A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.     

Immunogenetic markers in patients with Graves' disease

Summary 110 carefully characterized Caucasoid patients with Graves' disease were tested for HLA class I and class II antigens. Compared with Caucasian controls (n=193), the frequencies of HLA B8, Cw7 and DR3 were significantly increased (p_c<0.05). In the subgroups with and without exophthalmos, HLA A3 exhibited a negative but insignificant association with the eye involvement, while A19 and Cw2 showed positive, however even weaker correlations with eye disease. HLA DR5 was associated with relapsing thyrotoxicosis, whereas HLA DR7 and B12 were negatively correlated with relapse. These results confirm the positive correlation of HLA B8 and DR3 with Graves' disease and reveal a not yet observed association with Cw7. Reported correlations of antigen frequencies with eye disease and relapsing thyrotoxicosis could not be confirmed. Other previously unknown, however subtle differences in disease subgroups were observed.Abbreviations EF etiologic fraction - HLA Human leukocyte antigens - RR relative risk - TRAb TSH receptor antibodies - TSH Thyroid stimulating hormone     

Huntingtin interacts with cystathionine beta-synthase

We have screened a rat brain library to identify proteins which interact with the 5'-end of huntingtin (amino acids 1-171), including the polyglutamine tract, in the yeast two-hybrid system. We detected an interaction with cystathionine beta-synthase (CBS) [L-serine hydrolyase (adding homocysteine), EC 4.2.1.22], which was confirmed in vitro using His-tagged CBS expressed in Escherichia coli , which was able to specifically bind both rat and human full-length huntingtin. Neither normal nor expanded polyglutamine repeat alone interacted with CBS in the yeast two-hybrid system and nor did constructs containing SBMA or DRPLA with normal or expanded polyglutamine tracts. CBS therefore appears to bind specifically to huntingtin. CBS deficiency is associated with homocystinuria, which is known to affect various physiological systems, including the central nervous system. Homocysteine, one of the substrates of CBS, is known to accumulate in homocystinuria and is metabolized to homocysteate and homocysteine sulphinate, both known to be powerful excitotoxic amino acids. It has been suggested that Huntington's disease involves the action of excitotoxic amino acids and this interaction with CBS may suggest a mechanism for such excitotoxic damage.      

Severe malformations in males from families with osteopathia striata with cranial sclerosis

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by longitudinal striations of the long bones and sclerosis of the craniofacial bones. Affected patients show macrocephaly, ocular hypertelorism, frontal bossing, broad nasal bridge and abnormalities of the palate. Anomalies such as hearing loss, congenital heart defect, vertebral anomalies and mental impairment have also been reported. Pedigree analysis has suggested an autosomal dominant inheritance, but a recent report of a family with significantly more affected males than females suggested the possibility of X-linked inheritance. Here we describe a new family with OS-CS (the twelfth in the literature) with four affected individuals (two males and two females) spanning three generations. The affected male in the third generation was stillborn with multiple congenital anomalies, whereas the other three affected individuals had mild features. This family may represent another example of X-linked OS-CS where the mutated gene(s) is more severe in males.     

PATTERN OF SKIN DISEASES IN ARMED FORCES IN PUNE REGION

A total of 8123 Armed Forces personnel attended dermatological OPD from Jan 1989 to Dec 1994. On analysing the record it is found that 2953 (36.3%) cases had infective dermatosis and 5170 (63.7%) cases had non-infective dermatosis. Common infective dermatosis included fungal infections (17.2%), viral infections (7.7%), bacterial infections (3.6%) and arthropode infestations (7.8%). Common non-infective dermatosis included papulosquamous disorders (13.5%), pigmentary disorders (13.4%), eczemas (11.1%), acne (8.7%), alopecia (6.1%), urticaria (4.2%) and drug eruptions (1.9%).KEYWORDS: Armed Forces personnel, Infective dermatosis, Non-infective dermatosis     

Validation and regulatory acceptance of new carcinogenicity tests

The 3 Rs concept, which was developed by Russell and Burch in 1959, was implemented into the legal framework in the European Union(EU) for the protection of vertebrate animals used for experimental and other scientific purposes, when Directive 86/609/EEC was adopted in 1986. To reduce or replace animal testing for regulatory purposes, nonanimal tests must be independently validated to prove that they can provide information that is relevant and reliable for hazard prediction in vivo. At the end of the 1980s, no scientific concept existed for the formal validation ofin vitro toxicity tests, so a small group of European and American scientists developed a set of principles for experimental validation, which was accepted internationally by the OECD in 1996. A major breakthrough was the acceptance in the EU of the scientifically validated in vitro toxicity test for phototoxic potential in 2000, which was accepted by the OECD at the worldwide level in 2002. Taking the progress in the development and validation of alternative toxicity tests during the past decade into account, the current concepts of developing alternatives to the standard 2-year rodent bioassay for carcinogenicity testing are discussed.