Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects.

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.

Extracellular Vesicles of COVID-19 Patients Reflect Inflammation, Thrombogenicity, and Disease Severity.

Severe COVID-19 infections present with cytokine storms, hypercoagulation, and acute respiratory distress syndrome, with extracellular vesicles (EVs) being involved in coagulation and inflammation. This study aimed to determine whether coagulation profiles and EVs reflect COVID-19 disease severity. Thirty-six patients with symptomatic COVID-19 infection with mild/moderate/severe disease (12 in each group) were analyzed. Sixteen healthy individuals served as controls. Coagulation profiles and EV characteristics were tested by nanoparticle tracking analysis (NTA), flow cytometry, and Western blot. While coagulation factors VII, V, VIII, and vWF were comparable, significant differences were found in patients' D-Dimer/fibrinogen/free protein S levels compared to controls. Severe patients' EVs displayed higher percentages of small EVs (<150 nm) with increased expression of exosome marker CD63. Severe patients' EVs displayed high levels of platelet markers (CD41) and coagulation factors (tissue factor activity, endothelial protein C receptor). EVs of patients with moderate/severe disease expressed significantly higher levels of immune cell markers (CD4/CD8/CD14) and contained higher levels of IL-6. We demonstrated that EVs, but not the coagulation profile, may serve as biomarkers for COVID-19 severity. EVs demonstrated elevated levels of immune- and vascular-related markers in patients with moderate/severe disease, and may play a role in disease pathogenesis.

Effect of ingesting a meal and orthostasis on the regulation of splanchnic and systemic hemodynamics and the responsiveness of cardiovascular α1-adrenoceptors.

Postprandial orthostasis activates mechanisms of cardiovascular homeostasis to maintain normal blood pressure (BP) and adequate blood flow to vital organs. The underlying mechanisms of cardiovascular homeostasis in postprandial orthostasis still require elucidation. Fourteen healthy volunteers were recruited to investigate the effect of an orthostatic challenge (60°-head-up-tilt for 20 min) on splanchnic and systemic hemodynamics before and after ingesting an 800-kcal composite meal. The splanchnic circulation was assessed by ultrasonography of the superior mesenteric and hepatic arteries and portal vein. Systemic hemodynamics were assessed noninvasively by continuous monitoring of BP, heart rate (HR), cardiac output (CO), and the pressor response to an intravenous infusion on increasing doses of phenylephrine, an α1-adrenoceptor agonist. Neurohumoral regulation was assessed by spectral analysis of HR and BP, plasma catecholamine and aldosterone levels and plasma renin activity. Postprandial mesenteric hyperemia was associated with an increase in CO, a decrease in SVR and cardiac vagal tone, and reduction in baroreflex sensitivity with no change in sympathetic tone. Arterial α1-adrenoceptor responsiveness was preserved and reduced in hepatic sinusoids. Postprandial orthostasis was associated with a shift of 500 mL of blood from mesenteric to systemic circulation with preserved sympathetic-mediated vasoconstriction. Meal ingestion provokes cardiovascular hyperdynamism, cardiac vagolysis, and resetting of the baroreflex without activation of the sympathetic nervous system. Meal ingestion also alters α1-adrenoceptor responsiveness in the hepatic sinusoids and participates in the redistribution of blood volume from the mesenteric to the systemic circulation to maintain a normal BP during orthostasis.NEW & NOTEWORTHY A unique integrated investigation on the effect of meal on neurohumoral mechanisms and blood flow redistribution of the mesenteric circulation during orthostasis was investigated. Food ingestion results in cardiovascular hyperdynamism, reduction in cardiac vagal tone, and baroreflex sensitivity and causes a decrease in α1-adrenoceptor responsiveness only in the venous intrahepatic sinusoids. About 500-mL blood shifts from the mesenteric to the systemic circulation during orthostasis. Accordingly, the orthostatic homeostatic mechanisms are better understood.

High prevalence of fibromyalgia among Israeli school teachers.

