Effects of an endotoxin challenge on growth performance, carcass accretion rates, and serum hormone and metabolite concentrations in control pigs and those treated with recombinant porcine somatotropin

Barrows were restrictively fed starting at 20 kg BW to determine the effects of endotoxin on growth performance of control and somatotropin-treated pigs. The following treatments were used: 1) daily i.m. vehicle injection until 55 kg BW; 2) daily i.m. injections of 100 micrograms of recombinant porcine somatotropin (pST)/kg BW, until 55 kg; 3) i.v. saline injections for 7 d consecutively starting at 60 kg BW; 4) i.v. injections of 1 microgram of bacterial lipopolysaccharide (LPS)/kg BW for 7 d starting at 60 kg BW; and 5) the combined LPS+pST treatment, with pST injections from 20 kg through the 7 d of LPS treatment. Pigs evaluated for LPS effects were fed to 60 kg anticipating a weight loss. Pigs were bled at 0800 and 1100 at 55 kg and on d 7 of LPS treatment. Rectal temperatures were taken on d 7. Treatment with pST increased ADG by 13 to 20% and improved feed:gain by 17 to 23% before LPS treatment. During the 7 d of LPS injections, ADG and feed:gain did not differ, although feed efficiency was impaired and variable. Rectal temperatures at 1100 were progressively increased: control < LPS < LPS-pST (P < .01). Protein accretion was improved 27% by pST treatment, and lipid accretion was decreased 45% before LPS. Lipid stores decreased (P < .01) after LPS treatment in the pST-treated pigs. Lipopolysaccharide treatment and(or) decreased feed intake reduced the hyperinsulinemia and hyperglycemia (P < .01) associated with pST treatment. These results indicate that LPS induced a simulated septicemia and that the effects were not negated by pST treatment. The observed hyperthermia was additive, possibly due to increased lean body mass induced by pST combined with the pyrogenic effect of LPS.     

Definition and refinement of a region of loss of heterozygosity at 11q23.3-q24.3 in epithelial ovarian cancer associated with poor prognosis

Previous cytogenetic and loss of heterozygosity (LOH) data suggest that disruption of chromosome 11q23-qter occurs frequently in epithelial ovarian cancer and is associated with an adverse clinicopathological phenotype. Ten polymorphic microsatellite repeat loci were analyzed by PCR from the 11q22-q25 region between D11S35 and D11S968 in 40 ovarian tumors (including 31 epithelial ovarian cancers). Two distinct regions of loss were detected, suggesting possible sites for genes involved in epithelial ovarian neoplasia: a large centromeric region between D11S35 and D11S933 (11q22-q23.3) and a telomeric 8.5-Mb region lying between D11S934 and D11S1320 (11q23.3-24.3) not previously defined. LOH of the latter region but not the former one was significantly associated with poor survival, despite all tumors in this study having LOH somewhere on chromosome 11. This analysis provides a starting point for positional cloning.     

CYP2D6 allelic frequencies in young-onset Parkinson's disease

Parkinson's disease (PD) is thought to develop as a result of interactions between genetic susceptibility factors and environmental exposures. One candidate gene is CYP2D6, which codes for the debrisoquine 4-hydroxylase cytochrome P450. Impairment of debrisoquine 4-hydroxylase activity has been associated with an increased risk of PD in patients with younger age at disease onset. Genotyping studies in patients with an older age at onset have reported modest increases in risk associated with the CYP2D6 B and A alleles; however, the risk for young-onset PD has not been adequately evaluated. We designed a case-control study to investigate the role of nonfunctional CYP2D6 allelic risk factors for young-onset PD in a sizable patient population and compared the distributions of CYP2D6 genotypes between young-onset ( < or = 51 years) PD patients (n = 108) and controls (n = 236). In contrast with the results from genotyping studies conducted among patients with an older age at onset, there were no significant differences in CYP2D6 allelic frequencies between young-onset PD cases and controls. The frequency of the B allele was slightly lower in the young-onset PD cases than in the controls (0.14 versus 0.20) (X2 = 2.66, p = 0.10). The presence of one or more B alleles was not associated with an increased risk of young-onset PD (odds ratio 0.58; 95% CI 0.33 to 1.00), nor was the presence of one or more nonfunctional alleles (i.e., A, B, D, and D2) (odds ratio 0.68; 95% CI 0.41 to 1.13). This study suggests that the young-onset PD population may differ from the older-onset population with respect to risk factors.     

Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion

The hypothesis that chromosomal fragile sites may be "weak links" that result in hot spots for cancer-specific chromosome rearrangements was supported by the discovery that numerous cancer cell homozygous deletions and a familial translocation map within the FHIT gene, which encompasses the common fragile site, FRA3B. Sequence analysis of 276 kb of the FRA3B/FHIT locus and 22 associated cancer cell deletion endpoints shows that this locus is a frequent target of homologous recombination between long interspersed nuclear element sequences resulting in FHIT gene internal deletions, probably as a result of carcinogen-induced damage at FRA3B fragile sites.     

