Terminal vessel hyperperfusion despite organ hypoperfusion in familial dysautonomia

Patients with familial dysautonomia (FD) exhibit orthostatic hypotension as well as recumbent hypertension. In addition, during dysautonomic crises, patients have hypertensive blood pressure that is presumed to be secondary to episodic vasoconstriction, as well as swollen hands that are presumed to be secondary to vasodilatation. This discrepancy in vascular control is poorly understood, yet may provide insight into the pathophysiology of autonomic crises. To evaluate the pathological mechanisms of overall blood flow and end-organ perfusion, we assessed resting and post-ischaemic limb and skin blood flow in FD patients. In groups of 15 FD patients and 15 controls, we measured resting and post-ischaemic forearm blood flow using venous occlusion plethysmography, and superficial skin blood flow using laser Doppler flowmetry. At rest, arterial inflow was averaged from eight venous occlusion measurements and expressed as percentage volume change/min. Post-ischaemic plethysmographic inflow was determined from the peak influx during the first venous occlusion following 3 min of ischaemia. Transcutaneous forearm partial pressures of oxygen and carbon dioxide were monitored continuously. At rest, plethysmographic limb perfusion was lower in FD patients than in controls, while skin blood flow did not differ between the two groups. After ischaemia, hyperperfusion of the forearm and hand was less pronounced in FD patients than in controls, while skin blood flow was significantly higher in patients than in controls. Partial pressures of O(2) and CO(2) did not differ between the two groups. We conclude that the reduced overall limb perfusion in patients with FD is due to hypertension-induced structural changes to vessel walls, with an increase in resistance vessel rigidity. The exaggerated post-ischaemic skin perfusion in FD patients seems to be due to deficient sympathetic innervation of precapillary vessels and arteriovenous shunts and to denervation hypersensitivity of intradermal small nerve fibres. Both the reduced limb perfusion and the dysfunctional end-organ blood supply in FD patients are likely to be major contributors to the vasomotor instability observed in these subjects, particularly during periods of stress.     

Concurrent Accelerated Hyperfractionated Radiation Therapy and Carboplatin/etoposide in Patients With Malignant Glioma: Long-term break Results of A Phase II Study

Purpose: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. Material and methods: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200mg/m², and VP 16, 200mg/m², both given once weekly during the RT course. Results: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. Conclusions: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.     

Vinblastin-carboplatin for metastatic cutaneous melanoma as first-line chemotherapy and in dacarbazine failures

Medical Oncology - First-line treatments of metastatic melanoma are usually decarbazine (DTIC) and/or α-interferon based, with response rates in the range of at most 20–30%. In this...     

Obesity Treatment Using a Bioenterics Intragastric Balloon (BIB)—Preliminary Croatian Results

Aim of Study  

This study aims to assess the effectiveness, tolerance, safety, and patient satisfaction of obesity treatments using the Bioenterics intragastric balloon (BIB).     

Assessment of the cerebral vasomotor reactivity in internal carotid artery occlusion using a transcranial Doppler sonography and functional MRI.

BACKGROUND AND PURPOSE: Several methods are being used to assess cerebral vasomotor reactivity (CVR), including transcranial Doppler (TCD) sonography and blood oxygenation level-dependent functional magnetic resonance imaging (fMRI). The aim was to assess the correlation of TCD and fMRI in the CVR assessment. METHODS: Study group consisted of 28 patients (24 males, 4 females; aged 30-82, mean 63.1 +/- 10.0 years), presenting with 29 occluded internal carotid arteries. The TCD examination, including breath-holding/hyperventilation test (BH/HV) and breath-holding index (BHI), and fMRI examination were used for the assessment of CVR. fMRI employed a bimanual motor task within both a block paradigm and an event-related paradigm. Cohen's kappa was applied when statistically assessing correlation of the methods. RESULTS: The following correlations were found--between BH/HV and BHI 58.6%, kappa= .205; BH/HV and fMRI 65.5%, kappa= .322; BHI and fMRI 58.6%, kappa= .151; TCD (consistent result of both BH/HV and BHI test) and fMRI 70.6%, kappa= .414. CONCLUSIONS: In the evaluation of CVR, there is only a minimal correlation between the particular TCD tests (both BH/HV and BHI), and fMRI examination. However, there is a moderate correlation between TCD and fMRI in the case of congruity of both TCD tests.     

Radioiodination of mouse anti-III beta-tubulin antibodies and their evaluation with respect to their use as diagnostic agents for peripheral neuropathies.

