Allergen immunotherapy inhibits airway eosinophilia and hyperresponsiveness associated with decreased IL-4 production by lymphocytes in a murine model of allergic asthma

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37+/-17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement-related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71+/-23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1-2 seconds) of electrical microstimulation of STN could produce tremor arrest but were not found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.     

Risk of left ventricular dysfunction in patients with probable Alzheimer's disease with APOE*4 allele

OBJECTIVE: To examine the association between the APOE genotype and cardiovascular disease in Alzheimer's disease (AD) patients. DESIGN: Case register study of 100 consecutive referrals to a Memory Clinic where type of dementia and cardiovascular comorbidity were diagnosed and APOE genotype was determined. SETTING: The Memory Clinic, University Hospital Rotterdam Dijkzigt. PARTICIPANTS: One hundred Memory Clinic patients, 59 to 91 years of age, who attended the Memory Clinic in the period between January 1994 and March 1996. MEASUREMENTS: Relative risk of cardiovascular morbidity in probable AD, based on clinical and ECG findings. RESULTS: The diagnosis of probable AD was more frequent in APOE*4 allele-carrying AD patients. When comparing homozygotes for APOE*4 with homozygotes for APOE*3, a nine-fold increase in prevalence of cardiac ischemia on ECG was found in the former. When grouping parameters of left ventricular dysfunction, the prevalence was 7.2 (95% confidence interval 1.2-42.6) times greater in probable Alzheimer patients with APOE4/4. CONCLUSIONS: In patients with probable AD, APOE*4 is associated with cardiac disease indicative of left ventricular dysfunction.     

Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident

Analysis of germline mutation rate at human minisatellites among children born in areas of the Mogilev district of Belarus heavily polluted after the Chernobyl accident has been extended, both by recruiting more families from the affected region and by using five additional minisatellite probes, including multi-locus probe 33.6 and four hypervariable single-locus probes. These additional data confirmed a twofold higher mutation rate in exposed families compared with non-irradiated families from the United Kingdom. An elevated rate was seen at all three independent sets of minisatellites (detected separately by multi-locus probes 33.15, 33.6 and six single-locus probes), indicating a generalised increase in minisatellite germline mutation rate in the Belarus families. Within the Belarus cohort, mutation rate was significantly greater in families with higher parental radiation dose estimated for chronic external and internal exposure to caesium-137, consistent with radiation induction of germline mutation. The spectra of mutation seen in the unexposed and exposed families were indistinguishable, suggesting that increased mutation observed over multiple loci arises indirectly by some mechanism that enhances spontaneous minisatellite mutation.     

HMGI(Y) expression in human uterine leiomyomata. Involvement of another high-mobility group architectural factor in a benign neoplasm

Chromosomal rearrangements involving 6p21 have been observed in uterine leiomyomata and a variety of other benign tumors. The gene for HMGI(Y), a member of the high-mobility group (HMG) family of proteins, has been localized to 6p21. To determine whether rearrangements observed in this area alter HMGI(Y) expression, we analyzed HMGI(Y) DNA-binding activity in protein extracts from uterine leiomyoma and normal myometrium tissues. This report describes a uterine leiomyoma specimen with an inv(6)(p21q15). A genomic P1 clone that contains the HMGI(Y) region of chromosome 6 is found to span the inversion breakpoint by fluorescent in situ hybridization of metaphase chromosomes. Expression of HMGI(Y) protein in this leiomyoma specimen is increased dramatically as compared with the matching normal myometrial tissue. Elevated HMGI(Y) expression was also found in 8 of 16 leiomyomas without cytogenetically detectable chromosome 6p21 aberrations but not in any of the 9 matching myometrial tissues. Analysis of the genetic events involved in the pathobiology of these benign tumors will provide a basis for understanding the process of improper cellular growth and might be important in deciphering the multistep pathway of tumorigenesis.     

Mexiletine. A review of its therapeutic use in painful diabetic neuropathy

Mexiletine is an orally active local anaesthetic agent which is structurally related to lidocaine (lignocaine) and has been used for alleviating neuropathic pain of various origins. Mexiletine has been evaluated in several randomised, placebo-controlled trials in patients with painful diabetic neuropathy. The drug decreased mean visual analogue scale (VAS) pain ratings in all studies that used this measure, although in only 2 studies was this effect significantly greater than the often substantial responses seen with placebo. The clinical significance of these decreases is not clear. Statistically significant (vs placebo) reductions in VAS pain ratings were observed in 16 patients receiving mexiletine 10 mg/kg/day for 10 weeks in 1 study and in nocturnal (but not diurnal) pain in 31 patients receiving mexiletine 675 mg/day for 3 weeks in another. Retrospective analysis of another study revealed that mexiletine recipients (225 to 675 mg/day) who described their pain as stabbing, burning or formication on the pain-rating-index-total instrument of the McGill Pain Questionnaire, experienced statistically significant reductions in VAS pain scores after 5 weeks, compared with placebo recipients. Mexiletine generally did not have a significant influence on the quality of sleep in patients with diabetic neuropathy. In Japanese patients, statistically significant reductions in subjective pain ratings were achieved with mexiletine 300 mg/day in 1 study and with 450 mg/day in a further study. In controlled trials, the frequency of adverse events in patients receiving mexiletine for painful diabetic neuropathy ranged from 13.5 to 50%. Gastrointestinal complaints, of which nausea was the most frequent, were the most common adverse events in mexiletine recipients. Central nervous system complaints were uncommon, but included: sleep disturbance, headache, shakiness, dizziness and tiredness. Serious cardiac arrhythmias have not been reported in patients receiving mexiletine for painful diabetic neuropathy; however, transient tachycardia and palpitations have been reported. There are significant differences in the metabolism of mexiletine between people who have cytochrome P450 2D6 [CYP2D6; extensive metabolisers (EMs)] and those who lack this isoenzyme [poor metabolisers (PMs)]. EMs, but not PMs, are susceptible to drug interactions between mexiletine and drugs that inhibit CYP2D6 (e.g. quinidine). Moreover, mexiletine inhibits CYP2D6-mediated metabolism of metoprolol and cytochrome P450 1A2-mediated metabolism of theophylline. Phenytoin and rifampicin (rifampin) induce the metabolism of mexiletine. Clearance of mexiletine is impaired in patients with hepatic, but not renal, dysfunction. Hence, dosage adjustments may be necessary in patients with liver disease. CONCLUSIONS: Tricyclic antidepressants (TCAs) are the agents of choice for painful diabetic neuropathy; however, they are ineffective in approximately 50% of patients and are generally not well tolerated. Mexiletine is an alternative agent for the treatment of painful diabetic neuropathy in patients who have not had a satisfactory response to, or cannot tolerate, TCAs and/or other drugs.     

