sensitization. Results showed that application of burst-like SES to rat toes produced (i) rapid induction of hyperalgesia that lasted for more than 3 weeks, (ii) early increase of C-reflex activity followed by increased wind-up scores lasting for more than 1 week, and (iii) early increase followed by late decrease in BDNF protein levels and phosphorylated TrkB that lasted for more than 1 week. These changes were prevented by the TrkB antagonist cyclotraxin-B administered shortly before SES, while hyperalgesia was reversed by cyclotraxin-B administered 3 days after SES. Results suggest that mechanisms underlying central sensitization first involve BDNF release of probably neuronal origin, followed by brief increased expression of likely glial BDNF and pTrkB that could switch early phase sensitization into late one.