Postoperative pain relief following laparoscopic tubal sterilization with silastic bands

The value of urine flow cytometry (UFC) in diagnosing acute renal allograft rejection (AR) was recently established in a prospective double-blind study. In this study, we report the 1-year follow-up of three groups of patients identified during the previous study: group 1--stable patients (no ARs) with persistently negative UFCs (n=7); group II--patients who had early ARs (<3 months after transplantation), with positive UFCs that completely normalized with antirejection therapy (n=8); group III--stable patients (no ARs) with positive UFCs (n=7). By definition, group III consists of patients previously considered to have "false positive" UFCs. All patients received standard immunosuppressive therapy, with regimens that included cyclosporine at doses adjusted to maintain target levels. Serum creatinine (SCr) levels (mg/dl) were similar in all three groups at 1 month after transplantation. However, at 1 year after transplantation, SCr was 1.4 +/- 0.2 in group I, 2.0 +/- 0.9 in group II, and 1.9 +/- 0.3 in group III (P=0.004 group I vs. group III). There were no ARs clinically diagnosed during this follow-up period in any of the three groups of patients, but there were significantly higher SCr increments among group III patients after the 1 year of follow-up. The detection of an active urine sediment by flow cytometry in "clinically stable" allograft recipients may indicate ongoing, subclinical acute rejection activity, which in this study was found to be associated with worse renal function at the end of the first posttransplant year as compared with patients with persistently negative UFCs. Increased immunosuppression may be indicated for these patients with persistently positive UFCs.     

A PET study of Turner's syndrome: effects of sex steroids and the X chromosome on brain

Women with Turner's syndrome (TS) allow us to study the neurobiological associates of cognitive and behavioral abnormalities because they lack one/part of one X chromosome, and endogenous estrogen. We studied 13 healthy controls (mean age +/- SD, 28 +/- 6 years) and 16 TS subjects (mean age +/- SD, 26 +/- 6 years). We measured cognitive abilities using neuropsychological tests, and cerebral metabolic rates for glucose with positron emission tomography. Compared to controls, TS subjects had significant absolute hypermetabolism in most brain areas; however, normalized metabolism was significantly lower in TS subjects than controls in the insula and association neocortices bilaterally, and there were significant differences in functional metabolic associations of brain region pairs originating in occipital cortex bilaterally, and within the right hemisphere. There were significant correlations between right-left cognitive and metabolic asymmetries in the TS group. Also, within TS a preliminary analysis demonstrated "X chromosome dosage" effects in language ability and left temporal metabolism, asymmetry of right-left test scores, and parietal metabolism. We hypothesize that within TS: i) generalized brain hypermetabolism reflects global abnormalities in neuron packing; ii) neuronal abnormalities occur in association neocortex that differ in nature or extent from whole brain and are associated with significant differences in normalized metabolism; iii) cognitive deficits are related to brain metabolic abnormalities; and iv) social-behavioral problems may be related to abnormalities of brain metabolism. Moreover, in human brain the X chromosome involved in development of the association neocortices.     

Single-dose interaction study of diprafenone HCl and propranolol HCl in healthy volunteers

Using a 3 x 3 Latin Square design, a possible interaction between diprafenone HCl a class IC antiarrhythmic drug with nonspecific beta-antagonist activity and propranolol HCl was investigated in nine young, healthy, caucasian, male volunteers. The volunteers randomly received 3 single-dose treatments: (A) 200 mg DHCl, (B) 80 mg PHCl, and (C) 200 mg DHCl and 80 mg PHCl. Scheduled blood samples were taken and plasma concentrations of both diprafenone and propranolol were measured by sensitive and specific assay methods. Lead II electrocardiogram intervals at rest, heart rate during erect bicycle ergometry, and echocardiographic variables at rest and shortly after exercise were recorded. The data analysis used compartment model independent methods. There was no evidence for a pharmacokinetic interaction between the two drugs. With DHCl, two of the nine subjects showed greatly increased areas under the plasma concentration-time curves and apparent disposition half-lives in the presence and absence of PHCl, indicating that metabolism of diprafenone may be subject to pharmacogenetic polymorphism. There was evidence for a pharmacodynamic interaction between DHCl and PHCl regarding the negative chronotropic effect at rest and during exercise. There was no difference in the pharmacodynamics and tolerability of the three treatments in suspected "poor" and "extensive metabolizers" of DHCl.     

Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis

The hypothalamo-pituitary-adrenocortical (HPA) axis is the primary modulator of the adrenal glucocorticoid stress response. Activation of this axis occurs by way of a discrete set of neurons in the hypothalamic paraventricular nucleus (PVN). The PVN neuron appears to be affected by multiple sources, including (1) brainstem aminergic/peptidergic afferents; (2) blood-borne information; (3) indirect input from limbic system-associated regions, including the prefrontal cortex, hippocampus, and amygdala; and (4) local-circuit interactions with the preoptic-hypothalamic continuum. Analysis of the literature suggests that different classes of stressor employ different stress circuits. Severe physiologic ("systemic") stress appears to trigger brainstem/circumventricular organ systems that project directly to the paraventricular nucleus. In contrast, stressors requiring interpretation with respect to previous experience ("processive" stressors) reach the PVN by way of multisynaptic limbic pathways. Limbic regions mediating processive stress responses appear to have bisynaptic connections with the PVN, forming intervening connections with preoptic/hypothalamic GABAergic neurons. Stressors of the latter category may thus require interaction with homeostatic information prior to promoting an HPA response. The HPA stress response thus appears to be a product of both the physiologic importance of the stimulus and the specific pathways a given stimulus excites.