Abnormal cardiac function in the streptozotocin-induced non-insulin-dependent diabetic rat: noninvasive assessment with doppler echocardiography and contribution of the nitric oxide pathway

OBJECTIVES

We sought to evaluate in vivo and in vitro left ventricular (LV) geometry and function in streptozotocin-induced diabetic rats and the possible role of the nitric oxide (NO) pathway.

BACKGROUND

Diabetes results in cardiac dysfunction; however, the specific abnormalities are unknown. Because decreased NO contributes to abnormal vascular function in diabetics, we hypothesized that NO pathway abnormalities may contribute to diabetic cardiomyopathy.

METHODS

Control rats and those with non–insulin-dependent diabetes mellitus (NIDDM) underwent echocardiography, hemodynamic assessment, isolated heart perfusion and measurement of exhaled NO and LV endothelial constitutive nitric oxide synthase (ecNOS).

RESULTS

Diabetic rats had increased LV mass (3.3 ± 0.6 vs. 2.6 ± 0.3 g/g body weight [BW], p < 0.001) and cavity dimensions (diastolic 2.0 ± 0.1 vs. 1.8 ± 0.2 cm/cm tibial length [TL], p < 0.05). Diabetic rats had prolonged isovolumic relaxation time (IVRT) (40 ± 8 vs. 26 ± 6 ms, p < 0.0001), increased atrial contribution to diastolic filling (0.47 ± 0.09 vs. 0.30 ± 0.08 m/s, p < 0.0001), and elevated in vivo LV end-diastolic pressure (7 ± 6 vs. 2 ± 1 mm Hg, p = 0.04). Diabetic rats had increased chamber stiffness. Shortening was similar in both groups, despite reduced meridional wall stress in diabetics, suggesting impaired systolic contractility. Exhaled NO was lower in diabetic rats (1.8 ± 0.2 vs. 3.3 ± 0.3 parts per billion, p < 0.01) and correlated with Doppler LV filling. The ecNOS was similar between the groups.

CONCLUSIONS

Diabetic cardiomyopathy is characterized by LV systolic and diastolic dysfunction, the latter correlating with decreased exhaled NO. The NO pathway is intact, suggesting impaired availability of NO as contributor to cardiomyopathy.     

Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV

Journal of NeuroVirology - We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal...     

Mate choice theory and the mode of selection in sexual populations

Indirect new data imply that mate and/or gamete choice are major selective forces driving genetic change in sexual populations. The system dictates nonrandom mating, an evolutionary process requiring both revised genetic theory and new data on heritability of characters underlying Darwinian fitness. Successfully reproducing individuals represent rare selections from among vigorous, competing survivors of preadult natural selection. Nonrandom mating has correlated demographic effects: reduced effective population size, inbreeding, low gene flow, and emphasis on deme structure. Characters involved in choice behavior at reproduction appear based on quantitative trait loci. This variability serves selection for fitness within the population, having only an incidental relationship to the origin of genetically based reproductive isolation between populations. The claim that extensive hybridization experiments with Drosophila indicate that selection favors a gradual progression of "isolating mechanisms" is flawed, because intra-group random mating is assumed. Over deep time, local sexual populations are strong, independent genetic systems that use rich fields of variable polygenic components of fitness. The sexual reproduction system thus particularizes, in small subspecific populations, the genetic basis of the grand adaptive sweep of selective evolutionary change, much as Darwin proposed.     

Cingulo-opercular control network and disused motor circuits joined in standby mode

Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.

