The length‐dependent activation of contraction is equally impaired in impuberal male and female rats in monocrotaline‐induced right ventricular failure

The length‐dependent activation of contraction is attenuated in the failing myocardium of adult male rats. This pathological change is not seen in adult female rats, possibly because of a protective effect of sex hormones. The present study evaluated length‐dependent changes in isometric twitch, Ca²⁺ transient (CaT) and action potential (AP) in the right ventricular myocardium of impuberal healthy male and female rats (control) and in rats treated with a single injection of 50 mg/kg monocrotaline (MCT). Compared with sex‐matched control rats, MCT‐treated male and female rats exhibited increased right ventricular weight (134% and 142% of control, respectively), decreased left ventricular weight (72% and 79%), twitch attenuation (48.8 ± 2.7% and 57.5 ± 1.2%) and prolongation (125 ± 3% and 127 ± 2%), CaT attenuation (37.8 ± 0.4% and 39.1 ± 1.1%) and prolongation (114 ± 1% and 116 ± 1%) and AP prolongation at 90% repolarization (195 ± 2% and 203 ± 1%). The MCT‐treated male rats exhibited a 50% lower integral magnitude and an approximately 25% larger time‐to‐peak ‘bump’ compared with control male rats. These parameters in MCT‐treated female rats tended to show similar changes to those seen in the control female rats, with no significant difference between the two groups. In all groups, integral magnitude and time‐to‐peak ‘bump’ increased with length. In conclusion, the length‐dependent activation of contraction was equally blunted in the failing right ventricular myocardium of impuberal male and female rats. This was related to changes in CaT and AP, which were similar between male and female rats. Therefore, puberty is necessary for manifestation of the protective effects of sex hormones on this remodelling.     

Ventilatory efficiency during ramp exercise in relation to age and sex in a healthy Japanese population

BackgroundThe current understanding of ventilator efficiency variables during ramp exercise testing in the normal Japanese population is insufficient, and the responses of tidal volume (VT) and minute ventilation (V?E) to the ramp exercise test in the normal Japanese population are not known.MethodsA total of 529 healthy Japanese subjects aged 20–78 years underwent cardiopulmonary exercise testing using a cycle ergometer with ramp protocols. VT and V?E at rest, at anaerobic threshold, and at peak exercise were determined. The slope of V?E versus carbon dioxide (V?CO₂) (V?E vs. V?CO₂ slope), minimum V?E/V?CO₂, and oxygen uptake efficiency slope (OUES) were determined.ResultsFor males and females in their 20 s, peak VT (VTpeak) was 2192 ± 376 and 1509 ± 260 mL (p < 0.001), peak V?E (V?Epeak) was 80.6 ± 18.7 and 57.7 ± 13.9 L/min (sex differences p < 0.001), the V?E vs. V?CO₂ slope was 24.4 ± 3.2 and 25.7 ± 3.2 (p = 0.035), the minimum V?E/V?CO₂ was 24.2 ± 2.3 and 27.0 ± 2.8 (p < 0.001), and the OUES was 2452 ± 519 and 1991 ± 315 (p < 0.001), respectively. VTpeak and V?Epeak decreased with age and increased with weight and height. The V?E vs. V?CO₂ slope and minimum V?E/V?CO₂ increased with age, while conversely, the OUES decreased with age.ConclusionsWe have established the normal range of VT and V?E responses, the V?E vs. V?CO₂ slope, the minimum V?E/V?CO₂, and the OUES for a healthy Japanese population. Some of these parameters were influenced by weight, height, sex, and age. These results provide useful reference values for interpreting the results of cardiopulmonary exercise testing in cardiac patients.     

Review on acute pancreatitis attributed to COVID-19 infection

The coronavirus disease 2019 (COVID-19) is known to cause gastrointestinal symptoms. Recent studies have revealed COVID-19-attributed acute pancreatitis (AP). However, clinical characteristics of COVID-19-attributed AP remain unclear. We performed a narrative review to elucidate relation between COVID-19 and AP using the PubMed database. Some basic and pathological reports revealed expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, key proteins that aid in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the pancreas. The experimental and pathological evaluation suggested that SARS-CoV-2 infects human endocrine and exocrine pancreas cells, and thus, SARS-CoV-2 may have a direct involvement in pancreatic disorders. Additionally, systemic inflammation, especially in children, may cause AP. Levels of immune mediators associated with AP, including interleukin (IL)-1β, IL-10, interferon-γ, monocyte chemotactic protein 1, and tumor necrosis factor-α are higher in the plasma of patients with COVID-19, that suggests an indirect involvement of the pancreas. In real-world settings, some clinical features of AP complicate COVID-19, such as a high complication rate of pancreatic necrosis, severe AP, and high mortality. However, clinical features of COVID-19-attributed AP remain uncertain due to insufficient research on etiologies of AP. Therefore, high-quality clinical studies and case reports that specify methods for differential diagnoses of other etiologies of AP are needed.     

Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.     

