Analysis of the effects of a delay of surgery in patients with hip fractures: outcome and causes.

This study analyzed characteristics of hip fracture patients who did not undergo surgery within 24 hours after hospitalization, as recommended by the Belgian quality standards. Reasons for delay were analyzed. Delay in surgery for hip fracture was related to the medical condition of the patients. INTRODUCTION: To compare patients with optimal timing to patients with a delay in hip surgery, with respect to outcome (complications (postoperative) and mortality) and reasons for delay. METHODS: A retrospective analysis of medical records compared patients operated on within 24h (Group A) to patients operated on more than 24h after admission (Group B). A follow-up period of 5 years after release or up to the time of data collection was used. Reasons for delay in relation with mortality were analyzed descriptively. Descriptive statistics were used for patient demographics and complications. Relationships causing a delayed surgery and mortality were analyzed using binary logistic regression. Additionally, a survival analysis was provided for overall mortality. RESULTS: Respectively, 536 and 304 patients were included in Group A and B. The most prominent reason for delaying surgery was the patient not being medically fit (20.7%). Surgical delay was associated with more cardiovascular (p = 0.010), more pulmonary (p < 0.001), and less hematologic complications (p=0.037). Thirty-day mortality was higher with increasing age (p < 0.001), with hematologic (p < 0.001) or endocrine-metabolic complications (p = 0.001), and lower when no complications occurred (p = 0.004). Mortality at the end of data collection was higher for patients with delayed surgery (OR = 2.634, p < 0.001), an increased age (p = 0.006), male gender (p < 0.001), institutionalized patients (p = 0.009), pulmonary complication (p = 0.002), and having no endocrine-metabolic complications (p = 0.003). Survival analysis showed better survival for patients operated on within 24h (p < 0.001). CONCLUSIONS: Delayed surgery for patients with hip fractures was associated with bad additional medical conditions. Survival was higher for patients operated on within 24h of admission.

Impact of thyroid autoimmunity in euthyroid women on live birth rate after IUI.

Study question: Does thyroid autoimmunity (TAI) predict live birth rate in euthyroid women after one treatment cycle in IUI patients? Summary answer: TAI as such does not influence pregnancy outcome after IUI treatment. What is known already: The role of TAI on pregnancy outcome in the case of IVF/ICSI is largely debated in the literature. This is the first study to address this issue in the case of IUI. Study design, size, duration: This was a retrospective cohort study. A two-armed study design was performed: patients anti-thyroid peroxidase (TPO)+ and patients anti-TPO-. All patients who started their first IUI cycle in our fertility center between 1 January 2010 and 31 December 2014 were included. After exclusion of those patients with or being treated for thyroid dysfunction, 3143 patients were finally included in the study. Participants/materials, setting, methods: After approval by the institutional review board we retrospectively included all patients who started their first IUI cycle in our center between 1 January 2010 and 31 December 2014 with follow-up of outcome until 31 December 2015. Patients with clinical thyroid dysfunction were excluded (thyroid-stimulating hormone (TSH) <0.01 mIU/l; TSH >5 mIU/l) as were patients under treatment with levothyroxine or anti-thyroid drugs. These patients were then divided into two main groups: patients anti-TPO+ and patients anti-TPO- (= control group). Live birth delivery after 25 weeks of gestation was taken as the primary endpoint of our study. As a secondary endpoint, we evaluated differences in live birth delivery after IUI according to different upper limits of preconception TSH thresholds (<2.5 and <5.0 mIU/l). Furthermore, the influence of thyroid function (TSH, free thyroxine (fT4)), anti-TPO status, age, smoking, BMI, parity, ovarian reserve (anti-mullerian hormone (AMH) and FSH), IUI indication and IUI stimulation on live birth rate was analyzed. Main results and the role of chance: Between-group comparison did not show any significant difference between the anti-TPO+ and anti-TPO- group with respect to live birth delivery-, pregnancy- or miscarriage rate with odds ratio at 1.04 (95% CI: 0.63; 1.69), 0.98 (95% CI: 0.62; 1.55) and 0.74 (95% CI: 0.23; 2.39), respectively. In addition, there were no significant differences in live birth delivery-, pregnancy- or miscarriage rate when comparing subgroups according to TSH level (TSH ≥2.5 mIU/l vs. TSH <2.5 mIU/l) with an odds ratio at 1.05 (95% CI: 0.76; 1.47), 1.04 (95% CI: 0.77; 1.41) and  0.95 (95% CI: 0.47; 1.94), respectively. Limitations, reasons for caution: This study was powered for the primary aim, live birth rate. The limitations of this study are the absence of region-specific reference ranges for thyroid hormones and the absence of follow-up of TSH values during ART and subsequent pregnancy. Moreover, there was a time difference of 5 months between thyroid assessment and the start of stimulation. The area where the study was conducted corresponds to a mild iodine deficient area and data should be translated with caution to areas with different iodine backgrounds. Wider implications of the findings: Our findings indicate comparable pregnancy-, abortion- and delivery rates in women with and without TAI undergoing IUI. Moreover, we were unable to confirm a negative effect of TSH level above 2.5 mIU/l on live birth delivery rate. We therefore believe that advocating Levothyroxine treatment at TSH levels between 2.5 and 4 mIU/l needs to be considered with caution and requires further analysis in a prospective cohort study. Study funding/competing interest(s): No external funding was used for this study. No conflicts of interest are declared.

