Cochlear ablation in deafness mutant mice: 2-deoxyglucose analysis suggests no spontaneous activity of cochlear origin

Deafness mutant mice show no stimulus-related cochlear potentials as well as abnormal electrically-evoked responses recorded from the inferior colliculus. Abnormal spontaneous activity in the auditory periphery could result in abnormal development and/or maintenance of the central auditory pathways. We therefore assessed spontaneous activity of cochlear origin in the central nuclei of the mutants by ablating one cochlea and subsequently using the 2-deoxyglucose (2DG) technique to study metabolic activity. Any asymmetries in labeling in a given nucleus should be due to spontaneous activity in the cochlear nerve on the unoperated side. In control animals (+/dn mice undergoing unilateral cochlea ablation), statistically significant decreased 2DG labeling was observed in the ipsilateral PVCN and AVCN, and contralateral MNTB and IC; all receive primary excitatory input from the ablated ear. No significant differences in labeling between right and left sides were observed in any of the nuclei studied in the mutant animals. These findings suggest that there is no spontaneous activity of cochlear origin in these mutants, even though many cochlear nerve fibers and spiral ganglion cells survive.     

Haemoglobin A1 and congenital malformation

Two hundred and thirty pregnancies were studied in 196 diabetic women. Seven women with babies found to have major malformations had a higher median first trimester haemoglobin A1 (12.9%) than the median HbA1 (10.8%) in those with normal babies (p = 0.06). No relationship was found between the occurrence of minor malformations and first trimester maternal haemoglobin A1. Two of the seven congenital malformations were diagnosed antenatally at a time when therapeutic abortion could be offered. Expert antenatal ultrasound scanning should be offered to all pregnant diabetic women as poor glycaemic control at the time of conception and organogenesis, as evidenced by raised first trimester HbA1, predisposes to congenital malformation.     

Scoliosis in pediatric spinal cord-injured patients

One hundred thirty children who sustained spinal cord injuries between birth and age 21 years were reviewed to determine the progression rate of paralytic scoliosis and the effects of bracing and surgery. Patients were divided into two groups: those injured before and those injured after the adolescent growth spurt. Scoliosis developed in 97 and 52%, respectively. Bracing was effective in delaying progression in the preadolescent group. The progressive paralytic spinal deformity did not appear to be related to the level of injury. The older patient is at much less risk for paralytic scoliosis, but still requires routine examination.     

Methylxanthines and benign proliferative epithelial disorders of the breast in women

The relationship between methylxanthine intake (caffeine, theobromine and theophylline) and risk of benign proliferative epithelial disorders (BPED) of the breast was examined in a case-control study conducted in Adelaide, South Australia. The study involved 383 cases with biopsy-confirmed BPED, 192 controls whose biopsy did not show epithelial proliferation, and 383 unbiopsied community controls individually matched to cases on age and area of residence. Overall, there was relatively little variation in risk of BPED with total methylxanthine intake, or with intake of caffeine or theophylline, while there was a positive association between theobromine intake and risk of BPED, but only when cases were compared with biopsy controls. Total methylxanthine intake was positively associated with risk of BPED showing severe atypia, but the trend in risk was statistically significant only when community controls formed the comparison group. These data do not provide strong support for an association between methylxanthine intake and risk of BPED.     

HRAS1-selected, chromosome-mediated transformants vary in phenotype in vitro and tumorigenic potential in vivo

Transfection of mouse C127 cells with mitotic chromosomes isolated from a human EJ bladder carcinoma cell line gave rise, at high frequency, to foci of transformed cells. Independent, HRAS1-selected chromosome-mediated transformants displayed distinctive cellular morphologies in monolayer culture and colony-forming abilities in low-melting-point agarose. Subcutaneous inoculation of neonatally thymectomized, Ara-C-protected, total-body-irradiated CBA mice was used to compare the tumorigenic potential of each transformant. Significant quantitative and qualitative differences in tumorigenicity were found between transformants which correlated with differences in malignant phenotype observed in vitro. The sensitivity of the tumorigenicity assay is such that rare transformation events can be selected directly in vivo.     

Dipyridamole is superior to dobutamine for thallium stress imaging: a randomised crossover study.

