4p16.3 haplotype modifying age at onset of Huntington disease

Huntington disease (HD) is caused by an expanded CAG repeat sequence in the HD gene. Although the age at onset is correlated to the CAG repeat length, this correlation only explains approximately half of the variation in onset age. Less variation between siblings indicates that the variation is, in part, explained by genetic modifiers. We analyzed polymorphic loci within or close to the HD gene on the HD chromosome in Danish HD patients. We found one specific haplotype segregating with later age at onset, compared with patients with similar CAG repeat length and another haplotype. The nine Danish families in the study carrying this haplotype most likely have a common founder. Several of the polymorphic loci displayed alleles that may be specific to the late-onset haplotype, implicating that from this study we cannot determine which of the loci tested (or other polymorphic loci in this chromosomal area) do in fact contain genetic modifiers of age at onset.     

Bovine tuberculosis and the endangered Iberian lynx

We report the first case of bovine tuberculosis in a free-living Iberian lynx (Lynx pardina), an extremely endangered feline, from Doñana National Park in Spain. The isolate (Mycobacterium bovis) correlates by molecular characterization with other isolates from wild ungulates in the park, strongly suggesting an epidemiologic link. Mycobacterium bovis infects many animal species, with wild and free-ranging domestic ungulates being the main reservoirs in nature (1).     

Regressed retinopathy of prematurity: the relationship between clinical risk factors of the newborn period and regressed retinopathy of prematurity severity in a preterm born population of Stockholm county 1976-81

In a retrospective study, clinical risk factors of the neonatal period were correlated with the severity of regressed retinopathy of prematurity (ROP) in a population of preterm infants (bw less than 1500 g and or gestational age less than 33 weeks). At the age of 5-11 years 134 out of 528 preterm born infants (25.4%) were found to be under ophthalmic care. Reliable information on eye fundus status could be obtained in 105 of them. Regressed ROP was found in 61, the moderate form in 48 (9.1%) and the severe form in 13 (2.5%) patients. Twelve patients (2.3%) had visual acuity of less than 0.3 on the worst eye and two (0.4%) of these patients were blind from ROP. Twenty-four clinical factors of the newborn period were correlated with the severity of regressed ROP. The results suggest that long oxygen exposure in combination with other factors interfering with retinal vasotonus are associated with the degree of the disease developed.     

Distribution and accumulation of a mixture of arsenic,cadmium, chromium,nickel, and vanadium in mouse small intestine,kidneys, pancreas,and femur following oral administration in water or feed

Manufactured gas plant (MGP) sites are contaminated with coal tar and may contain metals such as arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), and vanadium (V). These metals are known to cause cancer or other adverse health conditions in humans, and the extent and cost of remediating MGP sites may be influenced by the presence of these metals. Studies assessed the distribution of these metals in female B6C3F1 mice ingesting (1) a metal mixture in water or (2) an MGP mixture in NIH-31 feed. The highest metal levels were measured in the small intestine and kidneys of mice receiving the metal mixture in water. For mice receiving the metal mixture in water, levels of As, Cd, and Cr, in the small intestine, levels of As, Cd, Cr, and V in the kidneys, levels of As and Cd in the pancreas, and levels of Cr and V in the femur were significantly greater than controls at 4, 8, 12, 16, and 24 wk. Except for Ni levels in the small intestine and femur and Cr levels in the kidneys, levels of metals were much lower in mice administered the MGP mixture in feed. The highest concentrations of metals in mice ingesting the MGP mixture in feed were found in the small intestine and kidneys, but few were significantly greater than controls. Levels of As in the small intestine at 6 and 18 wk and levels of Cr in the kidneys at 12, 18, and 24 wk were significantly greater than in controls. The data suggest that tissue burdens in small intestine, kidneys, pancreas, and femur of arsenic, cadmium, chromium, and vanadium are less when metals are present as an MGP mixture in feed than as a mixture in water. The reduced distribution and accumulation of metals in the organs of mice ingesting the MGP mixture in feed compared to the levels in organs of mice ingesting the metal mixture in water suggests that metals may be less likely to accumulate in humans ingesting MGP mixtures, thereby presenting a lower overall human health risk. The data presented indicate that the matrix in which metals are present will affect the uptake of individual metals and the organ specificity.     

Status cataplecticus induced by abrupt withdrawal of clomipramine

Introduction: Cataplexy is one of the main narcoleptic symptoms and is characterized by sudden loss of muscle tone triggered by emotional stimuli while consciousness is mantained. Clomipramine is an effective treatment of cataplexy. Cataplexy that occurs repeatedly for hours or days is referred to as status cataplecticus.Patients: We report three adults with narcolepsy in whom cataplexy was chronically and effectively treated with clomipramine (75-150 mg/day). For diverse reasons, these three patients had an abrupt withdrawal of clomipramine, and after 2-9 days patients showed an invalidant status cataplecticus characterized by a marked increase of the frequency, duration and severity of their cataplectic attacks that were now elicited by mild emotional stimuli. After introduction of anticataplectic agents (clomipramine in two patients and fluoxetine in one patient), status cataplecticus was resolved in less than a week.Conclusion: In patients with narcolepsy, abrupt withdrawal of chronic treatment with clomipramine may be associated with status cataplecticus. This condition may be resolved with the reintroduction of anticataplectic agents.     

Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer

OBJECTIVES: To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille Calmette-Guérin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression and differences in toxicity. PATIENTS AND METHODS: Five hundred patients with superficial bladder cancer (Ta, T1, Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weekly x six and thereafter fortnightly x six) either with the standard or RD instillation. RESULTS: All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (sd) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD (P=0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal (P=0.060 and P=0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease (P=0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e. 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms (P=0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose. CONCLUSION: Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with high-risk tumours. We recommend continuing to use the standard dose for high-risk tumours, while we consider the reduced dose safe and effective for intermediate-risk lesions and for maintenance schedules.