Effect of anticholinergic agents upon acquired nystagmus: a double-blind study of trihexyphenidyl and tridihexethyl chloride

We conducted a randomized, double-blind, crossover trial of two anticholinergic agents--trihexyphenidyl and tridihexethyl chloride (a quaternary anticholinergic that does not cross the blood-brain barrier)--in patients with acquired nystagmus and measured visual acuity and nystagmus before and at the end of 1 month on each medication. Of the 10 patients admitted to the study, only five completed trials of both drugs due to intolerance of medication or intercurrent illness. Of six patients who completed the trial of trihexyphenidyl, only one showed improvement. Of six patients who completed a trial of tridihexethyl chloride, four showed improvement. We conclude that (1) trihexyphenidyl is not a reliable treatment for acquired nystagmus, although occasional patients may benefit; (2) anticholinergic agents may suppress nystagmus by peripheral rather than central mechanisms; and (3) the side effects of anticholinergic agents limit their effectiveness in the treatment of nystagmus.     

Age trends in femur stresses from a simulated fall on the hip among men and women: evidence of homeostatic adaptation underlying the decline in hip BMD.

Age trends in proximal femur stresses were evaluated by simulating a fall on the greater trochanter using femur geometry from hip DXA scans of 5334 white men and women in the NHANES III survey. Expansion of femur outer diameter seems to counter net bone loss so that stresses remain similar across age groups, but stresses are higher in older women than in older men. INTRODUCTION: The age decline in hip BMD is caused by both bone loss and expansion of outer diameter that increases the region size over which mass is measured in a DXA scan. Because expansion has an opposing effect on structural strength, it may be a homeostatic adaptation to net bone loss to ensure that load stresses are kept within a narrow range. MATERIALS AND METHODS: Age trends in femur stresses were evaluated with an engineering beam simulation of a fall on the greater trochanter. Hip geometry was extracted from hip DXA scans using the Hip Structure Analysis (HSA) software on 2613 non-Hispanic white men and 2721 women from the third National Health and Nutrition Examination Survey (NHANES III). Using body weight as load, stresses were computed on the inferior-medial and superior-lateral femur neck at its narrowest point and the medial and lateral shaft 2 cm distal to the midpoint of the lesser trochanter. Stresses and the underlying geometries in men and women >50 years oaf age were compared with those 20-49 years of age. RESULTS: Compared with men <50 years of age, stresses in older men were 6% lower on both surfaces of the shaft, 4% lower on the inferior-medial neck, and not different on the superior-lateral neck. In women >50 years of age, stresses on the proximal shaft and inferior-medial neck remained within 3% of young values but were 13% greater on the superior-lateral neck. Neck stresses in young women were lower on the superior-lateral than the inferior-medial neck, but lateral stress increased to the level on the medial surface in older women. Stresses were higher in women than in men, with a greater gender difference in those >50 years of age. CONCLUSIONS: We conclude that femur expansion has a homeostatic effect in men and women that opposes bone loss so that stresses change little with age. Because expansion preserves stresses with progressively less bone mass, the process may reduce structural stability in the femoral neck under fall conditions, especially in the elderly female.     

Na+ currents near and away from endplates on human fast and slow twitch muscle fibers

Fast and slow twitch muscle fibers have distinct contractile properties. Here we determined that membrane excitability also varies with fiber type. Na⁺ currents (I_NA) were studied with the loose-patch voltage clamp technique on 29 histochemically classified human intercostal skeletal muscle fibers at the endplate border and <200 μm from the endplate (extrajunctional). Fast and slow twitch fibers showed slow inactivation of endplate border and extrajunctional I_NA and had increased I_NA at the endplate border compared to extrajunctional membrane. The voltage dependencies of I_NA were similar on the endplate border and extrajunctional membrane, which suggests thatboth regions have physiclogically similar channels. Fast twitch fibers had larger I_NA on the endplate border and extrajunctional membrane and manifest fast and slow inactivation of I_NA at more negative potentials than slow twitch fibers. For normal muscle, the differences between I_NA on fast and slow twitch fibers might: (1) enable fast twitch fibers to operate at high firing frequencies for brief periods; and (2) enable slow twitch fibers to operate at low firing frequencies for prolonged times. Disorders of skeletal membrane excitability, such as the periodic paralyses and myotonias, may impact fast and slow twitch fibers differently due to the distinctive Na⁺ channel properties of each fiber type. © 1993 John Wiley & Sons, Inc.     