OBJECTIVES: Fibromyalgia syndrome (FM), characterised by widespread pain and fatigue, has frequently been associated with stress in various models, including workplace related stress. In the current study we have evaluated the prevalence of FM symptoms among Israeli school teachers and have attempted to correlate such symptoms with work-related stress. METHODS: Individuals, all currently employed as school teachers in Israel, were recruited to the study. Participants were asked to answer a questionnaire evaluating symptoms of FM, based on the current diagnostic criteria, which include the widespread pain index (WPI) and the symptom severity scale (SSS). Participants were further questioned regarding stressful experiences during their work and about post-traumatic symptoms as well as regarding work performance and motivation. RESULTS: 321 participants were recruited (79.4% female, 20.6 male). 30 individuals (9.3%) of the sample fulfilled current criteria for a diagnosis of FM, with a rate of 11.4% among females and 1.5% among males. While specific symptoms such as fatigue and irritable bowel symptoms were negatively correlated with work performance, no significant difference was found between teachers with or without fibromyalgia regarding work attendance and performance. FM symptoms were strongly correlated with work-related stress and were strongly correlated with post-traumatic stress disorder (PTSD) related symptoms. Motivation to work was significantly lower among teachers fulfilling FM criteria, but other performance-related parameters did not differ between teachers fulfilling or not fulfilling FM criteria. CONCLUSIONS: Fibromyalgia symptoms are highly prevalent among Israeli school teachers, and may be related to stress encountered in the classroom. These results are relevant both for physicians treating individuals involved in educational careers as well as for educators and decision-makers involved in planning and managing educational strategies.

Effects of Acute Stress on Thrombosis.

Stress, the nonspecific response to any demand for change, is an adaptive response of the human body to various stimulants. As such, stress-induced hypercoagulation may represent an adaptive response to bleeding. Numerous epidemiological studies have revealed that a correlation exists between stress and thrombotic risk and biochemically, links of the relationship between psychological stress and coagulation pathways have been made. The stress reaction is coupled with neurohormonal changes mediated mainly by the sympathetic neural system and the hypothalamic-pituitary-adrenal axis. Singling out the specific pathways affecting coagulation in this complex response is hampered by many confounders. The mediators of the stress reaction (neurotransmitters and hormones) can directly affect platelets and the coagulation cascade and indirectly affect hemostasis via changes in hemodynamics. In this review, the authors will delineate the distinct neurobiological mechanisms that govern the effects of stress on coagulation, and report their recent findings.

Increased Sympathetic Outflow Induces Adaptation to Acute Experimental Pain.

BACKGROUND: There are interrelationships between the autonomic nervous system and pain. This study aims to explore the effect of different autonomic manipulations on pain perception and modulation. METHODS: Twenty healthy subjects (10 men and 10 women, mean age 25 ± 3 years) participated in this single-blinded, semi-randomized, controlled study, which included 2 study visits. Warm detection thresholds, heat pain thresholds, conditioned pain modulation (CPM), and pain adaptation were tested before and after administration of phenylephrine, clonidine, yohimbine, and saline. RESULTS: Changes in heart rate and blood pressure were found after all the pharmacological interventions. The only effect on pain measures was that yohimbine enhanced pain adaptation capacity while phenylephrine reduced it (P = 0.032). Several significant correlations were found between autonomic and pain parameters; greater decreases in heart rate after phenylephrine were associated with reduced pain ratings (r2 = 0.288, P = 0.018). In addition, enhanced pain adaptation was associated with higher total vascular resistance (r2 = 0.442, P = 0.01). CONCLUSIONS: Different effects of acute autonomic manipulations on experimental pain were found: an increase in sympathetic tone induced by yohimbine led to reduced pain sensitivity; a decrease in sympathetic tone with no effect on vagal-parasympathetic tone induced by phenylephrine led to reduction in pain adaptation capacity; and a decrease in sympathetic tone and increase in vagal parasympathetic tone by clonidine led to no change in pain adaptation capacity. While increased sympathetic outflow does facilitate pain adaptation, activation of either the sympathetic or parasympathetic limbs of the autonomic nervous system does not affect pain thresholds or CPM. Finally, a correlation exists between nociception and cardiovascular parameters only due to baroreflex activation.

