Estimation of coronary flow reserve by sestamibi imaging in patients with mild hypertension and normal coronary arteries.

AIM: Patients with hypertension may exhibit abnormal vasodilator capacity during pharmacological vasodilatation. We assessed coronary flow reserve (CFR) by sestamibi imaging in hypertensive patients with normal coronary vessels. METHODS: Twenty-five patients with untreated mild essential hypertension and normal coronary vessels and 10 control subjects underwent dipyridamole-rest Tc-99m sestamibi imaging. Myocardial blood flow (MBF) was estimated by measuring first transit counts in pulmonary artery and myocardial counts from tomograhic images. CFR was expressed as the ratio of stress to rest MBF. Coronary vascular resistances (CVR) were computed as the ratio between mean arterial pressure and MBF. RESULTS: Estimated MBF at rest was not different in patients and controls (1.11 ± 0.59 vs. 1.14 ± 0.28 counts/pixel/s; P=0.87). Conversely, stress MBF was lower in patients than in controls (1.55 ± 0.47 vs. 2.68 ± 0.53 counts/pixel/s; P<0.001). Thus, CFR was reduced in patients compared to controls (1.61 ± 0.58 vs. 2.43 ± 0.62; P<0.001). Rest and stress CVR values were higher in patients (P<0.001), while stress-induced changes in CVR were not different (P=0.08) between patients (-51%) and controls (-62%). In the overall study population, a significant relation between CFR and stress-induced changes in CVR was observed (r=-0.86; P<0.001). CONCLUSION: Sestamibi imaging may detect impaired coronary vascular function in response to dipyridamole in patients with untreated mild essential hypertension and normal coronary arteries. A mild increase in arterial blood pressure does not affect baseline MBF, but impairs coronary reserve due to the amplified resting coronary resistances.

Assessment of Residual Radioactivity by a Comprehensive Wireless, Wearable Device in Thyroid Cancer Patients Undergoing Radionuclide Therapy and Comparison With the Results of a Home Device: A Feasibility Study.

Objective: To investigate the feasibility of using a wireless wearable device (WD) in differentiated thyroid cancer (DTC) patients undergoing radionuclide therapy with I-131 (RAI) and protected hospitalization, this study compared the measurements of residual radioactivity obtained with those registered by a permanent environmental home device (HD). Methods: Twenty consecutive patients undergoing RAI hospitalized in restricted, controlled areas were enrolled. The patients underwent comprehensive monitoring of vital/nonvital parameters. We obtained 45580± 13 measurements from the WD, detecting the residual radioactivity for each patient during approximately 56 hours of hospitalization, collecting data 53 times per hour. The samples, collected during daily activities, were averaged every two hours, and the results correlated with those from the HD. Bland-Altman analysis was also used to evaluate the agreement between the two techniques. Results: A significant relationship between the WD and HD was observed (r = 0.96, p < 0.0001). Bland-Altman analysis recognized the agreement between measurements by the WD and HD. The mean value at the end of the first day of hospitalization was 80.81 microSv/h and 60.77 microSv/h (p = ns for WD and HD), whereas those at the end of the second day were 47.08 and 24.96 (p = ns). In the generalized linear model (GLM), a similar trend in performance across time was found with the two techniques. Conclusion: This study demonstrates good agreement between the residual radioactivity measures estimated by the WD and HD modalities, rendering them interchangeable. This approach will allow both the optimization of medical staff exposure and safer patient discharge. Abbreviations: wireless device (WD); differentiated thyroid cancer (DTC); radionuclide therapy with I-131 (RAI); home device (HD); generalized linear model (GLM).

Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience.

