In vivo circumvention of human colon carcinoma resistance to bleomycin.

Metabolic inactivation of bleomycin (BLM) by cysteine proteinase-like enzymes is thought to be a major mechanism of BLM tumor resistance. We now report that the human colon carcinoma COLO-205 is highly resistant to BLM and that E-64, a cysteine proteinase inhibitor, sensitizes COLO-205 to BLM. Treatment of COLO-205-bearing nude mice with either E-64 (40 mg/kg) or BLM (10 mg/kg) alone did not inhibit COLO-205 growth. However, pretreatment with E-64 prior to BLM prevented these xenografts from growing. Analysis by high performance liquid chromatography of in vivo BLM metabolism following [3H]BLM A2 treatment of COLO-205-bearing nude mice showed a different metabolic profile among the various organs and the tumor. Whereas [3H]BLM A2 was the only major radioactive peak detected in sera and tumors, several metabolites, including deamido-BLM A2, were found in kidney, liver, and lung as early as 15 min. Pretreatment of mice with E-64 inhibited tumor, kidney, and lung BLM A2 metabolism. Furthermore, pretreatment with E-64 increased BLM A2 accumulation in tumors (6.1-fold), kidney (4.0-fold), lung (2.8-fold), liver (1.8-fold), and serum (1.7-fold). E-64 pretreatment did not enhance the major toxicity of BLM, pulmonary fibrosis, as determined by both lung hydroxyproline levels and histopathology. Thus, the cysteine proteinase inhibitor E-64 affects the metabolic fate and the levels of accumulation of BLM in vivo. These results demonstrate that resistance of human COLO-205 tumors to BLM can be circumvented by E-64 without enhancement of the major side effect of BLM, suggesting a possible clinical use of this combination therapy.     

An investigation of the suitability of bra fit in women referred for reduction mammaplasty.

Reduction mammaplasty is rationed in NHS plastic surgery provision, despite abundant evidence that most women who undergo this operation obtain significant improvement in their physical health and quality of life. We suspected that women seeking reduction mammaplasty often wear ill-fitting bras, which may exacerbate some of their symptoms. Therefore, we studied 103 women who attended a nurse-run pre-assessment clinic, asking them what size bra they currently wore and then measuring them to see whether their bra size was correct. We also questioned bra manufacturers, designers and shop bra fitters about bra manufacture, sizing and fitting techniques, and we reviewed these findings. Of the 102 women suitable for inclusion in the study, all wore the wrong size bra. Their mean 'claimed' back measurement was 36 inches (range: 30-42 in.) and their mean cup size was F (range: C-J). We found that all but one underestimated their back measurement (by a mean of 4 in.; range: -2-10 in.) and overestimated their cup size (by a mean of three sizes; range: one size smaller to seven sizes larger) when compared with manufacturers' fitting guidelines. Multiple regression analysis used to assess the relationships of various factors to incorrect bra sizing showed a strong link (Pearson correlation=0.54; P<0.001) between obesity and inaccurate back measurement. The reasons why women with breast hypertrophy wear incorrectly fitting bras are discussed. We conclude that obesity, breast hypertrophy, fashion and bra-fitting practices combine to make those women who most need supportive bras the least likely to get accurately fitted bras, so exacerbating the symptoms for which they seek surgery.     

Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension

The renin-angiotensin system is involved in control of blood pressure and salt and fluid homeostasis. Genes for components of this system have been of major focus in research on the causation of the common, complex, polygenic trait, essential hypertension (HT). Association of an A→C variant at nucleotide 1166 of the angiotensin II type 1 receptor (AT₁R) gene with HT, but an absence of linkage of this locus with this disease, has been reported recently. Since confirmation in a different setting is imperative, we performed a cross-sectional case-control study of the A1166C variant in a well-characterized group of 108 Caucasian HT subjects with a strong family history (two affected parents) and early onset disease. Genotyping was by mismatch polymerase chain reaction/ Bfr I restriction fragment length polymorphism analysis. Frequency of the C¹¹⁶⁶allele was 0.40 in HTs and 0.29 in normotensives. The difference in genotype (χ²= 13, P = 0.0015) and allele (χ²= 5.3, P = 0.02) frequencies between the two groups was significant (odds ratio for CC vs AA+AC = 7.3 [95% CI, 1.9–31.9). The present results implicate the AT₁R gene, or a locus in linkage disequilibrium with the variant tested, in the causation of essential HT.     

