Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system (CNS). Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 10⁵ plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed on day 3 and declined on days 5 and 6 after infection. By contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals on days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.     

Prevalence and correlates of alcohol use disorders in the Singapore Mental Health Survey

Aims To establish the prevalence, correlates, comorbidity and treatment gap of alcohol use disorders in the Singapore resident population. Design The Singapore Mental Health Study is a cross‐sectional epidemiological survey. Setting A nationally representative survey of the resident (citizens and permanent residents) population in Singapore. Participants A total of 6616 Singaporean adults aged 18 years and older. Measurements The diagnoses were established using the World Mental Health Composite International Diagnostic Interview (WMH‐CIDI) diagnostic modules for life‐time and 12‐month prevalence of selected mental illnesses including alcohol use disorders. Findings The life‐time prevalence of alcohol abuse and alcohol dependence was 3.1% and 0.5%, while the 12‐month prevalence of alcohol abuse and alcohol dependence was 0.5% and 0.3%, respectively. The life‐time and 12‐month prevalence of alcohol use disorders was 3.6% and 0.8%, respectively. Those with alcohol use disorder had significantly higher odds of having major depressive disorder [odds ratio (OR) 3.1] and nicotine dependence (OR 4.5). Compared to the rest of the population, those with an alcohol use disorder had significantly higher odds of having gastric ulcers (OR 3.0), respiratory conditions (OR 2.1) and chronic pain (OR 2.1). Only one in five of those with alcohol use disorder had ever sought treatment. Conclusions The prevalence of alcohol use disorders is relatively low in the Singapore adult population. Comorbidity with mental and physical disorders is significant, emphasizing the need to screen people with alcohol use disorders for these comorbidities.     

Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog

The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release-inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo. Chga mice displayed extreme phenotypic changes, including: (a) decreased chromaffin granule size and number; (b) elevated BP; (c) loss of diurnal BP variation; (d) increased left ventricular mass and cavity dimensions; (e) decreased adrenal catecholamine, neuropeptide Y (Npy), and ATP contents; (f) increased catecholamine/ATP ratio in the chromaffin granule; and (g) increased plasma catecholamine and Npy levels. Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement or humanization of Chga mice. Loss of the physiological "brake" catestatin in Chga mice coupled with dysregulation of transmitter storage and release may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.     

Mental disorders: employment and work productivity in Singapore

Aim

To examine the association between mental disorders and work disability in the adult resident population in Singapore.

Method

Data are from the Singapore Mental Health Study, which was a household survey of a nationally representative sample. The main instrument used was the Composite International Diagnostic Interview (CIDI). Employment-related information was collected using the modified employment module of the CIDI.

Results

A total of 6,429 respondents were included in the analysis, 71 % (n = 4,594) were employed, 24.5 % (n = 1,522) were economically inactive and 4.5 % (n = 313) were unemployed. Among the employed, 2.3 % had a 12-month prevalence of at least one mental disorder, while 5.3 % of the unemployed had at least one mental disorder. The average number of work loss days (absenteeism) per capita among those with a mental disorder was 0.5 per month that is equivalent to an annualized national projection of approximately 0.3 million productivity days. The average work-cutback days (presenteeism) were 0.4 days among this group. Of the mentally ill in the workforce, a high proportion (86.5 %) did not ever seek help for problems related to mental health.

Conclusion

Our findings provide information on the significant consequences of mental disorders on the workforce in terms of lost work productivity, which could pave the way for a more rational allocation of scarce resources.     

From well-being to positive mental health: conceptualization and qualitative development of an instrument in Singapore

Purpose

There is no global definition of well-being. Cultural differences in the perception of well-being and the social and behavioral contexts further limit its measurement. Existing instruments are developed in Western societies that differ in their conceptualization of well-being from Asian populations. Moreover, very few instruments address the multidimensional construct of well-being.

Methods

Literature was reviewed to develop a priori conceptual framework of mental health and well-being. Concepts were identified based on specific criteria to guide the qualitative investigations. Finally, focus group discussions were conducted among adults belonging to the three major ethnicities in Singapore to identify salient domains of mental health and well-being.

Results

Mental well-being is a multidimensional construct constituting of positive affect, satisfaction, and psychological functioning. While well-being explains the functional and psychological components, positive mental health is a combination of these and the skills required to achieve them. Although there is an overlap between the concepts identified from the literature and those identified in Singapore, certain differences existed, particularly with the relevance attributed to family interactions and religiosity or spirituality. Similar findings were observed across the three ethnic groups.

Conclusion

Domains identified can be used to develop a culturally relevant instrument in Singapore.     

End-to-side venous anastomoses....a patency test.

A hitherto unpublished means of testing the patency across an end-to-side venous anastomosis is described. It relies on the elasticity of the venous walls to produce ballooning when the appropriate segments of the veins are occluded and blood is flowing unimpeded across the end-to-side anastomosis. It is foolproof, easy to perform and has no ambiguity in its interpretation.     

Catestatin--a novel neuropeptide in carcinoid tumors of the appendix

BACKGROUND: The aim of the study was to investigate the immunohistochemical distribution of the novel neuropeptide catestatin in carcinoid tumors. Catestatin, a novel 21 amino acid neuropeptide derived from chromogranin A, was determined immunohistochemically in 30 carcinoid tumors of the appendix and various carcinoid tumors of other localities. MATERIALS AND METHODS: Paraffin-embedded tissues from 30 carcinoid tumors of the appendix and 16 other carcinoid tumors (5 bronchus-, 5 stomach-, 2 small bowel-, 4 large bowel carcinoid tumors) were incubated with antibodies specific for catestatin, chromogranin A and chromogranin B. Immunohistochemical staining of catestatin was compared to staining with chromogranin A and B. Western blot analysis was performed in one patient with ileal carcinoid. RESULTS: Thirty patients (20 women, 10 men) with carcinoid tumors of the appendix and 16 patients with other localized carcinoid tumors were investigated. Twenty-six of the appendiceal tumors were localized in the apex of the appendix and 4 tumors in the midportion; none of the tumors was localized at the base of the appendix. Median tumor diameter was 10.7 mm (range 4-18 mm). Immunoreactivity to catesatatin was positive in 28 patients (negative in 2, 0-10% in 11 patients, 11-50% in 14 patients, 51-100% in 3 patients). In 16 patients with carcinoid tumors in various other localizations, catestatin was also expressed. Western blot analysis of ileal carcinoid showed abundant catestatin reactivity with accelerated processing of chromogranin A in the tumor tissue. CONCLUSION: Catestatin derived from chromogranin A, which is the most widely distributed marker of neuroendocrine tumors, is expressed in high frequency in carcinoid tumors of the appendix (93.3%).