Nitric oxide-sensitive guanylyl cyclase signaling affects CO2-dependent but not pressure-dependent regulation of cerebral blood flow.

Cerebrovascular CO2 reactivity is affected by nitric oxide (NO). We tested the hypothesis that sildenafil selectively potentiates NO-cGMP signaling, which affects CO2 reactivity. Fourteen healthy males (34 ± 2 yr) were enrolled in the study. Blood pressure (BP), ECG, velocity of cerebral blood flow (CBF; measured by transcranial Doppler), and end-tidal CO2 (EtCO2) were assessed at baseline (CO2 ~39 mmHg), during hyperventilation (CO2 ~24 mmHg), during hypercapnia (CO2 ~46 mmHg), during boluses of phenylephrine (25-200 µg), and during graded head-up tilting (HUT). Measurements were repeated 1 h after 100 mg sildenafil were taken. Results showed that sildenafil did not affect resting BP, heart rate, CBF peak and mean velocities, estimated regional cerebrovascular resistance (eCVR; mean BP/mean CBF), breath/min, and EtCO2: 117 ± 2/67 ± 3 mmHg, 69 ± 3 beats/min, 84 ± 5 and 57 ± 4 cm/s, 1.56 ± 0.1 mmHg·cm-1·s-1, 14 ± 0.5 breaths/min, and 39 ± 0.9 mmHg, respectively. Sildenafil increased and decreased the hypercapnia induced in CBF and eCVR, respectively. Sildenafil also attenuated the decrease in peak velocity of CBF, 25 ± 2 vs. 20 ± 2% (P < 0.05) and increased the eCVR, 2.5 ± 0.2 vs. 2 ± 0.2% (P < 0.03) during hyperventilation. Sildenafil did not affect CBF despite significant increases in the eCVRs that were elicited by phenylephrine and HUT. This investigation suggests that sildenafil, which potentiates the NO-cGMP signaling, seems to affect the cerebrovascular CO2 reactivity without affecting the static and dynamic pressure-dependent mechanisms of cerebrovascular autoregulation.

Pain Modulation and Autonomic Function: The Effect of Clonidine.

OBJECTIVE: The α2-agonist clonidine is an analgesic agent, whose yet uncertain action may involve either increase in pain modulation efficiency, change in autonomic function, and/or decrease in anxiety level. The present study aimed to examine the effect of oral clonidine on pain perception in healthy subjects in order to reveal its mode of action. DESIGN: Randomized, double-blind, placebo-controlled study. SUBJECTS: Forty healthy subjects. METHODS: Subjects received either 0.15 mg oral clonidine or placebo. We measured pain parameters of heat pain thresholds, tonic heat stimulus, mechanical temporal summation, offset analgesia (OA) and conditioned pain modulation (CPM); autonomic parameters of deep breathing ratio and heart rate variability indices obtained before, during, and after tonic heat stimulus; and psychological parameters of anxiety and pain catastrophizing. RESULTS: Clonidine decreased systolic blood pressure (P = 0.022) and heart rate (P = 0.004) and increased rMSSD (P = 0.020), though no effect was observed on pain perception, pain modulation, and psychological parameters. Autonomic changes were correlated with pain modulation capacity; for OA, the separate slope model was significant (P = 0.008); in the clonidine group, more efficient OA was associated with lower heart rate (r = 0.633, P = 0.005), unlike in the placebo group. CONCLUSIONS: The change in autonomic function that was related to the increase in pain modulation capacity, and the lack of change in anxiety, suggest a combined modulatory-autonomic mode of analgesic action for clonidine.

Is adenosine a modulator of peripheral vasoconstrictor responses?