Hepatitis B immunisation rates among infants in ethnic groups with high prevalences of hepatitis B surface antigen carriers

Abstract: To determine hepatitis B immunisation rates in infants from ethnic groups with hepatitis B surface antigen chronic carrier prevalence over 5 per cent, a questionnaire was sent to all Maternal and Child Health Centres in Victoria, requesting information on the hepatitis B and diphtheria–tetanus–pertussis (DTP) or combined diphtheria–tetanus (CDT) immunisation status for all infants born between 1 July 1992 and 30 June 1993 and at risk of hepatitis B infection because of maternal ethnicity. We received data on 3611 of 5744 infants (62.9 per cent) in targeted ethnic groups. Of these, 12.8 per cent had not received hepatitis B vaccine, and 81.6 per cent, 76.8 per cent and 64.0 per cent had received at least one, two and three doses respectively, while 84 per cent had received at least three doses of DTP vaccine and/or CDT vaccine. Coverage with DTP or CDT was higher than for hepatitis B vaccine ( P < 0.001), and coverage was better in areas with a higher percentage of infants in high–prevalence ethnic groups ( P < 0.001). Changes in the program in Victoria in terms of timing of the first dose of vaccine plus greater attention to follow–up may lead to improved hepatitis B immunisation rates among infants in targeted ethnic groups. Adoption of universal infant hepatitis B immunisation, by increasing familiarity with hepatitis B vaccine, is likely to be the best way to increase immunisation coverage for these infants.     

Pharmacokinetics of peptide T in patients with Acquired Immunodeficiency Syndrome (AIDS)

1. The pharmacokinetics of Dalal-peptide T-NH2 (peptide T) was determined during phase I clinical trials in patients with acquired immunodeficiecy disease (AIDS) and AIDS related complex (ARC). Drug levels were determined by specific RIA, and in some cases with HPLC analysis, after intraveneous (i.v.) or intranasal (i.n.), via metered sprayer, administration.

2. The plasma kinetics appeared to be bi-phasic with a first compartment half-life of 30 to 60 minutes and a second plasma clearence rate of 4 to 6 hours, observed for both routes of administration. Peptide T, in one individual was confirmed to be present at 6 hrs in plasma, determined after HPLC isolation followed by specific RIA.

3. Bioavailabilty, determined for a 2 mg test dose in six individuals was 9.3 ± 6.9 nmol/L. Peak plasma levels of 41 ± 30 nmol/L after 10 mg i.n., 2.8 ± 5.9 nmol/L after 2mg i.n., and 0.13 ± 0.07 nmol/L after 0.4 mg i.n. were observed. In two individuals tested, peptide T was detected in CSF at levels 20% of the corresponding plasma level 90 and 145 minutes post i.v. administration. Peptide T was not detected in urine. I.N. administration was well tolerated for times up to 21 months.     

A quantitative assessment of cross-sectional cortical bone remodeling in the femoral diaphysis following hip arthroplasty in elderly females

A quantitative assessment of cross-sectional cortical bone remodeling in the femoral diaphysis following hip arthroplasty was made by direct in vitro measurements of cross-sectional geometric properties. We obtained eight femora from four female cadavers ranging in age from 77 to 96 years. In three cases unilateral uncemented Austin Moore implants were used, and in one case a unilateral cemented Thompson prosthesis had been implanted. The time of implantation in the two specimens where this information could be obtained was greater than 40 months. Sections were made at 12 diaphyseal locations from the superior aspect of the lesser trochanter through the distal diaphysis. Section properties (areas and second moments of area, or area moments of inertia) were determined by tracing photographs of the cross-sections with a digitizer. In this sample of prosthetic femora, we found reductions in both total subperiosteal area (TA) and endosteal area (ENDA) relative to the contralateral unoperated side in most sections distal to the lesser trochanter. The average pairwise reduction in ENDA for this region was 21.1 mm2, reaching statistical significance in one distal diaphyseal section. The average decline in TA in this region was 10.2 mm2. Because the reduction in endosteal dimensions was generally greater than the reduction in subperiosteal dimensions, cortical area (CA) was maintained or increased throughout the distal 80% of this region in prosthetic femora with an average increase in CA of 9.3 mm2, reaching statistical significance in one mid-diaphyseal section. A completely different pattern of remodeling occurred in the two most proximal sections through the lesser trochanter and base of the femoral neck.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potent gp120-like neurotoxic activity in the cerebrospinal fluid of HIV-infected individuals is blocked by peptide T.

