24-hour blood pressure recording in patients with orthostatic hypotension.

Continuous intra-arterial blood pressure measurement and electrocardiograms were obtained in two ambulatory patients with orthostatic hypotension due to autonomic dysfunction. Systolic and diastolic arterial pressure presented marked variations which took place mainly during the day and were related to several physical activities; however, marked falls in blood pressure were also observed during sleep and at the moment of arousal. A peak incidence of hypotensive events was found in the afternoon, mainly in the hours following the afternoon meal. Recording was repeated after 3 weeks of treatment with propranolol, 40 mg t.i.d. In patient 1, beta blockade drastically reduced the number and severity of hypotensive episodes, while propranolol failed to control blood pressure in patient 2, who experienced a higher number of hypotensive events during treatment. Findings of this study may be relevant to the management of patients with orthostatic hypotension and should contribute to a more accurate characterization of blood pressure profile in autonomic dysfunction

Salmeterol, a \u3b22 Adrenergic Agonist, Promotes Adult Hippocampal Neurogenesis in a Region-Specific Manner.

Neurogenesis persists in the subgranular zone of the hippocampal formation in the adult mammalian brain. In this area, neural progenitor cells (NPCs) receive both permissive and instructive signals, including neurotransmitters, that allow them to generate adult-born neurons which can be functionally integrated in the preexisting circuit. Deregulation of adult hippocampal neurogenesis (ahNG) occurs in several neuropsychiatric and neurodegenerative diseases, including major depression, and represents a potential therapeutic target. Of interest, several studies suggested that, both in rodents and in humans, ahNG is increased by chronic administration of classical monoaminergic antidepressant drugs, suggesting that modulation of this process may participate to their therapeutic effects. Since the established observation that noradrenergic innervations from locus coeruleus make contact with NPC in the dentate gyrus, we investigated the role of beta adrenergic receptor (\u3b2-AR) on ahNG both in vitro and in vivo. Here we report that, in vitro, activation of \u3b22-AR by norepinephrine and \u3b22-AR agonists promotes the formation of NPC-derived mature neurons, without affecting NPC survival or differentiation toward glial lineages. Additionally, we show that a selective \u3b22-AR agonist able to cross the blood-brain barrier, salmeterol, positively modulates hippocampal neuroplasticity when chronically administered in adult na\uefve mice. Indeed, salmeterol significantly increased number, maturation, and dendritic complexity of DCX+ neuroblasts. The increased number of DCX+ cells was not accompanied by a parallel increase in the percentage of BrdU+/DCX+ cells suggesting a potential prosurvival effect of the drug on neuroblasts. More importantly, compared to vehicle, salmeterol promoted ahNG, as demonstrated by an increase in the actual number of BrdU+/NeuN+ cells and in the percentage of BrdU+/NeuN+ cells over the total number of newly generated cells. Interestingly, salmeterol proneurogenic effects were restricted to the ventral hippocampus, an area related to emotional behavior and mood regulation. Since salmeterol is commonly used for asthma therapy in the clinical setting, its novel pharmacological property deserves to be further exploited with a particular focus on drug potential to counteract stress-induced deregulation of ahNG and depressive-like behavior

Short high fat diet triggers reversible and region specific effects in DCX+ hippocampal immature neurons of adolescent male mice

Adolescence represents a crucial period for maturation of brain structures involved in cognition. Early in life unhealthy dietary patterns are associated with inferior cognitive outcomes at later ages; conversely, healthy diet is associated with better cognitive results. In this study we analyzed the effects of a short period of hypercaloric diet on newborn hippocampal doublecortin+ (DCX) immature neurons in adolescent mice. Male mice received high fat diet (HFD) or control low fat diet (LFD) from the 5th week of age for 1 or 2 weeks, or 1 week HFD followed by 1 week LFD. After diet supply, mice were either perfused for immunohistochemical (IHC) analysis or their hippocampi were dissected for biochemical assays. Detailed morphometric analysis was performed in DCX+ cells that displayed features of immature neurons. We report that 1 week-HFD was sufficient to dramatically reduce dendritic tree complexity of DCX+ cells. This effect occurred specifically in dorsal and not ventral hippocampus and correlated with reduced BDNF expression levels in dorsal hippocampus. Both structural and biochemical changes were reversed by a return to LFD. Altogether these studies increase our current knowledge on potential consequences of hypercaloric diet on brain and in particular on dorsal hippocampal neuroplasticity

Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study

Objective To examine the duration and magnitude of increased risk of venous thromboembolism after different types of surgery

Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease.

Objectives: Neuropsychiatric symptoms are common in patients with Alzheimer disease (AD). Treatment for both AD and psychiatric disturbances may affect the clinical observed pattern and comorbidity. The authors aimed to identify whether particular neuropsychiatric syndromes occur in untreated patients with AD, establish the severity of syndromes, and investigate the relationship between specific neuropsychiatric syndromes and AD disease severity. Design: Cross-sectional, multicenter, clinical study. Participants: A total of 1,015 newly diagnosed, untreated outpatients with AD from five Italian memory clinics were consecutively enrolled in the study from January 2003 to December 2005. Measurements: All patients underwent thorough examination by clinical neurologists/geriatricians, including neuropsychiatric symptom evaluation with the Neuropsychiatric Inventory. Results: Factor analysis revealed five distinct neuropsychiatric syndromes: the apathetic syndrome (as unique syndrome) was the most frequent, followed by affective syndrome (anxiety and depression), psychomotor (agitation, irritability, and aberrant motor behavior), psychotic (delusions and hallucinations), and manic (disinhibition and euphoria) syndromes. More than three quarters of patients with AD presented with one or more of the syndromes (N 790, 77.8%), and more than half exhibited clinically significant severity of symptoms (N 603, 59.4%). With the exception of the affective one, all syndromes showed an increased occurrence with increasing severity of dementia. Conclusions: The authors’ study supports the use of a syndrome approach for neuropsychiatric evaluation in patients with AD. Individual neuropsychiatric symptoms can be reclassified into five distinct psychiatric syndromes. Clinicians should incorporate a thorough psychiatric and neurologic examination of patients with AD and consider therapeutic strategies that focus on psychiatric syndromes, rather than specific individual symptoms