A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

OBJECTIVES: The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). METHODS: An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/µL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/µL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). RESULTS: For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. CONCLUSIONS: A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

A genetic variant in SLC6A20 is associated with Type 2 diabetes in white-European and Chinese populations.

AIMS: To investigate whether polymorphisms in SLC6A20 are associated with susceptibility to Type 2 diabetes. METHODS: In the Rotterdam Study, a prospective, population-based cohort (n = 5974), 22 tagging polymorphisms with minor allele frequencies>0.05 across SLC6A20 were studied. Replication studies were performed in an independent Dutch case-control study (DiaGene-Rotterdam Study 2 n = 3133), and in a Chinese Han case-control population (n = 2279). A meta-analysis of the results was performed. RESULTS: In the Rotterdam study, the minor alleles of rs13062383, rs10461016 and rs2286489 increased the risk of Type 2 diabetes (hazard ratio 1.37, 95% CI 1.15-1.63, hazard ratio 1.30 95% CI 1.09-1.54 and hazard ratio 1.20, 95% CI 1.07-1.35, respectively). In the DiaGene/Rotterdam Study 2, the A allele of rs13062383 increased the risk of Type 2 diabetes (odds ratio 1.45, 95% CI 1.19-1.76). In the Chinese Han study, the rs13062383 A allele also increased the risk of Type 2 diabetes (odds ratio 1.21, 95% CI 1.03-1.42). Meta-analysis showed a highly significant association of rs13062383 with Type 2 diabetes (odds ratio 1.35, 95% CI 1.21-1.47; P = 3.3 × 10⁻8). CONCLUSIONS: In conclusion, rs13062383 in SLC6A20 increased the susceptibility to Type 2 diabetes in populations with different genetic backgrounds.

High prevalence of diabetes mellitus in patients with liver cirrhosis.

AIMS: The reported prevalence of Type 2 diabetes mellitus in patients with liver cirrhosis is five times higher than in the general population. However, these data were never adjusted for classical risk factors for Type 2 diabetes. We therefore investigated the association between cirrhosis and Type 2 diabetes and adjusted for known risk factors for Type 2 diabetes. METHODS: We reviewed medical files for presence of Type 2 diabetes and potential confounders in 94 patients with cirrhosis (cases) and compared these with a control group of 107 patients with non-ulcer dyspepsia. Multiple logistic regression analysis was used to adjust for potential confounders. RESULTS: The aetiology of our cirrhosis population was alcohol (59%), viral hepatitis (10%), biliary cirrhosis (3%) or cryptogenic (28%). Prevalence of Type 2 diabetes was significantly higher in patients with cirrhosis than in control subjects: 35/94 (37%) vs. 7/107 (7%) (OR 8.5, 95% CI 3.5­20.2, P < 0.001). After adjustment for age, sex, family history of Type 2 diabetes, alcohol use and BMI, cirrhosis remained significantly associated with Type 2 diabetes (OR 13.6, 95% CI 4.3­42.9, P < 0.001). Most cases of Type 2 diabetes were already diagnosed before diagnosis of cirrhosis (21/35, 60%) or were incidentally found together with cirrhosis (5/35, 14%). CONCLUSIONS: Liver cirrhosis had a strong, independent association with Type 2 diabetes. Classical risk factors such as family history and BMI could not explain the high Type 2 diabetes prevalence in cirrhosis. Therefore, a liver-derived factor might aggravate glucose intolerance and cause Type 2 diabetes in cirrhosis. In addition, Type 2 diabetes might also cause cirrhosis through liver steatosis and fibrosis.

