A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutations

Wilson disease (WD) is a hereditary disorder, with recessive transmission and genetic heterogeneity. Several mutations of ATP7B, the gene underlying WD, were reported in many ethnic groups. In this study, mutation screening in ATP7B of 56 Saudi Arabian WD patients was undertaken. The clinical data of all patients were recorded. The entire ATP7B coding sequence, including intron-exon boundaries were screened for mutation by the polymerase chain reaction (PCR)-based mutation detection technique and DNA sequencing. Thirty-nine patients were symptomatic at presentation and 17 subjects were pre-symptomatic siblings of affected patients. Fourteen patients had neurological, 11 patients had mixed (hepatic and neurological), and 14 patients had hepatic presentations. Family history suggestive of WD was present in 72% of cases and 68% had consanguineous parents. Genetic analysis showed disease-causing mutations in three exons (exons 8, 19 and 21) of the ATP7B gene in 28 patients (50%). Mutations in exons 21 (18 cases) and 19 (one case) were unique for Saudis. This large series of Saudi patients with WD has shown wide variability in the genomic substrate of WD. There is no correlation between genotype and clinical presentation.     

Combined Excimer Laser and Topical Tacrolimus for the Treatment of Vitiligo: A Pilot Study

Background. Vitiligo is an acquired skin disorder that is characterized by well-defined, often symmetric white patches. Although current therapeutic modalities are directed toward increasing melanocyte melanin production, few treatment modalities address the immunologic nature of the disease.
Objective. To determine whether excimer laser, a known therapeutic modality, in combination with tacrolimus, a topical immunomodulator, accelerate response time and/or improve the degree of response in patients with this disorder.
Methods. Eight subjects diagnosed with vitiligo were recruited to participate in this institutional review board–approved double-blind, placebo-controlled study. Twenty-four symmetric vitiliginous patches (elbows, knees) from eight subjects received excimer laser treatment three times per week for 24 treatments or 10 weeks. Additionally, topical tacrolimus 0.1% ointment (Protopic) and placebo (Aquaphor) were applied to randomized patches (left or right) twice daily throughout the length of the trial. Vitiliginous patches were monitored with photographs at baseline, every 2 weeks, and 6 months after treatment. Biopsies were performed on subjects with significant results.
Results. Twenty vitiliginous patches from six subjects qualified for evaluation. Fifty percent of patches treated with combination excimer laser and tacrolimus achieved a successful response (75% repigmentation) compared with 20% for the placebo group. Subjects who responded successfully repigmented faster (19%) with combination therapy compared with excimer laser alone. Additionally, three subjects experienced transient hyperpigmentation in lesions treated with combination therapy.
Conclusion. Combining topical immunomodulators with known phototherapeutic modalities may represent a key advancement in the treatment of disease.     

Haemophilia in the developing world: successes,frustrations and opportunities

Summary. There is a need to bridge key gaps between high‐ and low‐income countries and individuals; between health policy and clinical practice; and between producers and users of healthcare technology and scientific evidence. The objective of this report was to perform a diagnosis of the situation in the developing world through a survey. This survey was conducted to gather specific information on various aspects related to haemophilia. Countries were chosen by their comparability in infant and adult mortality rates according to the regionalization proposed by the World Health Organization. These indicators are very sensitive to socioeconomic conditions, and have been widely used to study health inequalities. All regions, except Africa and the East Mediterranean, were represented. Africa was excluded because its indicators were not comparable. The East Mediterranean was not represented because of difficulties in contacting investigators. Twenty‐one country representatives were contacted, and 11 answered the questionnaire. Successes obtained by developing countries are based more on the skills and creativity of the local professionals than on the availability of state‐of‐the‐art technology. Frustrations were related to disease underregistration and the limited availability of treatment products. Haemophilia care in the developing world is not as fair as we would like it to be. Governments do not always cover treatment costs, and a very small percentage of the national health budgets is alotted to haemophilia care. The role of the World Federation of Hemophilia was considered crucial by all the investigators surveyed. Training programmes and supply of factor concentrates were the main contributions identified by the respondents.     

Self management of oral anticoagulation with the IN Ratio system: impact of a structured teaching program on patient's knowledge of medical background and procedures.

BACKGROUND: Self management of oral anticoagulation (OAC) decreases complication rates and improves quality of life. Manual and cognitive abilities of patients and patient training in a structured format are a precondition for this concept. Up to now, there is no evidence about knowledge increase from teaching programs. METHODS: Seventy-six patients (mean age, 57.4 years, 71% male) who started long-term OAC were included in the prospective multi-center study at three teaching centers representing different populations of anticoagulation patients: a department of cardiovascular surgery, an inpatient rehabilitation center and an anticoagulation clinic. The patients were trained in a structured education program for two days. For the evaluation, the patients performed standardized tests including 16 questions prior to start (T0), after each training unit (T1/T2) and 6 weeks later (T3). The primary endpoint was the percentage of > or =75% of patients who could answer > or =50% of questions correctly at T3. Secondary endpoints were the overall and item-specific percentages of correct answers at the end of each training unit (T1, T2) and at T3. In addition, the teaching program was rated by the patients on a six-point rating scale. RESULTS: Seventy-four out of 76 patients gave at least 50% correct answers at T3 (97.4%; 95% confidence interval, 90.8-99.7%). The average rates of correct answers developed from 40% (T0), 86% (T1), 94% (T2) to 96% (T3). The greatest increase of knowledge was observed with blood components, interpretation of International Normalized Ratio (INR) value, and the interaction of anticoagulation with other variables (e.g. drugs or infection). Patients rated the teaching program between 1 (best rating) and 2 at all time points. At T3, the patients reported less fear of complications and less limitations in their daily life than in earlier evaluations. CONCLUSION: The structured training program INRatio appears to be an appropriate instrument for instruction of INR self management. In comparison with baseline knowledge, the percentage of correctly answered questions was twice as high directly after the end of training and remained at a high level of >90% for at least 6 weeks.     

Prevalence of impaired glucose tolerance 6 years after gestational diabetes.

AIM: Prevalence of glucose metabolism disorders in women six years after gestational diabetes in the index pregnancy (GDM). METHOD: 227 Caucasian women who developed GDM between 1995 and 1996 were investigated; 173 women (BMI 27.5+/-6.0 kg/m2) received 75 g oGGT on average 5.8+/-2.0 years after delivery. RESULTS: Impaired glucose metabolism was found in 31.2%, IGT or IFG 19.1%, diabetes mellitus type 2 (DM2) 9.2%, diabetes mellitus type 1 (DM1) 2.3%, second GDM 0.6%. 27.2% (BMI 25-29.9 kg/m2) were overweight, 23.1% suffered from obesity (BMI 30-39.9 kg/m2) and 5.2% morbid obesity (BMI>or=40 kg/m2). In comparison to a healthy control group, women with DM2 at re-examination were: older in age (32.1+/-5.9 vs. 29.1+/-4.8 years, p<0.05), had higher BMI (29.4+/-6.9 vs. 24.6+/-4.8 kg/m2, p<0.05), higher fasting blood glucose (6.5+/-1.9 vs. 5.2+/-0.9 mmol/l, p<0.05), earlier diagnosis of GDM (25+/-8 vs. 29+/-5 SSW, p<0.05), more frequent insulin therapy during pregnancy (75 vs. 24%) and had significantly higher insulin- and C-peptide for all measures of the oGTT, whereas HbA1c was not different (4.9+/-0.5 vs. 4.8+/-0.3%, n. s.). CONCLUSION: In an average of 5.8 years after the diagnosis of GDM, the majority of women still have chronic insulin resistance. One third has either IGT, IFG or diabetes mellitus. Therefore, a long term follow-up is strongly recommended for women diagnosed with GDM.     

(3)He-particle-induced reactions on (nat)Sb for production of (124)I.

Excitation functions of the reactions (nat)Sb((3)He,xn)(124,123,121)I were measured from their respective thresholds up to 35 MeV, with particular emphasis on data for the production of the medically important radionuclide (124)I. The conventional stacked-foil technique was used. From the experimental data the theoretical yields of the three investigated radionuclides were calculated. The yield of (124)I over the energy range E9(30He) = 35 --> 13 MeV amounts to 0.95 MBq/microA h. The radionuclidic impurities are discussed. A comparison of (3)He- and alpha-particle-induced reactions on antimony for production of (124)I is given. The alpha-particle-induced reaction on enriched (121)Sb and the (3)He-particle-induced reaction on enriched (123)Sb would lead to comparable (124)I yields, but the level of impurities in the latter case would be somewhat higher.     

A Synergistic Effect Between PG490-88 and Tacrolimus Prolongs Renal Allograft Survival in Monkeys

This study was undertaken to determine if PG490-88 and tacrolimus (Tac) act synergistically to prevent renal allograft rejection in monkeys and to explore possible mechanisms of synergy between these agents. MHC-mismatched renal allografts were transplanted into cynomolgus monkeys after bilateral nephrectomy. Recipients were divided into the following groups: (i) no treatment; (ii) PG490-88 (0.03 mg/kg); (iii) Tac (1 mg/kg); (iv) PG490-88 (0.01 mg/kg) + Tac (1 mg/kg) and (v) PG490-88 (0.03 mg/kg) + Tac (1 mg/kg). Through synergy PG490-88 and Tac inhibited anti-CD3/PMA-induced T-cell proliferation and IFN-gamma expression in vitro. Tac monotherapy only marginally prolonged survival (27 +/- 3.2 days), while the combination of PG490-88 and Tac significantly prolonged graft survival to a median of 99 days (PG490-88 at 0.03 mg) and 38.5 days (PG490-88 at 0.01 mg/kg). Prolonged survival correlated with inhibited IgM production as well as reduced T-cell infiltration, IL-2 protein expression and NF-AT/NF-kappaB activity. We conclude that PG490-88 and a subtherapeutic dose of Tac significantly prolong renal allograft survival in monkeys through the synergistic inhibition of T-cell activation and a decrease in IFN-gamma production and NF-AT/NF-kappaB activity.