PURPOSE AND PATIENTS: The M.O.S.CA.TI. (Metastases of the Skeleton from CArcinoma of the ThyroId) is a multicenter, retrospective study investigating the real-life outcome and management of bone metastases (BM) in 143 patients (63 M, 80 F; median age 64 years, range 11-87) with differentiated thyroid carcinoma (DTC). RESULTS: Radio-active iodine (RAI) treatment was performed in 131 patients (91.6%), surgical approach and/or external radiotherapy in 68 patients (47.6%), and anti-resorptive bone-active drugs in 32 patients (22.4%; in 31 zoledronate and in one denosumab). At the start of treatment, 24 patients (75.0%) receiving anti-resorptive bone-active drugs had at least one clinical skeletal-related event (SRE) (p < 0.001). One or more clinical SREs (pathological fractures and/or malignant hypercalcemia and/or spinal cord compression) developed in 53 patients (37.1%). Development of SREs was significantly associated with metachronous BM (hazard ratio (HR) 2.04; p = 0.04), localization of BM to cervical spine (HR 3.89; p = 0.01), and lack of avid RAI uptake (HR 2.66; p = 0.02). Thirty-nine patients (27.3%) died in correlation with development of SREs (HR 6.97; p = 0.006) and localization of BM to the hip (HR 3.86; p = 0.02). Moreover, overall mortality was significantly decreased by RAI therapy (HR 0.10; p = 0.02), whereas no significant effects were induced by bone-active drugs (p = 0.36), external radiotherapy (p = 0.54), and surgery (p = 0.43) of BM. CONCLUSIONS: SREs are very frequent in BM from DTC and they impact patient survival. In the real life, the use of bone-active drugs is currently limited to zoledronate in patients with pre-existing SREs. In this clinical setting, RAI therapy, but not zoledronate, decreased mortality.

Gel electrophoresis of gold-DNA nanoconjugates.

Gold-DNA conjugates were investigated in detail by a comprehensive gel electrophoresis study based on 1200 gels. A controlled number of single-stranded DNA of different length was attached specifically via thiol-Au bonds to phosphine-stabilized colloidal gold nanoparticles. Alternatively, the surface of the gold particles was saturated with single stranded DNA of different length either specifically via thiol-Au bonds or by nonspecific adsorption. From the experimentally determined electrophoretic mobilities, estimates for the effective diameters of the gold-DNA conjugates were derived by applying two different data treatment approaches. The first method is based on making a calibration curve for the relation between effective diameters and mobilities with gold nanoparticles of known diameter. The second method is based on Ferguson analysis which uses gold nanoparticles of known diameter as reference database. Our study shows that effective diameters derived from gel electrophoresis measurements are affected with a high error bar as the determined values strongly depend on the method of evaluation, though relative changes in size upon binding of molecules can be detected with high precision. Furthermore, in this study, the specific attachment of DNA via gold-thiol bonds to Au nanoparticles is compared to nonspecific adsorption of DNA. Also, the maximum number of DNA molecules that can be bound per particle was determined.

Unraveling viscosity effects on the hysteresis losses of magnetic nanocubes.

Hysteresis losses in magnetic nanoparticles constitute the basis of magnetic hyperthermia for delivering a local thermal stress. Nevertheless, this therapeutic modality is only to be realised through a careful appraisal of the best possible intrinsic and extrinsic conditions to the nanoparticles for which they maximise and preserve their heating capabilities. Low frequency (100 kHz) hysteresis loops accurately probe the dynamical magnetic response of magnetic nanoparticles in a more reliable manner than calorimetry measurements, providing conclusive quantitative data under different experimental conditions. We consider here a set of iron oxide or cobalt ferrite nanocubes of different sizes, through which we experimentally and theoretically study the influence of the viscosity of the medium on the low frequency hysteresis loops of magnetic colloids, and hence their ability to produce and dissipate heat to the surroundings. We analyse the role of nanoparticle size, size distribution, chemical composition, and field intensity in making the magnetisation dynamics sensitive to viscosity. Numerical simulations using the stochastic Landau-Lifshitz-Gilbert equation model the experimental observations in excellent agreement. These results represent an important contribution towards predicting viscosity effects and hence to maximise heat dissipation from magnetic nanoparticles regardless of the environment.

Gold-iron oxide dimers for magnetic hyperthermia: the key role of chloride ions in the synthesis to boost the heating efficiency.

With the aim of producing Au-Fe x O y dimers with outstanding heating performances under magnetic hyperthermia conditions applicable to human patients, here we report two synthesis routes, a two-pot and a one-pot method. The addition of chloride ions and the absence of 1,2-hexadecanediol (HDDOL), a commonly used chemical in this synthesis, are the key factors that enable us to produce dimers at low temperature with crystalline iron oxide domains in the size range between 18-39 nm that is ideal for magnetic hyperthermia. In the case of two-pot synthesis, in which no chloride ions are initially present in the reaction pot, dimers are obtained only at 300 °C. In order to lower the reaction temperature to 200 °C and to tune the size of the iron oxide domain, the addition of chloride ions becomes the crucial parameter. In the one-pot method, the presence of chloride ions from the start of the synthesis (as counter ions of the gold salt precursor) enables a prompt formation of dimers directly at 200 °C. In this case, the reaction time is the main parameter used to tune the iron oxide size. A record value of specific absorption rates (SARs) up to 1300 W gFe-1 at 330 kHz and 24 kA m-1 was measured for dimers with an iron oxide domain of 24 nm in size.

