Risk factors in psychosis secondary to traumatic brain injury

Psychosis is a rare but devastating sequela of traumatic brain injury (TBI). This study examined risk factors for developing a psychosis secondary to TBI (PSTBI). Demographics of 25 inpatients with PSTBI were statistically analyzed for risk factors. Data from the PSTBI group were also compared with data from a control group of TBI patients without psychosis. Results indicate the PSTBI group was more likely to have had a previous congenital neurological disorder or to have sustained a head injury prior to adolescence. The PSTBI also had a higher proportion of males. Discussion focuses on potential models for developing PSTBI.     

IB-367, a protegrin peptide with in vitro and in vivo activities against the microflora associated with oral mucositis

Although the microflora associated with oral mucositis initiated by cytotoxic therapy is not well characterized, several studies suggest that reduction of the microbial load in the oral cavity has some clinical benefit. The MICs of IB-367, a synthetic protegrin analog, ranged from 0.13 to 64 microgram/ml for gram-positive bacteria (Streptococcus mitis, Streptococcus sanguis, Streptococcus salivarius, and Staphylococcus aureus) and from 0.06 to 8 microgram/ml for gram-negative species (Klebsiella, Escherichia, and Pseudomonas). IB-367 exhibited rapid, microbicidal activity against both log- and stationary-phase cultures of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. At concentrations near the MICs for these two organisms (4 and 2 microgram/ml, respectively), IB-367 reduced viability by more than 3 logs in less than 16 min. Similarly, IB-367 effected a 4-log reduction of the endogenous microflora in pooled human saliva within 2 min at 250 microgram/ml, a concentration readily attained by local delivery. After nine serial transfers at 0.5x the MIC, the MIC of IB-367 for MRSA and P. aeruginosa increased only two to four times. In a phase I clinical study with healthy volunteers, IB-367 was well tolerated, with no detectable systemic absorption. One hour after treatment with 9 mg of IB-367, the prevalence of gram-negative bacteria and yeast was reduced, and the density of the predominant gram-positive oral flora was decreased 1,000 times. IB-367's properties (speed of killing, breadth of spectrum, and lack of resistance) make the compound a strong candidate for the prophylaxis of oral mucositis. Phase II clinical trials with IB-367 are under way for this indication in immunocompromised subjects.     

Cyclin D1 amplification correlates with early recurrence of squamous cell carcinoma of the tongue

Amplification of CCND1 was studied in 23 tongue carcinoma patients by fluorescence in situ hybridization (FISH) using a paraffin embedded specimen. All the patients received complete resection of the primary site with or without neck dissection. CCND1 amplification was positive in 13 (56.5%) out of 23 cases. Correlations between CCND1 amplification and histological grading, T category, N category, and Stages were not significant. The 5-year disease-free survival rate, which was 23.1% for CCND1 amplification positive patients and 80.0% for negative patients, was significantly better for the CCND1 amplification negative patients (P=0.0070). Nine patients were examined by dual-color FISH with the probe for centromere of chromosome 11 and 11q13. In five patients, who had positive amplification for CCND1, cell numbers with a larger number of signals for 11q13 than the centromere of chromosome 11 were significantly higher than those of CCND1 amplification negative patients (P=0.013). This indicates that amplification of 11q13 occurs more frequently than aberration of chromosome 11 in CCND1 amplification positive patients. From these results, the amplification of CCND1 is a key factor in predicting the aggressiveness of tongue cancer. Furthermore, FISH proved to be a useful method for such evaluation.     

Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers

Our previous studies showed that mitotic checkpoint impairment is present in about 40% of human lung cancer cell lines but that mutations in the MAD mitotic checkpoint genes are infrequent. In the present study, we examined 44 lung cancer cases for the potential involvement of the other gene family involved in the mitotic checkpoint, i.e. BUB. We found that the BUB gene family members including BUB1, BUBR1 and BUB3 are not frequent targets for mitotic checkpoint defects in lung cancers, if present at all. Further studies are thus warranted to elucidate the molecular basis for the acquisition of mitotic checkpoint defects in order to better understand the molecular pathogenesis of lung cancers.     

