Risk of ocular manifestations in patients with giant cell arteritis: a nationwide study in Sweden.

OBJECTIVE: No large-scale nationwide study has determined the risk of ocular manifestations in patients with giant cell arteritis (GCA). The aim was to study the incidence and risk factors of ocular manifestations in patients with GCA in Sweden. METHOD: A national cohort was created by linking Swedish nationwide registers. GCA patients were identified from the Swedish Hospital Inpatient and Outpatient Registers between 2002 and 2010, and were followed until the development of ocular manifestations. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for ocular manifestations in patients with GCA compared to those without GCA. RESULTS: We identified 3737 males and 8311 females with GCA. A total of 1618 individuals had subsequent ocular manifestations, representing 13.4% of the GCA patients. The overall SIR of ocular manifestations was 6.96 (95% CI 6.63-7.31). The risk for disorders of the optic nerve or visual tract was particularly high (SIR = 51.68, 95% CI 46.12-57.73). Men with GCA had a higher risk than women, and GCA patients without polymyalgia rheumatica (PMR) symptoms had a higher risk than those with PMR symptoms. Living outside big cities was negatively associated with ocular manifestations in GCA patients, whereas hypertension and diabetes were associated with an increased risk of ocular manifestations. CONCLUSION: The overall risk of ocular manifestations was higher in GCA patients than in the general population, especially for men and for those without PMR symptoms.

Role of family history of venous thromboembolism and thrombophilia as predictors of recurrence: a prospective follow-up study.

BACKGROUND: Several studies have shown that the family history of venous thromboembolism (FHVTE) is a predictor of first venous thromboembolism (VTE). However its role in recurrent VTE is still controversial. OBJECTIVES: To investigate whether the presence of FHVTE is a risk factor for VTE recurrence in patients from a well-characterized Malmö thrombophilia study. METHODS: VTE patients from the Malmö Thrombophilia Study were followed from discontinuation of warfarin treatment until diagnosis of VTE recurrence or to the end of the study (maximum follow-up 9.8 years). RESULTS: There were 127 events of VTE recurrence (12.2%) registered during the follow-up. Multivariate Cox regression analysis in patients with unprovoked first VTE showed that FHVTE was associated with higher risk of VTE recurrence (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-2.9) compared with patients with no FHVTE. Stratification of data according to thrombophilia status of patients showed that compared with the reference group (no FHVTE or thrombophilia), thrombophilia together with FHVTE was associated with a higher risk of VTE recurrence (HR 3.2, 95% CI 1.8-5.9) than thrombophilia alone (HR 1.8, 95% CI 1.02-3.2) independent of DVT location and duration of warfarin treatment. FHVTE was mainly an important risk factor of VTE recurrence in women (HR 3.1, 95% CI 1.6-5.8) but not in men (HR 1.1, 95% CI 0.6-2.2). CONCLUSION: Our results show that FHVTE is a risk factor for VTE recurrence in patients who had unprovoked first VTE. Furthermore, presence of FHVTE may be an additional risk factor of VTE recurrence in thrombophilia-positive patients.

The association between apolipoprotein M and insulin resistance varies with country of birth.

BACKGROUND AND AIMS: Risk of type 2 diabetes mellitus (T2DM) differs according to ethnicity. Levels of apolipoprotein M (ApoM) have been shown to be decreased in T2DM. However, its role in different ethnicities is not known. We examined the differences in plasma ApoM levels in Swedish residents born in Iraq (Iraqis) and Sweden (Swedes) in relation to T2DM and insulin resistance (IR). METHODS AND RESULTS: Iraqis and Swedes, aged 45-65 years residing in Rosengård area of Malmö were randomly selected from census records and underwent an oral glucose tolerance test. Plasma levels of ApoM were quantified in 162 participants (Iraqis, n = 91; Swedes, n = 71) by a sandwich ELISA method. Age-, sex-, and body mass index (BMI) adjusted plasma ApoM levels differed by country of birth, with Swedes having 18% higher levels compared to Iraqis (p = 0.001). ApoM levels (mean ± SD) were significantly decreased in Swedes with T2DM (0.73 ± 0.18) compared to those with normal glucose tolerance (NGT) (0.89 ± 0.24; p = 0.03). By contrast, no significant difference in ApoM levels was found between Iraqis with T2DM (0.70 ± 0.17) and those with NGT (0.73 ± 0.13; p = 0.41). In multivariate linear regression analysis with an interaction term between IR and country of birth, low ApoM levels remained significantly associated with IR in Swedes (p = 0.008), independently of age, sex, BMI, family history of diabetes, HDL, LDL, and triglycerides, but not in Iraqis (p = 0.35). CONCLUSION: Our results show that ApoM levels differ according to country of birth and are associated with IR and T2DM only in Swedes.

