The threshold tracking nerve conduction study technique: Experience of clinical users unfamiliar with a research-grade neuronal excitability system.

Objective: To 1) explore if clinical electrophysiologists with different degrees of experience performing standard nerve conduction studies could run a threshold tracking nerve conduction study (TTNCS) protocol and 2) learn how clinical users view a research-grade TTNCSs neuronal excitability system. Methods: Five clinical electrophysiologists conducted a TTNCS session using QTracS and then completed a questionnaire describing their impressions. Results: All of the electrophysiologists completed the QTracS protocol on an initial attempt. Perceived strengths comprised the ease of preparatory steps and quick protocol speed. Identified drawbacks included an unwieldly user-interface. The electrophysiologists indicated that knowledge of TTNCS principles and applications would be critical for incorporation of the method into clinical use. Conclusions: This pilot study suggests that clinical electrophysiologists can carry out TTNCSs with a research-grade system. The development of a more user-friendly program, along with dedicated education and training, could lead to wider application of the TTNCS technique. Significance: Considered together with clinical presentation and other biomarkers, increased use of TTNCSs could provide improved assessment of neuromuscular disease and treatment response.

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor.

Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsense-mediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

Serum Fas and Bcl-2 in patients with epilepsy.

OBJECTIVES: The present study aimed to investigate the levels of the biochemical markers of apoptosis (soluble Fas and Bcl-2) in the sera of children and adolescents with idiopathic epilepsy. MATERIALS AND METHODS: The study included 30 children and adolescents (mean age 8.03 +/- 4.49 years) with idiopathic epilepsy, 16 of them were newly diagnosed, and 15 clinically healthy control subjects. Of the included patients, 22 had focal seizures and eight had generalized seizures. In addition to laboratory and radiological investigations needed for diagnosis and follow-up, soluble Fas (s.Fas) and Bcl-2 were assayed in sera of patients and controls by enzyme-linked immunosorbent assay technique. RESULTS: Serum levels of s.Fas and Bcl-2 were significantly higher in the patients group than in the control group; however, their levels were comparable in patients with different seizure types. Levels of s.Fas correlated positively with seizure severity and negatively with the duration from the last attack. Bcl-2 levels were positively correlated to each of the duration of epilepsy, the severity of seizures and its frequency. There was a significant positive correlation between serum levels of s.Fas and that of Bcl-2 and both were significantly increased in patients with uncontrolled epilepsy. CONCLUSION: The present data demonstrate that markers of apoptosis, both the proapoptotic Fas and the anti-apoptotic Bcl-2, were proportionately elevated in sera of patients with idiopathic epilepsy, and their levels were related to the seizure severity and frequency.

Dopaminergic system modulation of nociceptive response in long-term diabetic rats.

The present study examines the effects of dopaminergic system modulation on nociceptive response time in male diabetic rats. In this study, diabetes was induced by streptozotocin (STZ, 45 mg/kg) in adult male Sprague-Dawley rats. Insulin replacement therapy was initiated 6 weeks after the induction of diabetes for one-half of the diabetic group (1.5-2.5 IU/12 h/rat) and was continued throughout the duration of the study (up to 14 weeks). After 6 weeks of daily insulin replacement therapy, eight rats from each experimental group (STZ-diabetic, STZ-diabetic+insulin and nondiabetic control) were injected with either bromocriptine (BROM, 3 mg/kg/12 h), haloperidol (HALO, 1.5 mg/kg/12 h) or vehicle. Nociceptive response was measured by the hot plate (HP) latency test before the induction of diabetes (baseline), every 3 weeks for the first 12 weeks and then on days 5, 9 and 14 of treatment with dopaminergic agents. Animals were sacrificed 3 or 4 days after the last HP test and the brain, blood, spinal cord (SC), pituitary and adrenal glands (AD) were dissected for Met-enkephalin (ME) assay. The results show that nociceptive response of untreated diabetic animals increased gradually and significantly over the duration of this study. Administration of BROM and HALO significantly decreased and increased the nociceptive response, respectively, in all groups. However, the response of the diabetic group was more pronounced than that of the other two groups, especially for those treated with BROM. Daily insulin administration normalized nociceptive response to that of the nondiabetic controls. Diabetic animals receiving insulin replacement+BROM also showed normalized nociceptive response while the diabetic animals+HALO did not. Moreover, the administration of HALO and BROM resulted in an increase and decrease ME concentrations, respectively, in most tissues and brain regions examined. The effect of these dopaminergic agents on ME levels was greater in brain regions and tissues of the diabetic rats than in the diabetic groups receiving vehicle or in the nondiabetic control receiving these two agents. These data suggest that diabetes alters the sensitivity of the dopaminergic receptors and that altered response of the dopaminergic system could be indirectly involved in the modulation of nociception in diabetic rats possibly through the enhancement and/or deactivation of the endogenous Met-enkephalinergic system.