Detection of an Amadori product, 1-hexitol-lysine, in the anterior horn of the amyotrophic lateral sclerosis and spinobulbar muscular atrophy spinal cord: evidence for early involvement of glycation in motoneuron diseases

Glycation is a series of non-enzymatic reactions initiated by addition of reducing sugars to ɛ-amino group of lysine residues and α-amino group of the N terminus of proteins, leading to the formation of advanced glycation end products (AGE). It is thought to be involved in aging and various neurodegenerative conditions. In the present study using anti-1-hexitol-lysine (1-HL) antibody, Amadori product, an early glycation product, was detected in axonal spheroids in the anterior horn of amyotrophic lateral sclerosis and in atrophic neurons of spinobulbar muscular atrophy (SBMA, Kennedy disease with abnormally expanded triplet repeats in androgen receptor gene) but not in other regions of the central nervous system. Furthermore, Amadori product was undetectable in the tissues from age-matched controls. Thus, 1-HL formation could not reflect physiological aging. Received: 13 October 1998 / Revised: 31 March 1999     

Relationship between ALDH2 genotypes and choice of alcoholic beverages]

There are obviously individual differences in the choice for many kinds of alcoholic beverages such as beer, wine, whisky, sake, cocktail and so on. It is generally believed that these differences are related to acquired preferences in taste and smell, in addition to life style. However, the basis of these acquired preferences is not yet understood. It has been shown that around half of Japanese show a marked sensitivity to alcoholic beverages because of aversive reactions due to a catalytic deficiency in ALDH2 isozyme. Therefore, differences in ALDH2 genotypes may possibly influence the choice of alcoholic beverages because the individuals possessing the ALDH2*2 gene may prefer the alcoholic beverages containing lower concentrations of alcohol. A large population survey (320 males, 132 females) was conducted using questionnaires to investigate the relationship between ALDH2 genotypes and the choice of alcoholic beverages. Individuals with the homozygote of ALDH2*1 generally showed more preference for alcoholic beverages containing a higher concentration of alcohol than those with the heterozygote or the homozygote of ALDH2*2. It was noted that the latter groups preferred whisky and water, and sweet cocktails. Also, the choices for beer, whisky, and sake were significantly different between both genders. Our data suggested that individuals with ALDH2*2 prefer beverages with lower concentrations of alcohol due to an aversive reaction after drinking, and that there are obvious gender differences in the consumption as well as the choice for many alcoholic beverages.     

Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype.

We examined chromosomes and molecular aberrations in 21 patients with therapy-related leukemias (t-AML) or myelodysplastic syndromes (t-MDS). All patients showed abnormal karyotypes, and chromosomal losses of No. 5 and/or No. 7 (-5/5q- and/or -7/7q-) were identified in 12 patients. Among these 12, six patients (50%) harbored a TP53 mutation, and two of five examined showed microsatellite instability, suggesting replication error (RER+) phenotype. Meanwhile, among the other nine patients without -5/5q- and/or -7/7q-, none harbored a TP53 mutation, and none of five examined showed RER+ phenotype. Thus, TP53 mutations and RER+ phenotype were preferentially associated with specific chromosomal losses in t-AML/MDS. We then screened for mutational events in representative DNA mismatch repair genes; exons 5-7 and 12-15 of the hMSH2 gene and exon 9 of hMLH1. Notably, two unrelated patients showing RER+ phenotype had an identical missense alteration at codon 419 of hMSH2 in their marrow cells and fibroblasts, which were not found in 120 DNA samples from healthy volunteers or patients with other hematological disorders. Consequently, this study revealed a possible relationship of RER+ phenotype accompanying an hMSH2 alteration to the development of therapy-related AML/MDS in association with TP53 mutations and specific chromosomal losses, and suggests that some patients may be predisposed to myelodysplasia after chemotherapy for their primary tumor.     

