The relationship between loneliness and healthy aging indicators in Brazil (ELSI-Brazil) and England (ELSA): sex differences.

OBJECTIVES: This study aimed to estimate five harmonized healthy aging indicators covering functional ability and intrinsic capacity among older women and men from Brazil and England and evaluate their association with loneliness. STUDY DESIGN: This was a cross-sectional study. METHODS: We used two nationally representative samples of men and women aged ≥60 years from the Brazilian Longitudinal Study of Aging (ELSI-Brazil) wave 2 (2019-2021; n = 6929) and the English Longitudinal Study of Aging wave 9 (2018-2019; n = 5902). Healthy aging included five separate indicators (getting dressed, taking medication, managing money, cognitive function, and handgrip strength). Loneliness was measured by the 3-item University of California Loneliness Scale. Logistic regression models stratified by sex and country were performed. RESULTS: Overall, age-adjusted healthy aging indicators were worse in Brazil compared with England for both men and women. Considering functional ability, loneliness was negatively associated with all indicators (ranging from odds ratio [OR] = 0.26, [95% confidence interval (CI) 0.13-0.52] in English men regarding the ability to take medication to OR = 0.49 [95% CI 0.27-0.89] in Brazilian women regarding the ability to manage money). Considering intrinsic capacity, loneliness was negatively associated with a higher cognitive function (OR = 0.72; 95% CI 0.55-0.95 in English women) and a higher handgrip strength (OR = 0.61; 95% CI 0.45-0.83 in Brazilian women). Lonely women demonstrated lower odds of a higher number of healthy aging indicators than men in both countries. CONCLUSIONS: Country-specific social environments should be targeted by public policies to decrease loneliness and promote healthy aging later in life.

Antibodies from Rabbits Immunized with HIV-1 Clade B SOSIP Trimers Can Neutralize Multiple Clade B Viruses by Destabilizing the Envelope Glycoprotein.

The high viral diversity of HIV-1 is a formidable hurdle for the development of an HIV-1 vaccine. Elicitation of broadly neutralizing antibodies (bNAbs) would offer a solution, but so far immunization strategies have failed to efficiently elicit bNAbs. To overcome these obstacles, it is important to understand the immune responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens. To gain more insight, we characterized monoclonal antibodies (MAbs) isolated from rabbits immunized with Env SOSIP trimers based on the clade B isolate AMC008. Four rabbits that were immunized three times with AMC008 trimer developed robust autologous and sporadic low-titer heterologous neutralizing responses. Seventeen AMC008 trimer-reactive MAbs were isolated using antigen-specific single B-cell sorting. Four of these MAbs neutralized the autologous AMC008 virus and several other clade B viruses. When visualized by electron microscopy, the complex of the neutralizing MAbs with the AMC008 trimer showed binding to the gp41 subunit with unusual approach angles, and we observed that their neutralization ability depended on their capacity to induce Env trimer dissociation. Thus, AMC008 SOSIP trimer immunization induced clade B-neutralizing MAbs with unusual approach angles with neutralizing effects that involve trimer destabilization. Optimizing these responses might provide an avenue to the induction of trimer-dissociating bNAbs. IMPORTANCE Roughly 32 million people have died as a consequence of HIV-1 infection since the start of the epidemic, and 1.7 million people still get infected with HIV-1 annually. Therefore, a vaccine to prevent HIV-1 infection is urgently needed. Current HIV-1 immunogens are not able to elicit the broad immune responses needed to provide protection against the large variation of HIV-1 strains circulating globally. A better understanding of the humoral immune responses elicited by immunization with state-of-the-art HIV-1 immunogens should facilitate the design of improved HIV-1 vaccine candidates. We identified antibodies with the ability to neutralize multiple HIV-1 viruses by destabilization of the envelope glycoprotein. Their weak but consistent cross-neutralization ability indicates the potential of this epitope to elicit broad responses. The trimer-destabilizing effect of the neutralizing MAbs, combined with detailed characterization of the neutralization epitope, can be used to shape the next generation of HIV-1 immunogens to elicit improved humoral responses after vaccination.

