Differential effects of convulsive drugs on photically evoked after-discharge parameters

Since sub-convulsive doses of pentylenetetrazol (Metrazol) had been shown to augment photically evoked after-discharge (AD) patterns both in terms of elicitation threshold and amplitude of spindle bursts, it was questioned whether these observations were indicative of those that might be obtained with other drugs categorized in the general class of convulsive agents. It was found that picrotoxin and strychnine were ineffective in augmenting AD although, consistent with previous observations, Metrazol potentiated the elicitation of AD. Furthermore, Metrazol, when interacted with strychnine or picrotoxin, did not elicit augmented AD patterns. Repeated injections of Metrazol also did not result in additional increments in AD. These results can be related to the modes of action of the three convulsive agents.A major portion of this study was carried out at the Veterans Administration Hospital, Phoenix, Arizona. Additional financial support from the Research Division, Brigham Young University, is gratefully acknowledged.     

Ocular findings in Whipple's disease.

A 53-year-old man with treated, biopsy-proven Whipple's disease is described during the exacerbation of the disease, and several new findings not previously reported in association with this disease are presented. The unique combination of ocular signs included uveitis, glaucoma, epiphora, superficial punctate keratitis, and an unusual fibrovascular pannus involving the anterior chamber angles and corneal periphery of both eyes. These ocular abnormalities emphasize the need for thorough ophthalmologic evaluation of all patients with Whipple's disease.     

Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K

We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.     

Enzyme replacement therapy and intraepidermal innervation density in Fabry disease

We prospectively evaluated the effect of enzyme replacement therapy (ERT) on the intraepidermal nerve fiber density (IENFD) and thermal threshold in patients with Fabry disease, an X-linked disorder associated with a painful small-fiber neuropathy and decreased linear IENFD in a length-dependent pattern. Twenty-five hemizygous male patients with Fabry disease were enrolled in a 6-month, randomized, placebo-controlled ERT trial of 0.2 mg/kg of alpha-galactosidase A (agalsidase-alfa) every 2 weeks followed by an additional 12 months of open-label ERT for both populations. IENFD and thermal threshold were measured in the distal thigh at baseline, 6 months, and 18 months from initiation of the trial. We found no significant difference in IENFD between the treatment groups at 6 months. After an additional year of ERT, there was a significant reduction in IENFD in the patient group as a whole, attributable to the declining glomerular filtration rate. Thermal thresholds remained unchanged. We conclude that epidermal nerve fiber regeneration, as measured in the distal thigh, does not occur in this patient population after 12-18 months of ERT.     

Functional neuroimaging of the baboon during concurrent image-guided transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. However the underlying mechanisms of TMS-induced alterations in brain function are not well understood. As a result, treatment design parameters are determined ad hoc and not informed by any coherent theory or model. Once the mechanisms underlying TMS's modulatory effects on brain systems are better understood and modeled, TMS's potential as a therapeutic and/or investigative tool will be more readily explored and exploited. An animal model is better suited to study different TMS variables, therefore we developed a baboon model to facilitate testing of some of the current theoretical models of TMS interactions with brain regions. We have demonstrated the feasibility of this approach by successfully imaging cerebral blood flow (CBF) changes with H(2)(15)O positron emission tomography imaging during high-frequency, suprathreshold repetitive TMS in the primary motor cortex of five healthy, adult baboons.     

Use of the NICO Myriad device for tumor and cyst removals in a developing country

Purpose  

To describe the use of the NICO Myriad, a new side-cutting aspiration device for the resection of tumors, in a developing country.     

Physiological requirements for zinc

The estimates of zinc physiological requirements by the International Zinc Nutrition Consultative Group (IZiNCG) in 2004 were conspicuously low in comparison with those estimated by the Institute of Medicine (IOM) in 2001. The objective of this review is to explore the reasons for this gap and to reflect on lessons learned. All estimates of inevitable losses of endogenous zinc, especially intestinal excretion of endogenous zinc, were reviewed. An error in zinc menstrual losses, as well as a minor error in the linear regression of endogenous fecal zinc (EFZ) vs. total daily zinc absorption (TAZ) by IOM, were corrected. The review revealed an error by IZiNCG in selecting two data points for the linear regression of EFZ on TAZ. A second major reason for the "gap" is attributable to weighting of the data in the regression analysis by number of subjects per study by IZiNCG. Adjusting for these factors, together with use of the same reference data for body weights, resulted in satisfactory agreement between the two estimates of physiological requirements. The lessons to be learned from this review are discussed together with suggestions for future action by IOM as well as a constructive role for IZiNCG.