Behavioral responses to repeated cocaine exposure in mice selectively bred for differential sensitivity to pentobarbital.

Mice from the 20th generation of three lines divergently selected for response to pentobarbital-induced sedation times [long-sedation time (LST), short sedation time (SST), and randomly bred control (RBC)] were used to study cocaine-induced behavioral sensitization. These lines showed variable degrees of locomotor activities in response to cocaine. At a low cocaine dose and long withdrawal period (10 mg/kg, twice a day for 5 days followed by a 14-day withdrawal), the LST mice showed tolerance development. In response to cocaine, the locomotor activities of the SST were not significantly different from the RBC group. At a higher dose and a shorter withdrawal period (20 mg/kg, daily for 7 days followed by a 3-day withdrawal), the SST mice showed behavioral sensitization similar to the RBC mice, but the LST mice did not develop sensitization. The different responses in locomotor activity induced by cocaine suggest that genetic factors may play a role in determining the magnitude of response to this drug. Dopamine (DA) levels did not differ significantly in either striatum (STR) or nucleus accumbens (NAC) for the cocaine-treated animals to their corresponding saline-treated controls. The affinity (Kd) of D2 in the NAC decreased significantly, without changes in density (Bmax), in the cocaine-treated SST and RBC mice. On the other hand, the density of D2 binding sites in the SST and the RBC mice in the STR was significantly increased in cocaine-treated groups without change in Kd. The LST mice did not show any changes in the Kd and Bmax in either the STR or the NAC. Taken together, these findings suggest that the changes in the Kd of D2 in the NAC and the Bmax of D2 in the STR may contribute to the differences in locomotor responses to cocaine exposure in these mouse lines.

Divergent selection for pentobarbital-induced sedation times in mice.

Divergent selection for pentobarbital sedation-time response was practiced in mice for 9 generations. At the end of 9 generations of selection, the long-sedation-time line (LST) slept an average of 433 min; the short sedation time line (SST) slept an average of 29 min. The control line (C) slept an average of 71 min. These differences represent an almost 15-fold increase in sedation time for the LST compared to the SST line and a 6-fold increase compared to the C line. The SST line slept about 40% less than the C line after 9 generations of selection (measured in tenth generation progeny). Analysis of selection differentials and realized heritabilities indicated that selection response did not diminish after 9 generations of selection. Realized heritabilities for sedation time ranged from 0.43 to 0.83 for the LST line and from 0.55 to 0.81 for the SST line. Realized heritabilities did not decrease in magnitude due to selection progress, indicating that more progress can still be achieved. Comparing corrected (for environmental factors) to uncorrected heritabilities showed the importance of including a control line in selection experiments. Crossing of lines to study gene action responsible for this trait revealed that this trait was controlled by a number of genes with additive gene action without dominance, overdominance, epistasis, or maternal effects.

Changes in hemodynamics, ventricular remodeling, and ventricular contractility during normal pregnancy: a longitudinal study.

OBJECTIVE: To investigate the hemodynamic changes occurring in normal pregnancy and to see if these changes were associated with an increase in myocardial contractility. METHODS: In a longitudinal study, primigravidas were studied with echocardiography in early (15 +/- 1.8 weeks), mid (26 +/- 1.2 weeks), and late (36 +/- 1.0 weeks) gestation, as well as at 6 weeks postpartum. Cardiac dimensions were measured with two-dimensional and M-mode echocardiography and hemodynamic indices were calculated. All measurements were made with subjects in the left lateral decubitus position. Statistical analysis was performed with repeated measures analysis of variance. RESULTS: Seventy-six women with normal pregnancy outcomes completed all four studies. From the baseline study to late gestation, an increase in cardiac output of 27% (from [mean +/- standard error] 4.2 +/- 0.1 to 5.8 +/- 0.2 L/min, P = .001), and a decrease in total peripheral resistance of 33% (from 1356 +/- 69 to 941 +/- 37 dynes/second cm-5, P = .001) occurred. Over this same time period, left ventricular function, while demonstrating a small and non-significant increase in velocity of circumferential fiber shortening (from 1.25 +/- 0.02 to 1.27 +/- 0.02 cm/second), revealed a 12% decrease in wall stress (from 36.3 +/- 1.0 to 31.9 +/- 1.0 g/cm2, P = .001) and a 13% decrease in the load-independent wall stress to velocity of circumferential fiber shortening ratio (from 30.0 +/- 1.2 to 26.1 +/- 1.0, P = .01), implying enhanced intrinsic myocardial contractility. CONCLUSION: Normal pregnancy is characterized by enhanced myocardial performance.

Estrogen and cardiovascular function after menopause.

Nonrandomized trials of postmenopausal estrogen replacement have shown a benefit in the prevention of coronary artery disease. Less clear are the specific mechanisms by which this occurs. Estrogen has beneficial effects on the lipid profile, with significant elevations in high density lipoprotein cholesterol and reductions in low density lipoprotein cholesterol reported. Also, antioxidant properties have been ascribed to estrogen. In addition, estrogen has been shown to prevent paradoxic vasoconstriction in atherosclerotic coronary arteries after acetylcholine and may have calcium channel-blocking and alpha2-inhibiting properties. Other proposed mechanisms of cardiovascular protection include reductions in serum fibrinogen and increases in prostacyclin biosynthesis. There is some evidence that cardiovascular biomechanics may be mildly depressed after menopause and that estrogen may normalize these changes by increasing ventricular contractility and, possibly, relaxation. Far less is known about the cardiovascular effects of progesterone, but overall it does not appear that the less androgenic progestins substantially modify the effects of estrogen. Because more women > 50 years old die of cardiovascular disease than any other cause, further clinical investigations of the risks and benefits of estrogen replacement and combined estrogen and progesterone therapy are clearly needed.

Myocardial atrophy in acquired immunodeficiency syndrome--associated wasting.

This study evaluated the effects of acquired immunodeficiency syndrome wasting syndrome (AWS) on the heart in a population free of overt opportunistic infection or clinical evidence of cardiac disease. Data from 53 patients with AWS and 16 healthy age-matched controls were studied. By echocardiography, a significant reduction in left ventricular mass was found in patients with AWS that remained significantly reduced when corrected for body surface area. Mean ejection fraction was within the normal range in patients with AWS but was significantly less than in controls. End-systolic volume index was slightly elevated in patients with AWS. Although no difference in end-systolic wall stress was seen, the end-systolic wall stress-shortening relation differed significantly. These findings are consistent with myocardial atrophy and subtle left ventricular dysfunction in patients with AWS.

Hypothermic effect of ethanol in mice selected for differential sleep-time response to pentobarbital.

The hypothermic action of ethanol was investigated in genetically distinct lines of mice selected for sleep-time response to pentobarbital for six generations. Ethanol (3 g/kg, intraperitoneally) was administered to alcohol-naive males and females from each of the unselected control, long-, and short-sleep mouse lines. Rectal temperatures were measured immediately before, and at 15, 30, 60, 90, 120, and 240 min after ethanol injection. Eight female and eight male mice from each line were sacrificed at each time point, and trunk blood was collected for plasma ethanol analysis. The results show that short-sleep mice were less hypothermic (p < 0.05) compared to long-sleep mice at 15 and 30 min after ethanol administration. However, plasma ethanol concentrations were not significantly different between the mouse lines at any time point. Therefore, the line-dependent differential ethanol-induced hypothermia observed may be a result of differences in "brain sensitivity" rather than in the rates of ethanol metabolism among the mouse lines.

Unusual immunocytochemical and ultrastructural features of synovial fluid cells in multicentric reticulohistiocytosis. A case report.

We present the first report in which cells in synovial fluid from a patient with multicentric reticulohistiocytosis (MRH) were studied by immunocytochemistry for correlation with routine light and electron microscopy. MRH cells stained predominantly for lymphocyte-related surface antigens and not for the monocyte marker LEU M3 (CD14). These findings suggest a lymphocytic origin of MRH cells and not a histiocytic origin, as previously suggested. In addition, large numbers of membrane-bound, electron-dense, secretory-type granules were found ultrastructurally in the cytoplasm of these cells.

The effect of smoking on theophylline kinetics in healthy and asthmatic elderly males.