Pannexin channels increase propidium iodide permeability in frozen-thawed dog spermatozoa.

Pannexins (Panx) are proteins that form functional single membrane channels, but they have not yet been described in dogs. The aim of the present study was to detect Panx1, Panx2 and Panx3 in frozen-thawed dog spermatozoa using flow cytometry and immunofluorescence analyses, evaluating the relationship of these proteins with propidium iodide (PI) in frozen-thawed spermatozoa. Fresh and frozen-thawed dog spermatozoa from eight dogs were preincubated with 3µM PI with or without 15µM carbenoxolone (CBX) or 1mM probenecid (PBD), two Panx channel inhibitors, and then incubated with rabbit anti-Panx1, anti-Panx2 and anti-Panx3 antibodies (1:200). Panx immunolocalisation was assessed by fluorescence microscopy. Flow cytometry data were evaluated by analysis of variance. All three Panx proteins were found in dog spermatozoa: Panx1 was mostly localised to the acrosomal and equatorial segment, Panx2 was found in the posterior region of the head and tail and Panx3 was localised to the equatorial and posterior head segment. The percentage of PI-positive cells determined by flow cytometry was reduced (P<0.05) in the presence of Panx inhibitors. These results show that Panx proteins are present in dog spermatozoa and increase PI permeability in frozen-thawed dog sperm, suggesting that the percentage of PI-positive spermatozoa used as an indicator of non-viable cells may lead to overestimation of non-viable cells.

Fungal biodegradation of dibutyl phthalate and toxicity of its breakdown products on the basis of fungal and bacterial growth.

Phthalates are esters of phthalic acid that give flexibility to polyvinyl chloride. Diverse studies have reported that these compounds might be carcinogenic, mutagenic and/or teratogenic. Radial growth rate, biomass, hyphal thickness of Neurospora sitophyla, Trichoderma harzianum and Aspergillus niger, grown in two different concentrations of dibutyl phthalate (DBP) (500 and 1,000 mg/l) in agar and in submerged fermentation were studied. The inhibitory concentration (IC50) and the constant of biodegradation of dibutyl phthalate in Escherichia coli cultures were used to evaluate toxicity. The radial growth rate and thickness of the hypha were positively correlated with the concentration of phthalate. The pH of the cultures decreased as the fermentation proceeded. It is shown that these fungi are able to degrade DBP to non-toxic compounds and that these can be used as sole carbon and energy sources by this bacterium. It is demonstrated that the biodegradation of the DBP is directly correlated with the IC50. This is the first study that reports a method to determine the biodegradation of DBP on the basis of the IC50 and fungal growth, and the effect of this phthalate on the growth and thickness of hyphae of filamentous fungi in agar and in submerged fermentation.

Fine-mapping the immunodominant antibody epitopes on consensus sequence-based HIV-1 envelope trimer vaccine candidates.

The HIV-1 envelope glycoprotein (Env) trimer is the key target for vaccines aimed at inducing neutralizing antibodies (NAbs) against HIV-1. The clinical candidate immunogen ConM SOSIP.v7 is a stabilized native-like HIV-1 Env trimer based on an artificial consensus sequence of all HIV-1 isolates in group M. In preclinical studies ConM SOSIP.v7 trimers induced strong autologous NAb responses in non-human primates (NHPs). To fine-map these responses, we isolated monoclonal antibodies (mAbs) from six cynomolgus macaques that were immunized three times with ConM SOSIP.v7 protein and boosted twice with the closely related ConSOSL.UFO.664 immunogen. A total of 40 ConM and/or ConS-specific mAbs were isolated, of which 18 were retrieved after the three ConM SOSIP.v7 immunizations and 22 after the two immunizations with ConSOSL.UFO.664. 22 mAbs (55%) neutralized the ConM and/or ConS virus. Cross-neutralization of ConS virus by approximately one-third of the mAbs was seen prior to ConSOSL.UFO.664 immunization, albeit with modest potency. Neutralizing antibodies predominantly targeted the V1 and V2 regions of the immunogens, with an apparent extension towards the V3 region. Thus, the V1V2V3 region is immunodominant in the potent NAb response elicited by two consensus sequence native-like HIV-1 Env immunogens. Immunization with these soluble consensus Env proteins also elicited non-neutralizing mAbs targeting the trimer base. These results inform the use and improvement of consensus-based trimer immunogens in combinatorial vaccine strategies.