The envelope protein of the human immunodeficiency virus (gp120) causes neuronal death in developing murine hippocampal cultures or rat retinal ganglion cells. In HIV-infected individuals, gp120 released from HIV-infected macrophages or other cells in the brain has been proposed as the etiology for the pathophysiology of AIDS central nervous system (CNS) disease by diffusing to act at a distance to cause damage and/or death to neighboring neurons. In this study, 28 cerebrospinal fluid (CSF) samples from HIV-infected individuals (79% were WR stage 1 and 2) and neurological disease controls were tested, blind to the investigator, for the presence of in vitro neuronal killing activity. Neurotoxic activity was detected with peak effects at a 1:10(5) dilution in CSF from 9/18 HIV-infected individuals and 1/10 neurological disease controls. Thus half of CSF from early stages of HIV disease are characterized by the presence of neurotoxic activity which is not present in control CSF (Fischers exact test, P < 0.05). The neuronal toxicity by patient CSF could be prevented by peptide T (1 nM). A monoclonal antibody to mouse CD4, RL.172, also attenuated or prevented CSF-induced neuronal killing in all four CSF samples tested. In addition, an antiserum to peptide T previously shown to bind gp120 and neutralize both infectively and direct gp120 neurotoxicity, neutralized the CSF factor. gp120, or a modified small fragment, is suggested to be the responsible toxic molecular entity. These results may be relevant to the pathophysiology of HIV-related CNS disease and the mechanism by which peptide T causes improvements.     

Failure of the H2 antagonist cimetidine to reverse parasite antigen-specific lymphocyte unresponsiveness in experimental filariasis.

Using sera from 75 healthy donors, 68 rheumatoid arthritis (RA) patients, and 85 tuberculosis (TB) patients, we have examined the level of antibody of the three major classes binding to seven mycobacterial species, and to three control antigens. The major findings are that IgM binding to mycobacteria is reduced in RA patients who have HLA-DR7 (P = 0.008 for M. tuberculosis antigen), and that IgA binding to mycobacteria is reduced in RA patients who have HLA-DR2 (P = 0.007 for M. tuberculosis; P = 0.0004 for M. nonchromogenicum). These associations were not seen in TB, and were restricted to these antibody isotypes. We believe this is the first report of isotype specific Class II MHC-associated regulation of antibody levels in man. A possible interpretation of our data is that patients bearing these haplotypes are recognizing suppressor epitopes common to all the mycobacterial species tested. Since DR2 and DR7 have recently been shown to be associated with a significantly reduced risk of RA, our findings are compatible with the view that changes in immune responsiveness to mycobacterial antigens, or to autoantigens which cross-react with them, are relevant to RA.     

Age changes in geometry and mineral content of the lower limb bones

Subperiosteal expansion and increase in second moments of area with aging of eleven femoral and tibial cross-sections are documented in a large archaeological sample from the American Southwest. In contrast to these geometric changes, we found little change with age in bone mineral density measured using photon absorptiometry. Thus, the most significant structural changes with age in bone appear to involve its geometry and material characteristics other than its density. Variation in age-related geometric remodeling between cross-section locations and populations may be caused by differences in mechanical stress and strain levels in vivo in the lower limb.     

The effects of metiamide and H1 receptor blocking agents on anaphylactic response in guinea-pigs

The effects of metiamide and of four H₁ receptor blocking agents (mepyramine, promethazine, clemastine and ketotifene) on anaphylactic reaction were studied in the guinea-pig. The H₁ blockers conferred partial protection which shows that with the experimental protocol utilized (challenge injection with high doses of antigen), histamine plays a lesser role than other mediators released or synthesized. Metiamide (30.0 mg/kg i.v.) noticeably enhanced the increase in pulmonary resistance observed during anaphylactic reaction and reduced the protective effect of the H₁ antagonists on this parameter and on histamine release. These effects might be explained by an inhibition — at least partial — of the negative feed-back mechanism through which histamine controls its own release, or by a specific action of metiamide in high doses. The transient tachycardia initially observed in anaphylactic shock is partly related to stimulation of cardiac H₂ receptors by the histamine released, since it is suppressed by metiamide.