Family history of venous thromboembolism (VTE) and risk of recurrent hospitalization for VTE: a nationwide family study in Sweden.

BACKGROUND: Data concerning the importance of a family history of venous thromboembolism (VTE) for the risk of recurrent VTE are sparse. The aim of this nationwide study was to determine whether a family history of VTE is a risk factor for recurrent hospitalization for unprovoked VTE (deep vein thrombosis of the lower extremities or pulmonary embolism). METHODS: We linked Multigeneration Register data on individuals aged 0-77 years to the Swedish nationwide Hospital Discharge Register data for the period 1987-2009 to compare the risk of hospitalization for unprovoked recurrent VTE among individuals with and without a parental or sibling history of VTE. We calculated hazard ratios (HRs) to determine the familial HR for recurrent hospitalization for VTE. RESULTS AND CONCLUSIONS: The risk of recurrent VTE hospitalization was 1.20 (95% confidence interval [CI] 1.10-1.32) for individuals with affected parents, and 1.30 (95% CI 1.14-1.49) for those with affected siblings. The risk of recurrent VTE hospitalization in individuals with two affected parents was 1.92 (95% CI 1.44-2.58). There was an interaction between age at diagnosis of VTE and a family history of VTE, with a family history having a stronger effect on VTE risk in younger patients. We conclude that a family history of VTE is a modest risk factor for recurrent VTE hospitalization in Sweden.

Venous thromboembolism does not share strong familial susceptibility with pre-eclampsia/eclampsia: a nationwide family study in Sweden.

OBJECTIVE: Genetic variants associated with venous thromboembolism (VTE) have been suggested to be involved in the pathogenesis of pre-eclampsia/eclampsia (PEC/EC). This nationwide study aimed to determine whether VTE shares familial susceptibility with PEC/EC. DESIGN: Population-based cohort study. SETTING: Sweden. SAMPLE: A total of 941 841 Swedish women delivering their first child between 1987 and 2008. METHODS: Data from the Swedish Multigeneration Register were linked to the Swedish Hospital Discharge Register. The risk of PEC/EC was determined in primiparous women with a family history of VTE (in parents and/or siblings), compared with primiparous women without a family history of VTE. Odds ratios (ORs) were calculated by logistic regression. MAIN OUTCOME MEASURE: PEC/EC in first pregnancy. RESULTS: In total, 43 621 women had PEC/EC in association with their first pregnancy. The OR for PEC/EC in women with a family history of VTE was 1.06 (95% CI 1.01-1.11); however, a family history of VTE was associated with higher odds of PEC/EC among women with previous hypertension (OR 1.38, 95% CI 1.25-1.52). CONCLUSION: A family history of VTE is weakly associated with PEC/EC risk, and is not clinically useful for the prediction of PEC/EC. The results of the present study suggest that it is unlikely that strong disease-causing mutations shared by VTE and PEC/EC are common in the Swedish population. The novel association between family history and PEC/EC among the subgroup with previous hypertension needs further confirmation in future studies.

Occupational and socio-economic risk factors for giant cell arteritis: a nationwide study based on hospitalizations in Sweden.