The effect of smoking on theophylline kinetics was investigated in four groups of males over the age of 65 yr. The first group consisted of 14 healthy non-smoking males, the second group consisted of 8 healthy smoking males. The first and the second groups were administered a single oral dose of 300 mg tablet of sustained-release anhydrous theophylline product and serial blood samples were collected over 24 hr. The third group consisted of 22 clinically stable asthmatic non-smoking males, the fourth group consisted of 9 clinically stable asthmatic smoking males. The third and the fourth groups, were administered multiple oral doses equivalent to 300 mg of anhydrous theophylline from sustained-release Oxtriphylline every 12 hr for 72 hr; and blood samples were collected every two hours between 72-82 hrs. Serum theophylline concentrations were determined by HPLC. There were no significant differences between the smokers and non-smokers in observed maximum concentration (Cmax), its time (tmax), the area under the time-concentration curve (AUCo-t), and total body clearance rate (Cl). Aging appears to offset the known smoking inducing effect on the hepatic microsomal enzymes.

Theophylline kinetics in a geriatric group.

The influence of age, sex, and smoking on theophylline disposition was studied in 38 healthy subjects ranging in age from 26 to 81 yr. There were 8 young (less than 60 yr) and 30 geriatric (greater than 60 yr) subjects, including 28 men (8 smokers) and 10 women (3 smokers). A crossover experimental design was used. A single dose of theophylline elixir (5 mg/kg lean body weight [LBW]) was given as a reference product to all subjects. One week later a sustained-release (SR) theophylline tablet (8 and 6 mg/kg LBW) was given to the young and the geriatric subjects. Serum theophylline concentrations were determined by HPLC. Theophylline elimination (t1/2 beta) is shorter in the geriatric group (6.93 and 8.14 hr); total body theophylline clearance is greater in the geriatric group (44.39 and 32.97 ml/kg/hr), and the apparent volume of distribution is also greater in the geriatric group (26.29 and 22.97 l). Sex and smoking did not influence any of the parameters studied. In 93% of the geriatric subjects, serum theophylline levels of 8 to 20 micrograms/ml were reached at steady state with the SR tablet. Theophylline dose reduction based on an arbitrary age limit is not, therefore, invariably indicated.

Study of oxtriphylline SA in 50 asthmatics.

Fifty clinically stable patients with asthma on maintenance theophylline therapy, mean dose of 15 mg kg-1 per day, were switched to an equivalent dose (X 1.56) of oxtriphylline SA for seven doses. All subjects remained clinically stable after the change during the study period. Oxtriphylline SA appears to be useful for the maintenance treatment of asthma and can be safely substituted for other theophylline maintenance regimens.

Pharmacokinetics and bioavailability of three dyphylline preparations.

The pharmacokinetics and bioavailability of 3 oral dyphylline preparations, solution (S), regular (R) and sustained release (SR), were studied in 8 healthy subjects (mean age 25 years). A single dose of each preparation, 20 mg X kg-1, was given at one week intervals and multiple serum samples obtained over 24 h. Drug levels were measured by high performance liquid chromatography. No adverse effects were found. The dyphylline half-life for the solution was 2.16 +/- 0.18 h and for the tablet 2.59 +/- 0.56 h. The mean clearance rate for S was 13.6 +/- 1.7 h-1 and volume of distribution 43.0 +/- 3.91. Peak concentration (Cmax, micrograms X ml-1), time of peak (Tmax, h), area under the curve (AUC, micrograms X ml-1 X h) and relative bioavailability (RB, %), were determined for three preparations: Cmax S, 33.7 +/- 3.7; R, 27.7 +/- 4.2; SR, 10.4 +/- 1.5 Tmax: S, 0.33 +/- 0.0; R, 0.66 +/- 0.0; SR, 2.13 +/- 1.1 AUC: S, 108.4 +/- 12.1; R, 113.9 +/- 25.2; SR, 104.0 +/- 30.8 RB: Reference Product R, 105.00 +/- 16.00; SR, 100.00 +/- 25.00 The data confirm the short half-life of dyphylline, demonstrate a lack of toxicity for the 20 mg X kg-1 dose and establish bioequivalence for the products studied.

Cutaneous leishmaniasis in the Libyan Arab Republic: preliminary ecological findings.

Preliminary results show cutaneous leishmaniasis in Libya to be, sometimes at least, a rural zoonotic infection. The parasites are transmitted, probably by Phlebotomus papatasi, between the rodents Psammomys obesus and Meriones libycus. The banks and 'islands' in the main channel of seasonal wadis provide the right combination of vegetation and permanence for the maintenance of an intense focus.