Hepatocyte nuclear factor (HNF)1A and HNF4A substitution occurring simultaneously in a family with maturity-onset diabetes of the young.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by an early age at onset, autosomal dominant inheritance and a primary defect in the function of the B-cells of the pancreas. We report a family with two members carrying a substitution in both the hepatocyte nuclear factor (HNF)1A and HNF4A gene simultaneously. CASE REPORT: A 39-year-old man was referred because of mild diabetic retinopathy. Because of a dominant presentation of diabetes in his family, genetic testing was performed. Sequence analysis of the genes involved in MODY-1-3 revealed the presence of an amino acid substitution in the HNF1A as well as the HNF4A gene. Both substitutions were also detected in his mother. The HNF1A substitution has been described previously as pathogenic, whereas the HNF4A substitution had not been found previously. The HNF4A substitution was located in a conserved region of the protein and, additionally, the proband and his mother had high birthweights and low triglyceride levels, both of which are associated with pathogenic HNF4A substitutions. CONCLUSIONS: To our knowledge this is the first reported family carrying both a substitution of HNF1A and HNF4A gene simultaneously. The exact contribution of each substitution to the phenotype of our subjects remains to be further elucidated, however, given the high birthweights and the low triglyceride levels in those with both substitutions, it is reasonable that the HNF4A substitution is pathogenic.

[Schizophrenia and antipsychotics associated with the metabolic syndrome. An overview]. / Schizofrenie en antipsychotica: samenhang met het metabool syndroom.

BACKGROUND: Cardiovascular morbidity and mortality are higher in patients with schizophrenia than in the general population because the metabolic side-effects of antipsychotics and schizophrenia increase the risk of cardiovascular disease (cvd) and diabetes mellitus type 2 (DM2). The metabolic syndrome is defined in order to discover which patients have a high risk of developing cvd and DM2. AIM: To survey the current knowledge about the relationship between schizophrenia and the metabolic syndrome, the influence of the use of antipsychotics on the development of the metabolic syndrome, and the possible differences in the effects that first and second generation antipsychotics have on the syndrome. METHOD: The PubMed and Medscape databases were searched for relevant articles published between 2000 and July 2008. results Schizophrenia and the use of antipsychotics increase the prevalence of abdominal obesity, dyslipidemia and DM2 (i.e. the metabole syndrome). Second generation antipsychotics tend to cause a marked increase in the prevalence of abdominal obesity and dyslipidemia, whereas first generation antipsychotics hardly have any of these effects. Both first and second generation antipsychotics increase the risk of DM2. CONCLUSION: The metabolic syndrome has a significant effect on the morbidity and mortality of patients with schizophrenia because it increases the risk they will develop cvd and DM2. The risk increases still further if patients are taking antipsychotics. The risk of cvd can be decreased if patients with schizophrenia are screened in time and are monitored regularly.

Central diabetes insipidus: beware of Langerhans cell histiocytosis!

Langerhans cell histiocytosis (LCH) is a rare disorder, characterised by a monoclonal proliferation of aberrant histiocytes that accumulate in and infiltrate into different organs. When the hypothalamic-pituitary axis is involved, central diabetes insipidus (CDI) can be its first manifestation. Three cases of LCH with central diabetes insipidus were retrospectively analyzed: Case 1 is a 41-year old female presenting with polyuria and polydipsia. Diabetes insipidus was diagnosed and treated with desmopressin. MRI pituitary showed hypophysitis. Subsequently, she developed bone lesions and a biopsy demonstrated LCH. Case 2 is a 51-year old female presenting in 2009 with polyuria and polydipsia. Diabetes insipidus was diagnosed and treated with desmopressin. MRI pituitary revealed hypophysitis. LCH was suspected because of known pulmonary histiocytosis. Coexisting bone lesions were biopsied and confirmed LCH. Case 3 is a 44-year old female presenting with diabetes insipidus. She was treated with desmopressin as well. MRI of the pituitary gland showed impressive thickening of the infundibulum. A few months later, she developed skin lesions and a biopsy revealed LCH. Conclusively, LCH is a rare, elusive and probably underdiagnosed disease with a broad disease spectrum. Due to infiltration of the hypothalamic-pituitary axis, CDI can be the first manifestation, even before LCH is diagnosed. Therefore, LCH should be considered in the diagnostic workup of CDI.

