The effect of hypoxia on acquired drug resistance and response to epidermal growth factor in chinese hamster lung fibroblasts and human breast-cancer cells in vitro

Prolonged hypoxia induced transient drug resistance in Chinese hamster lung fibroblasts. Previously hypoxic cells were resistant to adriamycin and resistant to etoposide. Complete recovery of etoposide sensitivity was observed following re-aeration for 24 hr. A change in P-glycoprotein expression was unlikely to contribute to the resistance caused by hypoxia, since adriamycin resistance was not reversed by verapamil. However, alteration in the plasma membrane structure may be involved, since previously hypoxic cells were resistant to extracellular superoxide radical generated by the addition of xanthine/ xanthine oxidase. In contrast, adriamycin sensitivity was not altered by hypoxia in 3 human breast-cancer cell lines. MDA-468 and MCF-7/Adr differed in their response to EGF, independent of the presence of hypoxia. These results suggest that hypoxic-stress-induced drug resistance is not generalized.     

Neonatal exposure to estradiol prevents the expression of ovarian hormone-induced luteinizing hormone and prolactin surges in adulthood but not antecedent changes in neuropeptide Y or adrenergic transmitter activity: Implications for sexual differentiation of gonadotropin secretion

Sex differences in adult patterns of mating behavior and gonadotropin secretion in rats are determined in part by the presence or absence of gonadal steroids during a perinatal critical period. For example, male rats and female rats exposed neonatally to androgen do not exhibit LH surge patterns when treated appropriately with ovarian hormones in adulthood, and there is evidence that this may be due to a failure of ovarian hormones to activate the hypothalamic neuronal systems that stimulate LH secretion in such animals. Because considerable evidence suggests that estradiol formed centrally from testosterone is responsible for the permanent defeminization of mating behavior and gonadotropin secretion, the present studies compared normal females with normal males and with females treated neonatally with estradiol on the ability of ovarian hormones to induce several important neurochemical changes antecedent to the LH surge, including changes in neuropeptide Y (NPY) and LH-releasing hormone (LHRH) concentrations in the median eminence, as well as changes in turnover rates for catecholamine transmitters in the medial basal hypothalamus and medial preoptic area. Normal ovariectomized female rats responded to sequential treatment with estradiol followed by progesterone with afternoon LH and prolactin (PRL) surges, and with sequential accumulation followed by decline in concentrations of LHRH and NPY in the median eminence prior to the LH surge. In addition, administration of progesterone increased the turnover rates of norepinephrine (NE) and epinephrine (EPI) in the arcuate-median eminence region of normal females. Gonadectomized male rats receiving the same ovarian hormone treatment failed to exhibit LH or PRL surges and displayed none of the changes in neurotransmitter turnover or peptide concentrations characteristically seen in the normal female. Unexpectedly however, when females that were treated with estradiol benzoate on days 1–3 postpartum were ovariectomized and treated with ovarian hormones in adulthood, they showed the same accumulation/decline in median eminence NPY concentrations and the same activation of NE and EPI turnover in the arcuate-median eminence region as normal females, even though they showed no LH or PRL surges or changes in median eminence LHRH concentrations. These results suggest that estradiol may not mediate all of the defeminizing actions of androgen exerted during the early neonatal period, and particularly those actions that result in a lack of responsiveness in central noradrenergic, adrenergic and NPY systems in adulthood. However, an action of neonatal estradiol may result in uncoupling of the LHRH neurosecretory system from normal excitatory neurochemical influences.     

Indomethacin and cognitive function in healthy elderly volunteers.