Non-motor symptoms and cardiac innervation in SYNJ1-related parkinsonism.

INTRODUCTION: PARK20 is a rare autosomal recessive parkinsonism related to the SYNJ1 gene and characterized by early-onset of disease and atypical signs such as supranuclear vertical gaze palsy, dementia, dystonia, and generalized tonic-clonic seizures. OBJECTIVE: Non-motor features and cardiac sympathetic innervation were assessed in two siblings affected by parkinsonism who harboured the homozygous Arg258Gln mutation in the SYNJ1 gene. METHODS: The Non-Motor Symptoms, the SCOPA-AUT, the Mayo Sleep Questionnaires and polysomnography were used to investigate non-motor signs (NMS), autonomic dysfunction and REM Behavioural Disorder (RBD). Cognitive functions were examined by an extensive battery of neuropsychological tests. In addition, motor and sensory nerve conduction studies and evoked laser potentials were performed. Cardiac sympathetic innervation was assessed in the two patients by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, computing early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR). RESULTS: Among the non-motor symptoms and autonomic signs, case 1 had cold intolerance, drooling and dysphagia, while case 2 had pain and urinary dysfunction. Both cases showed mood and behavioural disorders. RBD were not found, whereas the neuropsychological assessment revealed a progressive cognitive impairment. Neurophysiological studies revealed no abnormalities. Indexes of cardiac sympathetic innervation in the two patients did not differ from those of control subjects. CONCLUSIONS: Our findings expand the phenotypic profile of SYNJ1-related parkinsonism. Preserved cardiac sympathetic function and absence of RBD suggest that PARK20 should be explained by a pathogenic mechanism different from Lewy Body pathology, or that the latter is not as widespread as idiopathic Parkinson's disease.

Relations of left ventricular mass and systolic function to endothelial function and coronary flow reserve in healthy, new discovered hypertensive subjects.

Left ventricular hypertrophy (LVH) is prognostically relevant, associated with major cardiovascular risk factors and with atherosclerosis. However, whether LVH is independently associated with impaired coronary flow reserve (CFR) and with endothelial dysfunction is disputed. We assessed the relationship of LV mass and systolic function to CFR and endothelial function in new discovered never treated subjects with essential arterial hypertension, but without coronary artery disease or microalbuminuria. LVH, ejection fraction (EF) and stress-corrected midwall shortening (MWS, a measure of myocardial contractility) were assessed by echocardiography. CFR was assessed by single-photon emission computed tomography and dipyridamole infusion. Endothelial function was evaluated by assessing 1-min postischaemic flow-mediated dilatation of the brachial artery (FMD); nitroglycerine-mediated dilatation (NMD) of the same brachial artery was used as measure of nonendothelium-dependent vasodilatation. In approximately 1 year, we enrolled 21 subjects who met stringent inclusion criteria (47+/-10 years old, 26.6+/-2.8 kg/m2, 78% men). Five patients showed LVH. Multivariate analyses showed a significant negative correlation of LV mass index with FMD (beta=-0.61, P<0.05) but not with NMD, neither with CFR. Stress-corrected MWS showed independent correlation with CFR (beta=0.51, P<0.05). Thus, in clinically healthy, new discovered hypertensive subjects, never treated and mostly in the early stage of arterial hypertension, LVH can be associated with endothelial dysfunction while maximal dipyridamole- dependent CFR may be preserved; nevertheless, a cardiac phenotype presenting with tendency to impaired myocardial contractility, assessed by stress-corrected MWS, showed association with lower CFR in the early stage of arterial hypertension.

Insulin resistance is associated with impaired cardiac sympathetic innervation in patients with heart failure.

AIMS: Insulin resistance (IR) represents, at the same time, cause and consequence of heart failure (HF) and affects prognosis in HF patients, but pathophysiological mechanisms remain unclear. Hyperinsulinemia, which characterizes IR, enhances sympathetic drive, and it can be hypothesized that IR is associated with impaired cardiac sympathetic innervation in HF. Yet, this hypothesis has never been investigated. Aim of the present observational study was to assess the relationship between IR and cardiac sympathetic innervation in non-diabetic HF patients. METHODS AND RESULTS: One hundred and fifteen patients (87% males; 65 ± 11.3 years) with severe-to-moderate HF (ejection fraction 32.5 ± 9.1%) underwent iodine-123 meta-iodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy to assess sympathetic innervation and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) evaluation to determine the presence of IR. From (123)I-MIBG imaging, early and late heart to mediastinum (H/M) ratios and washout rate were calculated. Seventy-two (63%) patients showed IR and 43 (37%) were non-IR. Early [1.68 (IQR 1.53-1.85) vs. 1.79 (IQR 1.66-1.95); P = 0.05] and late H/M ratio [1.50 (IQR 1.35-1.69) vs. 1.65 (IQR 1.40-1.85); P = 0.020] were significantly reduced in IR compared with non-IR patients. Early and late H/M ratio showed significant inverse correlation with fasting insulinemia and HOMA-IR. CONCLUSION: Cardiac sympathetic innervation is more impaired in patients with IR and HF compared with matched non-IR patients. These findings shed light on the relationship among IR, HF, and cardiac sympathetic nervous system. Additional studies are needed to clarify the pathogenetic relationship between IR and HF.

In vivo effects of cocaine on immune cell function.

Cocaine use has been shown to increase the risk of HIV infection in humans, and this increased risk cannot be explained by i.v. drug use alone. It is thought that this increased susceptibility may be a result of decreased immune responsiveness in cocaine addicts. Scientists are now using animal models to study the effects of cocaine on immune function in vivo under controlled conditions. Many facets of the immune system are being examined, which include immune cell number and distribution, cellular- and humoral-mediated immunity, cytokine production, and immunocompetence to challenges such as infection and tumor growth. The effects of cocaine on many of these functions are not yet clear. Often there are variations in the response of the immune system to cocaine. Potential confounding factors include variations in dose, duration of treatment, and route of administration of cocaine, as well as variations in assay protocols. In addition, there appear to be species differences in immune responses to cocaine. Although it is clear that more research is necessary to resolve the discrepancies, a sufficient number of trends are starting to emerge. This review will systematically evaluate the reported effects of cocaine on immune cell function in vivo. In addition, the possible mechanisms that may be contributing to the immune modulation observed with cocaine in vivo will be addressed. Further, data will be presented describing the effects of cocaine on the autonomic nervous system and the neuroendocrine system suggesting that inhibition of serotonin uptake may be an important component of the overall effects of cocaine on the immune system.

Mechanisms of cocaine-induced decreases in immune cell function.

Cocaine has previously been shown to decrease mitogen-induced T lymphocyte proliferation in rats following intravenous administration. However, in this report, it is demonstrated that central administration of cocaine (1-50 microg) had no effect on lymphocyte proliferation responses. Similarly, the quaternary derivative, cocaine methiodide, also suppressed lymphocyte proliferation only when administered peripherally (6.5 mg/kg), and not centrally (1-20 microg). These results suggest that the effects of cocaine were mediated through a peripheral mechanism. Since significant elevations in plasma corticosterone were observed with all routes of administration of cocaine, the effects of cocaine did not appear to be due entirely to activation of the HPA axis. Instead, the peripheral administration of the local anesthetic, lidocaine (5 mg/kg) or the monoamine reuptake inhibitor, RTI-55 (2-5 mg/kg), produced significant suppressive effects on proliferation. suggesting that both of these peripheral activities of cocaine may be involved in the alteration of lymphocyte responses.

Modulation of immune cell function following fluoxetine administration in rats.

Fluoxetine (FLX) and other specific serotonin uptake inhibitors (SSRIs) have become the drugs of choice for treating depression. However, only a limited number of studies have addressed the effects of FLX on immune cell function. Our lab has measured the effects of both acute and chronic FLX administration on two functions of cell-mediated immunity, mitogen-induced lymphocyte proliferation (MILP) and natural killer cell cytolytic activity (NKCA). In this article we report that acute FLX administration (10 mg/kg) resulted in a dose- and time-dependent decrease in MILP and NKCA. MILP was more sensitive than NKCA to FLX, requiring lower doses for inhibition; however, the effects were more transient. Following chronic FLX administration, these effects were no longer observed, suggesting that an apparent tolerance to these particular measures of cell-mediated immunity had developed. Finally, a single microinjection of FLX directly into the lateral ventricle produced similar suppressive effects on MILP and NKCA, suggesting that the immunomodulatory mechanism may have a central component.

