Molecular analysis of the fragile X syndrome

Summary The molecular analysis of human X-linked disease has progressed rapidly over the last few years owing to advances in power of mapping techniques. Physical DNA maps covering more than 5 million base pairs have been constructed for several chromosomal regions. Many of these regions have now also been cloned into overlapping cosmid and YAC contigs facilitating the search for disease genes. The recent identification of the mutation in the fragile X syndrome is such an example of the power of YAC technology in the characterization of human genetic disease mutations.     

Circulating inhibins and activin A during GnRH-analogue down-regulation and ovarian hyperstimulation with recombinant FSH for in-vitro fertilization-embryo transfer

OBJECTIVE We have investigated serial changes in plasma concentrations of inhibin A, inhibin B, pro αC and activin A in women undergoing stimulation with recombinant FSH in ‘long-protocol’ down-regulated cycles of IVF treatment. DESIGN Blood samples were collected during the entire IVF treatment cycle at points coinciding with the early follicular phase of the cycle preceding treatment, pituitary down-regulation, stimulation with recombinant FSH, ovulatory triggering, and the luteal phase of the cycle. In patients who achieved conception, blood samples were also taken during the first 2 weeks of pregnancy. All samples were analysed for inhibin A, inhibin B, pro αC, activin A and oestradiol. PATIENTS Fifteen women with normal ovarian function undergoing IVF treatment with tubal factor, mild endometriosis or idiopathic infertility. RESULTS During pituitary desensitization, both inhibin A and inhibin B were significantly (P<0.001, P=0.002, respectively) reduced whereas levels of pro αC and activin A were largely unaltered. Levels of both inhibins rose markedly (P<0.01) during FSH stimulation and a further rise in inhibin A was detected on the day after ovulatory trigger. Levels of both inhibin A and inhibin B then fell during and after oocyte pickup and continued to fall during the luteal phase. Activin A levels rose less markedly during gonadotrophin stimulation. Statistical analysis showed a high degree of correlation between the number of follicles (>10 mm) and serum inhibin A (r=0.65, P<0.01) and pro αC (r=0.65, P<0.01) concentrations during the late follicular phase. CONCLUSIONS These results indicate that ovarian production of dimeric inhibin A and B are gonadotrophin dependent, whereas activin A may have a significant gonadotrophin independent or extra-gonadal source. Inhibin A and pro αC may be useful markers for monitoring the effects of gonadotrophin stimulation.     

Severe disruptive vocalizers

OBJECTIVES: To describe the most severe disruptive vocalizers in nursing facilities, in regard to their clinical and behavioral characteristics, staff responses, and treatments used, and to report on their prognosis over 6 months. DESIGN: A longitudinal cohort study. SETTING: One hundred seven skilled nursing facilities. PARTICIPANTS: The 203 residents who were among the two most disruptive vocalizers in their respective facilities and who vocalized at least 2 hours a day. MEASUREMENTS: Telephone interviews of licensed nursing staff who cared for the subjects, conducted at baseline, 2, 4, and 6 months. Data gathered included subject demographics, physical function, diagnoses, medication and restraint use, behavioral problems, vocalization characteristics, treatments used, and status at follow-up. RESULTS: Subjects tended to have dementia, to be dependent in most activities of daily living, to have multiple medical problems, to be physically restrained (48%), and to be taking psychotropic medication (76%). Nearly all (95%) were audible at least 50 feet away, with loudness associated with more severe cognitive impairment (OR 4.90, P = .001). When subjects who primarily made nonverbal noises ("screamers") were compared with those whose predominant expressions were words ("talkers"), hearing impairment, severe cognitive impairment, and greater dependency in activities of daily living characterized the screamers. Staff reported trying a variety of treatments with all subjects, often with little success. Two months after enrollment, 66% of surviving subjects vocalized fewer hours than at baseline, and 45% were rated as improved. Independent predictors of improvement included greater ADL independence, hearing and vision problems, shorter length of stay, urinary incontinence, and use of a treatment other than one-on-one interventions. Nearly one-quarter of subjects (23.4%) died within 6 months. Baseline factors associated independently with a higher probability of death included age, use of activity intervention, physical abusiveness, and absence of wandering. CONCLUSION: Severe disruptive vocalization is associated with severe cognitive and physical impairment and with a high probability of mortality within 6 months. Subcategorization of severe vocalizers by vocalization type or other associated factors may be useful for prognostic and treatment purposes.     

