Early Electrophysiological Changes In Transgenic Rat Model Of Charcot-Marie-Tooth

Recently, a reliable transgenic rat model of human Charcot-Marie-Tooth type 1 A has been developed. So far, neurophysiological studies have been performed only in advanced stages of rat disease. Moreover, axonal involvement, which is known to occur in human CMT1A, has never been observed in this rat model. Affected rats show overexpression of Peripheral Myelin Protein (PMP-22) and a peripheral hypomyelinating neuropathy. We perfomed an electrophysiological study in two heterozygous PMP-22 transgenic rats and in one normal control, matched for age (3 weeks) and weight (average: 60 g). Recordings were performed in vivo by stimulating the sciatic nerve at both sciatic notch and ankle sites and recording the Hoffman reflex and direct muscle responses (CMAP). The H-reflex related SNCV and MNCV were calculated by measuring the distance between the sciatic notch and the ankle sites and the respective latencies. The two transgenic rats showed different levels of PMP-22 overexpression, as judged by quantitative PCR. The rat with a lower PMP-22 gene level showed a 30% reduction of MNCV compared to the normal control, while SNCV was not reduced. The CMAP was sized approximately 45% of the normal rat while the ratio between H wave amplitude and CMAP was 30% of the normal, the H wave amplitude being more affected than the CMAP. The action potentials in the rat with a higher transgene level were not recordable. Our data demonstrate that slowing of MNCV is an early finding in the CMT1A rat model. The marked reduction of H wave amplitude in front of a normal SNCV suggests a possible early axonal damage of sensory fibers. The entity of electrophysiological compromission positively correlated with the number of copies for PMP-22 gene. All together these considerations prove the sensitivity of this method, however further studies are needed to confirm these results and to prove that this model may be suitable to investigate the effects of therapeutic approaches.     

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study

High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches.     

Familial Cushing's disease with severe weight loss occurring in late childhood

We describe a rare case of familial Cushing's disease occurring in a 7-year-old boy, and 19 years of follow up. Our patient first presented soon after his maternal aunt had been treated for Cushing's disease. The clinical presentation was made complicated by the development of an intercurrent eating disorder resembling anorexia nervosa. This resulted in marked weight loss, and even though serum and urinary cortisol levels were elevated, many of the clinical stigmata of Cushing's disease were absent. Eating disorders are relatively uncommon in boys, and in this case there was an organic cause for the abnormal behaviour. This case shows, furthermore, that even the obesity of Cushing's disease can be overcome by the combination of diet and exercise.     

Ascorbate-2-phosphate in red cell preservation. Clinical trials and active components

A red cell additive solution (AS-005) containing ascorbate-2-phosphate (AsP) to maintain 2,3-diphosphoglycerate, plus adenine, phosphate, and mannitol to retain viability and reduce hemolysis, was evaluated by human clinical trials. A crossover design was used with another additive solution (Nutricel AS-3, Cutter Laboratories) serving as the control for each donor. Each additive solution was evaluated at 35 and 42 days of storage. There was no significant difference between the red cell viability of the two storage solutions at either time period. Split-bag, AS-005 in vitro studies at two temperatures (2.5 and 5.5 degrees C), both within the range of 1 to 6 degrees C approved by the American Association of Blood Banks and the Food and Drug Administration, resulted in dramatically different in vitro parameters, including a threefold difference in 2,3-diphosphoglycerate (2,3-DPG), a fivefold difference in glucose, and significant differences in pH and adenosine triphosphate. High-pressure liquid chromatography data confirmed the preliminary report that 1 to 2 percent (wt/wt) oxalate was present in preparations of AsP. In vitro storage data confirmed that oxalate is the active component of AsP that preserves 2,3-DPG during storage.     

Measurement of total-body cobalt-57 vitamin B12 absorption with a gamma camera

Previously described techniques for the measurement of the absorption of [57Co]vitamin B12 by total-body counting have required an iron room equipped with scanning or multiple detectors. The present study uses simplifying modifications which make the technique more available and include the use of static geometry, the measurement of body thickness to correct for attenuation, a simple formula to convert the capsule-in-air count to a 100% absorption count, and finally the use of an adequately shielded gamma camera obviating the need of an iron room.     

Renal duplication artifact in US imaging

To determine the appearance of artifactual renal duplication in ultrasound (US) imaging, the authors analyzed 22 examples of such duplication in 20 patients. The artifact appeared as a duplication of the collecting system in 18, as a suprarenal mass in three, and as upper-pole cortical thickening in one. It occurred in the left kidney in 15 patients, in the right kidney in three, and bilaterally in two. To determine the frequency of the artifact, 50 additional patients were scanned. It was identified in eight of these patients. Imaging characteristics and the results of in vitro modeling proved the artifact was due to sound beam refraction between the lower pole of the spleen or liver and adjacent fat. This artifact is much more common in the left kidney and occurs more frequently in obese patients. Knowledge of the appearance and cause of this artifact should help radiologists avoid diagnostic errors.