Biphasic effects of intrapipette cyclic guanosine monophosphate on L-type calcium current and contraction of guinea pig ventricular myocytes

The effects of intracellular cyclic guanosine monophosphate (cGMP) on L-type calcium current (lCa) and contraction of ventricular myocytes enzymatically isolated from guinea pig hearts were investigated to test the hypothesis that cGMP increases contractions along with ICa in these cells. ICa and contractions, elicited every 15 sec, were recorded simultaneously with a whole-cell voltage-clamp method and a video edge-detector, respectively. Cells were superfused with Tyrode's solution (22 degrees C); the pipette solution contained 120 mM potassium aspartate, 30 mM KCl, 4 mM ATP, 5 mM N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid), 0.01 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and various concentrations of cGMP, which entered the cell interior through the patch electrode. In the presence of 3 nM isoproterenol (ISO) in the bath, ICa was increased 3.2-fold. ICa was further increased by 20% with 30 microM cGMP; cell contractions were also increased by 32%. When ICa was maximal in the presence of 30 nM ISO, cGMP no longer increased ICa or contractions, an indication that the effects of cGMP and ISO were additive. When ICa was increased maximally (4.3-fold) by 100 microM isobutylmethylxanthine, a nonselective phosphodiesterase inhibitor, application of 100 microM cGMP in the pipette decreased ICa by 53% and cell shortening by 64%. Cyclic GMP changed contraction in parallel with ICa in the presence of either ISO or isobutylmethylxanthine. 5'-GMP had no significant effect on ICa or contraction in the presence of ISO or isobutyl-methylxanthine. Cyclic GMP alone, at 30 microM, increased ICa by 25%; this effect on basal ICa was reversed by removal of cGMP from the pipette solution. We conclude that intracellular cGMP had two effects on ICa and contraction, namely, 1) an increase caused by an action on cGMP-inhibited phosphodiesterase and 2) a decrease attributed to activation of cGMP-dependent protein kinase.     

New treatments for multiple sclerosis: a clinical perspective

A comprehensive screening program was initiated in Saudi Arabia in 1982 to determine the frequency of the sickle cell (Hb S) gene in the different regions of Saudi Arabia. Over a period of 10 years 30,055 samples were collected from 36 areas in the five provinces of Saudi Arabia; these were screened using electrophoretic techniques in alkaline and acid pH for the presence of Hb S in heterozygous and homozygous states. The overall prevalence of Hb AS was 7.36% and Hb SS was 1.06%, giving an Hb S gene frequency of 0.047. The results from the different regions were separated and the prevalence of Hb AS and Hb SS and Hb S gene frequencies were calculated in each province and each region. The prevalence of Hb AS and Hb SS cases ranged from O to 25.88% and O to 5.27%, respectively. No case of Hb AS or Hb SS were identified in certain areas of the central province (Al-Russ, Al-Unaiza, Al-Mesnab and Bkaria) and northern province (Qurayat and Al-Jouf). In the southern province both Hb S homozygotes and heterozygotes were encountered in all regions except Farasan Island. In all other regions the Hb S gene was encountered, but at a variable frequency. Applying Hardy-Weinberg equilibrium it was observed that in the majority of the regions the observed Hb S homozygotes were significantly higher compared to the number expected (p < 0.0001). This was believed to be due to bias as the samples were collected in the hospital. The Hb S gene frequency in the different regions ranged from 0 to 0.17 when the frequency was calculated on the basis of both Hb AS and Hb. SS cases, and 0 to 0.13 if the gene frequency was calculated after eliminating the Hb SS cases. A close correlation was observed between the Hb S gene frequency and malaria endemicity. This study shows that the Hb S gene occurs frequently in several regions of Saudi Arabia and there is an urgent need to implement control and prevention programs to reduce the number of Hb S homozygous cases.     

Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine

BACKGROUND: Substantial hematologic toxicity limits the use of azathioprine. OBJECTIVE: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity. DESIGN: Prospective cohort study. SETTING: Two rheumatology units. PATIENTS: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease. MEASUREMENTS: Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity. RESULTS: Six of 67 patients (9%) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018). CONCLUSION: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.     

Performing arts medicine in Maryland

The most established hormonal method of subsequent contraception is the so-called Yuzpe-method; another important method is placement of a copper coil. Hormonal subsequent contraception has no health-hazardous side effects, so there is nothing to prevent its use but a known pregnancy. More information about subsequent contraception and easier distribution are seen as important means of decreasing unwanted pregnancies as well as abortions.