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.

Proteolytic Vesicles Derived from Salmonella enterica Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation.

Proteolysis of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a crucial role in the immune response to bacterial infections. Here we report the secretion of MMPs associated with proteolytic extracellular vesicles (EVs) released by macrophages in response to Salmonella enterica serovar Typhimurium infection. Specifically, we used global proteomics, in vitro, and in vivo approaches to investigate the composition and function of these proteolytic EVs. Using a model of S. Typhimurium infection in murine macrophages, we isolated and characterized a population of small EVs. Bulk proteomics analysis revealed significant changes in protein cargo of naïve and S. Typhimurium-infected macrophage-derived EVs, including the upregulation of MMP-9. The increased levels of MMP-9 observed in immune cells exposed to S. Typhimurium were found to be regulated by the toll-like receptor 4 (TLR-4)-mediated response to bacterial lipopolysaccharide. Macrophage-derived EV-associated MMP-9 enhanced the macrophage invasion through Matrigel as selective inhibition of MMP-9 reduced macrophage invasion. Systemic administration of fluorescently labeled EVs into immunocompromised mice demonstrated that EV-associated MMP activity facilitated increased accumulation of EVs in spleen and liver tissues. This study suggests that macrophages secrete proteolytic EVs to enhance invasion and ECM remodeling during bacterial infections, shedding light on an essential aspect of the immune response.

Postoperative Pain Management Among Native and Non-native Israeli Citizens-Data From the European PAIN-OUT Registry.

PURPOSE: It has been widely reported that minority groups receive inferior emergency pain management. We aimed to determine whether this is true in the postoperative setting, as effective postoperative analgesia is an essential component of high quality medical care. DESIGN: A retrospective case-control study of paired 248 postsurgical Israeli patients. METHODS: Data were gathered from the European Union's "PAIN-OUT" registry. Quality of care measures, composite pain score, composite side effect score, and composite emotional score were analyzed. FINDINGS: Composite pain, side effect, and emotional scores were significantly higher among natives compared with non-natives. Opioid consumption did not differ between the two groups. CONCLUSIONS: In this study, immigration status was not a predictor of inferior postoperative analgesia. In contrast, non-natives benefited more from analgesic care. We suggest this stems from differing patient expectations and attitudes toward pain management between the groups, with higher expectations for analgesia on the part of native patients accounting for these observations.

Cardiovascular Autonomic Profile in Women With Premenstrual Syndrome.

Introduction: The premenstrual syndrome (PMS) is a constellation of somatic and psychogenic symptoms that appear during late luteal (LL) phase of the menstrual cycle. Since many symptoms could be related to the autonomic nervous system, we hypothesized that the sympathetic nervous system is perturbed in PMS. Methods: The cardiovascular autonomic profile of nine women with PMS (30.4 ± 2.5 years) were compared to that of nine healthy controls (30 ± 2.5 years) during their early follicular (EF) and LL phases of the menstrual cycle. Plasma norepinephrine (NE) concentrations, power spectral analysis of heart rate and systolic blood pressure (BP), and baroreflex sensitivity (BRS) were assessed during recumbency and a head-up tilt (HUT). Cardiovascular responsiveness to α1- and ß-adrenoreceptor agonists (phenylephrine and isoproterenol, respectively) were also assessed. Results: In the LL phase, the plasma NE concentrations in women with PMS during recumbency and a HUT were lower than those in women without PMS [180 ± 30 vs. 320 ± 50 pg/ml; p = 0.04 (recumbent), and 480 ± 70 vs. 940 ± 180 pg/ml: p = 0.02 (HUT)]. In the LL phase, the dose of phenylephrine required to increase systolic BP by 15 mmHg in women with PMS was significantly greater than that in women without PMS (202 ± 30 µg vs. 138 ± 20 µg; p = 0.02). Sympathetic and vagal cardiac control indices were comparable in the two groups in the menstrual phases. In women with PMS, the value of LF SBP in the LL phase was lower than that in the EF phase (0.98 ± 0.2 vs. 1.77 ± 0.4 mmHg2, p = 0.04). The increase in LF SBP in women with PMS in the LL phase during HUT was greater than that in the controls, 5.2 ± 0.9 vs. 3.1 ± 0.5 mmHg2, p = 0.045, and this increase was associated with a significant decrease in BRS. Conclusion: In women with PMS without psychogenic symptoms, the sympathetic control of their circulation is not dominant during the LL phase of their menstrual cycle.

Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity.