Deleterious versus neuroprotective effect of metabolic inhibition after traumatic spinal cord injury.

STUDY DESIGN: This work is an experimental and prospective study in adult, female, Long-Evans rats. OBJECTIVES: The aim of this study was to probe the effect of metabolic inhibition after an acute traumatic spinal cord injury (TSCI) using a standardized contusion model (NYU impactor) to know whether the metabolic inhibition is a 'secondary mechanism of injury' or a mechanism of protection. SETTING: All experimental procedures were carried out in the Mexico City. METHODS: Animals were divided into five groups: one sham and four with TSCI, including no treatment, rotenone (inhibitor of mitochondrial complex I), sodium azide (inhibitor of mitochondrial complex IV) and pyrophosphate of thiamine or non-degradable cocarboxylase as a metabolic reactivator. RESULTS: After TSCI, the metabolic inhibition with sodium azide treatment diminished the lipid peroxidation process (malondialdehyde levels by spectrophotometric procedures) and the damage to the spinal cord tissue (morphometric analysis), and increased the activity of creatine kinase and lactate dehydrogenase enzymes (P<0.05) (measured by spectrophotometric procedures 24 h after TSCI as well as after the functional recovery of the hind limb (evaluated weekly for 2 months by the BBB (Basso, Beattie and Bresnahan) scale)) when compared with the TSCI group without treatment. CONCLUSION: The results show that the partial and transitory inhibition of the aerobic metabolism after an acute TSCI could be a self-protection mechanism instead of being a 'secondary mechanism of injury'.

Intraparenchymatous adenomatoid tumor dependent on the rete testis: A case report and review of literature.

The adenomatoid tumor is the most frequent paratesticular tumor. It is a benign tumor, which in women is mainly found in the uterus and the fallopian tubes, while in men it is most frequently found in the epididymis. These lesions may also affect the testicular albuginea, the spermatic cord and, in exceptional cases, the testicular parenchyma, of which there are only 4 published cases, the ejaculatory ducts, prostate, etc. The clinical signs and imaging studies are, on many occasions, difficult to differentiate from malign intratesticular solid tumor, which can result in unnecessary orchidectomies. We present a new case of intraparenchymatous adenomatoid tumor dependent on the rete testis.

Effect of mobile phone text messaging for improving the uptake of influenza vaccination in patients with rare diseases.

OBJECTIVES: Influenza vaccine is recommended in some chronic medical conditions, including several rare diseases. The objectives of the study were to assess the effect of text message reminders on influenza vaccination uptake of patients with selected rare diseases and delayed vaccination, and to describe their characteristics. METHODS: Quasi-experimental pre-post intervention study performed along the 2016 influenza vaccination campaign in the Autonomous Community of Madrid. Unvaccinated patients diagnosed with a selected rare disease were targeted for intervention. SMS were sent to them at least one month after the beginning of the campaign, in four consecutive weeks. Those with no mobile phones available or no certainty of message reception, were assigned as controls. The association between the reception of the SMS and vaccination uptake was assessed using multiple poisson regression models. RESULTS: Of 69.040 patients with delayed vaccination, 87.2% received an SMS reminder in the asigned contact mobile telephone. Global influenza vaccine coverage reached 41.3%. The uptake of influenza vaccine was significantly higher among those receiving the reminder (9.3% vs. 7.1% in the control group, p < 0.001). Those who received a SMS reminder were 30% more likely to uptake seasonal influenza vaccine. By sex and age, the reception of the reminder was associated with a significantly higher probability of vaccination in men ≥65 years with at least a concurrent chronic condition (IRR: 1.58, CI95%: 1.25-2.00). Among women, this higher probability was detected in those between 14 and 64 years of age (IRR: 1.41, CI95%: 1.22-1.63), and ≥65 years without concurrent chronic conditions (IRR: 1.40, CI95%: 1.05-1.89). CONCLUSION: Although the intervention was modestly effective, it proved beneficial in some cases. It can be an additional strategy to improve vaccine uptake, since it is simple, feasible, affordable and easily scalable, particularly when immunization and target population data are available in population registries.

