Citations

Antibodies specific for the neuronal ganglionic nicotinic acetylcholine receptor (nAChR) are found in high titer in serum of patients with subacute autonomic failure. This clinical disorder is known as autoimmune autonomic neuropathy (AAN). Rabbits immunized with a neuronal nAChR α3 subunit fusion protein produce ganglionic nAChR antibodies and develop autonomic failure (experimental AAN, or EAAN). We used quantitative measures of autonomic function to demonstrate that this animal model of neuronal nAChR autoimmunity recapitulates the cardinal autonomic features of AAN in humans. The severity of dysautonomia in the rabbit ranges from isolated cardiovagal impairment to severe panautonomic failure with fixed mydriasis, gastroparesis, dry eyes, impaired heart rate variability, hypotension, and low plasma catecholamines. The severity of autonomic failure correlates with serum antibody levels. Immunohistochemical staining of superior cervical ganglia and myenteric plexus neurons demonstrates intact presynaptic nerve terminals and intact postsynaptic neurons containing cytoplasmic nAChR, but lacking surface nAChR. These findings define the autonomic physiology and histopathology of this novel animal model and support the concept that AAN in humans is a disorder of ganglionic cholinergic synaptic transmission caused by ganglionic nAChR antibodies.

In a congenital myasthenic syndrome with a severe endplate myopathy, patch-clamp studies revealed markedly prolonged acetylcholine receptor (AChR) channel openings. Molecular genetic analysis of AChR subunit genes demonstrated a heterozygous adenosine-to-cytosine transversion at nucleotide 790 in exon 8 of the epsilon-subunit gene, predicting substitution of proline for threonine at codon 264 and no other mutations in the entire coding sequences of genes encoding the alpha, beta, delta, and epsilon subunits. Genetically engineered mutant AChR expressed in a human embryonic kidney fibroblast cell line also exhibited markedly prolonged openings in the presence of agonist and even opened in its absence. The Thr-264-->Pro mutation in the epsilon subunit involves a highly conserved residue in the M2 domain lining the channel pore and is likely to disrupt the putative M2 alpha-helix. Our findings indicate that a single mutation at a critical site can greatly alter AChR channel kinetics, leading to a congenital myasthenic syndrome. This observation raises the possibility that mutations involving subunits of other ligand-gated channels may also exist and be the basis of various other neurologic or psychiatric disorders.

Abstract The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples. (Cancer Epidemiol Biomarkers Prev 2006;15(5):935–8)

Background— Although age-adjusted cardiovascular disease (CVD) mortality has declined over the past decades, controversies remain about whether this trend was similar across locations of death and disease categories and about the existence of age and sex disparities. Methods and Results— We examined CVD mortality trends in Olmsted County, Minnesota, between 1979 and 2003 using the categories defined by the American Heart Association, including coronary heart disease (CHD), non-CHD diseases of the heart, and noncardiac circulatory diseases. Data on demographics, cause, and location of death of all 6378 residents who died of CVD were analyzed. Although decreases in the age-adjusted rates occurred in all groups, the magnitude of the decline varied widely. Lesser annual declines were noted in out-of-hospital than in-hospital deaths (1.8% versus 4.8%; P <0.001), in older than in younger persons (1.5% at age ≥85 years versus 3.9% for those ≤74 years of age; P <0.001), and in women relative to men (2.5% versus 3.3%; P =0.007). Furthermore, although CHD showed a marked annual decrease (3.3%), more modest decrements were found for non-CHD diseases of the heart (2.1%) and noncardiac circulatory diseases (2.4%) ( P =0.02 and P =0.04 for the comparison with CHD decline, respectively). Conclusions— Over the past 25 years, CVD mortality declined markedly in the community, but there were large disparities in the magnitude of the decline, resulting in a shift in the distribution toward out-of-hospital and non-CHD deaths. Further reduction in CVD mortality will require strategies directed at elderly persons and women, in whom out-of-hospital rates have improved only minimally.