A new mutation in the calcium-sensing receptor gene causing hypocalcaemia: case report of a father and two sons.

BACKGROUND: Regulation of calcium is mediated by parathyroid hormone (PTH) and 1.25-dihydroxyvitamine D3. The calcium-sensing receptor (CaSR) regulates PTH release by a negative feedback system. Gain-of-function mutations in the CaSR gene reset the calcium-PTH axis, leading to hypocalcaemia. PATIENTS AND METHODS: We analysed a family with hypocalcaemia. The proband was a 47-year-old man (index, patient I1), who presented with paraesthesias in both limbs. He has two sons (patient II1 a nd I I2). The probands' lab results showed: serum calcium of 1.95 mmol/l, albumin 41 g/l, phosphate 0.81 mmol/l and PTH 6.6 ng/l (normal 15-65 ng/l). Based on this analysis, we suspected a hereditary form of hypocalcaemia and performed genetic testing by polymerase chain reaction and Sanger sequencing of the coding regions and intron boundaries of the CaSR gene. Genetic analysis revealed a new heterozygous mutation: c.2195A>G, p.(Asn732Ser) in exon 7. The lab results of patient II1 showed: serum calcium of 1.93 mmol/l, phosphate 1.31 mmol/l, albumin 41 g/l, and PTH 24.3 ng/l. His genotype revealed the same activating mutation and, like his father, he also lost his scalp hair at an early adolescent age. Patient II2 is asymptomatic, and has neither biochemical abnormalities, nor the familial CaSR gene mutation. He still has all his scalp hair. CONCLUSIONS: 1) The c.2195A>G, p.(Asn732Ser) mutation in exon 7 of the CaSR gene leads to hypocalcaemia, and has not been reported before in the medical literature. 2) Possibly, this mutation is linked to premature baldness.

Psoas abscess: report of a series and review of the literature.

We describe a series of twelve patients with a psoas abscess seen in a three-year period in a university hospital and a large teaching hospital in the Netherlands. In our series, five of the 12 patients had a primary psoas abscess. The predisposing conditions were intravenous drug use, diabetes mellitus, prostate carcinoma and haematoma in the psoas muscle in a patient with haemophilia A. Seven of the 12 patients had a secondary psoas abscess. Five cases were due to vertebral osteomyelitis including two cases of tuberculosis. In the other two cases it was due to colitis and urinary tract infection. It is remarkable that in our series there was only one patient with a psoas abscess secondary to a disease of the digestive tract, while this is the most common cause of a secondary psoas abscess in the literature. There were two cases of tuberculosis which is an emerging disease again.

Effects of benfluorex on insulin resistance and lipid metabolism in obese type II diabetic patients.

OBJECTIVE: To evaluate the change in lipids and insulin sensitivity in 10 obese type II diabetic patients after treatment with benfluorex or placebo for 2 wk. RESEARCH DESIGN AND METHODS: The study had a double-blind, cross-over design. Insulin sensitivity was measured with the euglycemic hyperinsulinemic glucose clamp technique at two different insulin infusion rates: 0.05 (clamp 1) and 0.10 U.kg-1.h-1 (clamp 2). RESULTS: Subanalysis of the glucose infusion rate under steady-state conditions in the last 30 min of clamp 2 yielded a glucose infusion rate of 5.36 and 3.87 mmol.kg-1.min-1 after benfluorex and placebo, respectively (P = 0.018). CONCLUSIONS: Benfluorex increases insulin sensitivity in obese type II diabetic patients.

Is the corrected QT interval a reliable indicator of the severity of diabetic autonomic neuropathy?