BACKGROUND: Local vasoconstrictor reflexes, the vascular myogenic response (VMR) and the veno-arterial reflex (VAR) are necessary for the maintenance of regional blood flow and systemic arterial blood pressure during orthostatic stress. Their molecular mechanism is unknown. We postulated that adenosine is involved in the activation of these local reflexes. METHODS: This hypothesis was tested in 10 healthy male volunteers (age 29 ± 3 years, BMI 24 ± 1 kg/m(2)). We used veno-occlusive plethysmography method for the assessment of forearm arterial blood flow at baseline and upon causing local venous congestion by inflating a second cuff to 40 mmHg for 4 min (VAR) and during placement of the forearm 40 cm below cardiac level for 4 min (VMR). These measurements were repeated after local infusion of either saline or aminophylline, non-selective adenosine blockers, using the Bier block method. RESULTS: Rest baseline forearm blood flow was comparable in both arms. Saline did not affect the baseline forearm blood flow. However, aminophylline causes a significant increase in baseline forearm blood flow of 34 ± 6 % (p = 0.002). VAR demonstrated a decrease in forearm blood flow of 49 ± 4.5 % and after saline infusion it remained unchanged, 49 ± 5 % (p = 0.92). However, aminophylline causes significant decrease in the VAR by 35 ± 3 % (p = 0.02). But, both, saline and aminophylline did not affect the VMR. CONCLUSION: Arterial vasoconstriction triggered by venous congestion, which is the veno-arterial reflexis seems to be modulated by adenosine, at least partially. This "sensory" reflex requires further pharmacologic physiologic investigation.

The Relationships Between Parasympathetic Function and Pain Perception: The Role of Anxiety.

BACKGROUND: Previous studies have identified relationships between autonomic function and pain perception. Anxiety was found to influence both autonomic and pain responses. We examined the effect of anxiety level on parasympathetic function and pain perception as well as on the relationships between these 2 systems. METHODS: Thirty healthy females were divided into high- and low-anxiety groups according to their trait anxiety levels. Parasympathetic function was obtained using heart rate variability, deep breathing, and Valsalva ratios. Pain perception parameters of heat pain thresholds, pain rating of supra-thresholds stimulus, mechanical temporal summation, and conditioned pain modulation response were examined. RESULTS: The low-anxiety and high-anxiety groups exhibited no significant differences in the parasympathetic function and pain perception parameters. Assessment of the associations revealed that in the high-anxiety group, higher mean ratings of the tonic heat pain stimulus were significantly correlated with higher rMSSD (r2 = 0.358, P = 0.019), but this was not found for the low-anxiety group (P = 0.282). In addition, in the high-anxiety group, efficient conditioned pain modulation response was correlated with higher deep breathing ratio (r2 = 0.363, P = 0.023); however, in the low-anxiety group, the correlation did not reach significance (P = 0.109). CONCLUSIONS: This study demonstrates the role of anxiety level on the relationships between parasympathetic function and pain perception. We suggest that a situation of high anxiety leads to higher norepinephrine levels that can influence both parasympathetic function and pain perception, thus explaining the significant relationships found between these 2 systems only in subjects with high anxiety.

Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain. METHODS: Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo. RESULTS: THC significantly reduced the LF/HF ratio compared with placebo (interaction effect F(1,11) = 20.5; p < 0.005) and significantly improved CPM responses (interaction effect F(1,9) = 5.2; p = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster p-FDR < 0.005]. CONCLUSIONS: THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation. CLINICAL TRIAL REGISTRY NUMBER: NCT02560545.

High prevalence of fibromyalgia symptoms among healthy full-term pregnant women.

The impact of fibromyalgia on the course of pregnancy is not clearly defined. We evaluate the frequency of FMS symptoms among full-term healthy pregnant women and the impact on the course of delivery. The 2011 modification of the ACR 2010 criteria for FMS diagnosis was used as well as the FIQ, SF-36 and AIMS questionnaires. The 1990 ACR classification criteria were documented. Data were collected relating to course of the delivery, induction, length of stage 1, 2 and 3 of delivery, epidural anesthesia, artificial rupture of membranes, instrumental delivery and cesarean section. A VAS recording pain intensity during delivery was documented. Out of 100 women recruited, 27 (27 %) fulfilled Modified FMS criteria. Only one of these women fulfilled ACR 1990 criteria, women who fulfilled the ACR criteria differed significantly from women who did not fulfill these criteria on a broad range of parameters including widespread pain and fatigue, social functioning, emotional well-being, role limitation and physical functioning. A significant correlation was found between length of stage 2 and results of the FIQ as well as with components of the SF-36. The intensity of pain during birth however was not correlated with the presence of FMS criteria. FMS symptoms were highly prevalent among healthy pregnant women at term. The presence of such symptoms may impact on the course of delivery and the need for anesthesia. Evaluating for features of centrally mediated pain may be of clinical relevance for physicians involved in the treatment of pregnant women.

