Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin.

1. Capsazepine is a synthetic analogue of the sensory neurone excitotoxin, capsaicin. The present study shows the capsazepine acts as a competitive antagonist of capsaicin. 2. Capsazepine (10 microM) reversibly reduced or abolished the current response to capsaicin (500 nM) of voltage-clamped dorsal root ganglion (DRG) neurones from rats. In contrast, the responses to 50 microM gamma-aminobutyric acid (GABA) and 5 microM adenosine 5'-triphosphate (ATP) were unaffected. 3. The effects of capsazepine were examined quantitatively with radioactive ion flux experiments. Capsazepine inhibited the capsaicin (500 nM)-induced 45Ca2+ uptake in cultures of rat DRG neurones with an IC50 of 420 +/- 46 nM (mean +/- s.e.mean, n = 6). The 45Ca2+ uptake evoked by resiniferatoxin (RTX), a potent capsaicin-like agonist was also inhibited. (Log concentration)-effect curves for RTX (0.3 nM-1 microM) were shifted in a competitive manner by capsazepine. The Schild plot of the data had a slope of 1.08 +/- 0.15 (s.e.) and gave an apparent Kd estimate for capsazepine of 220 nM (95% confidence limits, 57-400 nM). 4. Capsazepine also inhibited the capsaicin- and RTX-evoked efflux of 86Rb+ from cultured DRG neurones. The inhibition appeared to be competitive and Schild plots yielded apparent Kd estimates of 148 nM (95% confidence limits, 30-332 nM) with capsaicin as the agonist and 107 nM (95% confidence limits, 49-162 nM) with RTX as agonist. 5. A similar competitive inhibition by capsazepine was seen for capsaicin-induced [14C]-guanidinium efflux from segments of adult rat vagus nerves (apparent Kd = 690 nM; 95% confidence limits, 63 nM-1.45 microM).(ABSTRACT TRUNCATED AT 250 WORDS)     

A study of 100 high risk lupus pregnancies.

Certain subgroups of lupus patients and those with circulating antiphospholipid antibodies (aPL) in particular, suffer a high rate of fetal loss. Over the past 4 years, we have prospectively studied 100 pregnancies in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome. In addition to conventional methods of monitoring SLE and fetal development, we have also used Doppler flow assessment of placental perfusion from the 14th wk of pregnancy onward. Patients with the antiphospholipid syndrome and previous history of thrombotic events were treated with daily heparin (10,000 IU) and low-dose aspirin (75 mg). Those without a history of thrombosis were treated with low-dose prednisolone, azathioprine, or hydroxychloroquine. Pregnancy loss was reduced from 81.3% in 101 previous pregnancies to 36.8% in 100 pregnancies managed by us. None of the patients who received hydroxychloroquine throughout the pregnancy presented fetal malformations. Careful management and close monitoring of the lupus pregnancy has substantially improved fetal outcome.     

Symptoms of irritable bowel syndrome in a British urban community: consulters and nonconsulters.

Because the prevalence of the irritable bowel syndrome (IBS) in the general population is unknown, a questionnaire of intestinal symptoms was administered to a stratified random sample of 1058 women and 838 men. Subjects were asked if they had consulted a physician about such symptoms. One or more symptoms occurred frequently in 47% of women and 27% of men. Diagnosable IBS, defined as three or more symptoms, was present in 13% of women and 5% of men. Abdominal pain was the most common symptom, and recurrent intestinal pain was reported by 20% of women and 10% of men. All symptoms were more common in women except runny or watery stools. Most symptoms including pain were unrelated to age. Only half the people with diagnosable IBS had consulted a physician about it. The likelihood of consulting a physician was directly proportional to the number of symptoms and was similar in men and women after controlling for the number of symptoms. Of individual symptoms, the one most strongly associated with consulting was abdominal pain, especially in men. It is concluded that IBS is prevalent at all ages, especially in women, that it is nearly always painful, and that people with multiple symptoms are more likely to consult a physician.     

Enteroviruses in recreational waters of Northern Ireland.

Virus surveillance of Northern Ireland recreational waters, between April 1986 and May 1989 demonstrated widespread enteroviral contamination of coastal and inland waters. In 1986, enteroviruses were detected in 4 of 46 (8.7%) water samples, collected from 6 coastal bathing waters. In 1987, 49 of 107 (45.8%) samples, from 16 coastal bathing waters, yielded enteroviruses; 33 of the enterovirus positive samples passed one or both of the coliform standards outlined by the European Economic Community (EEC) bathing water directive (76/160/EEC). Enteroviruses were also detected in 33 of 39 (84.6%) samples tested from 3 inland recreational waters.     

Extrapulmonary cryptococcosis in children with acquired immunodeficiency syndrome

There is a paucity of published information available on extrapulmonary cryptococcosis (EC) in children infected with human immunodeficiency virus, the etiologic agent of the acquired immunodeficiency syndrome. We surveyed investigators in pediatric acquired immunodeficiency syndrome around the country regarding their experience with EC. Investigators from 33 (87%) of 38 institutions responded and information on 13 patients from 11 institutions was analyzed. EC was the acquired immunodeficiency syndrome indicator disease in 9 (69%) of 13 patients. Median age was 8 years with a range of 2 to 17 years. Human immunodeficiency virus risk factors were transfusion (5 patients), hemophilia (4 patients) and perinatal exposure (4 patients). Meningitis, seen in 62% of patients, was the most common clinical manifestation. Although 2 patients with fulminant disease died before therapy was started, 10 (91%) of 11 had a clinical response to amphotericin B with or without flucytosine. Our study indicates a spectrum of EC in pediatric human immunodeficiency virus infection ranging from fulminant, fatal fungemia to chronic meningitis and fever of unknown origin. Cryptococcosis was generally not the cause of death in patients who initially responded to amphotericin B therapy. Optimal antifungal therapy, including the role of fluconazole, warrants further study.     

Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS).

We assessed the inter-rater reliability of the 100-point International Cooperative Ataxia Rating Scale (ICARS). Three neurologists independently rated videotaped ICARS examinations of 22 subjects with genetically determined ataxias (spinocerebellar ataxia [SCA] Type 1 in 11; SCA Type 2 in 1; Friedreich's ataxia in 10) and 4 controls. Scores on live ICARS assessment had ranged from 0 to 7 for controls and 11 to 74 for ataxic subjects (clinically very mildly affected to wheelchair-bound). Inter-rater correlation was very high for the total score (Kendall's omega 0.994, 95% confidence interval, 0.988-0.997), and high to very high for each component subscore (0.791 for speech to 0.994 for posture/gait). All correlations were significant at P < 0.00001. The ICARS exhibits very high inter-rater reliability even without prior observer standardisation and is sensitive to a range of ataxia severities from very mild to severe.     

Fetal heart rate changes during diabetic ketosis

A case of diabetic ketosis during pregnancy is presented in which the fetal heart rate tracing demonstrated tachycardia complicated by late and severe variable decelerations. Intravenous administration of insulin resulted in prompt abolition of the deceleration patterns. The implications of these findings are discussed.