Direction of temperature control in the thermal biofeedback treatment of vascular headache

In order to test for the specific therapeutic effects of thermal biofeedback (TBF) for hand warming on vascular headache (HA), 70 patients with chronic vascular HA were randomly assigned to TBF for hand warming, TBF for hand cooling, TBF for stabilization of hand temperature, or biofeedback to suppress alpha in the EEG. Patients in each condition initially had high levels of expectation of therapeutic benefit and found the treatment rationales highly credible. Participants in each condition received 12 treatment sessions on a twice-per-week basis. Based on daily HA diary data gathered for 4 weeks prior to treatment and 4 weeks after treatment, HA Index was significantly (p = .003) reduced as was HA medication consumption. There were no differential reductions in HA Index or Medication Index among the four conditions. Global self-reports of improvement gathered at the end of the post-treatment monitoring period also did not differ among the four conditions. We were unable to demonstrate a specific effect of TBF for hand warming on vascular HA activity.     

The treatment of patients with benign prostatic hyperplasia using the selective alpha-blocker alfuzosin

40 patients with benign prostatic hyperplasia (BPH) were treated with the alpha-blocker alfuzosin which was administered per os twice a day in a dose 5 mg. The treatment brought about a decrease of the mean symptom score from 19.6 to 12.2, of quality of life from 5.2 to 2.1, of residual urine from 152 to 82 ml. Mean and maximal urinary flow rates rose by 35 and 45%, respectively. The level of prostate-specific antigen over the treatment course did not change. The findings of the trial evidence for high efficacy of alfuzosin in the treatment of urination disorders in BPH patients.     

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. RESULTS: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. CONCLUSIONS: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.     

Demonstration of protein-protein interaction specificity by NMR chemical shift mapping

Chemical shift mapping is becoming a popular method for studying protein-protein interactions in solution. The technique is used to identify putative sites of interaction on a protein surface by detecting chemical shift perturbations in simple (1H, 15N)-HSQC NMR spectra of a uniformly labeled protein as a function of added (unlabeled) target protein. The high concentrations required for these experiments raise questions concerning the possibility for non-specific interactions being detected, thereby compromising the information obtained. We demonstrate here that the simple chemical shift mapping approach faithfully reproduces the known functional specificities among pairs of closely related proteins from the phosphoenolpyruvate:sugar phosphotransferase systems of Escherichia coli and Bacillus subtilis.     

Radiofrequency catheter ablation of sustained monomorphic ventricular tachycardia in hypertrophic cardiomyopathy

INTRODUCTION: Incessant monomorphic ventricular tachycardia (VT) with a right bundle branch block morphology and a northwest axis is a rare arrhythmic complication in a patient with hypertrophic cardiomyopathy and apical left ventricular aneurysm. METHODS AND RESULTS: The origin of this VT was localized using the following criteria: the presence of entrainment without fusion, equal intervals from the stimulus to the beginning of the QRS complex and from the electrogram to the QRS complex during VT, and the first postpacing interval identical to the tachycardia cycle length. Radiofrequency energy applied to the septoapical part of the apical left ventricular aneurysm terminated the tachycardia within 2 seconds. CONCLUSION: Using criteria to guide radiofrequency (RF) ablation of VT in patients with coronary artery disease, an incessant monomorphic VT in a patient with hypertrophic cardiomyopathy was successfully ablated.     

Evidence for increased seizure susceptibility in rats exposed to cocaine in utero

The effect of (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105), a novel cognition enhancer, on adenylate cyclase activity was investigated in cultured neurons of the mouse cerebral cortex. NS-105 (10(-7) and 10(-6) M) inhibited forskolin-stimulated cyclic AMP formation, an action that was dependent on pertussis toxin-sensitive G proteins. Conversely, in pertussis toxin-pretreated neurons, NS-105 (10(-7)-10(-5) M) significantly enhanced the forskolin-stimulated cyclic AMP formation, and this action was completely reversed by cholera toxin. A metabotropic glutamate receptor agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3R-ACPD) produced similar bi-directional actions on the cyclic AMP formation. Both of these inhibitory and facilitatory actions of NS-105 and 1S, 3R-ACPD were blocked by L(+)-2-amino-3-phosphopropinoic acid (L-AP3). NS-105 (10(-6) M) and 1S, 3R-ACPD (10(-4) M) significantly enhanced isoproterenol- and adenosine-stimulated cyclic AMP formation. The enhancement of such Gs-coupled receptor agonists-stimulated cyclic AMP formation was also produced by quisqualate but not by L(+)-2-amino-4-phosphonobutanoate (L-AP4). The phosphoinositides hydrolysis was enhanced by 1S, 3R-ACPD (10(-4) M) but not by NS-105 (10(-6) M), however, 1S, 3R-ACPD-induced increase in phosphoinositides turnover was attenuated by NS-105. These findings suggest that NS-105 stimulates metabotropic glutamate receptor subclasses that are coupled both negatively and positively to adenylate cyclase, but it acts as an antagonist at the receptor subclasses that are linked to phosphoinositides hydrolysis.     