Diagnostic approaches to syncope in Internal Medicine Departments and their effect on mortality.

Most data on mortality and investigational approaches to syncope comes from patients presented to emergency departments (ED). The aim of this study is to report intermediate term mortality in syncope patients admitted to Internal Medicine Departments and whether different diagnostic approaches to syncope affect mortality. Methods and results A single-center retrospective-observational study conducted at the Tel Aviv "Sourasky" Medical Center. Data was collected from electronic medical records (EMRs), from January 2010 to December 2020. We identified 24,021 patients, using ICD-9-CM codes. Only 7967 syncope patients were admitted to Internal Medicine Departments and evaluated. Logistic regression models were used to determine the effects of diagnostic testing per patient in each department on 30-day mortality and readmission rates. All-cause 30-day mortality rate was 4.1%. There was a significant difference in the number of diagnostic tests performed per patient between the different departments, without affecting 30-day mortality. The 30-day readmission rate was 11.4%, of which 4.4% were a result of syncope. Conclusion Syncope patients admitted to Internal Medicine Departments show a 30-day all-cause mortality rate of ∼4%. Despite the heterogeneity in the approach to the diagnosis of syncope, mortality is not affected. This novel information about syncope patients in large Internal Medicine Departments is further proof that the diagnosis of syncope requires a logic, personalized approach that focuses on medical history and a few tailored, diagnostic tests.

Associations of vaccine status with characteristics and outcomes of hospitalized severe COVID-19 patients in the booster era.

BACKGROUND: The resurgence of COVID-19 cases since June 2021, referred to as the fourth COVID-19 wave, has led to the approval and administration of booster vaccines. Our study aims to identify any associations between vaccine status with the characteristics and outcomes of patients hospitalized with severe COVID-19 disease. METHODS: We retrospectively reviewed all COVID-19 patients admitted to a large tertiary center between July 25 and October 25, 2021 (fourth wave in Israel). Univariant and multivariant analyses of variables associated with vaccine status were performed. FINDINGS: Overall, 349 patients with severe or critical disease were included. Patients were either not vaccinated (58%), had the first two vaccine doses (35%) or had the booster vaccine (7%). Vaccinated patients were significantly older, male predominant, and with a higher number of comorbidities including diabetes, hyperlipidemia, ischemic heart disease, heart failure, immunodeficient state, kidney disease and cognitive decline. Time from the first symptom to hospital admission was longer among non-vaccinated patients (7.2 ± 4.4 days, p = 0.002). Critical disease (p<0.05), admissions to the intensive care unit (p = 0.01) and advanced oxygen support (p = 0.004) were inversely proportional to the number of vaccines given, lowest among the booster vaccine group. Death (20%, p = 0.83) and hospital stay duration (8.05± 8.47, p = 0.19) were similar between the groups. CONCLUSION: Hospitalized vaccinated patients with severe COVID-19 had significantly higher rates of most known risk factors for COVID-19 adverse outcomes. Still, all disease outcomes were similar or better compared with the non-vaccinated patients.

The Cardio-Hepatic Relation in STEMI.

