Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia.

Nondystrophic myotonias are characterized by muscle stiffness triggered by voluntary movement. They are caused by mutations in either the CLCN1 gene in myotonia congenita or in the SCN4A gene in paramyotonia congenita and sodium channel myotonias. Clinical and electrophysiological phenotypes of these disorders have been well described. No concomitant mutations in both genes have been reported yet. We report five patients from three families showing myotonia with both chloride and sodium channel mutations. Their clinical and electrophysiological phenotypes did not fit with the phenotype known to be associated with the mutation initially found in SCN4A gene, which led us to screen and find an additional mutation in CLCN1 gene. Our electrophysiological and clinical observations suggest that heterozygous CLCN1 mutations can modify the clinical and electrophysiological expression of SCN4A mutation.

[Myopathy-lipomatosis associated with A8344G mitochondrial DNA mutation]. / Myopathie-lipomatose par mutation A8344G de l'ADN mitochondrial.

We report the clinical features of two unrelated patients, a 51-year-old woman and a 54-year-old man, presenting proximal myopathy with lipomatosis. In both patients, muscle biopsies showed numerous ragged-red fibers. Molecular analysis were performed with denaturating gradient gel electrophoresis (DGGE) on muscle, blood, hair, buccal and urinary cells. The A8344G mutation of the tRNA-lysine gene of the mitochondrial DNA was detected in all tissues at high levels (more than 80 p cent). None of the patients had a contributive family history, and signs of central nervous system involvement were absent. These observations confirm that lipomatosis may be encountered in mitochondrial disorders and is tightly associated with the A8344G mutation.

Analysis of the rutile-ring method of frequency-temperature compensating a high-Q whispering gallery sapphire resonator.

The rutile-ring method of dielectrically frequency-temperature compensating a high-Q whispering gallery (WG) sapphire resonator is presented. Two and three-dimensional finite element (FE) analysis has been implemented to design and analyze the performance of such resonators, with excellent agreement between theory and experiment. A high-Q factor of 30 million at 13 GHz and compensation temperature of 56 K was obtained. It is shown the frequency-temperature compensation can occur either because the rutile adds a small perturbation to the sapphire resonator or because of a mode interaction with a resonant mode in the rutile. The characteristics of both of these methods are described, and it is shown that for high frequency stability, it is best to compensate perturbatively.

Compact, high-Q, zero temperature coefficient, TE011 sapphire-rutile microwave distributed Bragg reflector resonators.

Some novel new resonator designs based on the distributed Bragg reflector are presented. The resonators implement a TE011 resonance in a cylindrical sapphire dielectric, which is confined by the addition of rutile and sapphire dielectric reflectors at the end faces. Finite element calculations are utilized to optimize the dimensions to obtain the highest Q-factors and zero frequency-temperature coefficient for a resonator operating near 0 degree C. We show that a Q-factor of 70,000 and 65,000 can be achieved with and without the condition of zero frequency-temperature coefficients, respectively.

Mitochondrial DNA transfer RNA gene sequence variations in patients with mitochondrial disorders.

Many different pathogenic mutations in the mitochondrial (mt) transfer RNA (tRNA) genes have been reported for patients with mitochondrial encephalomyopathy. Although some of them are recurrent, most have only been described once and appear to be restricted to one patient or to one family. The incidence of mt tRNA gene alterations is not known, even though the frequency of some recurrent mutations has been analysed both in patients and in the general population. In this study, we describe the results of stepwise screening for sequence variations in the mt tRNA genes of 166 patients selected according to several criteria. Extensive sequence analysis of the tRNA genes was performed using denaturing gradient gel electrophoresis. A total of 31 patients (19%) were found to harbour significant levels of a pathogenic mutation, thus confirming the importance of mt tRNA mutations in human pathology. Forty-three different sequence variations were found, illustrating the great diversity of the mtDNA sequence in humans. The functional assessment of all these sequence variations represented a difficult task; it was mostly based on indirect data, such as the phylogenetic conservation of modified nucleotides and the proportions of variant species in different tissues of the index case or in blood of maternal relatives. Direct demonstration of a correlation between the proportion of heteroplasmic sequence variations and the cytochrome c oxidase defect was performed at the single muscle-fibre level. Eleven heteroplasmic sequence variations were found, six of which are new mutations. One is a known Caucasian polymorphism but the other 10 are pathogenic. Two of them are the well-known pathogenic MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (A3243G) and MERRF (myoclonic epilepsy with ragged-red fibres) (A8344G) point mutations. They were found in 23 patients. The eight other mutations were restricted to one patient. The pathogenic nature of these mutations was demonstrated directly for five of them and hypothesized from indirect arguments for the other three. Thirty-two homoplasmic sequence variations were found. Twenty-nine were considered to be polymorphisms, even though 15 of these were found for the first time in our patients and two others had been reported previously as pathogenic. The pathogenic nature of three homoplasmic variants remains questionable.

Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss.

The aim of this study was to investigate the potential role of adipose cytokines in the obesity-associated insulin resistance. To that end, we compared: 1) serum concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), and leptin in eight healthy lean control females and in android obese female without (n = 14) and with (n = 7) type 2 diabetes; and 2) the levels of these cytokines both in serum and in sc adipose tissue in the 14 obese nondiabetic women before and after 3 weeks of a very low-calorie diet (VLCD). As compared with lean controls, obese nondiabetic and diabetic patients were more insulin resistant and presented increased values for leptin, IL-6, TNFalpha, and C-reactive protein. In the whole group, IL-6 values were more closely related to the parameters evaluating insulin resistance than leptin or TNFalpha values. VLCD resulted in weight loss and decreased body fat mass (approximately 3 kg). Insulin sensitivity was improved with no significant change in both serum and adipose tissue TNFalpha levels. In contrast, VLCD induced significant decreases in IL-6 and leptin levels in both adipose tissue and serum. These results suggest that, as for leptin, circulating IL-6 concentrations reflect, at least in part, adipose tissue production. The reduced production and serum concentrations after weight loss could play a role in the improved sensitivity to insulin observed in these patients.

Subcutaneous adipose tissue expression of plasminogen activator inhibitor-1 gene during very low calorie diet in obese subjects.

OBJECTIVE: To determine whether changes in subcutaneous adipose tissue plasminogen activator inhibitor-1 (PAI-1) expression influence plasma PAI-1 level during weight loss in obese humans. DESIGN: Study of the variations of PAI-1 levels both in plasma and in subcutaneous abdominal adipose tissue in 15 volunteer non-diabetic obese subjects, body mass index (BMI) 40.4.+/-1.9 kg/m2, aged 48+/-3 y, before and after a 3 week very low calorie diet (VLCD) programme (3.9+/-0.1 MJ/day). MEASUREMENTS: Plasma and adipose tissue PAI-1 protein levels were measured by enzyme-linked immunosorbent assay and PAI-1 mRNA levels were quantified by quantitative RT-competitive PCR. RESULTS: VLCD induced weight loss (5.8+/-0.8 kg) and decreased plasma PAI-1 concentration (-26% (P<0. 01)). Surprisingly, PAI-1 mRNA and protein abundance in subcutaneous adipose tissue increased by 87% (P<0.05) and by 44% (P<0.01), respectively. CONCLUSION: These data indicate thus that changes in subcutaneous adipose tissue PAI-1 expression are not involved in the decrease of plasma PAI-1 levels during VLCD in obese subjects. International Journal of Obesity (2000)24, 70-74

High-Q whispering gallery traveling wave resonators for oscillator frequency stabilization.

Usually a frequency-stabilized standing wave resonator-oscillator incorporating a resonator as a frequency discriminator requires a circulator to separate the injected and reflected wave, A ferrite circulator is a noisy device and can limit the phase noise or frequency stability. Moreover, we show that the noise in a circulator varies, and detailed low noise measurements are necessary to choose an appropriate quiet circulator. Thus, by realizing a configuration that does not require a circulator, an improvement in performance and reliability can be obtained. A solution to this problem is to design a high-Q whispering gallery traveling wave (WGTW) resonator. This device naturally separates the injected and reflected wave in the same way as a ring cavity at optical frequencies, without degrading the frequency discrimination. Q-factor measurements of a WGTW sapphire resonator are presented, along with a derivation of critical parameters to maximize the frequency discrimination. New measurements of noise in ferrite circulators and isolators have also been made, which is followed with a discussion on oscillator design.