Mapping of the gene for X-linked dominant Charcot-Marie-Tooth neuropathy.

We performed a clinical study and linkage analysis on 278 subjects (66 affected) belonging to eight families with X-linked dominant Charcot-Marie-Tooth (CMT) neuropathy. This form affects 11.8% of CMT patients in Iowa. Motor nerve conduction velocities (MNCVs) were significantly slowed consistent with type 1 CMT. Fifty-six obligate carriers manifested mild distal weakness, localized areflexia, pes cavus, and slowing on MNCVs. Seven X-linked restriction fragment length polymorphisms mapping in the Xp11-q21 region were tested for linkage against CMT. Two-point linkage results showed the highest lod scores with PGK1, DXS159, and DXYS1. Multipoint linkage analysis excluded the CMT gene from being telomeric to either DXS14 or DXYS1, with over 1,000:1 odds. The highest location scores were at PGK1 and 1 cM proximal to DXS159.     

Accommodative hysteresis under static and dynamic stimulus conditions

The influence of continuous variation in dioptric demand on the accommodative hysteresis induced at near distances was examined in 14 visually-normal young adults. Tonic accommodation was measured before and after 10 minutes of sustained focus using a constant stimulus at 5 D, 6.5 D, and 8 D, as well as a stimulus which slowly and alternately increased and decreased over the continuous range from 5 D to 8 D. For approximately half the subjects, dioptric demand had to be very high (8 D) under static conditions to produce moderate but significant hysteresis, yet little or no attenuation of the effect occurred under the dynamic condition. For other subjects who consistently showed very large tonic changes (1.4 D or more) under static conditions, the hysteresis effect generated under dynamic conditions was greatly reduced (approximately 50 per cent) in magnitude. These findings suggest that the degree to which continuous variation in dioptric demand will disrupt the adaptive process may depend on individual differences in the rate and/or maximum level of tonic accommodative change. Such a relationship could have bearing on the particular strategy recommended for individuals who tend to experience blur at distance following nearwork.     

Human ovarian-carcinoma cell lines and companion xenografts: a disease-oriented approach to new platinum anticancer drug discovery

Summary A disease-oriented approach to the discovery of novel platinum anticancer drugs has been established through the setting up of parallel human ovarian-carcinoma cell lines and xenografts. The correlation between in vitro and in vivo antitumour activity was determined for four reference platinum agents (cisplatin, carboplatin, iproplatin and tetraplatin) in eight companion lines. Two methods of assessing antitumour effect were used in vitro (tritiated thymidine incorporation and sulforhodamine B staining) and three were applied in vivo [28-day treated/control (T/C) ratio, growth delay and specific growth delay]. In vitro, large differences in cytotoxicity across the cell lines were observed for each drug. This was also reflected in the xenografts for cisplatin and carboplatin and, to a lesser extent, for iproplatin. A correlation analysis of in vitro vs in vivo data revealed a high, statistically significant positive correlation for cisplatin and a strong positive correlation for carboplatin. However, for the two platinum(IV) drugs, the correlation was less good. In particular, tetraplatin was markedly less active in vivo (showing a general lack of activity against all of the tumour lines) than its in vitro potency against the cell lines predieted, resulting in poor correlation coefficients. These human tumour panels may be valuable for the elucidation of both cellular/molecular and corresponding in vivo pharmacological mechanisms of platinum drug resistance. Moreover, the HX/62 and SKOV-3 tumour lines, which exhibit a level of intrinsic resistance to the four reference agents both in vitro and in vivo (and which were derived from patients who had not received prior platinum therapy), represent particularly useful evaluation models for the discovery of novel broad-spectrum platinum drugs.This study was supported by grants to the Institute of Cancer Research from the Cancer Research Campaign and the Medical Research Council, the Johnson Matthey Technology Centre and Bristol Myers Squibb Oncology     

Novel therapeutic approaches for multiple myeloma

Summary: Multiple myeloma (MM) affects 15 000 new patients annually in the US, with 50 000 total patients, and remains incurable. Our preliminary in vitro and animal studies suggest a role for MM–host interactions in regulating MM cell growth, drug resistance, and migration in the bone marrow. Importantly, treatment strategies which target mechanisms whereby MM cells grow and survive in the bone marrow, including thalidomide and its potent immunomodulatory derivatives and proteasome inhibitor PS‐341, can overcome classical drug resistance in preclinical and early clinical studies.     

Multipoint linkage analysis of spinocerebellar ataxia and markers on chromosome 6

Heterogeneity among the spinocerebellar ataxias (SCA) has been shown on clinical, biochemical, and genetic criteria. Among the autosomal dominant SCAs, several kindreds have shown loose linkage to the HLA loci on chromosome 6, while linkage in other kindreds has been rejected. The advent of multipoint linkage analysis allows the use of several marker loci simultaneously, thus increasing the amount of usable information. We have reanalyzed linkage data from a large kindred with SCA and provide evidence for a telomeric location of the SCA gene in this family. Knowledge of the relative gene location will ease the identification of the SCA gene by reducing the size of the chromosomal regions that must be examined.     

Repair of severed peripheral nerves: Comparison of the “de Medinaceli” and standard microsuture methods

The return of function following transection of the rat sciatic nerve has been assessed after repair by either standard microsurgical techniques (i.e., the use of microsutures to coapt the severed ends) or the new repair technique introduced by de Medinaceli and coworkers. The regeneration after transection was compared with that following sciatic nerve crush, i.e., a lesion in which the return of function is near optimal. Return of function was monitored serially using walking track analysis (i.e., the sciatic functional index, which indicates overall functional performance), the ability to spread the toes (which indicates intrinsic function in the foot), and the determination of muscle twitch tension of the middle digit. Function in the nerve crush group returned to within the normal range by 53 days, but function in the transection and repair groups did not return to normal before the rats were perfused at 85 postoperative days. However, the function regained when nerves were repaired with the de Medinaceli technique was significantly superior to that regained after repair with microsutures. Histological examination of the repair site (at 85 days) revealed that the regenerated nerve fibers in the de Medinaceli group crossed the site of anastomosis in a relatively orderly fashion, whereas they were more randomly arranged when microsutures were used. However, there was no statistical difference between the two groups in the number of regenerated fibers present in the distal stump. The increase in function in the de Medinaceli group may therefore arise primarily from an increase in the proportion of regenerating fibers which reach appropriate targets.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.