Understanding and use of inhaler medication by asthmatics in specialty care in Trinidad: a study following development of Caribbean guidelines for asthma management and prevention

STUDY OBJECTIVES: Following the development of the Caribbean Guidelines for Asthma Care, we examined the utilization of inhaled medications in asthmatic patients in Trinidad, West Indies. SETTING: Chest Clinic, Ministry of Health, Trinidad. PARTICIPANTS: Physician-diagnosed asthmatic patients who attended the Chest Clinic between July 1998 and August 2000. MEASUREMENTS AND RESULTS: A consecutive sample of patients who were > 7 years of age (n = 402) was interviewed about compliance with, understanding of, and use of inhaler medication. The inhaler technique of these patients was directly observed. Inhaled steroid therapy was prescribed in 83% of patients but were prescribed the least in elderly patients (63%) and children (62%). Salbutamol was prescribed in 98% of patients, and ipratropium and sodium cromoglycate were selectively prescribed in elderly men and children, respectively. Only 33% of patients used the inhaler correctly, and children and the elderly were the least efficient in its use. The use of a spacer device was advised in 19% of patients, including only 6% of the elderly patients. Explanations for different inhaler therapies were given to 62% of patients, and 53% of patients could describe these reasons. The reported 40% noncompliance rate among patients in the sample was primarily a result of long waiting periods at the pharmacy (58%) and the personal cost incurred on purchasing the medication (52%). CONCLUSIONS: Educating patients, with a focus on children and the elderly, in inhaler techniques and reinforcing understanding of asthma medications can improve asthma management in Trinidad. Asthma caregivers in the Caribbean should ensure the appropriate dissemination of the guidelines and should outline strategies for their implementation.     

Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: The JACC study

Evidence for association between serum total homocysteine (tHcy) level and cardiovascular disease is limited in Asian populations. We conducted a nested case-control study under JACC Study. A total of 39,242 subjects aged 40-79 years provided serum samples at baseline surveys between 1988 and 1990. Control subjects were selected by matching for sex, age, community and year of serum storage. Serum tHcy levels were measured by high-performance liquid chromatography. During the 10-year follow-up, there were 444 deaths due to total cardiovascular disease, including 310 total stroke (131 hemorrhage and 101 ischemic strokes) and 134 coronary heart diseases. The risks of mortality from ischemic stroke, coronary heart disease, and total cardiovascular disease were significantly higher in individuals with the highest serum tHcy quartile (>or=15.3micromol/L) than in those with the lowest quartile (<10.5micromol/L); the respective multivariable odds ratios (95% CI) were 4.35 (1.12-16.9), 3.40 (1.17-9.86), and 1.68 (1.02-2.77). The multivariable odds ratios associated with a 5-micromol/L increase in tHcy were 1.49 (1.01-2.18), 2.01 (1.21-3.35), and 1.15 (1.00-1.32), respectively. High serum tHcy levels were associated with increased mortality from ischemic stroke, coronary heart disease and total cardiovascular disease among Japanese.     

Mobilizing individual social capital resources for HIV care support: results of a pilot intervention in St. Petersburg,Russia

ABSTRACT

Half of HIV-positive persons in Russia are on antiretroviral therapy (ART), and only 27% are virally suppressed. A feasibility pilot intervention to mobilize social capital resources for HIV care support was conducted in St. Petersburg. Out-of-care or ART-nonadherent HIV-positive persons (n?=?24) attended a five-session intervention to increase access social capital resources (i.e., family, friends, or providers) to mobilize supports for entering care, initiating care, and adhering to ART. HIV care indicators were assessed at baseline, an immediate followup (FU-1), and 6-month followup (FU-2) points. At FU-1, participants more frequently discussed their care experiences with others, verifying the intervention’s mechanism of action. Participants increased in scales of medication taking adherence (p?=?0.002, FU-1; p?=?0.011, FU-2), self-efficacy (p?=?0.042; FU-1), and outcome expectancies (p?=?0.016, FU-2). Among persons not on ART, HIV Medication Readiness scale scores increased at FU-1 (p?=?0.032) but became attenuated at FU-2. Participants tended to more frequently keep care appointments (79%, baseline to 90%, FU-1, p?=?0.077); to have undetectable viral load (54%, baseline to 74%, FU-2; p?=?0.063); and to have fewer past-month days with delayed or incomplete medication doses (7.8, baseline to 4.2, FU-1; p?=?0.084). This novel social capital intervention is promising for improving HIV care-related outcomes and warrants a full-scale evaluation.     

Unexpected Resistance to X-Irradiation in a Strain of Hybrid Mammalian Cells

The radiosensitivities of a strain of mouse fibroblasts (Cl-1D), of rat pituitary cells (GH(1)2C(1)), and of a hybrid between the two (alpha-RST) have been studied. Their mean chromosome numbers were 50, 70, and 111, respectively. The hybrid cells were much more resistent to radiation than either of the parent strains. The range of the D(0) (reciprocal of the slope, and therefore a measure of radiosensitivity) for the linear portion of the survival curves for each cell line was: Cl-1D, 134-142 R; GH(1)2C(1), 154-170 R; and alpha-RST, 248-274 R. There were no significant differences in the magnitude of the shoulder or extrapolation number of the survival curves, nor in the ability of the three cell strains to accumulate and repair sublethal radiation damage. It appears unlikely that the unusual resistance of the hybrid strain is simply related to the increase in chromosome number; more likely, it involves some interaction between the two genomes. The study of somatic cell hybrids may offer further insight into the factors controlling the radiosensitivity of mammalian cells.     

Influenza vaccination in the elderly boosts antibodies against conserved viral proteins and egg-produced glycans

Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of cross-reactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an egg-produced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine-H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galβ1-4GalNAcβ), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza.