Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy

BACKGROUND: It is unclear what anticopper drug to use for patients with Wilson disease who present with neurologic manifestations because penicillamine often makes them neurologically worse and zinc is slow acting. OBJECTIVE: To evaluate the frequency of neurologic worsening and drug adverse effects with ammonium tetrathiomolybdate. DESIGN: Open-label study of 55 untreated patients (22 of them new) presenting with neurologic Wilson disease treated with tetrathiomolybdate varying from 120 to 410 mg/d for 8 weeks and then followed up for 3 years. Neurologic function was assessed with scored neurologic and speech tests. SETTING: A university hospital referral setting. PATIENTS: All untreated, newly diagnosed patients with neurologic Wilson disease. INTERVENTION: Treatment with tetrathiomolybdate. MAIN OUTCOME MEASURES: Neurologic function was evaluated by neurologic and speech examinations. Drug adverse effects were evaluated by complete blood cell counts and biochemical measures. RESULTS: Only 2 (4%) of 55 patients treated with tetrathiomolybdate showed neurologic deterioration, compared with an estimated 50% of penicillamine-treated patients. Five of the 22 new patients exhibited bone marrow suppression and 3 had aminotransferase elevations. These numbers are higher than in the original 33 patients and appear to be due primarily to a more rapid dose escalation. CONCLUSIONS: Tetrathiomolybdate shows excellent efficacy in patients with Wilson disease who present with neurologic manifestations. With rapid escalation of dose, adverse effects from bone marrow suppression or aminotransferase elevations can occur.     

Alzheimer disease in the US population: prevalence estimates using the 2000 census

CONTEXT: Current and future estimates of Alzheimer disease (AD) are essential for public health planning. OBJECTIVE: To provide prevalence estimates of AD for the US population from 2000 through 2050. DESIGN: Alzheimer disease incidence estimates from a population-based, biracial, urban study, using a stratified random sampling design, were converted to prevalence estimates and applied to US Census Bureau estimates of US population growth. SETTING: A geographically defined community of 3 adjacent neighborhoods in Chicago, Ill, applied to the US population. PARTICIPANTS: Alzheimer disease incidence was measured in 3838 persons free of AD at baseline; 835 persons were evaluated for disease incidence.Main Outcome Measure Current and future estimates of prevalence of clinically diagnosed AD in the US population. RESULTS: In 2000, there were 4.5 million persons with AD in the US population. By 2050, this number will increase by almost 3-fold, to 13.2 million. Owing to the rapid growth of the oldest age groups of the US population, the number who are 85 years and older will more than quadruple to 8.0 million. The number who are 75 to 84 years old will double to 4.8 million, while the number who are 65 to 74 years old will remain fairly constant at 0.3 to 0.5 million. CONCLUSION: The number of persons with AD in the US population will continue to increase unless new discoveries facilitate prevention of the disease.     

Hypobaric hypoxia modifies constitutive nitric oxide synthase activity and protein nitration in the rat cerebellum

Ischemic hypoxia provokes alterations in the production system of nitric oxide in the cerebellum. We hypothesize that the nitric oxide system may undergo modifications due to hypobaric hypoxia and that may play a role in high altitude pathophysiology. Therefore, changes in the nitric oxide system of the cerebellum of rats submitted to acute hypobaric hypoxia were investigated. Adult rats were exposed for 7 h to a simulated altitude of 8235 m (27000 ft.) and then killed after 0 h or 1, 3, 5 and 10 days of reoxygenation. Nitric oxide synthase calcium-dependent and -independent activity, immunoblotting and immunohistochemistry of neuronal, endothelial, and inducible nitric oxide synthase, and nitrotyrosine were evaluated. Immunoreactivity for neuronal nitric oxide synthase slightly increased in the baskets of the Purkinje cell layer and in the granule cells, after 0 h of reoxygenation, although no changes in neuronal nitric oxide synthase immunoblotting densitometry were detected. Calcium-dependent activity significantly rose after 0 h of reoxygenation, reaching control levels in the following points, and being coincident with a peak of eNOS expression. Nitrotyrosine formation showed significant increments after 0 h and 1 day of reoxygenation. Nitrotyrosine immunoreactivity showed an intracellular location change in the neurons of the cerebellar nuclei and in addition, an appearance of nitration in the soma of the Purkinje cells was detected. No changes in inducible nitric oxide synthase activity, immunoblotting or immunohistochemistry were detected. We conclude that at least part of the nitric oxide system is involved in cerebellum responses to hypobaric hypoxia.     

Effects of valproic acid,carbamazepine, and phenobarbitone on the fatty acid composition of erythrocyte membranes in children

PURPOSE: To investigate a possible relation between antiepileptic drugs (AEDs) and the fatty acid composition of membranes. METHODS: Fatty acid (FA) composition of erythrocytes was studied in children with epilepsy receiving AED monotherapy. Children taking valproate (VPA, n = 28), carbamazepine (CBZ, n = 17), or phenobarbitone (PB, n = 14) were compared with healthy controls (n = 25). FAs were measured by capillary-gas chromatography (GC-FID). RESULTS: Significant changes (p < 0.05) in the FA composition of membranes were found. In children treated with VPA, C13:0 was decreased (8.2 +/- 2% vs. 10.7 +/- 4% in controls) and C14:0 increased (1.4 +/- 0.5% vs.1 +/- 0.5% in controls). C17:0 again was reduced (9.9 +/- 4% vs. 13.2 +/- 6% in controls), whereas the long-chained acids were enhanced: C18:2n-6 (6 +/- 2.4% vs. 3.9 +/- 2.5% in controls), and C20:4n-6 (1.9 +/- 1.7% vs. 1.4 +/- 0.5% in controls). The nonidentified FAs also increased with VPA therapy: 2.5 +/- 0.8% versus 1.7 +/- 0.9% in controls. Children treated with CBZ showed only minimal changes of FA composition: C13:0 was decreased compared with controls (8 +/- 2% vs. 10.7 +/- 4%). No changes were seen in patients taking PB. The mean corpuscular volume (MCV) showed important differences between the study groups: MCV was 84.7 +/- 6.0 fl during VPA therapy (p < 0.001) and 85.7 +/- 4.1 fl with CBZ (p < 0.001). During PB, the MCV increased to 82.87 +/- 3.29 fl compared with controls (78.73 +/- 4.92 fl; p < 0.01). CONCLUSIONS: VPA therapy is associated with changes of the FA composition of membranes, which is not the case with PB therapy. The implications of this finding remain to be established.     

Furosemide terminates limbic status epilepticus in freely moving rats

PURPOSE: To evaluate the anticonvulsant properties of furosemide and to determine sedative side effects compared with pentobarbital and diuretic side effects compared with saline-treated controls in an experimental model of limbic status epilepticus. METHODS: Self-sustaining status epilepticus was induced in rats by continuous electrical stimulation of the perforant path. Five minutes after the end of the stimulation, animals were given 100 mg/kg furosemide, 30 mg/kg pentobarbital, or an equal amount of saline, intraperitoneally. After administration of the substance, animals were monitored clinically and electrographically for 3 h regarding status epilepticus, level of sedation, and diuresis. RESULTS: In seven of 10 animals, furosemide terminated status epilepticus after 68 +/- 26 min, whereas pentobarbital was successful in all animals after 5 +/- 0.8 min. In contrast to pentobarbital, sedation did not occur with furosemide. Weight loss after furosemide was 10.2 +/- 1.7% compared with 6.5 +/- 1.1% in animals given saline (p < 0.001). CONCLUSIONS: The results suggest that furosemide may serve as an alternative or additional agent for refractory complex partial status epilepticus in patients in whom common anesthetics are not justifiable.     

CEACAM1-4S,a cell-cell adhesion molecule,mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture

In a 3D model of breast morphogenesis, CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) plays an essential role in lumen formation in a subline of the nonmalignant human breast cell line (MCF10A). We show that mammary carcinoma cells (MCF7), which do not express CEACAM1 or form lumena when grown in Matrigel, are restored to a normal morphogenic program when transfected with CEACAM1-4S, the short cytoplasmic isoform of CEACAM1 that predominates in breast epithelia. During the time course of lumen formation, CEACAM1-4S was found initially between the cells, and in mature acini, it was found exclusively in an apical location, identical to its expression pattern in normal breast. Lumena were formed by apoptosis as opposed to necrosis of the central cells within the alveolar structures, and apoptotic cells within the lumena expressed CEACAM1-4S. Dying cells exhibited classical hallmarks of apoptosis, including nuclear condensation, membrane blebbing, caspase activation, and DNA laddering. Apoptosis was mediated by Bax translocation to the mitochondria and release of cytochrome c into the cytoplasm, and was partially inhibited by culturing cells with caspase inhibitors. The dynamic changes in CEACAM1 expression during morphogenesis, together with studies implicating extracellular matrix and integrin signaling, suggest that a morphogenic program integrates cell-cell and cell-extracellular matrix signaling to produce the lumena in mammary glands. This report reveals a function of CEACAM1-4S relevant to cellular physiology that distinguishes it from its related long cytoplasmic domain isoform.     

