Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.     

Development of a brief screening instrument: the HANDS

BACKGROUND: The present study was designed to develop a briefer screening scale of approximately 10 items which maintained the validity of the Zung Self-Rating Depression Scale in a sample similar to that attending National Depression Screening Day (NDSD), as well as a more general audience. METHODS: We first administered 70 items from a variety of existing rating scales to 40 subjects who answered an ad for depressed subjects and 55 who answered an ad for non-depressed subjects, all of whose diagnoses were confirmed by the Structured Clinical Interview for DSM-IV (SCID). Based on the correlation between each item and the diagnostic criterion, we reduced the number of items to 17 which we then administered to another 45 subjects who answered an ad similar to that used for NDSD and also underwent a SCID interview. Based on these results, we arrived at the final 10-item Harvard Department of Psychiatry/NDSD scale (HANDS) with the assistance of the item-response theory. The items are scored for frequency of occurrence of each symptom over the past 2 weeks. Total scores range from 0 to 30. RESULTS: The 10-item scale (HANDS) has good internal consistency and validity: a cutpoint score of 9 or greater gave sensitivity of at least 95% in both studies. Although specificity was lower for all scales in the self-selected population, the HANDS performed at least as well as the 20-item Zung Scale, the 21-item Beck Depression Inventory-II and the 15-item Hopkins Symptom Depression Checklist. CONCLUSION: The 10-item HANDS performs as well as other widely used longer self-report scales and has the advantage of briefer administration time.     

Orosensory Perception of Fat/Sweet Stimuli and Appetite-Regulating Peptides before and after Sleeve Gastrectomy or Gastric Bypass in Adult Women with Obesity

The aim of this study was to explore the impact of bariatric surgery on fat and sweet taste perceptions and to determine the possible correlations with gut appetite-regulating peptides and subjective food sensations. Women suffering from severe obesity (BMI > 35 kg/m²) were studied 2 weeks before and 6 months after a vertical sleeve gastrectomy (VSG, n = 32) or a Roux-en-Y gastric bypass (RYGB, n = 12). Linoleic acid (LA) and sucrose perception thresholds were determined using the three-alternative forced-choice procedure, gut hormones were assayed before and after a test meal and subjective changes in oral food sensations were self-reported using a standardized questionnaire. Despite a global positive effect of both surgeries on the reported gustatory sensations, a change in the taste sensitivity was only found after RYGB for LA. However, the fat and sweet taste perceptions were not homogenous between patients who underwent the same surgery procedure, suggesting the existence of two subgroups: patients with and without taste improvement. These gustatory changes were not correlated to the surgery-mediated modifications of the main gut appetite-regulating hormones. Collectively these data highlight the complexity of relationships between bariatric surgery and taste sensitivity and suggest that VSG and RYGB might impact the fatty taste perception differently.     

Clinical manifestations and outcomes of coronavirus disease-19 in heart transplant recipients: a multicentre case series with a systematic review and meta-analysis

Available data on clinical presentation and mortality of coronavirus disease-2019 (COVID-19) in heart transplant (HT) recipients remain limited. We report a case series of laboratory-confirmed COVID-19 in 39 HT recipients from 3 French heart transplant centres (mean age 54.4 ± 14.8 years; 66.7% males). Hospital admission was required for 35 (89.7%) cases including 14/39 (35.9%) cases being admitted in intensive care unit. Immunosuppressive medications were reduced or discontinued in 74.4% of the patients. After a median follow-up of 54 (19–80) days, death and death or need for mechanical ventilation occurred in 25.6% and 33.3% of patients, respectively. Elevated C-reactive protein and lung involvement ≥50% on chest computed tomography (CT) at admission were associated with an increased risk of death or need for mechanical ventilation. Mortality rate from March to June in the entire 3-centre HT recipient cohort was 56% higher in 2020 compared to the time-matched 2019 cohort (2% vs. 1.28%, P = 0.15). In a meta-analysis including 4 studies, pre-existing diabetes mellitus (OR 3.60, 95% CI 1.43–9.06, I² = 0%, P = 0.006) and chronic kidney disease stage III or higher (OR 3.79, 95% CI 1.39–10.31, I² = 0%, P = 0.009) were associated with increased mortality. These findings highlight the aggressive clinical course of COVID-19 in HT recipients.     

Integral storage and voiding reflexes. Neurophysiologic concept of continence and micturition

It is a common clinical misconception to regard the spinal micturition reflex center as fundamentally overactive and dependent on cerebral inhibition. Initiation and cessation of micturition is simplistically viewed as a manifestation of voluntary withdrawal and resumption of inhibitory corticospinal "regulation'. This view is in conflict with basic neurophysiologic experimental data. Actually, the organization of the micturition reflex is extremely complex. It is affected by multiple sources of facilitative and inhibitory influence, peripheral as well as central. During the past half century, at least twelve reflexes involved in urine storage and coordinated micturition have been described by various neurologic investigators. In this article the integral reflexes are identified and described. A functional organization of the integral reflexes which includes a modern concept of their role in the physiology of urine storage and micturition is presented. It is implicit that overactivity or functional failure of any one or combination of the integral reflexes may cause a significant disorder of lower urinary tract function.     

Surgical management of malignant melanoma using dynamic lymphoscintigraphy and gamma probe-guided sentinel lymph node biopsy: the Emory experience

Sentinel lymph node (SLN) biopsy is revolutionizing the surgical management of primary malignant melanoma. It allows accurate nodal staging which targets patients who may benefit from regional lymphadenectomy and systemic therapy. This is a retrospective review of patients treated at Emory University for stage I and II malignant melanoma with gamma probe-guided SLN biopsy from 1/1/94 to 6/30/98. Three hundred sixty patients (males 228, females 132) were identified. Primary melanoma sites included: head and neck 58, trunk 148, and extremities 154 (upper 71, lower 83). Primary tumor staging was T1 9, T2 134, T3 153, and T4 64. SLNs were successfully identified in 99.7 per cent of patients and 98.9 per cent of nodal basins mapped. In 275 (76.6%) cases a single draining nodal basin was identified. In 84 (23.3%) cases there were multiple draining nodal basins. Positive SLNs were identified in 63 patients (17.5%). SLN positivity by tumor staging was T1 0 per cent, T2 9.0 per cent, T3 22.2 per cent, and T4 26.6 per cent. The overall recurrence rate was 11.9 per cent. Recurrences by SLN status were SLN+, 27 per cent, and SLN-, 8.8 per cent. Regional recurrence occurred in 7 (2.4%) of the 297 with negative SLN biopsies and 7 (11.1%) of the 63 with positive SLN biopsies. Dynamic lymphoscintigraphy and gamma probe-guided SLN localization was successful in more than 98 per cent of cases. Patients with negative SLN biopsies have a low risk of recurrence.