OBJECTIVES: Socio-economic and occupational factors may contribute to risk of immune-mediated disorders. The importance of these factors in giant cell arteritis (GCA) is unknown. This is the first nationwide study with the aim of investigating possible associations between socio-economic status (SES)/occupation and hospitalization for GCA. METHOD: A nationwide database was constructed by linking Swedish census data to the Hospital Discharge Register to obtain data on all first hospitalizations with a main diagnosis of GCA in Swedish adults between 1970 and 2008. Standardized incidence ratios (SIRs) and 95% confidence intervals were calculated for different occupations. Three cohorts were defined based on 53 occupational titles recorded in Swedish census data in 1970, 1980, and 1990. RESULTS: In individuals aged over 50 years, 3293 males and 4726 females were hospitalized with GCA. Only minor or inconsistent associations were observed for education and SES and GCA. Some occupations were associated with increased risk of GCA. However, the risks were modest or not consistent between the three cohorts investigated. Only male fishermen, whalers, and sealers had an SIR of > 2 (2.14). However, the risk of GCA was only increased in one cohort. Both women (0.83) and men (0.83) born outside Sweden had a lower risk of GCA. The adjustment variables hypertension, diabetes, chronic obstructive pulmonary disease (COPD), and coronary heart disease (CHD) were associated with higher risk of GCA. CONCLUSIONS: Occupation and SES are not strong risk factors for GCA. However, GCA was associated with co-morbidities and country of birth, calling for further studies.

Effects of pH, sodium chloride, and curing salt on the infectivity of Toxoplasma gondii tissue cysts.

Toxoplasma gondii is one of the most common zoonotic parasites in the world. The parasite causes no or mild symptoms in immunocompetent humans. However, a high potential hazard exists for seronegative pregnant women and immunocompromised patients. The consumption of meat containing tissue cysts or oocyst-contaminated vegetables and fruits or the handling of cat feces poses a high risk of infection with T. gondii. It is known that raw minced meat, raw fresh sausages, and locally produced raw meat products are possible causes of T. gondii infection. The infectivity of T. gondii tissue cysts in meat products depends, among other factors, on the pH and the salt concentration. Therefore, the impact of these two factors on the tissue cysts was examined. For this purpose, dissected musculature and brain from experimentally infected mice (donor mice) were placed in a cell culture medium (RPMI 1640). The medium was adjusted to different pH values (pH 5, 6, and 7) with lactic acid and to different salt concentrations (2.0, 2.5, and 3.0%) with sodium chloride (NaCl) or nitrite-enriched curing salt (NCS) for the various tests. After storage at 4°C for different time periods, the materials were fed to bioassay mice. Later, the brains were examined for presence of T. gondii to assess the infectivity. The data show that T. gondii tissue cysts have a high pH tolerance. Cysts were infectious in the muscle for up to 26 days (pH 5). In contrast to their tolerance to pH, cysts were very sensitive to salt. Muscle cysts survived at an NaCl concentration of up to 2.0% only, and for no longer than 8 days. At NaCl concentrations of 2.5 and 3.0%, the cysts lost their infectivity after 1 day. When NCS instead of NaCl was used under the same conditions, T. gondii muscle cysts retained infectivity for only 4 days at 2.0%. Consequently, NCS (NaCl plus 0.5% nitrite) has a stronger effect on T. gondii cysts than does common table salt. Sausages produced with low NaCl concentration and short contact times pose a potential risk for susceptible individuals.

Mothers, places and risk of hospitalization for childhood asthma: a nationwide study from Sweden: epidemiology of allergic disease.