BACKGROUND: Hepatic injury secondary to congestive heart failure is well described, however, only limited data exist about the possible impact of acute cardiac dysfunction on the liver. We aimed to explore the possible cardio-hepatic interaction in patients with myocardial infarction. MATERIAL AND METHODS: A single-center retrospective cohort study of 1339 ST elevation myocardial infarction (STEMI) patients who underwent primary coronary intervention between June 2012 to June 2019. Echocardiographic examinations were performed to assess left ventricular ejection fraction (LVEF) and central venous pressure (CVP). Patients were stratified into four groups by their LVEF and CVP levels: LVEF ≥ 45%, and CVP ≤ 10 mm/Hg (n = 853), LVEF < 45% with CVP ≤ 10 mm/Hg (n = 364), EF ≥ 45%, with CVP > 10 mm/Hg (n = 61), and LVEF < 45% with CVP > 10 mm/Hg (n = 61). Patients were evaluated for baseline and peak liver enzymes including alanine transaminase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin. RESULTS: Greater severity of cardiac dysfunction was associated with worse elevation of liver enzymes. We found a graded increase in mean levels of maximal ALT, first and maximal ALP, and first and maximal GGT values. Using propensity score matching to estimate the impact of cardiac dysfunction on liver injury, we chose patients with the worst cardiac function parameters: (LVEF < 45% and CVP >10 mm/Hg; n = 61) and compared them to matched patients with better cardiac function (n = 45). We found a significantly higher level of maximal ALT, first and maximal ALP, and GGT values in the group with the worst cardiac function parameters (p < 0.05). CONCLUSIONS: Among patients with STEMI, the combination of decreased LVEF and venous congestion was associated with liver enzymes elevation suggesting a possible cardio-hepatic syndrome.

COVID-19-Associated Hyper-Fibrinolysis: Mechanism and Implementations.

The emerging novel coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 presents with high infectivity, morbidity and mortality. It presenting a need for immediate understanding of its pathogenicity. Inflammation and coagulation systems are over-activated in COVID-19. SARS-CoV-2 damages endothelial cell and pneumocyte, resulting in hemostatic disorder and ARDS. An influential biomarkers of poor outcome in COVID-19 are high circulating cytokines and D-dimer level. This latter is due to hyper-fibrinolysis and hyper-coagulation. Plasmin is a key player in fibrinolysis and is involved in the cleavage of many viruses envelop proteins, including SARS-CoV. This function is similar to that of TMPRSS2, which underpins the entry of viruses into the host cell. In addition, plasmin is involved in the pathophysiology of ARDS in SARS and promotes secretion of cytokine, such as IL-6 and TNF, from activated macrophages. Here, we suggest an out-of-the-box treatment for alleviating fibrinolysis and the ARDS of COVID-19 patients. This proposed treatment is concomitant administration of an anti-fibrinolytic drug and the anticoagulant.

Effects of Workplace-Related Factors on the Prevalence of Fibromyalgia among Israeli Kindergarten Teachers.

Background: Fibromyalgia syndrome (FMS), a chronic widespread pain disorder, has been associated with various models of stress, including those that are workplace-related. In a previous study, we have documented the significantly increased prevalence of FMS among schoolteachers, as well as correlating symptoms with stressful workplace-related factors. In the current study, we have focused on the specific population of kindergarten teachers and attempted to document both the prevalence of FMS symptoms among this group and the association with stress and symptoms of posttrauma. Methods: All participants in the study were working as kindergarten teachers in Israel at the time of the study. Participants responded to a questionnaire documenting FMS symptom, which included the widespread pain index (WPI) and symptom severity scale (SSS), which together constitute the suggested American College of Rheumatology (ACR) FMS diagnostic criteria. Additional items on the questionnaire documented work motivation and performance, the occurrence of workplace-related stressful events, and the presence of posttraumatic symptoms. Results: 242 participants were recruited to the current study, including 239 (98.8%) females and 3 (1.2%) males. 62 individuals (25.6%) were found to fulfill ACR FMS criteria. Significant differences in work performance were found between teachers fulfilling FMS criteria compared with those not fulfilling criteria. Thus, FMS-positive teachers reported significantly higher rates of missing workdays, leaving work early, and a lower quality of interaction with children in the kindergarten and with peers and supervisors. Motivation to work was also significantly lower among these individuals. The widespread pain index (WPI) and symptom severity scale (SSS), which together constitute the components of the FMS diagnostic criteria, were positively correlated with both stress and posttraumatic symptoms. In addition, widespread pain, disordered sleep, difficulty with concentration, and other FMS symptoms were strongly correlated with many specific stressful factors at the workplace, including the number of children in the kindergarten, interaction with parents, lack of optimal physical conditions in the classrooms, and various demands on behalf of the educational system. Conclusion: FMS symptoms were found to be highly prevalent among Israeli kindergarten teachers, at a rate that greatly exceeds the prevalence in the general Israeli population. Stressful work-related events appear to be positively associated with the occurrence of FMS symptoms and may serve as triggers for their development. Healthcare professionals treating individuals engaged in this occupation should be vigilant for the occurrence of symptoms that are clinically associated with FMS and overlapping functional disorders.