OBJECTIVE: We investigated whether the corrected QT interval correlated with two other tests for diagnosing autonomic dysfunction in 60 type I diabetic patients with proven peripheral neuropathy. The mean age +/- SD was 48.3 +/- 11.2 yr, the mean duration of diabetes was 24.9 +/- 11.4 yr, and the mean HbA1 was 9.3 +/- 2.4%. RESEARCH DESIGN AND METHODS: All patients underwent three autonomic function tests: 1) the standard five cardiovascular Ewing tests, each scored 0 (normal), 0.5 (borderline), or 1.0 (abnormal). We used the sum of the abnormal findings for the analysis, the cardiovascular autonomic score; 2) measurement of the corrected QT interval taken from a routine electrocardiogram recording; and 3) static and dynamic pupillometry: measurement of dark adapted pupil diameter as percentage of total iris diameter and of pupil constriction latency using an infrared light reflex technique. RESULTS: No significant correlation was found between age, duration of diabetes, or HbA1 and any of the autonomic function tests, except for one between age and cardiovascular autonomic score (r = 0.3202, P = 0.0126). Corrected QT interval did not correlate with cardiovascular autonomic score, pupil diameter, or constriction latency. A significant inverse correlation was found between cardiovascular autonomic score and pupil diameter (r = -0.4861, P < 0.001) and constriction latency (r = 0.3783, P < 0.001). Pupil diameter and constriction latency correlated well (r = -0.4276, P < 0.001). CONCLUSIONS: The corrected QT interval did not correlate with cardiovascular autonomic tests nor pupillometry results. The corrected QT interval therefore should not be used for the diagnosis of the severity of diabetic autonomic neuropathy.

Effects of oral erythromycin on fasting and postprandial antroduodenal motility in patients with type I diabetes, measured with an ambulatory manometric technique.

OBJECTIVE: The aim of this double-blind crossover study was to evaluate the effects of oral erythromycin (250 mg t.i.d.) on fasting and postprandial gastrointestinal motility and gastrointestinal symptoms in patients with type I diabetes. RESEARCH DESIGN AND METHODS: Antroduodenal motility was recorded with an ambulatory manometric technique for a 20-h period, including a high-caloric high-fat dinner and a low-caloric low-fat breakfast and a long fasting period, after 2 weeks erythromycin and placebo treatment in 12 patients with type I diabetes. During the manometric study, plasma glucose concentrations were assessed by frequent self-testing. Gastrointestinal symptoms were scored daily to assess the severity of the symptoms (range 0-3). RESULTS: Oral erythromycin decreased the migrating motor complex cycle length from 118.9 +/- 46.0 to 86.2 +/- 25.3 min (P = 0.03) by shortening phase II from 68.7 +/- 23.5 to 48.5 +/- 19.4 min (P < 0.05). The total number of duodenal phase III increased from 48 to 62 (P = 0.075). However, the degree of antral participation to duodenal phase III did not increase. Erythromycin significantly decreased the duration of the postprandial period after dinner (from 417.0 +/- 137.9 to 348.8 +/- 93.8 min, P = 0.04). During this shorter postprandial period, the number of antral contractions (P < 0.01) and the antral motility index increased (P < 0.03), and early phase III activity at the level of the duodenum was abolished. In diabetic patients with antral hypomotility, after dinner, the mean symptom score improved significantly, from 2.07 +/- 0.86 to 1.52 +/- 0.63 (P = 0.018). CONCLUSIONS: This ambulatory antroduodenal manometric study showed that oral erythromycin (250 mg t.i.d.) improves both fasting and postprandial antroduodenal motor activity after a high-caloric meal in patients with type I diabetes. Furthermore, in diabetic subjects with postprandial antral hypomotility, erythromycin reduces dyspeptic symptoms.

Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group.

OBJECTIVE: To study the prevalence of and risk factors for asymptomatic bacteriuria (ASB) in women with and without diabetes. RESEARCH DESIGN AND METHODS: A total of 636 nonpregnant women with diabetes (type 1 and type 2) who were 18-75 years of age and had no abnormalities of the urinary tract, and 153 women without diabetes who were visiting the eye and trauma outpatient clinic (control subjects) were included. We defined ASB as the presence of at least 10(5) colony-forming units/ml of 1 or 2 bacterial species in a culture of clean-voided midstream urine from an individual without symptoms of a urinary tract infection (UTI). RESULTS: The prevalence of ASB was 26% in the diabetic women and 6% in the control subjects (P < 0.001). The prevalence of ASB in women with type 1 diabetes was 21%. Risk factors for ASB in type 1 diabetic women included a longer duration of diabetes, peripheral neuropathy, and macroalbuminuria. The prevalence of ASB was 29% in women with type 2 diabetes. Risk factors for ASB in type 2 diabetic women included age, macroalbuminuria, a lower BMI, and a UTI during the previous year. No association was evident between current HbA1c level and the presence of ASB. CONCLUSIONS: The prevalence of ASB is increased in women with diabetes and might be added to the list of diabetic complications in these women.

Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study).

OBJECTIVE: To compare efficacy and tolerability of saquinavir soft gelatin capsule (SQV-SGC) formulation and indinavir, both given as part of a triple drug regimen containing zidovudine and lamivudine, in HIV-1-infected individuals. DESIGN: Randomized, open label, multicentre study. PATIENTS: A total of 70 patients who were antiretroviral-naive and who had a CD4 cell count < 500 x 10(6)/I and/or > 10000 HIV RNA copies/ml plasma and/or HIV-related symptoms. Subjects were assigned randomly to zidovudine 200 mg three times per day plus lamivudine 150 mg twice per day plus either SQV-SGC 1200 mg three times per day (SQV-SGC group) or indinavir 800 mg three times per day (indinavir group). Data are presented for all patients up to week 24. RESULTS: Mean baseline CD4 cell counts (+/- SE) were 301+/-29 x 10(6) cells/l and 310 +/-43 x 10(6) cells/l in the SQV-SGC and indinavir groups, respectively. The log10 median baseline HIV RNA load was 5.00 copies/ml in the SQV-SGC group and 4.98 copies/ml in the indinavir group. No difference in antiretroviral effect between the treatment arms could be demonstrated. Intention-to-treat analysis (last observation carried forward [LOCF]) at week 24 revealed that RNA levels decreased to < 50 copies/ml in 74.3% of patients in the SQV-SGC group and in 71.4% of the patients in the indinavir group (P = 0.78). In the on-treatment analysis the proportion of patients < 50 copies/ml at week 24 was 88.0% in the SQV-SGC group and 84.6% in the indinavir group (P = 0.725). Intriguingly, the mean increase of CD4 cells in the first 24 weeks was 162+/-20 x 10(6) cells/l in the SQV-SGC group and 89+/-21 x 10(6) cells/l in the indinavir group (P = 0.01), but preliminary data indicate that this difference in CD4 cell count gain may disappear after 24 weeks of treatment. Both regimens were generally well tolerated. CONCLUSION: During the first 24 weeks of the study, we found no difference in antiviral potency between the indinavir group and the SQV-SGC group. A significantly higher CD4 response in the SQV-SGC group was observed.

Congenital hypothyroidism caused by a premature termination signal in exon 10 of the human thyroid peroxidase gene.

The molecular basis of a total iodide organification defect causing severe congenital hypothyroidism has been elucidated. The defect occurred in a family in which two of five siblings were affected. Thyroid tissue from one patient was available for investigation. The total thyroid peroxidase (TPO) messenger ribonucleic acid level was reduced and consisted mainly of the alternatively spliced form of TPO missing exon 10 (TPO-2). No TPO-1 (wild-type) protein was detected by Western blotting. The TPO-2 translation product of a slightly smaller mol wt was present in thyroid tissue of this patient. TPO activity was absent and thyroglobulin was not iodinated, showing that iodination in vivo did not occur. Denaturing gradient gel electrophoresis and subsequent sequencing revealed in both alleles of the patients a C-->T transition of nucleotide 1708 of the TPO gene, involving a CpG dinucleotide. The mutation introduces a premature termination signal in exon 10 of the TPO gene, preventing the synthesis of enzymatic active peroxidase.

Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodide uptake in nontoxic nodular goiter.