Medical care of injuries caused intentionally by domestic violence

OBJECTIVE: To describe and analyze the causes of emergency care services for intentional injuries, especially those caused by domestic violence, at four public hospitals in Mexico City. MATERIAL AND METHODS: A cross-sectional study was conducted between January and April 1998, which included variables related with the victim, the aggressor, and the medical care provided to the victim. A questionnaire was applied to individuals who had been injured intentionally. Statistical analysis of data consisted of simple frequencies, the chi 2 test, and odds ratios (OR) with 95% confidence intervals (CI). A logistic regression model was also used to adjust for variables associated with the injury requiring emergency medical care. RESULTS: A total of 598 cases of intentional injuries were analyzed, 16% of which were due to domestic violence. Females were the most frequent victims (76%), followed by young people between 15 and 29 years old (46%). Variables associated with medical care due to injuries by domestic violence were: age 30 or older (OR 2.36, 95% CI 1.13-4.90), female gender (OR 8.60 95% CI 4.25-17.40), history of injuries (OR 4.93 95% CI 2.03-11.95), home as place of occurrence (OR 36.25 95% CI 16.59-79.18), and low education level (OR 2.33 95% CI 1.03-5.26). CONCLUSIONS: Study findings are consistent with those from other studies and call for enforcement of the Mexican Official Norm for Medical Care of Domestic Violence (Norma Oficial Mexicana para la Atención Médica de la Violencia Familiar) established in March 2000.     

Optical coherence tomography in contact dermatitis and psoriasis

Optical coherence tomography (OCT) is a new noninvasive imaging technique. In this study, it was used for the investigation of contact dermatitis and psoriasis. In these common inflammatory skin diseases the value of OCT for quantification and monitoring of the changes in comparison with other bioengineering methods was evaluated. Repeated measurements were performed in healthy volunteers after experimental induction of irritant contact dermatitis and in patients with psoriasis. In the OCT images, the thickness of the epidermis and the signal attenuation coefficient in the upper dermis were evaluated. The changes were compared with measurements of transepidermal water loss, hydration, skin colour and surface roughness, and with high-frequency ultrasound measurements. In irritant dermatitis and psoriasis, thickening of the epidermis was detected and could be monitored over time. The light scattering in the upper dermis was lower than in healthy skin. This was interpreted to be due to the inflammation and oedema, leading to a less-dense arrangement of the collagen fibres. The changes in the OCT images did not significantly correlate with the changes shown by the other methods. OCT is an interesting tool for investigation of inflammatory skin diseases. It is a simple method for determination of epidermal thickness and therefore provides, in addition to other methods, information on the severity of the disease and on treatment effects.     

Difference between real and perceived power of dermoscopical methods for detection of malignant melanoma

Clear proceedings in detection of malignant melanoma and monitoring of melanocytic nevi (MN) have been achieved by dermoscopy in recent years: sensitivity to 95% is possible for experts. Does patients' confidence in methods for detection of malignant melanoma most important for adherence in follow-up reflect this diagnostic power? A self-administered survey was performed in 210 consecutive patients at 13 private dermatological practices and the department of Dermatology of the University of Regensburg. Confidence was assessed by a 5-step ordinal scale ranging from 1 to 5 (higher values indicate higher confidence) and willingness-to-pay (wtp) as health-economic instrument for naked-eye inspection (NEI), handheld dermoscopy (HHD), digital dermoscopy (DD), and teledermoscopy (TD); additional, wtp for a hypothetical method promising 100% accuracy. Data of 143 patients (response rate 69.5%; mean age 37 years, 58% female) could be analysed. Mean confidence was 1.9 0.9 for NEI, 2.8 0.9 for HHD, 4.5 0.7 for DD, and 4.7 0.5 for TD. Mean wtp per examination was 0.64% 1.1 of monthly income for NEI, 1.1% 1.9 for HHD, 2.8% 3.3 for DD, 3.1% 4.6 for TD, and 5.0% 7.8 for hypothetical method. Differences between methods were statistically significant. Compared to the hypothetical method, NEI achieved only 14.9%, HHD 24.8%, DD 58.4%, and TD 60% of maximum confidence. This study was performed without any influence on routine information for patients. Results therefore represent patients' actual knowledge of dermoscopical methods in daily dermatological practices. Patients' confidence was highest for TD, HHD was clearly underestimated. Willingness-to-pay in HHD, DD, and TD was at least 40% below a hypothetical method promising 100% accuracy. Better information about diagnostic accuracy of methods available is necessary to increase patients' knowledge and confidence.     

Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis

We conducted a double-blind, placebo-controlled, multicenter, randomized trial to test the hypothesis that 300 mg of tobramycin solution for inhalation administered twice daily for 28 days would be safe and result in a profound decrease in Pseudomonas aeruginosa (Pa) density from the lower airway of young children with cystic fibrosis. Ninety-eight subjects were to be randomized; however, the trial was stopped early because of evidence of a significant microbiological treatment effect. Twenty-one children under age 6 years were randomized (8 active; 13 placebo) and underwent bronchoalveolar lavage at baseline and on Day 28. There was a significant difference between treatment groups in the reduction in Pa density; no Pa was detected on Day 28 in 8 of 8 active group patients compared with 1 of 13 placebo group patients. We observed no differences between treatment groups for clinical indices, markers of inflammation, or incidence of adverse events. No abnormalities in serum creatinine or audiometry and no episodes of significant bronchospasm were observed in association with active treatment. We conclude that 28 days of tobramycin solution for inhalation of 300 mg twice daily is safe and effective for significant reduction of lower airway Pa density in young children with cystic fibrosis.