OBJECTIVE: This study examines whether neighbourhood deprivation increases the risk of hospitalization for childhood asthma, after accounting for individual-level maternal socio-demographic characteristics. DESIGN: An open cohort of all singleton children aged 2-11 years was followed between January 1, 1995 and December 31, 2006. Childhood residential addresses were geocoded and classified according to the level of neighbourhood deprivation. Data were analysed by multilevel logistic regression, with individual-level characteristics (sex, age, maternal marital status, family income, maternal educational attainment, maternal immigration status, maternal urban/rural status, mobility, maternal asthma history and maternal smoking) at the first level and level of neighbourhood deprivation at the second level. RESULTS: During the study period, among a total of 866,860 children, 17,682 (2.0%) were hospitalized with childhood asthma. Age-adjusted hospital rates for childhood asthma increased with increasing level of neighbourhood deprivation. In the study population, 1.9% and 2.3% of children in the least and most deprived neighbourhoods, respectively, were affected by childhood asthma. Hospital rates of childhood asthma increased with increasing neighbourhood-level deprivation across all individual-level maternal socio-demographic categories, including marital status, educational attainment, urban/rural status, maternal history of asthma and smoking. The odds ratio (OR) for those living in high-deprivation neighbourhoods vs. those living in low-deprivation neighbourhoods was 1.23 (95% confidence interval, 1.16-1.30). High neighbourhood deprivation remained significantly associated with childhood asthma risk after adjustment for maternal socio-demographic characteristics (OR=1.08, p = 0.016). CONCLUSIONS: This study is the largest so far on neighbourhood influences on childhood asthma. Our results suggest that neighbourhood characteristics affect the risk of hospitalization for childhood asthma independent of maternal socio-demographic characteristics.

Experimental Toxoplasma gondii oocyst infections in turkeys (Meleagris gallopavo).

Toxoplasma (T.) gondii is a protozoan parasite with a broad range of intermediate hosts. Humans are often infected by ingestion of tissue cysts in raw or undercooked meat or meat products. Turkeys as food-producing animals can also serve as intermediate hosts. The aim of the present study was to investigate occurrence and predilection sites of T. gondii infection in turkeys after oral infection with oocysts. Experimental infections with different doses of T. gondii oocysts were performed in 36 turkeys to mimic natural infection. Systemic distribution of parasitic stages was investigated by screening 14 different tissues including the edible tissues heart, liver, thigh, breast and drumstick muscle. Parasite detection was based on a conventional nested polymerase chain reaction (PCR). Animals were sacrificed 6-12 weeks after infection. Results demonstrated parasite spreading over the whole organism after oral infection by oocysts. Most frequently affected tissues were brain (47.2% of all brains were positive for T. gondii) and thigh muscle (25.0% positive samples). Other muscles were regularly T. gondii-positive, all other sampled tissues were positive at least once. Thus, edible tissues are one of the predilection sites of T. gondii in turkeys which renders raw or undercooked turkey meat a potential risk for parasite transmission to humans. Data were compared to results from previous parenteral turkey infections with tachyzoites. With the exception of brain, liver and breast muscle affection, no significant differences were observed between both infection routes. Both infection models could be used for research purposes with certain advantages and disadvantages.

Tissue tropism of Toxoplasma gondii in turkeys (Meleagris gallopavo) after parenteral infection.

Turkeys are known to be natural hosts for the zoonotic protozoan parasite Toxoplasma gondii. The objective of the present study was to gain further knowledge of possible predilection sites of T. gondii infection in this species after parenteral application of tachyzoites. A total of 38 turkeys were infected with different doses of T. gondii tachyzoites. Birds were killed either 6 to 8 or 10 to 12 weeks after the experimental infection. Fourteen different tissues per bird were investigated by a nested polymerase chain reaction (PCR) for the presence of the parasites' DNA. T. gondii DNA was found in any type of tissue analysed; in 86.1 % of all infected birds, at least one sample was tested positive. Over all intravenously infected birds, 15.4 % of all analysed samples contained T. gondii DNA. Most frequently affected tissues were liver (43.3 % positive samples), breast muscle (26.7 % positive samples) and heart (20.0 % positive samples), while the brain was less frequently positive (6.7 %). The number of positive tissues varied from zero to seven tissues per animal with at least one T. gondii-positive edible tissue sample in 80 % of all intravenously infected birds. Still, the results did not indicate defined target tissues or a cyst distribution pattern. Nonetheless, edible organs were most frequently parasitised. The number of positive findings did not differ between the early and the late examination time points. Therefore, a persistence of the tissue stages until the end of the study (12 weeks after infection) is concluded.

