Implication of the visual system in the regulation of activity cycles in the absence of solar light: 2-[I-125]iodomelatonin binding sites and melatonin receptor gene expression in the brains of demersal deep-sea gadiform fish

Relative eye size, gross brain morphology and central localization of 2-[I-125]iodomelatonin binding sites and melatonin receptor gene expression were compared in six gadiform fish living at different depths in the north-east Atlantic Ocean: Phycis blennoides (capture depth range 265-1260 m), Nezumia aequalis (445-1512 m), Coryphaenoides rupestris (706-1932 m), Trachyrincus murrayi (1010-1884 m), Coryphaenoides guentheri (1030 m) and Coryphaenoides (Nematonurus) armatus (2172-4787 m). Amongst these, the eye size range was 0.15-0.35 of head length with a value of 0.19 for C.(N.) armatus, the deepest species. Brain morphology reflected behavioural differences with well-developed olfactory regions in P.blennoides, T.murrayi and C. (N.) armatus and evidence of olfactory deficit in N. aequalis, C. rupestris and C. guentheri. All species had a clearly defined optic tectum with 2-[I-125] iodomelatonin binding and melatonin receptor gene expression localized to specific brain regions in a similar pattern to that found in shallow-water fish. Melatonin receptors were found throughout the visual structures of the brains of all species. Despite living beyond the depth of penetration of solar light these fish have retained central features associated with the coupling of cycles of growth, behaviour and reproduction to the diel light-dark cycle. How this functions in the deep sea remains enigmatic.

Mutant GABA(A) receptor gamma 2-subunit in childhood absence epilepsy and febrile seizures

Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants(1,2). We have found a mutation in a gene encoding a GABA, receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS), There is a recognized genetic: relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the gamma2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

Childhood absence epilepsy and febrile seizures: A family with a GABAA receptor mutation

Although several genes for idiopathic epilepsies from families with simple Mendelian inheritance have been found, genes for the common idiopathic generalized epilepsies, where inheritance is complex, presently are elusive. We studied a large family with epilepsy where the two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS), which offered a special opportunity to identify epilepsy genes. A total of 35 family members had seizures over four generations. The phenotypes comprised typical CAE (eight individuals); FS alone (15), febrile seizures plus (FS+) (three); myoclonic astatic epilepsy (two); generalized epilepsy with tonic-clonic seizures alone (one); partial epilepsy (one); and unclassified epilepsy despite evaluation (two). In three remaining individuals, no information was available. FS were inherited in an autosomal dominant fashion with 75% penetrance. The inheritance of CAE in this family was not simple Mendelian, but suggestive of complex inheritance with the involvement of at least two genes. A GABA(A) receptor gamma2 subunit gene mutation on chromosome 5 segregated with FS, FS+ and CAE, and also occurred in individuals with the other phenotypes. The clinical and molecular data suggest that the GABA(A) receptor subunit mutation alone can account for the FS phenotype. An interaction of this gene with another gene or genes is required for the CAE phenotype in this family. Linkage analysis for a putative second gene contributing to the CAE phenotype suggested possible loci on chromosomes 10, 13, 14 and 15. Examination of these loci in other absence pedigrees is warranted.

Does affective learning exist in the absence of contingency awareness?

The proposal that affective learning, the learning of likes and dislikes, can exist in the absence of contingency awareness, whereas signal learning, the learning of stimulus relationships, cannot, was investigated in a differential conditioning paradigm that was embedded in a visual masking task. Startle magnitude modulation and changes in verbal ratings served as measures of affective learning, whereas skin conductance was taken to reflect signal learning. Awareness was assessed online with an expectancy dial and in a postexperimental questionnaire. Both between-subject comparisons of verbalizers and nonverbalizers and within-subject comparisons of verbalizers before and after verbalization failed to reveal any evidence for learning, whether affective or otherwise, in the absence of knowledge of the stimulus contingencies. (C) 2001 Academic Press.

Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load

Primary infection with the human herpesvirus, Epstein-Barr virus (EBV), may result in subclinical seroconversion or may appear as infectious mononucleosis (IM), a lymphoproliferative disease of variable severity. Why primary infection manifests differently between patients is unknown, and, given the difficulties in identifying donors undergoing silent seroconversion, little information has been reported. However, a longstanding assumption has been held that IM represents an exaggerated form of the virologic and immunologic events of asymptomatic infection. T-cell receptor (TCR) repertoires of a unique cohort of subclinically infected patients undergoing silent infection were studied, and the results highlight a fundamental difference between the 2 forms of infection. In contrast to the massive T-cell expansions mobilized during the acute symptomatic phase of IM, asymptomatic donors largely maintain homeostatic T-cell control and peripheral blood repertoire diversity. This disparity cannot simply be linked to severity or spread of the infection because high levels of EBV DNA were found in the blood from both types of acute infection. The results suggest that large expansions of T cells within the blood during IM may not always be associated with the control of primary EBV infection and that they may represent an overreaction that exacerbates disease. (C) 2001 by The American Society of Hematology.

Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol

Aims Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect charges in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers. to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption. Methods Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (Mean +/- s.d.) was calculated as the ratio of the amount excreted in urine and thearea-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported. Results The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/-3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F). Conclusions This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes call be used to simultaneously investigate pathways of renal drug elimination.

Genetic monogamy in the absence of paternity guards: the Capricorn silvereye, Zosterops lateralis chlorocephalus, on Heron Island

We investigated the genetic mating system of a socially monogamous passerine bird, the Capricorn silvereye Zosterops lateralis chlorocephalus, on an island of the Great Barrier Reef. There were no cases of extrapair paternity (EPP) among 122 offspring from 53 broods detectable by minisatellite or microsatellite DNA fingerprinting. Behavioral observations of paired birds showed that this was not a consequence of efficacious paternity guards and that females did not engage in extrapair copulation (EPC). Frequency of intrapair copulations was also low, with only 14 cases observed during 199 hours of observations of the 11 focal pairs in the fertile periods of females, and this was consistent with anatomical features of the cloacal protuberance in males. In this population, young birds form life-time pair bonds soon after gaining independence but females are obviously not attempting EPC possibly to redress this early mate choice. This is despite the fact that they breed in high density with a synchronous start and asynchronous spread of laying in a protracted season and males do not positively exhibit mate guarding behavior when females are fertile. Our results support high fidelity of socially monogamous birds on islands and are consistent with the hypothesis that sexual selection is reduced where genetic variation in fitness is limited.

Zygosity Diagnosis in the Absence of Genotypic Data: An Approach Using Latent Class Analysis

For zygosity diagnosis in the absence of genotypic data, or in the recruitment phase of a twin study where only single twins from same-sex pairs are being screened, or to provide a test for sample duplication leading to the false identification of a dizygotic pair as monozygotic, the appropriate analysis of respondents' answers to questions about zygosity is critical. Using data from a young adult Australian twin cohort (N = 2094 complete pairs and 519 singleton twins from same-sex pairs with complete responses to all zygosity items), we show that application of latent class analysis (LCA), fitting a 2-class model, yields results that show good concordance with traditional methods of zygosity diagnosis, but with certain important advantages. These include the ability, in many cases, to assign zygosity with specified probability on the basis of responses of a single informant (advantageous when one zygosity type is being oversampled); and the ability to quantify the probability of misassignment of zygosity, allowing prioritization of cases for genotyping as well as identification of cases of probable laboratory error. Out of 242 twins (from 121 like-sex pairs) where genotypic data were available for zygosity confirmation, only a single case was identified of incorrect zygosity assignment by the latent class algorithm. Zygosity assignment for that single case was identified by the LCA as uncertain (probability of being a monozygotic twin only 76%), and the co-twin's responses clearly identified the pair as dizygotic (probability of being dizygotic 100%). In the absence of genotypic data, or as a safeguard against sample duplication, application of LCA for zygosity assignment or confirmation is strongly recommended.

Association of severe coronary stenosis with subclinical left ventricular dysfunction in the absence of infarction

Background. Regional left ventricular (LV) dysfunction may occur in patients with coronary artery disease (CAD) in the absence of infarction, but the causes of this phenomenon are unclear. We sought to identify whether changes in regional LV function were related to stenosis severity, using sensitive new ultrasound markers of function. Methods: We studied 67 individuals with no history of infarction and with normal LV systolic function: 49 patients with CAD and 18 control subjects without CAD. All patients underwent color Doppler tissue imaging, integrated backscatter (IB), anatomic M-mode echocardiography, and strain rate imaging to detect changes in structure and function. Peak early and late diastolic myocardial velocity, cyclic variation of IB, wall thickness, and percent wall thickening were measured in each basal and mid segment. Strain rate and peak systolic strain were calculated in each wall. CAD was defined as greater than or equal to 50% diameter stenosis. Normokinetic segments (n = 354) subtended by CAD were divided according to stenosis severity into 3 groups: group 1 (subtended by 50%-69% stenosis); group 2 (subtended by 70%-98% stenosis); and group 3 (subtended by greater than or equal to99% stenosis). Each parameter in each group was compared with that in 216 segments from control subjects. Results: Segments subtended by significant CAD showed lower peak early and late diastolic myocardial velocity compared with control segments. Group 3 showed significantly lower myocardial velocities than group 2 for both peak early (4.8 +/- 1.8 vs 6.0 +/- 2.0 cm/s, P