Acellular dermal matrix used in diabetic foot ulcers: Clinical outcomes supported by biochemical and histological analyses

Diabetic foot ulcer (DFU) is a diabetes complication which greatly impacts the patient’s quality of life, often leading to amputation of the affected limb unless there is a timely and adequate management of the patient. DFUs have a high economic impact for the national health system. Data have indeed shown that DFUs are a major cause of hospitalization for patients with diabetes. Based on that, DFUs represent a very important challenge for the national health system. Especially in developed countries diabetic patients are increasing at a very high rate and as expected, also the incidence of DFUs is increasing due to longevity of diabetic patients in the western population. Herein, the surgical approach focused on the targeted use of the acellular dermal matrix has been integrated with biochemical and morphological/histological analyses to obtain evidence-based information on the mechanisms underlying tissue regeneration. In this research report, the clinical results indicated decreased postoperative wound infection levels and a short healing time, with a sound regeneration of tissues. Here we demonstrate that the key biomarkers of wound healing process are activated at gene expression level and also synthesis of collagen I, collagen III and elastin is prompted and modulated within the 28-day period of observation. These analyses were run on five patients treated with Integra® sheet and five treated with the injectable matrix Integra® Flowable, for cavitary lesions. In fact, clinical evaluation of improved healing was, for the first time, supported by biochemical and histological analyses. For these reasons, the present work opens a new scenario in DFUs treatment and follow-up, laying the foundation for a tailored protocol towards complete healing in severe pathological conditions

Long-Term Prognostic Impact of Right Ventricular Dysfunction in Patients with COVID-19

The characteristics and clinical course of hospitalized patients with coronavirus disease 2019 (COVID-19) have been widely described, while long-term data are still poor. The aim of this study was to evaluate the long-term clinical outcome and its association with right ventricular (RV) dysfunction in hospitalized patients with COVID-19. This was a prospective multicenter study of consecutive COVID-19 patients hospitalized at seven Italian Hospitals from 28 February to 20 April 2020. The study population was divided into two groups according to echocardiographic evidence of RV dysfunction. The primary study outcome was 1-year mortality. The propensity score matching was performed to balance for potential baseline confounders. The study population consisted of 224 patients (mean age 69 \ub1 14, male sex 62%); RV dysfunction was diagnosed in 63 cases (28%). Patients with RV dysfunction were older (75 vs. 67 years, p < 0.001), had higher prevenance of coronary artery disease (27% vs. 11%, p = 0.003), and lower left ventricular ejection fraction (50% vs. 55%, p <0.001). The rate of 1-year mortality (67% vs. 28%; p 64 0.001) was significantly higher in patients with RV dysfunction compared with patients without. After propensity score matching, patients with RV dysfunction showed a worse long-term survival (62% vs. 29%, p <0.001). The multivariable Cox regression model showed an independent association of RV dysfunction with 1-year mortality. RV dysfunction is a relatively common finding in hospitalized COVID-19 patients, and it is independently associated with an increased risk of 1-year mortality

The Effects of Granulocyte Colony-Stimulating Factor in Patients with a Large Anterior Wall Acute Myocardial Infarction to Prevent Left Ventricular Remodeling. A 10-Year Follow-Up of the RIGENERA Study

Background: the RIGENERA trial assessed the efficacy of granulocyte-colony stimulating factor (G-CSF) in the improvement of clinical outcomes in patients with severe acute myocardial infarction. However, there is no evidence available regarding the long-term safety and efficacy of this treatment. Methods: in order to evaluate the long-term effects on the incidence of major adverse events, on the symptom burden, on the quality of life and the mean life expectancy and on the left ventricular (LV) function, we performed a clinical and echocardiographic evaluation together with an assessment using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Seattle Heart Failure Model (SHFM) at 10-years follow-up, in the patients cohorts enrolled in the RIGENERA trial. Results: thirty-two patients were eligible for the prospective clinical and echocardiography analyses. A significant reduction in adverse LV remodeling was observed in G-CSF group compared to controls, 9% vs. 48% (p = 0.030). The New York Heart Association (NYHA) functional class was lower in G-CSF group vs. controls (p = 0.040), with lower burden of symptoms and higher quality of life (p = 0.049). The mean life expectancy was significantly higher in G-CSF group compared to controls (15 +/- 4 years vs. 12 +/- 4 years, p = 0.046. No difference was found in the incidence of major adverse events. Conclusions: this longest available follow-up on G-CSF treatment in patients with severe acute myocardial infarction (AMI) showed that this treatment was safe and associated with a reduction of adverse LV remodeling and higher quality of life, in comparison with standard-of-care treatment

Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease

KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate transfer RNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical, and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction, and immuno-hematological problems are emerging phenotypes in KARS1-related disorder. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients