Endocrinology in aging

Aging is a time of reduced adaptability to metabolic perturbation. This is particularly true in endocrinology which, after all, is the science of chemically regulated biologic systems. There is no evidence that equilibrium concentrations of the principal hormones are altered with age. However, the systems utilized to reach those equilibria become progressively taxed, and new equilibria may be achieved reflecting that regulatory problem. Thus, with advancing age there are significant alterations in hormone production, metabolism, and action. Some of these changes may play a role in the pathophysiology of senescence, although the evidence for that is limited. The magnitude of age-related alterations is highly variable and sex dependent. Whereas only subtle changes occur in pituitary dynamics, adrenal gland physiology, and thyroid function, the changes in glucose homeostasis, reproductive function, and calcium metabolism are more apparent. In the elderly, the interpretation of endocrine tests should reflect the nutritional status of the patient and the presence of coexisting illnesses. In this review, we describe the principles of endocrinology in the geriatric population and elaborate on the changes in specific glandular functions with aging. We also define strategies of evaluation and management protocols appropriate for the elderly with suspected endocrine dysfunction.     

Endogenous opioids and the exercise-induced augmentation of natural killer cell activity

Based on prior observations that both beta-endorphin and exercise stimulate natural killer (NK) cell activity, we have examined the hypothesis that the release of endogenous opioids during the stress of acute exercise may mediate this NK cell augmentation. Eight healthy young women underwent a maximal bicycle ergometer exercise test with prior in vivo administration of a placebo and an opioid antagonist, naloxone (100 micrograms/kg), in a randomized, blind protocol. Exercise after the placebo injection was accompanied by a dramatic rise in NK activity, as well as an increase in the percentage of lymphocytes bearing the NK cell surface markers Leu 11a and Leu 19. Significant stimulation of NK activity was observed with beta-endorphin in vitro before exercise, but after exercise, beta-endorphin had a nonsignificant inhibitory effect. When these experiments were carried out in the presence of naloxone in vivo, the rise in NK activity after exercise was no longer significant. Naloxone did not significantly alter the rise in Leu 11a+ or Leu 19+ cell after exercise, as compared with the placebo. Finally, when naloxone was given to the subjects beforehand, exercise no longer completely blocked the in vitro beta-endorphin stimulation of NK cells. In conclusion, our observations that the exercise-induced augmentation of NK activity and the lack of effect of beta-endorphin in vitro on NK activity after exercise are both significantly attenuated by prior administration of naloxone suggest that the opioid system may play a major role in the modulation of NK cells during physiologic stress.     

Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions

BackgroundSubanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment.MethodsThirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report.ResultsTwenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37–0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η _p²=0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36).ConclusionA short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01945047","term_id":"NCT01945047"}}NCT01945047     

Establishing Normative Dynamic Postural Control Values in Elite Female Handball Players

BackgroundLower extremity injuries among young female handball players are very common. The modified Star Excursion Balance Test (mSEBT) is a valid clinical tool to assess dynamic postural control and identify athletes with higher risk of injury. However, its interpretation is difficult since performance on this test is highly sport dependent. No normative values on the mSEBT exist in handball.PurposeThe aim of this investigation was to establish normative ranges of mSEBT performance in young, healthy female handball players to help practitioners when interpreting risk estimates.Study designCross-Sectional StudyMethodsAthletes from 14 elite teams were recruited during a national tournament and performed 3 trials in the anterior (ANT), posteromedial (PM), posterolateral (PL) directions of the mSEBT. Means, standard deviations and 95% confidence intervals (95%CI) of normalized reached distances were calculated for each direction and the composite score (COMP). Level of asymmetry between dominant and non-dominant limbs were calculated for each direction using Bland Altman analyses. Group differences were weighed against the established mSEBT minimum detectable differences (MDD) to compare scores between limbs and across different player positions.ResultsOne-hundred and eighty-eight females (16.8±0.9 years) were tested. Mean reach distances were 65.2±5% (64.7-65.7), 110.0±6.2% (109.3-110.6), 107.1±6.2% (106.5-107.8) and 94.1±4.9% (93.6-94.6) for the ANT, PM, PL directions and COMP score respectively. Bias and limits of agreement for limb asymmetry were -0.23% (-5.85%, 5.38%) for ANT, -0.83% (-8.80%, 7.14%) for PM, 0.33% (-8.51%, 9.17%) for PL and -0.27% (-4.88%, 4.33%) for COMP score. No meaningful differences were observed between limbs or across player positions since the values did not exceed the MDD and all 95%CIs overlapped.ConclusionThis study provides normative performance values for dynamic postural control as measured by the mSEBT among young, healthy, elite female handball players. Considering the high incidence of injury in this population, these values can be used for injury risk reduction and return to sport decisions. Further prospective studies are needed to established specific cut-off scores in this population.Level of evidence2c     

Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T‐wave parameters

BackgroundThe T wave of the electrocardiogram (ECG) reflects ventricular repolarization. Repolarization heterogeneity is associated with reentrant arrhythmias. Several T‐wave markers (including QT interval) have been associated with ventricular arrhythmias, but studies linking such markers to underlying local repolarization time (RT) inhomogeneities are lacking. We aimed to investigate the relation of several T‐wave markers to controlled drug‐induced regional RT gradients in intact pig hearts.MethodsRepolarization time gradients were created by regional infusion of dofetilide and pinacidil in four atrially paced porcine Langendorff‐perfused hearts placed inside a torso tank. From the 12‐lead ECG on the torso tank, the mean, maximum, and dispersion (max–min) of QT_time, JT_time, T_peak–end, T_width, TQ_ratio, dV/dt_max, T_area, T_amp, and T‐upslope duration were determined, as well as upslope end difference between leads V₁ and V₆.ResultsTemporal T‐wave parameters T_peak–end, T_width, and TQ_ratio show a significant and high correlation with RT gradient, best reflected by mean value. T_area (mean, max and dispersion) and dV/dt_max dispersion show only a moderate significant correlation. T‐upslope duration shows a significant correlation in particular for mean values. Mean, maximum, or dispersion of QT_time and V₁–V₆ upslope end difference were not significantly correlated with RT gradient.ConclusionComposite 12‐lead ECG T‐wave parameters T_peak–end, T_width, TQ_ratio, upslope duration, and T_area show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QT_time do not reflect local RT heterogeneity. The composite T‐wave metrics may thus provide better insights in arrhythmia susceptibility than traditional QT_time metrics.     

Genetic and genomic analysis of acute lymphoblastic leukemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials

Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and <1% of patients, respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1^plus profile was identified in over a third (28/77) of cases of B-cell precursor ALL. The genetic good-risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP arrays and 9% (2/23) of NGS samples, and represent novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with 5-year event-free and overall survival rates of 17% and 24%, respectively, across the cohort, indicating a need for novel therapeutic strategies.     

Dynamics and Patterning of 5-Hydroxytryptamine 2 Subtype Receptors in JC Polyomavirus Entry

The organization and dynamics of plasma membrane receptors are a critical link in virus-receptor interactions, which finetune signaling efficiency and determine cellular responses during infection. Characterizing the mechanisms responsible for the active rearrangement and clustering of receptors may aid in developing novel strategies for the therapeutic treatment of viruses. Virus-receptor interactions are poorly understood at the nanoscale, yet they present an attractive target for the design of drugs and for the illumination of viral infection and pathogenesis. This study utilizes super-resolution microscopy and related techniques, which surpass traditional microscopy resolution limitations, to provide both a spatial and temporal assessment of the interactions of human JC polyomavirus (JCPyV) with 5-hydroxytrypamine 2 receptors (5-HT₂Rs) subtypes during viral entry. JCPyV causes asymptomatic kidney infection in the majority of the population and can cause fatal brain disease, and progressive multifocal leukoencephalopathy (PML), in immunocompromised individuals. Using Fluorescence Photoactivation Localization Microscopy (FPALM), the colocalization of JCPyV with 5-HT₂ receptor subtypes (5-HT_2A, 5-HT_2B, and 5-HT_2C) during viral attachment and viral entry was analyzed. JCPyV was found to significantly enhance the clustering of 5-HT₂ receptors during entry. Cluster analysis of infected cells reveals changes in 5-HT₂ receptor cluster attributes, and radial distribution function (RDF) analyses suggest a significant increase in the aggregation of JCPyV particles colocalized with 5-HT₂ receptor clusters in JCPyV-infected samples. These findings provide novel insights into receptor patterning during viral entry and highlight improved technologies for the future development of therapies for JCPyV infection as well as therapies for diseases involving 5-HT₂ receptors.     

Outbreak of OXA-48-producing Enterobacterales in a haematological ward associated with an uncommon environmental reservoir,France, 2016 to 2019

The hospital water environment, including the wastewater drainage system, is increasingly reported as a potential reservoir for carbapenemase-producing Enterobacterales (CPE). We investigated a persistent outbreak of OXA-48 CPE (primarily Citrobacter freundii) in a haematological ward of a French teaching hospital by epidemiological, microbiological and environmental methods. Between January 2016 and June 2019, we detected 37 new OXA-48 CPE-colonised and/or ‑infected patients in the haematological ward. In October 2017, a unit dedicated to CPE-colonised and/or ‑infected patients was created. Eleven additional sporadic acquisitions were identified after this date without any obvious epidemiological link between patients, except in one case. Environmental investigations of the haematological ward (June–August 2018) identified seven of 74 toilets and one of 39 drains positive for OXA-48 CPE (seven C. freundii, one Enterobacter sakazakii, one Escherichia coli). Whole genome comparisons identified a clonal dissemination of OXA-48-producing C. freundii from the hospital environment to patients. In addition to strict routine infection control measures, an intensive cleaning programme was performed (descaling and bleaching) and all toilet bowls and tanks were changed. These additional measures helped to contain the outbreak. This study highlights that toilets can be a possible source of transmission of OXA-48 CPE.