1. The aim of this randomised, double-blind four way crossover study was to assess the interaction between the new calcium antagonist, lacidipine and atenolol, in patients with mild to moderate hypertension. 2. Sitting blood pressure at 4 h post-dosing with lacidipine (4 mg) and atenolol (100 mg) alone was significantly lower compared with placebo (137/89 +/- 3/3 mmHg; 142/89 +/- 5/3 mmHg; and 154/98 +/- 5/3 mmHg respectively; P < 0.001). Co-administration of both drugs produced a significant additive effect compared with atenolol and lacidipine alone (124/80 +/- 4/2 mmHg; P < 0.002). 3. Heart rate on treatment with lacidipine alone was significantly greater at 4 h compared with placebo (86 +/- 1 beats min-1 and 74 +/- 2 beats min-1 respectively; P < 0.001). When both drugs were used in combination, there was a significant decrease in pulse rate compared with lacidipine alone (58 +/- 1 beats min-1 and 86 +/- 1 beats min-1 respectively; P < 0.001). 4. Home blood pressure recordings confirmed the statistically significant reduction in blood pressure on co-dosing (120/82 +/- 10/2 mmHg) compared with lacidipine (140/92 +/- 5/3 mmHg) and atenolol (146/90 +/- 6/3 mmHg) given alone (P < 0.05). 5. Lacidipine alone produced a significant exercise tachycardia compared with atenolol alone and the atenolol/lacidipine combination (97 +/- 8 beats min-1; 65 +/- 4 beats min-1 and 75 +/- 7 beats min-1 respectively; P < 0.001). Exercise tolerance was not adversely affected by the co-administration of both lacidipine and atenolol.     

Antifungal potential of disulfiram.

Disulfiram, an alcohol antagonistic drug has been on the market since 1949 with 80% bioavailability and an established safety profile. Recently it has been reported as a P-glycoprotein efflux pump modulator. Herein we report its antifungal potential. The MIC50 and MIC90 of disulfiram for yeast isolates is 4 and 8 microg/ml, respectively, and the MIC range is 1-16 micro g/ml for both fluconazole sensitive and resistant strains. Interestingly, disulfiram also showed fungicidal activity on Aspergillus spp. with MIC50 and MIC90 of 2 and 8 microg/ml, respectively.     

Other genomic disorders and congenital heart disease

Congenital heart disease (CHD) is the common birth defect worldwide. Despite its recognized burden on public health, the etiology in the vast majority of individuals remains unknown. Chromosomal abnormality plays an important role, frequently observed as large cytogenetically visible rearrangement or small submicroscopic structural variation in the genome. Several genomic disorders are now recognized that are increasingly responsible for CHD with variable penetrance. Single gene disorders, epigenetic alterations, and environmental etiologies are also significant contributors. Our understanding of the genetic basis of CHD has increased exponentially with the escalating use of next generation sequencing to identify ever so small submicroscopic genomic imbalances at the level of coding exons in CHD. This review focuses on genomic disorders other than 22q11.2 deletion, that are major players in the etiology of human cardiac malformations.     

Asthma as a risk factor for respiratory complications after adenotonsillectomy in children with obstructive breathing during sleep.

BACKGROUND: Children with asthma are at increased risk for obstructive breathing during sleep. Adenotonsillectomy, the treatment of choice for obstructive breathing during sleep, is associated with significant postoperative respiratory morbidity. OBJECTIVE: To determine whether asthma is a risk factor for respiratory complications after adenotonsillectomy in children with obstructive breathing during sleep. METHODS: This case-control study compared 115 children aged 3 to 18 years with respiratory complications after adenotonsillectomy (study group) with 115 children without respiratory complications after adenotonsillectomy (control group). RESULTS: The postoperative respiratory complications ranged from oxygen desaturation to respiratory failure that required mechanical ventilation. The study group had a higher proportion of children with asthma (P < .01). Logistic regression analysis showed that asthma increases the odds of postoperative respiratory complications to 4.4 (95% confidence interval, 2.13-9.0), after controlling for age, weight greater than the 97th percentile for age, sex, race, and medical conditions other than asthma. CONCLUSIONS: In children with obstructive breathing during sleep, the presence of asthma is associated with an increased risk of respiratory complications after adenotonsillectomy.