Therapeutic delay and reduced functional status six months after thrombolysis for acute myocardial infarction

Thrombolytic therapy decreases the mortality rate in patients with acute myocardial infarction (AMI), and the timing of thrombolysis has proved to be critical for decreasing the short-term mortality rate. Much less is known about the longer term consequences of delays in thrombolysis, particularly for outcomes other than the mortality rate. We assessed the effect of time to thrombolysis and other clinical predictors on cardiac functional status 6 months after AMI. We used InTIME II, a multicenter trial, to test the efficacy of alteplase and lanoteplase. This component of the trial was conducted in 147 North American centers. Patients were > or =18 years of age with ST-elevated AMI. Functional status was measured by the Duke Activity Status Index, which was administered 6 months after AMI. After multivariate adjustment for baseline characteristics, delay in presentation to hospital and delay in initiation of thrombolysis were significantly and independently associated with decreased cardiac functional status 6 months later. Each additional hour from symptom onset to hospital presentation was associated with a 16% increase (95% confidence interval 3% to 31%) in the likelihood of functional impairment (Duke Activity Status Index score < or =30). In addition, each additional delay of 1 hour from hospital presentation to thrombolysis independently increased the probability of functional impairment by 38% (12% to 71%). Thus, in patients with AMI, earlier presentation to the hospital and more rapid initiation of thrombolysis could prevent significant decreases in functional status months after the initial infarct.     

Lone aortic regurgitation, sacroiliitis, and HLA B27. Case history and frequency of association.

An account of aortic regurgitation complicating ankylosing spondylitis is given. Twenty patients with lone aortic regurgitation and without overt spondylitis were examined clinically and radiologically and tissue typed. No evidence of sacroiliitis could be found in any patient. HLA B27 was absent from this group, and no significant disturbance in antigen frequency was noted.     

Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle

OBJECTIVES: We aimed to determine if botulinum toxin injection into the pyloric sphincter improves gastric emptying and reduces symptoms in patients with idiopathic gastroparesis. METHODS: Patients with idiopathic gastroparesis not responding to prokinetic therapy underwent botulinum toxin (80-100 U, 20 U/ml) injection into the pyloric sphincter. Gastric emptying scintigraphy was performed before and 4 wk after treatment. Total symptom scores were obtained from the sum of eight upper GI symptoms graded on a scale from 0 (none) to 4 (extreme). RESULTS: Ten patients were entered into the study. The mean percentage of solid gastric retention at 4 h improved from 27+/-6% (normal < 10%) before botulinum toxin injection into the pylorus to 14+/-4% (p = 0.038) 4 wk after treatment. The symptom score decreased from 15.3+/-1.7 at baseline to 9.0+/-1.9 (p = 0.006) at 4 wk, a 38+/-9% decrease. Improvement in symptoms tended to correlate with improved gastric emptying of solids (r = 0.565, p 0.086). CONCLUSIONS: This initial pilot study suggests that botulinum toxin injection into the pylorus in patients with idiopathic gastroparesis improves both gastric emptying and symptoms.     

Anatomy of the pulmonary veins in patients with atrial fibrillation and effects of segmental ostial ablation analyzed by computed tomography

INTRODUCTION: The anatomic arrangement of pulmonary veins (PVs) is variable. No prior studies have quantitatively analyzed the effects of segmental ostial ablation on the PVs. The aim of this study was to determine the effect of segmental ostial radiofrequency ablation on PV anatomy in patients with atrial fibrillation (AF). METHODS AND RESULTS: Three-dimensional models of the PVs were constructed from computed tomographic (CT) scans in 58 patients with AF undergoing segmental ostial ablation to isolate the PVs and in 10 control subjects without a history of AF. CT scans were repeated approximately 4 months later. PV and left atrial dimensions were measured with digital calipers. Four separate PV ostia were present in 47 subjects; 3 ostia were present in 2 subjects; and 5 ostia were present in 9 subjects. The superior PVs had a larger ostium than the inferior PVs. Patients with AF had a larger left atrial area between the PV ostia and larger ostial diameters than the controls. Segmental ostial ablation resulted in a 1.5 +/- 3.2 mm narrowing of the ostial diameter. A 28% to 61% focal stenosis was present 7.6 +/- 2.2 mm from the ostium in 3% of 128 isolated PVs. There were no instances of symptomatic PV stenosis during a mean follow-up of 245 +/- 105 days. CONCLUSION: CT of the PVs allows identification of anatomic variants prior to catheter ablation procedures. Segmental ostial ablation results in a significant but small reduction in ostial diameter. Focal stenosis occurs infrequently and is attributable to delivery of radiofrequency energy within the PV.     

Modern approaches to the treatment of breast cancer

Breast cancer is the most common cause of cancer death in women in this country. Until recently, the traditional treatment has been radical surgery with or without radiation therapy for patients with primary breast cancer, and palliative endocrine therapy followed by chemotherapy for patients with advanced disease. These treatments have met with limited effectiveness in terms of eradicating the disease. Studies in the past decade have given cause for optimism for breast cancer patients. Adjuvant systemic therapy after local treatment appears promising for certain subsets of patients with primary breast cancer. The development of estrogen receptor assays has markedly changed our approach to the disease and improved patient care. Estrogen receptor is an important prognostic factor and is useful in planning appropriate therapy for patients with primary breast cancer as well as those with advanced disease. Further research is urgently needed to improve the dismal survival of certain women with this common malignancy.