Cerebral Emboli during Cardiac Surgery in Children

Background: Microemboli occur commonly during cardiac surgery in adults, and, when present, increase the risk of neuropsychological deficits. Their incidence and significance during correction of congenital heart disease is unknown. The authors hypothesized that microemboli would occur before bypass with right-to-left cardiac shunts and would also occur in large numbers when the aortic crossclamp was released in children during repair of congenital heart defects.

Methods: In 25 children studied with carotid artery Doppler, embolic signals were counted and timed in relation to 13 intraoperative events. Patients were classified as either at high risk (obligate right-to-left shunt or uncorrected transposition of the great arteries) or at low risk (net left-to-right shunt or simple obstructive lesions) for paradoxical (venous to arterial) emboli.

Results: The median number of emboli detected was 122 (range, 2-2,664). Forty-two percent of all emboli were detected within 3 min of release of the aortic crossclamp. The high-risk group had significantly more emboli (median, 66; range, 0-116) during the time interval before cardiopulmonary bypass than did the low-risk group (median, 8; range, 0-73), with P < 0.01. There was no significant difference between the high-and low-risk groups in the total number of emboli detected. There was no apparent association between number of emboli and gross neurologic deficits.     

Reduced stimulation of helper T cells by Ki-ras transformed cells.

A number of viral genes and cellular oncogenes inhibit major histocompatibility complex (MHC) antigen expression at the cell surface. In the case of inhibition of class I MHC antigens by viral genes this results in a reduced recognition by antigen-specific cytotoxic T cells. The activated Ki-ras cellular oncogene carried by the Ki-murine sarcoma virus (Ki-MuSV) in contrast inhibits class II MHC (or Ia) antigen expression on transformed cells. We have studied how transformation with Ki-ras affects recognition by alloreactive helper T cells. We found that the Ki-ras inhibition of class II MHC antigen expression led to greatly reduced stimulation of alloreactive T cells to proliferate and to secrete interferon-gamma (IFN-gamma). These findings support our hypothesis that the ability of an oncogene to reduce class II MHC antigen expression is crucial to its ability to produce tumour cells.     

Parallel angioplasty dilatation catheter and guide wire: A new technique for the dilatation of calcified coronary arteries

Percutaneous transluminal coronary angioplasty (PTCA) of heavily calcified rigid coronary arteries has decreased success and increased complication rates. Three cases are presented describing a new technique for the dilatation of severely calcified coronary arteries that were not dilatable by conventional angioplasty methods. This technique involves the use of a balloon dilatation catheter system parallel to a guide wire. © 1993 Wiley-Liss, Inc.     

Alcohol and the adolescent trauma population

Trauma is the leading killer of children and adolescents between 1 and 21 years of age. Alcohol-impaired driving represents the single greatest cause of mortality and morbidity of children over the age of 6. We retrospectively reviewed 878 consecutive adolescent (age range, 16 to 20 years) trauma admissions for blood alcohol concentration (BAC). Four hundred sixty-seven patients had BAC drawn, 258 were BAC-negative (group I), 209 (48%) were BAC-positive (group II). The adolescent drinkers were then compared with a group of 748 adult drinkers (group III). Groups I and II differ in sex, age, time of day of the accident, Injury Severity Score, Glasgow Coma Score, and Revised Trauma Score, whereas group II and III differ by type of accident, type of injury, socioeconomic factors (bad debt), time of day of the injury, and BAC. There were no significant differences in TRISS predicted survival, actual survival, nor mean length of stay. We conclude that (1) alcohol is a significant contributor to injury during adolescence, and (2) adolescent drinkers differ from adult drinkers in their habits, demographics, and socioeconomic status. These socioeconomic differences have implications for the access to and cost-effectiveness of interventions.     

Eight Days of Cyclosporine Overdose: A Case Report

A 25–year-old woman was admitted to the hospital because of rising trough cyclosporine concentrations thought to be due to self-administration of 4 times the normal dosage of the drug for 8 days. Her symptoms included colicky central abdominal pains and urinary retention; her serum creatinine concentrations were elevated. Whole blood cyclosporine and metabolite concentrations were measured by high-performance liquid chromatography and monoclonal radioimmunoassays. The highest reported trough cyclosporine concentration was 5877 ng/ml, and AM1 (M17) concentration was 3425 ng/ml. A cyclosporine half-life of 91 hours was calculated. Nine days after the agent was discontinued the patient's serum creatinine concentration had returned to normal and her symptoms resolved. Due to the availability of three sizes of cyclosporine capsules, and the need for frequent dosage changes, continued vigilance is necessary to ensure that patients understand their drug regimen.