Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS.

An open-label dose-escalation trial was performed to assess the safety and tolerability of high doses of coenzyme Q10 (CoQ10) in ALS. CoQ10, a cofactor in mitochondrial electron transfer, may improve the mitochondrial dysfunction in ALS. In this study, CoQ10 was safe and well tolerated in 31 subjects treated with doses as high as 3,000 mg/day for 8 months.

A clinical trial of creatine in ALS.

BACKGROUND: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. METHODS: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. RESULTS: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. CONCLUSION: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

The use of non-invasive positive pressure ventilation (NIPPV) in ALS patients. A need for improved determination of intervention timing.

We present our experience with 27 patients with symptoms of alveolar hypoventilation, a precursor to respiratory failure, to demonstrate variability in symptoms, physiologic status and outcome of intervention. They represent 27 consecutive patients who tolerated NIPPV for more that 4 hours per 24-h period for more than 2 weeks. All patients received neurological consultation, electromyography and met criteria for ALS according to El Escorial diagnostic criteria. To assess respiratory status, spirometry was measured in sitting and when possible, in the supine positions. Resting arterial blood gases were available in 22 patients. Orthopnea was the most common symptom at the time of institution of NIPPV. No correlation existed between age at institution of NIPPV, duration of effective use of this technology or vital capacity and duration of effective use of NIPPV. The lack of correlation between vital capacity at the institution of NIPPV and duration of its effectiveness suggest that more sensitive indicators for the onset of alveolar hypoventilation must be defined, particularly since the principal benefit from its use is relief of symptoms of alveolar hypoventilation.

Physician assistants and the practice of neurology.

This is the first study of how physician assistants (PAs) function in neurology practice. Forty-six PAs who work full-time in a neurology practice were surveyed by telephone and by mail; 100% responded to all telephone survey questions on aspects of practice, and almost all responded to the mailed survey. Of these, 26 worked in a group practice; the average duration of neurology experience was 7 years. Diagnoses seen by these PAs were similar to those seen in most neurology practices. The scope of findings is limited but suggests that, in neurology settings where PAs are employed, they perform a broad range of functions. Furthermore, PAs in most neurology practices likely assist in off-loading patients whose requirements for care are considered "routine" by the PAs' supervising physician(s).

Cairo is working. USA. The Hague Forum.

PIP: In the interest of improving the quality of life for all people, the US remains committed to working in a global partnership to achieve the goals of the International Conference on Population and Development (ICPD). The ICPD's goals will be promoted through the spread of ideas and knowledge, beginning with education, especially for women and girls. It also involves the leadership of public officials at every level, the work of community-based nongovernmental organizations and religious institutions, the mass media, and neighbor-to-neighbor communication. The Cairo plan recommends the kinds of services all women and families need, through both the public and private sectors, to help ensure that children are born wanted and that they survive and thrive. Although progress is uneven in achieving the goals of the ICPD, and threatened by the HIV/AIDS pandemic and economic crises, the program of action is working. Progress made in the US is reviewed.^ieng

The prognostic value of thyrotropin receptor antibody measurement in the early stages of treatment of Graves' disease with antithyroid drugs.

In most trials, at least 50% of patients with Graves' disease treated with antithyroid drugs (ATD) relapse after achieving euthyroidism. At present, there are no definitive prognostic parameters available early in treatment to indicate those likely to achieve long-term remission. Because thyrotropin receptor antibodies (TRAb) are specific for Graves' disease, the possibility that their rate of change early in treatment (0 to 6 months) might be such an indicator was explored. TRAb were measured both as thyrotropin binding inhibitory immunoglobulins (TBII) and as thyroid-stimulating antibodies (TSAb) in 85 patients with untreated Graves' disease at 6-month intervals throughout their ATD treatment. The patients in the study were treated for a minimum period of 12 months and were categorized retrospectively into two groups depending on whether or not they remained in remission after ATD treatment. Remission was deemed as reached in patients who remained euthyroid for a minimum period of 15 months after cessation of ATD. The mean initial TBII and TSAb values in the nonremission group were significantly higher than in the remission group (p < 0.001 for both parameters). The rates of fall in mean TBII levels were similar for each group in the first 6 months of treatment, but while they continued to fall in the remission group over the next 6 to 12 months, mean values for the nonremission group plateaued and failed to fall to control levels within that period. These results indicate that changes in TRAb levels, measured either as TBII or TSAb, occur more rapidly in the second 6 months of treatment in patients who ultimately achieve remission than those who do not. If TBII fall to control levels by 12 months, the patient has at least a 70% chance of ultimately achieving remission with ATD treatment alone.

Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria.

In 47 patients with diabetic nephropathy (29 type I, 18 type II) renal function and blood pressure (BP) (treated with or without an angiotensin-converting enzyme [ACE] inhibitor, enalapril [10 mg], in 38 hypertensive patients) were followed over 4 years. A percutaneous renal biopsy was performed in all patients initially and repeated in a representative 19 patients with treated hypertension after 4 years. Mean glomerular volume (MGV), interstitial fibrosis (IF), capillary volume, and sclerosed glomeruli (GS) were measured histomorphometrically. Mean fall in creatinine clearance (CCr) was 11.8% after 4 years with no difference between treatment groups or type of diabetes. BP both initially and during treatment correlated with initial and final serum creatinine and CCr (P < 0.01). There were no histomorphometric differences between type I and type II patients or hypertension treatment groups. Initial IF correlated with initial and final serum creatinine and CCr (P < 0.05) in all patients and type I patients alone, MGV correlated inversely with CCr in type I patients (P < 0.05). After 4 years, IF (24.8 vs. 30.0%, P < 0.01) and GS (26 vs. 37%, P < 0.05) increased significantly, and increase in IF correlated with fall in CCr (P < 0.01). Proteinuria and HbA1 did not correlate with indexes of function or structure. In this longitudinal study of patients with diabetic nephropathy, there was a close relation between BP and renal function but no difference between treatment with enalapril and other hypertensive agents. The correlations between renal function and histology at entry and after 4 years suggest that IF is a co-determinant of renal function in diabetic nephropathy.

Microalbuminuria in diabetes.

This statement summarises current understanding of the role of microalbuminuria in diabetic nephropathy and describes its natural history and clinical relevance. It outlines core facts and makes recommendations for the management of patients with persistent microalbuminuria.

Microalbuminuria: prognostic and therapeutic implications in diabetes mellitus.

Thirty years following the development of the first radioimmunoassay for albumin, microalbuminuria is widely acknowledged as an important predictor of overt nephropathy in patients with Type 1 diabetes and of cardiovascular mortality in Type 2 diabetes. In addition, there is accumulating evidence to suggest that diabetic patients with microalbuminuria may have more advanced retinopathy, higher blood pressure, and worse dyslipidaemia than patients with normal albumin excretion rates. Recent studies have focused on the role of intervention, principally with antihypertensive therapy and intensive glycaemic control, in reducing microalbuminuria. While successful in reducing urinary albumin excretion it remains to be established whether such therapies will be translated into a reduction in renal failure and decreased cardiovascular morbidity and mortality.

Intrathecal thyrotropin-releasing hormone does not alter the progressive course of ALS: experience with an intrathecal drug delivery system.

Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system. Since TRH crosses the blood-brain barrier poorly, if at all, we postulated that the negative parenteral clinical trials could be a result of insufficient drug-receptor interaction. We thus carried out a blinded, placebo-controlled, crossover study of intrathecal TRH in 36 patients by delivery through an implanted, constant infusion pump achieving a steady-state CSF level comparable with that shown to be effective in tissue culture experiments. Utilizing a quantitative measurement technique to assess motor unit loss, we did not observe any alteration of the progressive course during 6 months on TRH and 6 months on saline placebo. However, the implanted pump delivery system proved to be safe, reliable, and well tolerated.

A clinical-histological study of individuals with diabetes mellitus and proteinuria.

Coexistent renal pathology with diabetic glomerulosclerosis was found in 38 of 136 (28%) consecutive renal biopsies performed primarily for proteinuria in individuals with diabetes mellitus. The histological lesions found were glomerulonephritis (14), focal tubulointerstitial disease (23), and amyloidosis (1). Significant microscopic haematuria was present in 66% of all patients and did not help to distinguish non-diabetic disease. The severity of diffuse diabetic glomerular disease was independently associated with duration of diabetes, raised plasma creatinine, the presence of hypertension, clinical retinopathy and neuropathy, but not with type of diabetes, degree of proteinuria or glycosylated haemoglobin at the time of biopsy. Diffuse interstitial fibrosis was related to the severity of glomerular disease and, if severe, also with a significantly (p less than 0.01) higher plasma creatinine. Coexisting renal disease was found to be associated with a significantly higher plasma creatinine (p less than 0.01) independent of the severity of diabetic glomerulopathy. Coexistent pathology is a not uncommon finding in renal biopsies from diabetic patients with proteinuria. These lesions and their underlying causes may not only influence the renal function and natural history of renal disease in diabetic individuals, but may also determine the response of proteinuria to therapy.