The importance of polymerization and galloylation for the antiproliferative properties of procyanidin-rich natural extracts.

Grape (Vitis vinifera) and pine (Pinus pinaster) bark extracts are widely used as nutritional supplements. Procyanidin-rich fractions from grape and pine bark extract showing different mean degrees of polymerization, percentage of galloylation (percentage of gallate esters) and reactive oxygen species-scavenging capacity were tested on HT29 human colon cancer cells. We observed that the most efficient fractions in inhibiting cell proliferation, arresting the cell cycle in G(2) phase and inducing apoptosis were the grape fractions with the highest percentage of galloylation and mean degree of polymerization. Additionally, the antiproliferative effects of grape fractions were consistent with their oxygen radical-scavenging capacity and their ability to trigger DNA condensation-fragmentation.

[Influence of initial protocolized treatment with steroids in length of stay and costs of community acquired pneumonia]. / Influencia de la protocolización del tratamiento inicial con corticoides en la estancia y costo de las neumonías adquiridas en la comunidad. Estudio prospectivo 2015.

OBJECTIVE: The aim of the study was to analyze the impact of steroid treatment in patients with community acquired pneumonia (CAP), both in length of stay and economical cost of admission at a clinical university hospital. METHODS: Prospective study of admitted patients with the diagnosis of CAP, both in Internal Medicine and Infectious diseases department. The study was conducted from January to march 2015; patients receiving steroids from diagnosis to end of antibiotic treatment were classified as group I; otherwise, they were considered in group II. Administration of steroids was done according to the criteria of the responsible. Cost was stablished according to CAP Diagnostic Related Group (DRG). RESULTS: Prevalence of patients younger than 65 year-old was higher in group I (p<0.05). In bivariate analyses, mean admission time was lower in group I (5.37 vs 8.88 days) (p<0.0005) and also economical cost (2,361 euros vs 3,907 euros) (p<0.0005). In multivariate analysis, factors independently associated to higher cost (>3,520 euros) were COPD (OR=2.602; 95% CI 1.074-6.305) and group II (patients with no steroids) (OR=6.2; p=0,007). CONCLUSIONS: No administration of steroids in patients with CAP was associated, together with COPD, with higher economical cost (evaluated by DRG/length of stay).

Functional fatty fish supplemented with grape procyanidins. Antioxidant and proapoptotic properties on colon cell lines.

This work shows the properties of grape procyanidins with additional anticarcinogenic properties for increasing the shelf life of functional seafood preparations. Galloylated procyanidins (100 ppm, 2.7 mean degree of polymerization, 25% galloylation) extended the shelf life of minced horse mackerel muscle stored at 4 degrees C more than 8 days compared to controls without addition of polyphenols. The levels of endogenous alpha-tocopherol, EPA, and DHA of fish muscle were also preserved after 10 days at 4 degrees C. Therefore, the presence of procyanidins increased the stability of a product based on minced fish muscle during cold storage and maintained its functionality associated with the presence of polyunsaturated fatty acids and alpha-tocopherol. In addition, grape procyanidins showed a significant capacity to induce apoptosis in colon cancer cells (HT29 cell line) while being inactive in noncancer control cells (IEC-6). Thus, the product based on fatty fish muscle supplemented with grape procyanidins appears to be a stable functional food offering the combined action of omega-3 fatty acids and natural polyphenols.

Kinetic study of alpha-chymotrypsin-catalyzed synthesis of kyotorphin.