Disuse is a powerful paradigm for inducing plasticity that has uncovered key organizing principles of the human brain (1–4). Monocular deprivation—prolonged covering of one eye—revealed that multiple afferent inputs can compete for representational territory in the primary visual cortex (1). Similar competition between afferents also shapes the somatomotor system. Manipulations such as peripheral nerve deafferentation, whisker trimming, and limb constraint all drive plasticity in the primary somatosensory and motor cortex (2–4). Most plasticity studies to date have used focal techniques, such as microelectrode recordings, to study local changes in brain function. As a result, little is known about how behavior and experience shape the brain-wide functional networks that support complex cognitive operations (5).The brain is composed of networks of regions that cooperate to perform specific cognitive functions (5–8). These functional networks show synchronized spontaneous activity while the brain is at rest, a phenomenon known as resting-state functional connectivity (FC) (9–11). FC can be measured noninvasively in humans using resting-state functional MRI (rs-fMRI) and has been used to parse the brain into canonical functional networks (12, 13), including visual, auditory, and somatomotor networks (14, 15); ventral and dorsal attention networks (8, 16); a default mode network with roles in internally directed cognition and episodic memory (7, 11); a salience network thought to assess the homeostatic relevance of external stimuli (17); a frontoparietal control network supporting error processing and moment-to-moment adjustments in behavior (18–20); and a cingulo-opercular control network (CON), which maintains executive control during goal-directed behavior (18, 19, 21). Each functional network likely carries out a variety of additional functions.A more recent advance in human neuroscience has been the recognition of individual variability in network organization (22–25). Most early rs-fMRI studies examined central tendencies in network organization using group-averaged FC measurements (10, 12, 13). Recent work has demonstrated that functional networks can be identified in an individual-specific manner if sufficient rs-fMRI data are acquired, an approach termed precision functional mapping (PFM) (22, 23, 26–30). PFM respects the unique functional anatomy of each person and avoids averaging together functionally distinct brain regions across individuals.We recently demonstrated that PFM can be used to follow the time course of disuse-driven plasticity in the human brain (31). Three adult participants (Nico, Ashley, and Omar) were scanned at the same time of day for 42 to 64 consecutive days (30 min of rs-fMRI per day) before, during, and after 2 wk of dominant upper-extremity casting (Fig. 1 A and B). Casting caused persistent disuse of the dominant upper extremity during daily behaviors and led to a marked loss of strength and fine motor skill in all participants. During casting, the upper-extremity regions of the left primary somatomotor cortex (L-SM1_ue) and right cerebellum (R-Cblm_ue) functionally disconnected from the remainder of the somatomotor network. Disused motor circuits also exhibited large, spontaneous pulses of activity (Fig. 1C). Disuse pulses did not occur prior to casting, started to occur frequently within 1 to 2 d of casting, and quickly waned after cast removal.Open in a separate windowFig. 1.Experimental design and spontaneous activity pulses. (A) Three participants (Nico, Ashley, and Omar) wore casts covering the entire dominant upper extremity for 2 wk. (B) Participants were scanned every day for 42 to 64 consecutive days before, during, and after casting. All scans included 30 min of resting-state functional MRI. (C) During the Cast period, disused somatomotor circuits exhibited large pulses of spontaneous activity. (C, Left) Whole-brain ANOVA showing which brain regions contained disuse-driven pulses. (C, Right) Time courses of all pulses recorded from the disused primary somatomotor cortex.Somatomotor circuits do not function in isolation. Action selection and motor control are thought to be governed by complex interactions between the somatomotor network and control networks, including the CON (18). Prior studies of disuse-driven plasticity, including our own, have focused solely on somatomotor circuits. Here, we leveraged the whole-brain coverage of rs-fMRI and the statistical power of PFM to examine disuse-driven plasticity throughout the human brain.     

Health literacy and diabetic foot ulcer healing

The adherence by patients to diabetic foot ulcer therapy is often difficult. The goal of this study was to begin to understand how a patient's health literacy affects their foot ulcer management decisions. Initially using a cross‐sectional study design, we evaluated diabetics with foot ulcers within 4 weeks of being asked to participate in a longitudinal study. We assessed health literacy using measures of general health literacy, diabetes health literacy, diabetes self‐efficacy, and diabetes numeracy. Individuals enrolled in the study had higher health literacy based on the Short Test of Functional Health Literacy in Adults [33.8 (SD 2.3) versus 27.3 (SD 9.6); p = 0.009] as compared to individuals who previously declined an invitation to enroll in the study. Furthermore, patients with lower Short Test of Functional Health Literacy in Adults scores had larger (p = 0.04) and older (p = 0.125) wounds (markers for poorer prognosis). Other measures of literacy showed similar results. In conclusion, those with diminished health literacy were less likely to enroll in an investigational study and had wounds that were less likely to heal.     

Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life

Objective Testosterone levels are commonly lowered in men with diabetes, but it is unclear how these relate to symptoms of hypogonadism and quality of life. We sought to investigate the relationship between testosterone levels, symptoms of androgen deficiency, erectile function and quality of life in men with type 1 and type 2 diabetes. Design and subjects Cross‐sectional study of 115 men with type 2 diabetes, 93 men with type 1 diabetes and 121 healthy controls. Measurements Total, bioavailable and free testosterone levels were measured or calculated by Vermuelen’s formula. Quality of life and symptom scores were assessed by the Audit of Diabetes Dependent Quality of Life (ADDQoL), androgen deficiency in the aging male (ADAM) and International Index of Erectile Function (IIEF) questionnaires. Results Forty‐five and sixty‐one per cent of men with type 2 diabetes had low total and calculated free testosterone (CFT) levels, respectively. Total testosterone (TT) levels were not lowered in men with type 1 diabetes, but 32% had low CFT. After adjustment for age and waist circumference, only CFT in men with type 2 diabetes (?0·037 nm , 95% CI ?0·075 to ?0·0003, P = 0.048) remained lowered compared with controls. CFT correlated weakly with ADAM (r = ?0·26, 95% CI ?0.42 to ?0·08, P = 0·006), IIEF (r = 0.19, 95% CI 0.01–0.37, P = 0.042) and ADDQoL (r = 0.21, 95% CI 0·03 to 0·38, P = 0·022) scores in men with type 2, but not type 1 diabetes. Age exerted the predominant effect on erectile function in both groups, in a model incorporating age, testosterone level and complications. Conclusions Testosterone levels are strongly affected by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and erectile function. Testosterone levels do not appear to be a major determinant of quality of life in patients with diabetes.     

Approaches to identifying appropriate medication adherence assessments for HIV infected individuals with comorbid bipolar disorder

Assessing medication adherence in already difficult-to-treat HIV-infected subpopulations presents a unique challenge. The objective of this study was to compare different approaches to assessing medication adherence: (1) electronic medication monitoring, (2) standardized self-report questionnaire, and (3) self-report visual analogue scale, and to determine whether antiretroviral therapy (ART) adherence measures differed for HIV-infected persons with bipolar disorder (HIV+?/BD+) as compared to HIV-infected persons without bipolar disorder (HIV+?/BD-). ART adherence was assessed for 74 HIV-positive participants using the Medication Event Monitoring System (MEMS), AIDS Clinical Trials Group (ACTG) adherence questionnaire, and visual analogue scale (VAS). Participants were classified as adherent or nonadherent on each measure by previously validated cutscores. Correlations and logistic regressions were used to examine associations between adherence measures and demographic and clinical variables. In the HIV+?/BD- group, significant correlations existed between each self-report measure and the MEMS. Males comprised 81% of the study population. Participants averaged 44 years of age and 13 years of education. No significant correlations were found among adherence measures in the HIV+?/BD+ group. Among participants reporting adherence on either self-report measure but classified as nonadherent based on MEMS, 94% had a diagnosis of bipolar disorder. Bipolar disorder was a significant predictor of adherence classification discordance among self-report measures. Our findings suggest that it remains difficult to assess ART adherence among HIV-positive individuals with bipolar disorder. Combined approaches of self-report and objective measures may be the best way to estimate adherence, and may provide the best basis for interventions designed to improve adherence in difficult-to-treat populations.     

Ophthalmic manifestations in the COVID-19 clinical spectrum

Purpose:The aim of this study was to determine the frequency and various types of ophthalmic manifestation of patients with COVID-19.Methods:This is a prospective observational study conducted on patients with SARS-Co-V-2 infection, at a dedicated tertiary COVID-19 hospital in South India from April 1 to July 31, 2020. At the time of their admission to the COVID hospital, demographic data such as name, age, sex was recorded. A thorough history regarding the onset, duration, progression, nature of symptoms and its associated factors, medication history, treatment history were elicited and documented. Ocular examination was performed under torchlight by an ophthalmologist posted for COVID duty. Further investigations including imaging were sought for, depending on clinical indications. Serial follow-up examinations of all patients were carried out every 72 hours or when patients complained of any ocular symptoms whichever earlier, until discharge. All relevant data were compiled and statistically analyzed.Results:A total of 2742 patients were examined. Of them, 1461 (53.28%) were males and 1281 (46.72%) were females. The mean age (±SD) was 39.46 ± 17.63 years. None of the patients in our study had any ocular symptoms or signs as the presenting complaint at the time of their admission. On subsequent follow-up, only 20 (0.72%) developed ocular manifestations, of which 19 (95%) had features suggestive of Bilateral viral conjunctivitis. However, 1 (5%) patient had orbital cellulitis secondary to pansinusitis.Conclusion:Ophthalmic manifestations in the clinical spectrum of COVID-19 infection are uncommon and unlikely to be the presenting clinical impression. However, it has broadened our view to a wider spectrum of COVID-19 presentations enhancing our clinical acumen for staunch detection of COVID-19 suspects in our daily practice, augmenting early diagnosis and management and also break the chain of transmission for the greater good of humanity.