OBJECTIVE: To characterize the functional brain changes involved in δ-9-tetrahydrocannabinol (THC) modulation of chronic neuropathic pain. METHODS: Fifteen patients with chronic radicular neuropathic pain participated in a randomized, double-blind, placebo-controlled trial employing a counterbalanced, within-subjects design. Pain assessments and functional resting state brain scans were performed at baseline and after sublingual THC administration. We examined functional connectivity of the anterior cingulate cortex (ACC) and pain-related network dynamics using graph theory measures. RESULTS: THC significantly reduced patients' pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex. Moreover, the degree of reduction was predictive of the response to THC. Graph theory analyses of local measures demonstrated reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated with individual pain reduction. CONCLUSION: These results suggest that the ACC and DLPFC, 2 major cognitive-emotional modulation areas, and their connections to somatosensory areas, are functionally involved in the analgesic effect of THC in chronic pain. This effect may therefore be mediated through induction of functional disconnection between regulatory high-order affective regions and the sensorimotor cortex. Moreover, baseline functional connectivity between these brain areas may serve as a predictor for the extent of pain relief induced by THC.

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.

Anti-oxidative treatment with vitamin E improves peripheral vascular function in patients with diabetes mellitus and Haptoglobin 2-2 genotype: A double-blinded cross-over study.

Vascular dysfunction in both conduit arteries and small vessels is a major contributor to the development of cardiovascular disease (CVD) in diabetes mellitus (DM). In diabetes there is a process of systemic chronic inflammation accompanied by high oxidative stress causing a subsequent decrease in vascular reactivity and negatively affect the metabolic processes responsible for functioning of the microvasculature. Vitamin E is classified as an antioxidant due to its ability to scavenge lipid radicals and terminate oxidative chain reactions. We conducted a double-blinded cross-over study with vitamin E versus placebo in individuals with type 2DM and the Hp2-2 genotype and assessed different aspects of peripheral vascular function in these patients. Twenty patients completed the study with 10 individuals in each study cohort. We were able to show significant improvement of indirect indices of vascular function following 8weeks of treatment with vitamin E. This improvement was consistent for weeks even after stopping the vitamin E treatment. We concluded that a pharmacogenomic rationale utilizing the Hp genotype might potentially provide cardiovascular benefit with vitamin E.

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.

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.

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.

Sex differences in the relationships between parasympathetic activity and pain modulation.

Higher parasympathetic activity is related to lower pain perception in healthy subjects and pain patients. We aimed to examine whether this relationship depends on sex, in healthy subjects. Parasympathetic activity was assessed using time- and frequency-domain heart rate variability indices and deep breathing ratio. Pain perception parameters, consisting of heat pain thresholds and pain ratings of supra-thresholds stimuli, as well as pain modulation parameters of mechanical temporal summation, pain adaptation, offset analgesia and conditioned pain modulation (CPM) response were examined. Forty healthy subjects were examined (20 men). Women demonstrated higher parasympathetic activity compared to men (high frequency power of 0.55±0.2 and 0.40±0.2, respectively, p=0.02) and less pain reduction in the offset analgesia paradigm (-35.4±29.1 and -55.0±31.2, respectively, p=0.046). Separate slopes models analyses revealed sex differences such that a significant negative correlation was observed between higher rMSSD (the root mean square of successive differences) and higher pain adaptation in men (r=-0.649, p=0.003) but not in women (r=0.382, p=0.106). Similarly, a significant negative correlation was found between higher rMSSD and higher efficiency of the CPM response in men (r=-0.510, p=0.026) but not in women (r=0.406, p=0.085). Sex hormones levels, psychological factors or baseline autonomic activity can be possible explanations for these sex differences. Future autonomic interventions destined to change pain modulation should consider sex as an important intervening factor.

Use of a new exsanguination tourniquet in internal fixation of distal radius fractures.

We describe our experience using a new device that results in a bloodless field in open repair of distal radius fractures. The device, an exsanguinating tourniquet (HemaClear model/40, OHK Medical Devices, Haifa, Israel), replaces the traditional methods of limb elevation, Esmarch bandaging, pneumatic tourniquet pressurizing and the associated components. HemaClear/40 is an elastic silicon ring with a tubular elastic sleeve rolled onto it. The device has attached straps that, when pulled, unroll the sleeve, rolling the ring mesially on the limb. The pressure exerted by rolling HemaClear/40 is supra-systolic thereby exsanguinating the limb and occluding the arterial inflow. Our experience in 49 patients demonstrated quick application, superior exsanguination and that the device could be placed on the forearm instead of the upper arm. No side effects or complications were noted. In our opinion, the fact that HemaClear/40 is a sterile, single-patient device makes it superior over the traditional technology.

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.

Haptoglobin genotype and endothelial function in diabetes mellitus: a pilot study.

Endothelial function (EnF) is impaired in patients with diabetes mellitus (DM) due in large part to an increase in oxidative stress. Haptoglobin (Hp) is a potent antioxidant protein which is encoded by two different alleles (1 and 2) with the Hp 1 protein being a superior antioxidant to the Hp 2 protein. We hypothesized that DM individuals with the Hp 2-2 genotype would have greater endothelial dysfunction as compared to DM individuals with the Hp 1-1 genotype. We studied EnF in 16 Hp 2-2, 14 Hp 1-1 DM individuals and 14 healthy subjects. DM patients' groups were matched in terms of age, cardiovascular risk factors and metabolic characteristics. EnF was assessed using post-ischemic reactive hyperemia and strain gauge plethysmography and expressed either as the maximal flow after the ischemic period or as the area under the flow-time curve (AUC). We showed that EnF indices, AUC and maximal flow, were also higher in the healthy and Hp 1-1 groups compared with Hp 2-2 genotype group (615 +/- 60 and 600 +/- 40 vs. 450 +/- 50 ml dl(-1), 29 +/- 2.6 and 25 +/- 3 vs. 14 +/- 1.8 ml min(-1) dl(-1), P < 0.003 and P < 0.05, for AUC and maximal flow, one-way ANOVA, respectively). We concluded that Hp 2-2 diabetic patients had a worse EnF than controls and Hp 1-1 diabetic subjects.

Long-standing, neglected sacroiliitis with remarked sacro-iliac degenerative changes as a result of Brucella spp. infection.

BACKGROUND: Osteoarticular disease is universally the most common complication of brucellosis. Sacro-iliac joint (SIJ) is the most frequent osteoarticular location of involvement. Sacroiliitis (SI) usually is associated with acute form of the disease, thus frank SIJ destruction caused by brucellosis is rare. PURPOSE: To report the case of a patient suffering from severe, prolonged lumbar pain with sciatica, refractory to medical treatment, in which the correct and misdiagnosed cause of her pain was a long-standing, neglected brucellar SI. STUDY DESIGN: Case report. METHODS: Scintigraphy and imaging methods (computed tomography, magnetic resonance imaging). RESULTS: The result of the delayed diagnosis was a pronounced degeneration of the SIJ. CONCLUSIONS: Sacroiliitis as a result of infection with Brucella might cause severe joint degeneration if left untreated.

Penile and systemic endothelial function in men with and without erectile dysfunction.

BACKGROUND: Assessment of endothelial function can provide essential information about the mechanisms of cardiovascular disease. Emerging data show that erectile dysfunction (ED) can precede the symptoms of ischemic heart disease, and this suggests that endothelial dysfunction is the link between these two clinical entities. OBJECTIVE: To evaluate penile and systemic endothelial function in subjects with and without ED. DESIGN, SETTING, AND PARTICIPANTS: Fifty-nine subjects were enrolled in the study. According to their International Index of Erectile Function (IIEF) ED domain scores, they were divided into two groups: 40 patients with ED and 19 men without ED (control group). Hemodynamic measurements, penile endothelial function, and forearm endothelial function were assessed in all participants using veno-occlusive plethysmography. MEASUREMENTS: We measured baseline blood flow in both the forearm and the penis and calculated the corresponding vascular resistances. Postischemic changes in blood flow were recorded serially in both organs for the evaluation of endothelial function. Area under the flow-time curve (AUC), and maximal blood flow after ischemia were considered to be the indices of endothelial function. RESULTS AND LIMITATIONS: General characteristics of the two groups of participants were comparable except for age (40.5+/-3.3 yr in the control group vs 53.3+/-2.3 yr in the ED group). Baseline forearm blood flow was similar in the two groups, but the penile blood flow was significantly lower in men with ED compared with that in the men without ED: 6.2+/-0.6 versus 8.6+/-0.6 ml/min per 100ml of tissue (p=0.006). Penile vascular resistance was higher in the ED group compared with the control group. The indices of forearm endothelial function were comparable in both groups (p=0.70 for the AUCs). However, indices of penile endothelial function were significantly higher in the control group compared with those of the ED group (AUC: 950 units+/-130 vs 450+/-80 units, p=0.001). CONCLUSIONS: The use of veno-occlusive plethysmography for evaluating penile endothelial function is simple and reliable and provides new information on the pathophysiology of ED at the level of penile vasculature. This is the first study that provides evidence of impaired penile endothelial function without the presence of a significant peripheral endothelial dysfunction. Furthermore, these results provide further support for the notion that the development of ED could predict the future onset of cardiovascular disease.

SPECT/CT-plethysmography--non-invasive quantitation of bone and soft tissue blood flow.