Effects of Cigarette Smoking on Cardiac Autonomic Responses: A Cross-Sectional Study.

It has been suggested that some of the adverse, long-term cardiovascular outcomes of smoking are mediated by impaired autonomic nervous system (ANS) activity. Yet, this association is currently inconclusive. Heart rate variability (HRV) and the deep breathing test (DBT) represent common quantitative markers of ANS activity due to their simplicity and reliability. This large cross-sectional study was designed to assess the effect of active smoking on ANS function as manifested by HRV or DBT abnormalities. Electrocardiograms were recorded at rest for 5 min and during forced metronomic breathing. HRV and DBT were calculated according to accepted standards. Participants were divided into two groups based on current smoking status. The study included 242 healthy volunteers (196 nonsmokers and 46 smokers). There were no significant differences in age, sex, and BMI between groups. Cumulative smoking exposure burden (CSEB) for the study group was 5.3 ± 1.3 pack-years. Comparative analysis of HRV and DBT parameters according to smoking status revealed no significant differences between groups. Significant (p < 0.05), yet weak or moderate correlations (r < 0.7) were found between CSEB and abnormal change in HRV parameters consistent with sympathetic overactivity and decreased parasympathetic tone. In conclusion, smoking for a relatively short period in healthy adults does not seem to lead to significant impairment in ANS function. Yet, the consequences of smoking seem to be amplified when cumulative exposure burden increases.

Effect of chronic sildenafil treatment on penile endothelial function: a randomized, double-blind, placebo controlled study.

PURPOSE: Although the effect of phosphodiesterase type 5 inhibitors on endothelial function in the systemic circulation has been extensively studied, its effect on penile endothelial function remains unexplored. Therefore, we evaluated the effect of daily sildenafil on penile endothelial function. MATERIALS AND METHODS: A total of 60 patients with erectile dysfunction were randomized blindly to daily placebo or 50 mg sildenafil for 4 weeks. Penile and forearm blood flow as well as endothelial function indices were measured at baseline and after 4 weeks using venoocclusive strain gauge plethysmography for both organs. Sequential changes in flow, maximal blood flow and area under the curve induced by reactive hyperemia after 5 minutes of transient ischemia were considered indices of endothelial function. RESULTS: There were 34 patients treated with sildenafil and 19 on placebo who completed the study. The general characteristics of both groups were comparable. Mean +/- SEM baseline penile blood flow was 6.2 +/- 1.4 and 7.0 +/- 0.6 ml/dl per minute for the placebo and sildenafil groups, respectively (p = 0.54). Baseline forearm blood flow was similar in both groups. At baseline penile AUC was 420 +/- 50 and 520 +/- 50 (p = 0.18), and in the forearm it was 445 +/- 40 and 410 +/- 40 (p = 0.45) for the placebo and sildenafil groups, respectively. After 4 weeks on the assigned drug penile blood flow increased to 11.2 +/- 2 ml/dl per minute in the sildenafil group (p = 0.02) and remained unchanged in the placebo group. After 4 weeks penile AUC increased to 720 +/- 65 in the sildenafil group (0.04) and remained unchanged in the placebo group. Placebo and sildenafil did not affect the indices of forearm endothelial function. CONCLUSIONS: Daily sildenafil significantly improves penile blood flow and penile endothelial function indices without causing any relevant systemic effects.