A kinetic analysis of reaction-rate data obtained during a series of optimization experiments of the alpha-chymotrypsin-catalyzed synthesis of kyotorphin has been performed. The kinetic data have been fitted to a model equation derived from a proposed sequential mechanism, which has been further simplified to a first-order equation as a function of the substrate consumption. Statistical tests performed validate the model, since the fitted constants were statistically significant. In addition, the activation energy of the process has been calculated and resulted to be 32.5 +/- 2.3 kJ/mol which is within the range of other enzymatic reactions.

Enzymatic synthesis of X-Phe-Leu-NH2 in low water content systems: influence of the N-alpha protecting group and the reaction medium composition.

The influence of eight different N-terminal protecting groups (For, Ac, Boc, Fmoc, Mal, Pheac, Aloc and Z) on the alpha-chymotrypsin-catalyzed synthesis of the dipeptide derivative X-Phe-Leu-NH2 in organic media was studied. Groups such as Ac, For, Boc, Z, Mal, Pheac and Alloc always rendered good peptide yields (92% to 99%) either in acetonitrile or in ethyl acetate. Good correlations were found between molecular and physico-chemical characteristics of the N-alpha moiety such as the hydrophobicity (log P), ovality and dipole moment and the global reaction rate parameter k'. High k' values were obtained with the less hydrophobic groups, Ac, For and Mal, that have ovality values close to one and the highest dipole moments. Furthermore, it was found that the relative rate of hydrolysis and aminolysis of the acyl-enzyme intermediate expressed as the partition parameter p is affected by the N-alpha moiety of the acyl donor. Correlations between this parameter and the dipole moment of the protecting group were observed.

Conjugation of catechins with cysteine generates antioxidant compounds with enhanced neuroprotective activity.

Antioxidant compounds derived from the conjugation of (-)-epicatechin and (-)-epicatechin 3-O-gallate with cysteine and cysteine derivatives protected HT-22 nerve cells (EC50 between 36 and 65 microM) from death triggered by glutamate while underivatized (-)-epicatechin was almost inactive (EC50=610 microM). Differences in free radical scavenging capacity (DPPH assay) could not account for the improvement in neuroprotective activity upon derivatization of (-)-epicatechin with thiols. Moreover, while the gallate-containing compounds are more efficient radical scavengers than their non-galloylated counterparts, they are only equally or less potent as neuroprotective agents. Although all of the conjugates were able to scavenge mitochondrially generated reactive oxygen species (ROS) inside the cells, the majority of their neuroprotective activity appeared to be dependent upon their ability to maintain glutathione levels. These results suggest that a mechanism other than ROS scavenging is involved in the neuroprotective action exerted by the epicatechin conjugates.

Risk factors in interstitial pneumonitis following allogenic bone marrow transplantation.

Total body irradiation is part of the preparatory regimen for allogeneic bone marrow transplantation because of its cytotoxic and immunosuppressive properties. A major toxicity of bone marrow transplantation has been interstitial pneumonitis, which may be, in part, related to the lung irradiation. One hundred and sixty-one consecutive patients receiving allogeneic bone marrow transplantation for leukemia and aplastic anemia at Johns Hopkins Hospital (1968-1979) were retrospectively studied. The present study demonstrated that lung shielding to 600 rad maximum in single dose total body irradiation, fractionation of total body irradiation in comparison to single dose total body irradiation, and absence of graft versus host disease in the leukemia patients, each reduced the risk of interstitial pneumonitis. Total body irradiation significantly reduced the leukemia recurrence rate and/or the failure of remission induction.

Multimodality treatment of patients with advanced ovarian carcinoma.

A multimodality treatment program has been applied to ovarian carcinoma at the Johns Hopkins Hospital since August 1975. Forty-nine patients were subdivided into 23 patients with maximally resected Stage III micrometastatic, and 26 patients with significant retained disease, 20 with Stage III macrometastatic and 6 with Stage IV. After initial pilot studies, those patients with minimally retained disease entered a randomized prospective study. Antiovarian antiserum was used in one arm of the study; in both study arms colloidal P-32, delayed split whole abdominal irradiation, and maintenance melphalan were used. For the 23 patients with micrometastatic disease the cumulative survival and survival without evidence of disease at four years is 78 and 34% respectively. Twenty-six patients with macrometastatic disease were treated with or without intraperitoneal antiserum and multiagent chemotherapy; their cumulative one year survival is 50%. The lack of significant toxicity of intraperitoneal antiovarian antiserum and the results of multimodality therapy indicate the feasibility of this therapeutic approach to further improve ovarian cancer therapy.