Preserved blood flow to bone and soft tissue is essential for their normal function. To date only numerous methods are suitable for direct bone blood flow (BBF) measurement. Here, we introduce a novel quantitative method for bone and soft tissue blood flow (BBF and SBF, respectively) measurement. It involves a combination of SPECT/CT imaging for blood pool localization in a specific region of interest ("soft" and "hard" tissues composing a limb) with veno-occlusive plethysmography. Using it, we measured BBF and SBF in the four limbs of 10 healthy subjects. At steady state blood flow measurements in the four limbs were similar, ranging between 5.5-6.5 and 1.87-2.48 ml per 100 ml of tissue per minute for BBF and SBF, respectively. Our results are comparable to those in the literature. We concluded that SPECT/CT-plethysmography appears to be a readily available and easy to use method to measure BBF and SBF, and can be added to the armamentarium of methods for BBF measurements.

Exaggerated vasoconstriction in complex regional pain syndrome-1 is associated with impaired resistance artery endothelial function and local vascular reflexes.

OBJECTIVE: Local regulatory mechanisms and microvascular function play a major role in the pathogenesis of hemodynamic and trophic changes in patients with complex regional pain syndrome-1 (CRPS). Venoarteriolar and venoarteriolar-myogenic reflexes (VAR, VMR, respectively) as well as endothelial-dependent vasodilatation are important contributors to local vasoregulation. We examined whether VAR and VMR as well as resistance artery endothelial function are damaged in affected limbs of patients with CRPS. METHODS: We measured reactive hyperemic response as an index of resistance artery endothelial function, VAR and VMR in extremity soft-tissue vasculature in patients with CRPS. RESULTS: Baseline blood flow values were not different between CRPS affected and unaffected upper and lower limbs. Resistance artery endothelial function indices, i.e., values of maximal flow after ischemia and the area under the flow-time curve (AUC), were significantly higher in the unaffected versus CRPS-affected upper limbs (19 +/- 3 vs 16 +/- 3 ml*min(-1)*dl(-1) and 373 +/- 71 vs 319 +/- 70 units, for maximal flow AUC, respectively) and lower limbs (9 +/- 2 vs 6 +/- 1.5 ml*min(-1)*dl(-1) and 160 +/- 51 vs 130 +/- 42 units, for maximal flow and AUC, respectively). Flow indices reflecting VAR were lower in the lower, but not upper CRPS-affected limbs compared with unaffected contralaterals (2 +/- 0.24 vs 1.55 +/- 0.3 ml*min(-1)*dl(-1); p = 0.027). Microvascular myogenic reflex-VMR indices, however, were not different in the upper or in the lower CRPS-affected limbs compared with their unaffected contralaterals. CONCLUSION: Impaired balance exists in CRPS-affected limbs between vascular regulation systems responsible for vasoconstriction and vasodilation.

Hormonal and volume dysregulation in women with premenstrual syndrome.

Premenstrual syndrome (PMS) presents with emotional and physical symptoms. Although the emotional symptoms have been extensively studied, the pathophysiology of the fluid-retention symptoms is not currently known. We tested the hypothesis that the fluid regulatory mechanisms are disturbed in PMS. Nine regularly menstruating women with PMS were compared with 9 healthy age-matched women. Hemodynamic parameters and upright plasma volume shift (extrapolated from changes in hematocrit), plasma renin activity (PRA), and plasma aldosterone and sex hormones were measured at different times during the menstrual cycle. During the early follicular and the midluteal phases, the plasma volume shift, supine and upright PRA, and plasma aldosterone were similar in both groups, and none of the participants had edema. However, during the late luteal phase, ankle edema was present only in women with PMS, and their maximal plasma volume shift was lower compared with controls (11.7+/-1.3 versus 15.6+/-0.6; P=0.004). The area under the curve (estimates the amount of the total plasma shift during 30 minutes standing) was 300+/-28 and 406+/-16 in PMS and controls, respectively (P=0.01). PRA and aldosterone levels were higher during the late luteal phase in women with PMS compared with controls (supine PRA: 1.4+/-0.3 [PMS] versus 1.1+/-0.4 [control; P value not significant], upright PRA: 3.9+/-0.08 versus 1.6+/-0.3 ng/mL per hour [P=0.015], supine plasma aldosterone: 131+/-30 versus 68+/-17 pg/mL [P=0.09], and upright plasma aldosterone: 208+/-40 versus 102+/-16 pg/mL [P=0.03]). We, therefore, conclude that women with PMS have increased plasma fluid-regulatory hormones and disturbed fluid distribution only during their late luteal menstrual phase.