Lack of induction of substance P gene expression by hypoxia and absence of neurokinin 1-receptor mRNAs in the rat carotid body

Peripheral chemoreceptors are commonly thought to respond to hypoxia by releasing neurotransmitters from the type 1 cells of the carotid body; these molecules then bind to post-synaptic receptors on the carotid sinus nerve. The tachykinin substance P (SP) may act as an important neurotransmitter/neuromodulator in hypoxic chemotransmission in peripheral arterial chemoreceptors. In order to elucidate the role of SP in modulating hypoxic chemotransmission, we have used quantitative in situ hybridization histochemistry, to determine the effect of hypoxia on SP gene induction, and the localization of neurokinin 1 (NK-1) receptor mRNA in the carotid body and petrosal ganglia complex in rats at 21 days post-natal age. For comparison, we also determined: (1) the effect of hypoxia on tyrosine hydroxylase (TH) gene induction and (2) the localization of the mRNA encoding the D2-dopamine receptor. SP mRNA was not detected in the rat carotid body during normoxia and its expression was not induced after a 1 h of exposure to hypoxia (10% O2/90% N2), a stimulus that was sufficient to cause a significant increase (P < 0.01) in TH mRNA levels in the carotid body. Both SP and TH mRNAs were abundantly expressed in multiple cells in the petrosal and the jugular ganglia. However, these mRNAs were not co-localized and SP and TH mRNA levels were not affected by hypoxia in these ganglia. Although D2-dopamine receptor mRNA was abundantly expressed in the rat carotid body, we found no evidence of NK-1 receptor mRNA in the carotid body. In contrast, both NK-1 receptor mRNA and D2-dopamine receptor mRNA were present in petrosal ganglion cells. In the rat, SP does not appear to modulate hypoxic chemotransmission by being made in and released from type 1 cells in the carotid body, and neither does SP modulate the activity of type 1 cells by binding to NK-1 receptors on these cells.     

Contribution of growth hormone and IGF-I to early diabetic nephropathy in type 1 diabetes

In children and adolescents with type 1 diabetes, we have reported an association between duration of puberty and the prevalence of nephromegaly and microalbuminuria (MA), which are early markers of diabetic nephropathy. Growth hormone (GH), IGF-I, testosterone, and prorenin are potential mediators of this effect. This study examined the relationship of these hormonal factors to kidney volume (KV) and MA in 155 subjects (78 males, age 13.2 +/- 3.5 years [mean +/- SD]) with similar diabetes duration (6.83 +/- 1.6 years) but varying pubertal experience (0-10 years). KV (by ultrasound), plasma IGF-I, testosterone, prorenin, and NaLi countertransport, and urinary albumin, urinary GH, and urinary IGF-I from three 24-h collections were measured. Multiple regression analysis showed that BSA (P < 0.0001) and urinary IGF-I (P = 0.001) were significantly associated with KV. MA subjects (albumin excretion rate 15-200 microg/min) had higher urinary IGF-I (P = 0.005) and urinary GH (P = 0.05) compared with normoalbuminuric subjects. Only 9% of the variance in urinary IGF-I could be attributed to plasma IGF-I (r = 0.30, P < 0.0001). Testosterone and prorenin were not associated with MA, but they were associated with KV in univariate analyses. The strong association of urinary IGF-I with KV, a marker for glomerular hypertrophy, and of both urinary IGF-I and urinary GH with MA suggests a role for these growth factors in the development of human diabetic nephropathy. Together, these data support animal studies that have shown that renal GH and IGF-I may contribute significantly to the pathogenesis of early diabetic nephropathy.     

Intracavitary ultrasound phased arrays for prostate thermal therapies: MRI compatibility and in vivo testing

A 62 element MRI-compatible linear phased array was designed and constructed to investigate the feasibility of using transrectal ultrasound for the thermal therapeutic treatment of prostate cancer and benign prostatic hyperplasia. An aperiodic design technique developed in a previous study was used in the design of this array, which resulted in reduced grating lobe levels by using an optimized random distribution of unequally sized elements. The element sizes used in this array were selected to be favorable for both grating lobe levels as determined by array aperiodicity and array efficiency as determined by width to thickness ratios. The heating capabilities and MRI compatibility of the array were tested with in vivo rabbit thigh muscle heating experiments using MRI temperature monitoring. The array produced therapeutic temperature elevations in vivo at depths of 3-6 cm and axial locations up to 3 cm off the central axis and increased the size of the heated volume with electronic scanning of a single focus. The ability of this array to be used for ultrasound surgery was demonstrated by creating necrosed tissue lesions in vivo using short high-power sonications. The ability of the array to be used for hyperthermia was demonstrated by inducing therapeutic temperature elevations for longer exposures. Based on the acoustic and heating performance of this array, it has the potential to be clinically useful for delivering thermal therapies to the prostate and other target volumes close to body cavities.