OBJECTIVE--To assess the value of dobutamine over dipyridamole as a pharmacological stressing agent in myocardial perfusion imaging with thallium-201. DESIGN--Stress and redistribution tomographic images were taken in a group of patients in a randomised crossover study of both agents. The scans were scored to give a value for the stress and redistribution images and a reversibility score (redistribution--stress). All patients had coronary angiography that was also scored. Differences between the two agents were compared by a paired t test. PATIENTS--30 patients aged 51-70 years with chest pain thought to be caused by myocardial ischaemia. 11 had had previously myocardial infarction. RESULTS--Dipyridamole caused adverse symptoms in six patients whereas dobutamine caused symptoms in 21 patients (chi 2 = 15.15, p < 0.0001). Dobutamine stress took considerably longer than dipyridamole (31 v 6 minutes) and cost more (17 pounds v 1.50 pounds). There were no significant differences between the agents in terms of total stress or redistribution scores, but regional analysis showed that dipyridamole showed significantly more defects during stress at the apex and lateral wall (p < 0.05), with no significant difference at redistribution. Dipyridamole stress also caused significantly more reversible defects at the apex (p < 0.05) and gave a better correlation than dobutamine with coronary score (dipyridamole r = 0.80, p < 0.001 v dobutamine r = 0.64, p < 0.001). In six patients who had continued to take beta blockers the results of dobutamine stress did not correlate with coronary score, r = 0.34 (NS), whereas dipyridamole studies were not affected. CONCLUSION--Compared with dobutamine, dipyridamole was as effective in producing overall perfusion defects and more effective in provoking defects at the apex and lateral segment. The dipyridamole study correlated better with coronary score and was not affected by concurrent beta blocker treatment. It was also better tolerated by the patients, was less time consuming, and was much cheaper.     

A comparison of micronucleus frequency and radiation survival in lymphoblastoid cell lines

The relationship between the formation of micronuclei (MN) followingthe treatment of cell lines with ionizing radiation and theradiation survival of cell lines is important as the MN assayhas the potential to predict radiation survival. Studies investigatingthe relationship have reached conflicting conclusions. We examinedthe relationship between MN formation and radiation survivalmeasured by a clonogenic assay in six lymphoblastoid cell linesover a dose range of 0–2.0 Gy. We did not find a predictiverelationship between the radiation induced MN frequency andthe radiation survival in these cell lines. Possible reasonsfor the lack of correlation include variations in the percentageof scorable cells after irradiation and culture with cytochalasinB, different numbers of cells in the G₁ phase of the cell cycleat the time of irradiation, a greater toleration of the lossof MN by hyperdiploid cell lines compared to diploid cell linesand quantitative differences in the conversion of chromosomalfragments into MN for the cell lines.     

Thymic function in HIV infection

Current models hold that CD4+ depletion occurs as a result of direct and indirect effects of HIV, which both kill peripheral CD4+ cells and prevent adequate regeneration. Although age-associated involution diminishes thymic reserve and HIV is clearly thymotoxic, clinical trials have nonetheless shown that large proportions of patients who sustain adequate control of viral replication with highly active antiretroviral therapy (HAART) will demonstrate some evidence for thymic-dependent immune reconstitution, which is associated with improved immune competence. Furthermore, patients with insufficient or absent immune reconstitution following HAART generally lack evidence for thymopoiesis. Current studies are focused on improving our understanding of the causes for thymic failure in HIV infection. Recent work has demonstrated that some HIV strains, especially those that are CXCR4 trophic, are more thymotoxic and may contribute to irreversible thymic damage in this population.     

At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

Gyrate atrophy of the choroid and retina (GA) is an inherited chorioretinal degeneration caused by deficiency of ornithine delta-aminotransferase (OAT; L-ornithine: 2-oxo-acid aminotransferase; EC 2.6.1.13). GA is one of the "Finnish genetic diseases," a group of several rare monogenic disorders that occur with increased frequency in the Finnish population. Using a combination of RNase A protection, genomic cloning, and polymerase chain reaction amplification of genomic DNA, we found one of two missense mutant OAT alleles to be present in each of 16 Finnish GA pedigrees. The first mutation R180T, in which arginine-180 is replaced by threonine, was present in homozygous form in patients from two pedigrees. The second mutation L402P, in which leucine-402 is replaced by proline, was present in homozygous form in patients from 14 pedigrees. Neither mutation was present in 19 Finnish controls. L402P was not present in 18 non-Finnish GA patients but R180T was found in an American GA patient. We constructed full-length mutant cDNAs by amplifying patient cDNA with the polymerase chain reaction and cloning a restriction fragment containing the mutation into an otherwise normal human OAT cDNA. These mutant cDNAs were then expressed in CHO-K1 cells, which lack endogenous OAT. Both R180T and L402P inactivate OAT. These results show molecular heterogeneity in GA alleles even in the Finnish population.