Radioiodine (131I) is increasingly used as treatment for volume reduction of nontoxic, nodular goiter. A high dose of 131I is often needed because of low thyroid radioiodide uptake (RAIU). We investigated whether pretreatment with a single, low dose of recombinant human TSH (rhTSH; Thyrogen, Genzyme Transgenics Corp.) enhances RAIU in 15 patients with nontoxic, nodular goiter (14 women and 1 man; aged 61+/-11 yr). Four patients were studied twice, and 1 patient was studied 3 times. RAIU was measured both under basal conditions and after pretreatment (im) with rhTSH, given either 2 h (0.01 mg; n = 7) or 24 h [0.01 mg (n = 7) or 0.03 mg (n = 7)] before 131I administration (20-40 microCi). Serum levels of TSH, free T4 (FT4), and total T3 were measured at 2, 5, 8, 24, 48, 72, 96, and 192 h after rhTSH administration. After administration of 0.01 mg rhTSH, serum TSH rose from 0.7+/-0.5 to a peaklevel of 4.4+/-1.1 mU/L (P < 0.0001), FT4 rose from 16.0+/-2.6 to 18.5+/-3.7 pmol/L (P < 0.0001), and T3 rose from 2.10+/-0.41 to 2.63 - 0.66 nmol/L (P < 0.0001). After administration of 0.03 mg rhTSH, TSH rose from 0.6+/-0.4 to 15.8+/-2.3 mU/L (P < 0.0001), FT4 rose from 15.2+/-1.5 to 21.7+/-2.9 pmol/L (P < 0.0001), and T3 rose from 1.90+/-0.43 to 3.19+/-0.61 nmol/L (P < 0.0001). Peak TSH levels were reached at 5-8 h and peak FT4 and T3 levels at 8-96 h after rhTSH administration. Administration of 0.01 mg rhTSH 2 h before 131I increased 24-h RAIU from 30+/-11% to 42+/-10% (P < 0.02), 0.01 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 29+/-10% to 51+/-10% (P < 0.0001), and 0.03 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 33+/-11% to 63+/-9% (P < 0.0001). After administration of 0.01 mg rhTSH 2 h before 131I, 24-h RAIU did not increase in 1 patient, whereas the increase in 24-h RAIU was less than 10% in 2 other patients. In contrast, administration of rhTSH 24 h before 131I increased 24-h RAIU by more than 10% in all 14 patients (by >20% in 10 and by >30% in 6). In conclusion, pretreatment with a single, low dose of rhTSH in patients with nontoxic, nodular goiter increased RAIU considerably. Our observations hold promise that administration of rhTSH before 131I therapy for nontoxic, nodular goiter will allow treatment with lower doses of 131I in these patients.

Nerve function and oxidative stress in diabetic and vitamin E-deficient rats.

Nerve dysfunction in diabetes is associated with increased oxidative stress. Vitamin E depletion also leads to enhanced presence of reactive oxygen species (ROS). We compared systemic and endoneurial ROS activity and nerve conduction in vitamin E-depleted control and streptozotocin-diabetic rats (CE- and DE-), and in normally fed control and diabetic animals (CE+ and DE+). Nerve conduction was reduced in both diabetic groups. Vitamin E depletion caused a small further nerve conduction deficit in the diabetic, but not in the control animals. The combination of vitamin E deficiency and streptozotocin-diabetes (group DE-) appeared to be lethal. In the remaining groups, an important rise in sciatic nerve malondialdehyde (MDA) was observed in the vitamin E-depleted control rats. In contrast, plasma MDA levels were elevated in group DE+ only, whereas hydrogen peroxide levels were increased in group CE-. Endoneurial total and oxidized glutathione and catalase were predominantly elevated in group DE+. These data show that nerve lipid peroxidation induced by vitamin E depletion does not lead to reduced nerve conduction or changes in antioxidant concentrations as observed in STZ-diabetes. The marked systemic changes in MDA and antioxidants suggest that nerve dysfunction in experimental hyperglycemia is rather a consequence of systemic than direct nerve damage.

Amelioration by the Ca2+ antagonist, nimodipine of an existing neuropathy in the streptozotocin-induced, diabetic rat.

1. Neuropathy is a frequently diagnosed complication in diabetic patients but an effective treatment does not exist. 2. The development of neuropathy in streptozotocin-induced diabetic rats was monitored by measuring the motor and sensory nerve conduction velocity in the sciatic nerve. 3. A significant decrease in sensory and motor nerve conduction velocity was apparent in young, 14-week-old diabetic rats as compared to non-diabetic, age-matched controls 4 weeks after the induction of diabetes with streptozotocin. 4. Intraperitoneal treatment with the Ca2+ channel blocker, nimodipine, from week 4 onwards, in a dosage of 10 mg kg-1 or 20 mg kg-1 intraperitoneally per 48 h, resulted in a significant increase in sensory and motor nerve conduction velocity whereas treatment with 5 mg kg-1 intraperitoneally per 48 h was not effective. 5. One-year-old, adult, diabetic rats treated with nimodipine 20 mg kg-1 (treatment started again 4 weeks after induction of diabetes mellitus) also showed an increase of both sensory and motor nerve conduction velocity as compared to diabetic rats treated with placebo. 6. It is concluded that nimodipine ameliorates existing experimental diabetic neuropathy in streptozotocin-induced diabetic rats in both young and adult animals.