Vascular syndromes.

Patients with suspected transient ischemic attacks are frequently seen in the Emergency Department. Accurate diagnosis is crucial but often very difficult because signs and symptoms often will have resolved when the patient is seen. This article reviews the details of the history and physical examination that may help to establish a correct diagnosis.

An emergency department approach to first-time seizures.

The patient with an apparent first seizure presents a diagnostic and therapeutic challenge to the emergency department or primary care physician. Proper management of these patients requires a systematic diagnostic evaluation and assessment of the risks and benefits of treatment. Such an assessment requires that the following issues be addressed: Was the attack truly a seizure? Was this seizure truly the first seizure for this patient? Why did the seizure occur? Was the seizure a symptom of an acute neurologic or medical illness, a remote neurologic injury, or did the attack occur without evident cause? How extensive (and expensive) should the diagnostic evaluation be? If a cause for the seizure is identified, is direct therapy available or necessary? What is the likelihood of a recurrent attack? Will treatment with anticonvulsant drugs significantly reduce the risk of subsequent seizures? What are the risks of anticonvulsant drug treatment? Is anticonvulsant drug therapy appropriate for this patient at this time? It should be clear from the preceding discussion that definitive answers to such questions are not possible. The clinical data are always incomplete and uncertain and sometimes erroneous. Considerable clinical judgment is always needed. Nonetheless, we can hope that conscientious, systematic assessment will lead to the best possible treatment for each of our patients.

Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release.

OBJECTIVES: We have previously reported that acute administration of the specific serotonin reuptake inhibitor (SSRI), fluoxetine, resulted in a decrease in mitogen-induced blood lymphocyte proliferation. The present studies further examine the specificity of this response to serotonin reuptake systems and the potential role of endogenous serotonin in mediating these effects. METHODS: Male Sprague-Dawley rats were treated intraperitoneally with the SSRIs, fluoxetine (6-10 mg/kg) or sertraline (20 mg/kg), dopamine and norepinephrine reuptake inhibitors, GBR 12909 and desipramine, respectively (6 mg/kg) or the serotonin precursor, 5-hydoxytryptophan (5-HTP, 50 mg/kg) 2 h prior to sacrifice. The serotonin-depleting agents, p-chlorophenylalanine (PCPA, 2 x 200 mg/kg) or the serotonin-lesioning agent, p-chloroamphetamine (PCA, 2 x 10 mg/kg) were administered intraperitoneally 5-7 days prior to fluoxetine (10 mg/kg) administration. RESULTS: Unlike the SSRIs, which significantly suppressed lymphocyte proliferation responses, selective norepinephrine or dopamine reuptake inhibition had no effect on lymphocyte proliferation. Elevation of extracellular serotonin levels with the serotonin precursor, 5-HTP, resulted in a similar decrease in lymphocyte proliferation as that seen with SSRI administration. Conversely, decreases in endogenous serotonin following PCA or PCPA treatment prevented the fluoxetine-induced decreases in lymphocyte proliferation. CONCLUSIONS: These results suggest that decreases in mitogen-induced lymphocyte proliferation following acute fluoxetine administration were due to elevations in extracellular serotonin following reuptake inhibition.

Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin blood levels in renal transplant recipients.

Thirty-one renal transplant recipients, submitted to treatment with cyclosporin in association with other immunosuppressive agents, were also treated for 9 months with two hydroxymethylglutaryl coenzyme A reductase inhibitors, simvastatin (10 mg/day) or pravastatin (20 mg/day), for concomitant hypercholesterolemia and hypertriglyceridemia. Both drugs significantly decreased total cholesterol and triglyceride serum levels, but they did not modify whole-blood trough concentrations of polyclonal and monoclonal cyclosporin or polyclonal/monoclonal cyclosporin ratio. No alterations of the clinical and laboratory parameters investigated were found. The results of this study show the efficacy and safety of hydroxymethylglutaryl coenzyme A reductase inhibitors in the treatment of hyperlipidemia in kidney transplant patients.