Gamma-irradiation deregulates cell cycle control and apoptosis in nevoid basal cell carcinoma syndrome-derived cells.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by nevi, palmar and plantar pits, falx calcification, vertebrate anomalies and basal cell carcinomas. It is well known in NBCCS that gamma-irradiation to the skin induces basal cell carcinomas or causes an enlargement of the tumor size, although the details of the mechanism remain unknown. We have established lymphoblastoid cell lines from three NBCCS patients, and we present here the first evidence of abnormal cell cycle and apoptosis regulations. A novel mutation (single nucleotide deletion) in the coding region of the human patched gene, PTCH, was identified in two sibling patients, but no apparent abnormalities were detected in the gene of the remaining patient. Nevertheless, the three established cell lines showed similar features in the following analyses. Flow cytometric analyses revealed that the NBCCS-derived cells were accumulated in the G2M phase after gamma-irradiation, whereas normal cells showed cell cycle arrest both in the G0G1 and G2M phases. The fraction of apoptotic cells after gamma-irradiation was smaller in the NBCCS cells. The level of p27 expression markedly decreased after gamma-irradiation in the NBCCS cells, although the effects of the irradiation on the expression profiles for p53, p21 and Rb did not differ in normal and NBCCS cells. These findings may provide a clue to the molecular mechanisms of tumorigenesis in NBCCS.     

Effect of clarithromycin and other macrolides on the sulfoxidation and 5-hydroxylation of lansoprazole in dogs.

The purpose of this study was to evaluate a possible interaction between lansoprazole and clarithromycin as well as other macrolides in dogs. Lansoprazole (30 mg) was orally administered to male beagle dogs, with or without oral pretreatment with 200-mg clarithromycin twice a day for 5 d. The experiments had a randomized cross-over design with a two-week washout period between dosing regimens. Clarithromycin pretreatment for 5 d resulted in a significant increase in the area under the serum lansoprazole concentration-time curve (AUC), whereas the area for a lansoprazole metabolite, lansoprazole sulfone, was significantly reduced, as was the maximum serum concentration (Cmax) of lansoprazole sulfone. When the effects of clarithromycin on the metabolism of lansoprazole were studied using dog liver microsomes, it was found that clarithromycin significantly inhibited the formation of lansoprazole sulfone but not another metabolite, 5-hydroxylansoprazole. These results suggest that co-medication of lansoprazole with clarithromycin may produce a synergistic effect caused by the increased serum levels of lansoprazole of benefit in Helicobacter pylori eradication.     

Long-term follow-up results of a Pilot Phase II study of multidrug chemotherapy (MVP-CAB) in patients with advanced urothelial cancer.

BACKGROUND: To determine the long-term effects and toxicity of multidrug chemotherapy for advanced urothelial cancer. METHODS: Forty patients with metastatic urothelial cancer were treated with a new combination chemotherapy, MVP-CAB (methotrexate, doxorubicin, vincristine, cyclophosphamide, bleomycin and cisplatin every 28 days). Of the 40 patients, 26 had not undergone prior chemotherapy or radiotherapy; the remaining 14 patients had undergone prior cisplatin-based chemotherapy. RESULTS: The clinical response rate to MVP-CAB therapy for all 40 patients was 63% [complete response (CR), six patients; partial response (PR), 19 patients]. The median duration of the effects was 22 and 13 months in the patients with CR and PR, respectively. The clinical response rate for the 26 patients without prior chemotherapy was 77% (CR, four patients; PR, 16 patients). The rate for the 14 patients with prior chemotherapy was 36% (CR, two patients; PR, three patients). The response rate according to metastatic site was highest for the liver (80%), followed by the lymph nodes (74%) and lungs (67%). The effect on bone metastasis was poor (22%). There was good compliance with the MVP-CAB chemotherapy regimen and toxicity was tolerable. The 1-, 3- and 5-year overall survival rates were 42.5, 10 and 5%, respectively. CONCLUSIONS: MVP-CAB combination chemotherapy was found to be effective for the treatment of advanced urothelial cancer, especially for liver metastasis.