The monoclonal antibody TU-20 and its scFv fragment were radiolabeled with 125 I in order to develop new imaging agents against the specific neuronal marker III beta-tubulin. The reaction via chloramine-T using thiosulfate as a stopping reductant was determined as the most convenient way for radioiodination. The preserved immunological properties of radioiodinated species were estimated by ELISA, electrophoresis, and immunohistochemistry with autoradiography. Biodistribution studies revealed a different behavior of radioiodinated TU-20 and its scFv.     

Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) are a broad class of ubiquitous environmental pollutants with known or suspected carcinogenic properties. Tumor promotion is a cell-proliferative step of cancer that requires the removal of cells from growth suppression via the inhibition of gap-junctional intercellular communication (GJIC). Inhibition of GJIC measured with an in vitro WB-F344 rat liver epithelial cell system was used to assess the relative potencies of 13 PAHs suggested by the U.S. Environmental Protection Agency (EPA) as the principal contaminants and 22 other PAHs, most of them identified in environmental samples. Maximal inhibition of GJIC was detected after 30 min of exposure, followed by a recovery in intercellular communication after an additional 30 min of exposure, suggesting a transient character of inhibition. Although microM concentrations of PAHs were required to reach the inhibition level equal to the model tumor promoter phorbol 12-myristate 13-acetate (IC50 = 8 nM), 12 of the PAHs under study were found to be strong inhibitors of GJIC (strongest effects were observed with fluoranthene, picene, 5-methylchrysene and nine additional PAHs). The other nine PAHs, including benzo[a]pyrene, inhibited GJIC only up to 50-75% of the control level. Interestingly, several high molecular weight PAHs with known strong carcinogenic properties possessed only weak (dibenzopyrenes) or no inhibition potency (dibenzofluoranthenes, naphtho[2,3-a]pyrene and benzo[a]perylene). Based on the IC50 values related to the reference PAH benzo[a]pyrene, we suggested arbitrary values of inhibition equivalency factors (GJIC-IEFs) ranging from 0 (noninhibiting PAHs) to 10.0 (strongest inhibitors), suitable for the purposes of environmental risk assessment.     

Determinants of ventilation during high-frequency jet ventilation

To better define the variables unrelated to ventilator frequency that affect gas transport during high-frequency jet ventilation (HFJV), we performed experiments in anesthetized paralyzed dogs (n = 8). The independent effects of changing driving pressure (300, 200, 150 kPa), catheter used for HFJV delivery (14-gauge and jet port of endotracheal tube), inspiratory time (30%, 50%, and 70%), and injector cannula diameter (12-gauge, 14-gauge, and 16-gauge) on minute volume (VE ), gas exchange, and cardiac output were studied at a ventilatory frequency of 100 min⁻¹. V_E increased with increasing driving pressure and inspiratory time. Entrainment decreased with increasing inspiratory time or when HFJV was delivered either via the jet port of the endotracheal tube, or via a jet cannula with distal side holes. Arterial PCO₂ varied inversely with V_E. Arterial oxygenation increased with hypocarbia, whereas venous admixture and cardiac output were unchanged. Several factors affect the ventilator-delivered and entrained volumes during HFJV, which in turn affect gas exchange. The determinants of gas exchange during HFJV appear to be similar to those described for conventional low-frequency positive-pressure ventilation.     

Severity of metabolic syndrome unfavorably influences oxidative stress and fatty acid metabolism in men

Metabolic syndrome (MS) is defined by the clustering of several components (MSC), which include abdominal fat accumulation, impaired glucose homeostasis, hypertriglyceridemia, lowered high-density lipoprotein cholesterol, increased blood pressure, and hyperuricemia. Metabolic syndrome is also accompanied by increased oxidative stress and inflammation as well as by altered composition of esterified fatty acids (FA). Therefore, we have investigated 210 men (categorized into six groups with increasing number of MSC) to find trends in the extent of oxidative stress, FA pattern and frequency of pathological alleles of the selected candidate genes for lipid metabolism. Increasing number of MSC was connected with the raised serum glucose and insulin, increased concentrations of conjugated dienes in low-density lipoprotein (all p < 0.0001), and high frequency of e2 and e4 alleles of the apolipoprotein E gene (p < 0.005). However, the last significance was lost after the adjustment for age. The incidence of 54Thr allele for intestinal isoform of the fatty acid-binding protein (FABP-2) gene was comparable in all groups. The most important findings were the raised content of saturated FA and the increased activities of Delta9 and Delta6 desaturases (all p < 0.0001), and the decreased content of polyunsaturated FA n-6 family and the decreased activity of Delta5 desaturase (both p < 0.001) in connection with increasing number of MSC. In conclusion, the severity of MS is connected with the progression of oxidative stress and the unfavorable changes in the FA composition. These changes are independent of the studied gene polymorphisms.