Antinociceptive activity of glycosidic enkephalin analogues.

The antinociceptive activity of two new enkephalin analogues: N1.5-(beta-D-glucopyranosyl)[D-Met2, Pro5]enkephalinamide and N1.5-(beta-D-galactopyranosyl)[D-Met2, Pro5]enkephalinamide was assessed using the tail immersion and paw pressure behavioural tests. Both enkephalin analogues appear to be more active than morphine when injected either into the fourth ventricle or intrathecally; the galactose analogue is more than 5000 times more active than morphine when injected into the fourth ventricle. The analgesic effects produced by the analogues are partially reversed by SC naloxone (0.1 mg/kg) and totally reversed when the dose of naloxone used was 1 mg/kg, suggesting that the analogues act upon more than one type of opiate receptor (mu/delta).

Study of h-TSH immunoreactive adenohypophyseal cells following treatment with methymazole.

The TSH-producing adenohypohyseal cells of Wistar rats were studied after treatment with orally administered methymazole by the PAP immunocytochemical method. These cells were compared with those of normal animals. The effects of methymazole were different in the females to those observed in males. In both sexes, the numerical density (number of TSH cells per 1000 microns 2) increased after treatment. The cellular and cytoplasmic areas increased in the females while they decreased in the males. The nuclear area and the nuclear area/cytoplasmic area ratio increased in the males and decreased in the females following treatment with methymazole. This treatment caused the appearance of large, intensely stained cells, with an eccentric nucleus and cytoplasmic processes accompanied by weakly stained cells that were situated close to blood vessels.

Development of hypertension in rats during chronic exposure to cold.

Resting systolic, diastolic, and mean blood pressures (MBP), as well as heart rates, of unanesthetized, unrestrained, cold-acclimated (CA, 4 wk, 6 degrees C) rats were measured by direct arterial cannula and compared with those of controls maintained at 25 degrees C. Exposure to cold increased all these measurements significantly. Mean heart weight of CA rats was also increased significantly above that of controls. The responsiveness of MBP and heart rate to administration of the beta-adrenergic agonist, isoproterenol (3, 5, and 8 micrograms/kg ip), to unanesthetized, unrestrained, CA rats during exposure to air at 6 degrees C was similar to, and possibly less than, that of warm-acclimated (WA) rats measured at 25 degrees C. Acute administration of the alpha-adrenergic agonist, phenylephrine (100 micrograms/kg ip), to CA rats while in air at 6 degrees C induced less of a change in MBP from pretreatment level than was observed in WA rats. However, no differences were observed between groups when changes in heart rate from pretreatment level were compared. A similar statement may be made for a higher dose of phenylephrine (150 micrograms/kg ip), although MBP were elevated to higher levels in both groups with the higher dose. Abrupt exposure of WA rats to cold (6 degrees C) resulted in a sharp increase in heart rate and a more gradual increase in MBP over a period of 1 h. Removal of CA rats from 6 to 25 degrees C resulted in a gradual decrease in heart rate with no significant change in MBP during the ensuing hour.(ABSTRACT TRUNCATED AT 250 WORDS)

New glycosylpeptides with high antinociceptive activity.

The antinociceptive activity of two new synthetic glucoside and galactoside enkephalinamide analogues was studied. The effects produced by the new analogues were compared with those obtained with [D-Met2,Hyp5]enkephalinamide and with morphine. The analogues were injected into the fourth ventricle and intrathecally. Tail immersion and paw pressure behavioural tests were used to assess antinociception. One of the analogues studied, O1,5-[beta-D-galactopyranosyl] [D-Met2,Hyp5]enkephalinamide appears to be 57,000 times more potent than morphine.