Abstract We studied whether oophorectomy performed after menopause is associated with an increased risk of hip or vertebral fractures in 6295 Study of Osteoporotic Fractures participants. There was no association between postmenopausal oophorectomy and the risk of hip or vertebral fractures. Introduction: Bilateral oophorectomy after natural menopause has been associated with an increased risk of osteoporotic fractures, potentially because of a decline in serum estradiol and testosterone levels after the oophorectomy. We prospectively tested this hypothesis in the Study of Osteoporotic Fractures (SOF). Materials and Methods: We studied 6295 white women ⩾65 years of age participating in the SOF who were not taking estrogen therapy at baseline. Hip fracture analyses included 708 hip fractures; vertebral fracture analyses included 267 incident vertebral fractures. Baseline serum estradiol and free testosterone values were available in a small subset of participants. Results and Conclusion: There were no significant differences in age, weight, or BMD between the women who underwent postmenopausal oophorectomy (n = 583) and those who did not (n = 5712). Free testosterone levels were significantly lower among women who had a postmenopausal oophorectomy. A history of postmenopausal oophorectomy was not associated with an increased risk of hip (hazard ratio [HR] = 1.1; 95% CI = 0.9-1.5) or vertebral fracture (HR = 0.7; 95% CI = 0.5-1.2). The relationship between oophorectomy and hip fracture was not altered by adding serum estradiol level (HR = 1.3; 95% CI = 0.5-3.2) or serum free testosterone level (HR = 1.7; 95% CI = 0.8-3.7) to the model. In summary, postmenopausal oophorectomy was not associated with an increased risk of hip or vertebral fracture in this cohort. These results are in contrast to previous findings, suggesting that the relationship between postmenopausal oophorectomy and fractures is not fully elucidated and that incidental oophorectomy after menopause should still be considered carefully in each potential patient.

Abstract Measures of musculoskeletal rehabilitation play an integral part in the management of patients with increased fracture risk because of osteoporosis or extraskeletal risk factors. This article delineates current scientific evidence concerning nonpharmacologic approaches that are used in conjunction with pharmacotherapy for prevention and management of osteoporosis. Fractures caused by osteoporotic fragility may be prevented with multidisciplinary intervention programs, including education, environmental modifications, aids, and implementation of individually tailored exercise programs, which are proved to reduce falls and fall-related injuries. In addition, strengthening of the paraspinal muscles may not only maintain BMD but also reduce the risk of vertebral fractures. Given the strong interaction between osteoporosis and falls, selection of patients for prevention of fracture should be based on bone-related factors and on risk factors for falls. Rehabilitation after vertebral fracture includes proprioceptive dynamic posture training, which decreases kyphotic posturing through recruitment of back extensors and thus reduces pain, improves mobility, and leads to a better quality of life. A newly developed orthosis increases back extensor strength and decreases body sway as a risk factor for falls and fall-related fractures. Hip fractures may be prevented by hip protectors, and exercise programs can improve strength and mobility in patients with hip fracture. So far, there is no conclusive evidence that coordinated multidisciplinary inpatient rehabilitation is more effective than conventional hospital care with no rehabilitation professionals involved for older patients with hip fracture. Further studies are needed to evaluate the effect of combined bone- and fall-directed strategies in patients with osteoporosis and an increased propensity to falls.

Paraneoplastic cerebellar degeneration (PCD) is an autoimmune disease that can be associated with cancer of the breast, lung, and ovary. The clinical presentation of PCD commonly includes ataxia, visual disturbances, and dysarthria. The speech disturbances associated with PCD have not been well characterized, despite general acceptance that dysarthria is often part of the initial presentation. A retrospective study was conducted of the speech, language, and swallowing concerns of patients with PCD evaluated at the Mayo Clinic in Rochester, MN, between 1990 and 2001. Prospective speech and language assessments were then conducted with 5 patients who had PCD. While ataxic dysarthria was the most common speech diagnosis, a spastic component was recognized frequently enough to suggest that the subacute (days to weeks) emergence and progression of an ataxic or mixed ataxic-spastic dysarthria in the setting of a more diffuse cerebellar ataxia should raise suspicions about PCD and justify further investigation of a possible immune-related etiology.