Family history and risk of hospital treatment for varicose veins in Sweden.

BACKGROUND: Family history has been suggested as a risk factor for varicose veins, but recall bias may inflate the familial risks. The aim of this nationwide study was to determine familial risks for hospital treatment for varicose veins. METHODS: Data from the Swedish Multi-Generation Register of people aged 0-76 years were linked to Hospital Discharge Register data for 1964-2008. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were treated in hospital for varicose veins and compared with those whose relatives were not. Only main diagnoses of varicose veins were considered. RESULTS: A total of 39 396 people had hospital treatment for varicose veins. The familial SIR among offspring with one affected parent was 2·39 (95 per cent confidence interval 2·32 to 2·46). The SIR for those with one affected sibling was 2·86 (2·76 to 2·97). SIRs were increased in both men and women. The SIR for individuals with two or more affected siblings or with two affected parents was 5·88 (5·28 to 6·53) and 5·52 (4·77 to 6·36) respectively. The SIR for the wives of men treated for varicose veins was 1·69 (1·59 to 1·80); that for the husbands of women treated for varicose veins was 1·68 (1·58 to 1·79). CONCLUSION: Using the Swedish Hospital Discharge Register, and thereby eliminating recall bias, family history of hospital treatment for varicose veins was associated with an increased risk of similar treatment among relatives. The increased spousal risk suggests a contribution from non-genetic factors.

Parental history and venous thromboembolism: a nationwide study of age-specific and sex-specific familial risks in Sweden.

BACKGROUND: The value of parental history as a risk indicator for venous thromboembolism (VTE) has not been determined in a nationwide setting. OBJECTIVES: To perform the first nationwide study of age-specific and sex-specific familial VTE risks in offspring of parents hospitalized for VTE. PATIENTS/METHODS: The Swedish Multigeneration Register of 0-75-year-old subjects was linked to the Hospital Discharge Register for 1987-2007. Standardized incidence ratios (SIRs) were calculated for individuals whose parents were hospitalized for VTE as compared with those whose parents were unaffected. RESULTS: Among 45,362 hospitalized offspring cases with VTE, 4865 offspring of affected parents were identified with a familial SIR of 2.00 (95% confidence interval [CI] 1.94-2.05). Familial SIR was slightly higher for male offspring than for female offspring (2.08, 95% CI 2.00-2.16 vs. 1.91, 95% CI 1.84-1.99). The risk in offspring was further increased when both parents were affected (3.97, 95% CI 3.40-4.61), with high familial risks at ages 20-29 years (10.00, 95% CI 5.91-15.84). The familial risks for VTE among offspring were increased from the age of 10 years up to 75 years, with familial SIRs of 3.96 (95% CI 3.13-4.94) at age 10-19 years and 1.48 (95% CI 1.17-1.84) at ages 70-75 years. However, the absolute incidence rate increased with age. CONCLUSIONS: Parental history is potentially useful for risk assessments of VTE, although age needs to be considered. Our results support the use of an age-dependent multicausal model to estimate the risk of VTE.

Familial risks of unusual forms of venous thrombosis: a nationwide epidemiological study in Sweden.

OBJECTIVE: This is the first nationwide study to determine familial risks of unusual forms of venous thrombosis amongst offspring of affected parents and amongst siblings. DESIGN AND SETTINGS: The Swedish Multigeneration Register of 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the period 1987-2007. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalized for venous thromboembolism (VTE), as determined by the International Classification of Diseases, compared to those whose relatives were not affected by VTE. RESULTS: The total number of hospitalized patients with VTE was 45 362, of which 1824 (4.0%) were affected by a rare thrombotic condition. The familial SIRs in cases with a history of VTE in parents or siblings were significantly increased for migrating thrombophlebitis (1.81; 95% confidence interval (CI) 1.40-2.31), portal vein thrombosis (2.35; 95% CI 1.77-3.06), vena cava thrombosis (1.96; 95% CI 1.42-2.64) and cerebral venous thrombosis (1.74; 95% CI 1.30-2.28). Budd-Chiari syndrome (SIR, 0.92; 95% CI 0.24-2.38) and renal vein thrombosis (SIR, 1.72; 95% CI 0.62-3.77) were not significantly associated with parental or sibling history of VTE; however, these two conditions were very rare, and therefore, we cannot draw any definite conclusions from this finding. CONCLUSIONS: Family history is an important risk factor for most unusual forms of VTE. Moreover, even the paraneoplastic phenomenon, migrating thrombophlebitis (Trousseau's syndrome), is associated with a family history of VTE. Thus, our data suggest that most rare forms of VTE have a familial background.

Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo.

A randomized, controlled, cross-over trial compared single doses of 50 mg diclofenac potassium sachets and tablets with placebo in 328 patients with migraine pain, treating 888 attacks. For the primary endpoint 24.7% of the patients were pain free at 2 h postdose with sachets, 18.5% for tablets and 11.7% for placebo. Treatment differences were significant for sachets vs. placebo (P<0.0001), tablets vs. placebo (P=0.0040) and for sachets vs. tablets (P=0.0035). The numbers needed to treat compared with placebo to achieve pain free at 2 h were 7.75 [95% confidence interval (CI) 5.46, 13.35] for sachets and 15.83 (95% CI 8.63, 96.20) for tablets. Sachets were also statistically superior to tablets for sustained headache response, sustained pain free and reduction in headache intensity within the first 2 h postdose measured on a visual analogue scale (P<0.05). Onset of analgesic effect was 15 min for sachets and 60 min for tablets. Fewer patients needed rescue medication, and there were marked improvements in accompanying symptoms and working ability with both sachets and tablets vs. placebo. No safety issues were identified. This study demonstrates that sachets offer patients suffering from migraine pain a more effective treatment with a faster onset of analgesia when compared with tablets.

Effect of an exercise training program on endothelial dysfunction in diabetic and non-diabetic patients with severe chronic heart failure.

BACKGROUND: Endothelial dysfunction is found both in patients with chronic heart failure and in patients with insulin-treated type 2 diabetes mellitus. This endothelial dysfunction leads to a significant reduction in endothelium-derived vasodilation. Physical exercise can have a positive effect on endothelial dysfunction in patients with coronary artery disease, chronic heart failure and diabetes mellitus. It is not clear, however, whether an exercise program influences endothelial function in diabetics with chronic heart failure. Our study was thus aimed at investigating whether a special exercise program would affect endothelial function. Comparisons were made with insulin-treated type 2 diabetics and with non-diabetics suffering from chronic heart failure. METHODS: 42 patients with severe chronic heart failure (LVEF < or = 30%), insulin-dependent diabetics (n=20, mean age 67+/-6 yrs, 16 male, 4 female), non-diabetics (n=22, mean age 68+/-10 yrs, 20 male, 2 female) participated in a 4-week exercise program consisting of ergometer and special muscle strength training. Before (T1) and at the end (T2) of the training program endothelium-dependent and endothelium-independent vasodilatory capacity were assessed by brachial artery diameter measurement. RESULTS: At the end of the training program, there were no significant results within the two groups. The endothelium-dependent vasodilation changed between T1 and T2 as follows: In the diabetic group, the endothelium-dependent vasodilation at T1 and T2 was 5.1+/-3.6 and 4.9+/-2.5%, respectively. For the non-diabetics, the endothelium-dependent vasodilation was 6.8+/-4.5 and 7.6+/-4.0% at T1 and T2, respectively. The endothelium-independent vasodilation in the diabetics was 10.5+/-5.6 at T1 and dropped to 8.7+/-4.1% at T2. The results for the non-diabetics were 13.2+/-5.8 and 12.3+/-6.3% at T1 and T2, respectively. The LVEF in the diabetics was 24.2+/-3.4% at T1, increasing to 27.8+/-5.8% at T2. In the non-diabetics, the LVEF was 22.9+/-3.8 at T1 vs. 28.6+/-6.9% at T2. In the groups of diabetics, the maximum oxygen uptake (VO2-max) was 10.3+/-3.9 at T1 vs. 11.4+/-2.8 ml/kg/min at T2 and in the group of non-diabetics 10.0+/-3.1 vs. 13.5+/-5.0 ml/kg/min. No correlations were found between the change in endothelium-dependent vasodilation and the increase in oxygen uptake. CONCLUSION: In our study, a program of physical exercise had no influence on endothelium-dependent or endothelium-independent vasodilation in insulin-treated type 2 diabetics or in non-diabetics with considerably reduced ejection fraction. In both groups, however, an exercise-related influence on medical parameters and physical performance could be observed.

Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS1.

Inherited deficiency of protein S constitutes an important risk factor of venous thrombosis. Many reports have demonstrated that causative mutations in the protein S gene are found only in approximately 50% of the cases with protein S deficiency. It is uncertain whether the protein S gene is causative in all cases of protein S deficiency or if other genes are involved in cases where no mutation is identified. The aim of the current study was to determine whether haplotypes of the protein S gene cosegregate with the disease phenotype in cases where no mutations have been found. Eight protein S-deficient families comprising 115 individuals where previous DNA sequencing had failed to detect any causative mutations were analyzed using four microsatellite markers in the protein S gene region. Co-segregation between microsatellite haplotypes and protein S deficiency was found in seven of the investigated families, one family being uninformative. This suggests that the causative genetic defects are located in or close to the protein S gene in a majority of such cases where no mutations have been found.

Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients.

We investigated the efficacy and tolerability of short-term treatment with tropisetron, a selective, competitive 5-HT3-receptor antagonist in fibromyalgia. The trial was designed as a prospective, multicenter, double-blind, parallel-group, dose-finding study. We randomly assigned 418 patients suffering from primary fibromyalgia to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily for 10 days. Clinical response was measured by changes in pain score, visual analog scale, tender point count and ancillary symptoms. Responders were prospectively defined as patients showing a 35% or higher reduction in pain score. Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) than placebo (26.2%) (p < 0.05). In the visual analog scale, the group administered 5 mg tropisetron showed a significant improvement (p < 0.05) and the group administered 10 mg tropisetron showed a nonsignificant clinical benefit. The number of painful tender points was significantly reduced (p = 0.002) in the 5 mg tropisetron group. Regarding ancillary symptoms, the 5 mg tropisetron group showed a significant improvement (p < 0.05) in sleep and dizziness. The patients' overall assessment of efficacy was significantly higher for 5 mg (p = 0.016) and 10 mg (p = 0.002) tropisetron than for placebo. The safety and tolerability of tropisetron was good; gastrointestinal tract symptoms were the most frequently reported adverse events. Short-term treatment of fibromyalgia patients with 5 mg tropisetron for 10 days proved to be efficacious and well tolerated. In this study a bell-shaped dose-response curve was seen.

[Rational therapy of Alzheimer dementia based on current clinical studies]. / Rationale Therapie der Alzheimer-Demenz auf der Grundlage aktueller klinischer Studien.

Several preparations are currently available for the treatment of Alzheimer's dementia. To date only some of these drugs could show evidence of efficacy that would justify a recommendation for their therapeutic use. In the present survey, the results of five controlled clinical trials with acetylcholinesterase inhibitors versus Ginkgo-biloba extract have been analysed. The trials conducted with the acetylcholinesterase altogether have a larger patient population, an acceptable significance level of therapeutic effect as well as a lower rate of drop outs. Based on the documentation presented here, only the approved acetylcholinesterase inhibitors are currently to be recommended under strict scientific criteria for use in the treatment of Alzheimer's dementia.

Efficacy and tolerability of tropisetron in primary fibromyalgia--a highly selective and competitive 5-HT3 receptor antagonist. German Fibromyalgia Study Group.

OBJECTIVE: Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. METHODS: In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. RESULTS: Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p=0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p<0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p<0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p=0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. CONCLUSIONS: This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen.