Vasopressin release and firing of supraoptic neurosecretory neurones during drinking in the dehydrated monkey

A close relationship exists between drinking and the release of vasopressin, the two main factors responsible for the maintenance of body water content. Whereas the participation of peripheral factors, such as oropharyngeal stimulation, seems obvious in the metering of fluid intake and in thirst satiation, very little is known about their influence on vasopressin release. In the present experiments, the influence of drinking on vasopressin release was studied using both biochemical and electrophysiological approaches.In one group of monkeys made thirsty by water deprivation, the subsequent drinking of water during a 5–8 min induced: i) a short-term response, consisting of an abrupt fall in plasma vasopressin concentration which was independent of osmolality, occurred at the time of drinking and was partly reversed after the cessation of drinking, and ii) a longer lasting response, consisting of a slow diminution of plasma vasopressin concentration as the intestinal absorption of water progressed. In another group of thirsty monkeys, extracellular recordings were made during drinking from cells which were identified as neurosecretory neurones of the supraoptic nucleus, a number of them being considered vasopressin secreting on the basis of their phasic pattern of firing. Their firing decreased considerably during the periods of water intake and recovered to control levels immediately after-wards.The decrease in vasopressin release at the onset of water intake, the diminution in the firing rate of the neurones, the short latency and the reversibility of these events after cessation of drinking, suggest that a reflex inhibition of vasopressin-secreting neurones occurs which is probably induced by peripheral stimuli and most likely via oropharyngeal or other visceral receptors. It is postulated that this reflex inhibition of vasopressin release may participate in some active manner in the anticipatory mechanisms of thirst satiation.     

Sleep related breathing disorders in older men: A search for underlying mechanisms

—The incidence of sleep-related breathing disorders (SRBDs) associated with hemoglobin desaturation was determined by nocturnal polygraphic evaluations in 26 healthy men, aged 55–70 years. Sixteen subjects (62%) had abnormal rates of at least 12 episodes per hour of sleep: 8 had occlusive, and 8 had central apnea or hypopnea. During waking ten of 16 SRBD subjects and only one subject without SRBDs exhibited either an elevated nasopharyngeal airway resistance (n=4) or a reduced ventilatory response to hypercapnia (n=4) and/or hypoxia (n=3). However, these abnormalities were not related to the type or severity of SRBDs, and 6 subjects with SRBDs demonstrated no respiratory defect. We conclude that SRBDs have a very high incidence in older males and are not usually secondary to pulmonary cardiac, neurological, or behavioral disorders. Additionally, we hypothesize that abnormalities in ventilatory control or upper airway resistance contribute to SRBDs, but depression of brain stem reticular formation activity during sleep plays a primary role in these disorders. Factors related to both aging and SRBDs are reviewed. These include reduced chemoreceptor responses, altered steroid hormone metabolism, and use and metabolism of hypnotic drugs and alcohol.     

Performance characteristics of four immunoassays for antiepileptic drugs on the IMMULITE 2000 automated analyzer

Carbamazepine, phenobarbital, phenytoin, and valproic acid are commonly used antiepileptic drugs that show complicated pharmacokinetic behavior Nonisotopic immunoassays are used routinely to monitor these drugs, and assay specificity is important to obtain accurate results. By using samples from subjects receiving each of these antiepileptic medications, competitive immunoassays for them were evaluated on an IMMULITE 2000 automated chemiluminescent analyzer (Diagnostic Products, Los Angeles, CA). Phenytoin assays were evaluated using an additional set of samples from patients with abnormal renal function. All 4 methods were linear, had imprecision of less than 10%, and compared well with other commercial immunoassays. A positive bias was observed for phenytoin measured in samples from uremic patients compared with a high-performance liquid chromatography reference method. The molar cross-reactivity of carbamazepine-10,11-epoxide was 12% in the carbamazepine assay. Phenytoin metabolites and fosphenytoin had substantial cross-reactivity in the phenytoin assay. All antiepileptic drug assays performed well and are suitable for use in monitoring patients receiving antiepileptic drug therapy. One possible exception is the phenytoin assay with samples from patients with renal insufficiency.     

Heart tumors in children and adults: clinicopathological study of 59 patients from a surgical center.

BACKGROUND: Heart tumors are rare lesions with variegated histological types. Their clinicopathological features could be more comprehensively categorized. METHODS: This is a 19-year retrospective study of 17 infants/toddlers (<2 years of age) and 42 patients aged between 14 and 79 years (mean = 51.5) in a surgical center. RESULTS: Congenital tumors (n = 17; 29%), including rhabdomyomas (n = 9), ventricular fibromas (n = 6), and hemangiomas (n = 1), required surgery mainly because of mass effect. Familial myofibromatosis was the only embolic congenital lesion. Acquired benign tumors (n = 28; 47%) included myxomas (n = 21), fibroelastomas (n = 3), myofibroblastic inflammatory tumors (n = 2), and lipomas (n = 2). Eight (29%) were revealed by systemic embolization. These benign noncongenital tumors were all treated by complete resection, except for an incompletely resected lipoma of the mitral valve. Postoperative arrhythmia (n = 1) and pericardial effusion (n = 3) were the only complications. Primary sarcomas (n = 8; 14%) were mostly vascular tumors (five of eight), and patients with high-grade tumors had a mean survival of 15 months (n = 5). Cardiac metastases (n = 6; 10%) were from carcinomas (n = 3) or sarcomas (n = 3); apart from a necrotic metastasis, all patients died (mean survival of 6 months). CONCLUSIONS: This study shows that, regardless of patients' age, heart tumors can be classified as: (a) congenital lesions, which are spontaneously nonprogressive or regressive lesions possibly requiring surgery mainly because of mass effect; (b) acquired benign tumors, which are lesions requiring surgery often because of embolization risk; and (c) primary and secondary malignant tumors, which are lesions with globally poor prognosis but with some indications for resection.     

Fornix transection impairs conditional visuomotor learning in tasks involving nonspatially differentiated responses.

Rhesus monkeys learned a series of conditional visuomotor associations involving two-dimensional "objects" that instructed one of three responses: tapping a touch screen, steady contact with the screen for a brief period, or steady contact for a longer period. Relative to controls, fornix-transected monkeys were impaired in the acquisition of new associations and in the retention of preoperatively learned ones. These findings challenge the view that the hippocampal system participates in associative learning only when spatial information is relevant to either the stimulus or the response.     

Molecular determinants of human uveal melanoma invasion and metastasis

The molecular analysis of cancer has benefited tremendously from the sequencing of the human genome integrated with the science of bioinformatics. Microarray analysis technology has the potential to classify tumors based on the differential expression of genes. In the current study, a collaborative, multidisciplinary approach was utilized to study the molecular determinants of human uveal melanoma invasion and metastasis. Uveal melanoma is considered the most common primary intraocular cancer in adults, resulting in the death of approximately 50% of patients affected. Unfortunately, at the time of diagnosis, many patients already harbor microscopic metastases, thus underscoring a critical need to identify prognostic markers indicative of metastatic potential. The investigative strategy consisted of isolating highly invasive vs. poorly invasive uveal melanoma cells from a heterogeneous tumor derived from cells that had metastasized from the eye to the liver. The heterogeneous tissue explant MUM-2 led to the derivation of two clonal cell lines: MUM-2B and MUM-2C. Further morphological and functional analyses revealed that the MUM-2B cells were epithelioid, interconverted (expressing mesenchymal and epithelial phenotypes) highly invasive, and demonstrated vasculogenic mimicry. The MUM-2C cells were spindle-like, expressed only a vimentin mesenchymal phenotype, poorly invasive, and were incapable of vasculogenic mimicry. The molecular analysis of the MUM-2B vs. the MUM-2C clones resulted in the differential expression of 210 known genes. Overall, the molecular signature of the MUM-2B cells resembled that of multiple phenotypes – similar to a pluripotent, embryonic-like genotype. Validation of select genes that were upregulated and down-regulated was conducted by semiquantitative RT-PCR measurement. This study provides a molecular profile that will hopefully lead to the development of new molecular targets for therapeutic intervention and possible diagnostic markers to predict the clinical outcome of patients with uveal melanoma. This revised version was published online in July 2006 with corrections to the Cover Date.     

Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility

BACKGROUND: Male fertility largely depends on the quality of sperm production, which may be affected by environmental and genetic factors. In this study, we explored a possible role of the polymerase gamma (POLG) gene polymorphism, recently reported to be associated with male infertility in some populations. METHODS: The polymorphic CAG repeat (usually 10 codons long) in the POLG gene was studied in 1298 male subjects: 429 patients with infertility/subfertility, and 869 controls (495 men from the general population with unknown fertility and 374 recent fathers). In all subjects, the POLG polymorphism was assessed in relation to their semen quality, and--in the fertile controls--with biological fecundity measured as waiting time-to-pregnancy (TTP) for the couples. In the patients lacking the common POLG allele, the outcome of the assisted reproductive techniques (ART) for the couples was evaluated. RESULTS: The absence of one (10/ not equal to 10) or both common POLG alleles (not equal to 10/not equal to 10) was more frequent among the subfertile patients than among fertile controls (P=0.021 and P=0.04 respectively). The estimated predictive value for infertility in a man homozygous for the POLG polymorphism was 15.5% (95% CI: 4.8-51%). There was a positive association with sperm concentration: 14.3% of the normospermic subfertile patients were homozygous for the absence of the common POLG allele (not equal to 10/not equal to 10), in comparison with 2.3% of unselected controls (P=0.001) and 0.9% of the fertile men (P=0.0001). No association with sperm motility, morphology and TTP was found. Spermatozoa of the three not equal to 10/not equal to 10 patients treated with IVF retained the ability to penetrate the egg, but the fertilization rate was low. Nine homozygous not equal to 10/ not equal to 10 patients were treated with ICSI, resulting in pregnancy in seven couples. CONCLUSIONS: The POLG gene polymorphism should be considered as a possible contributing factor in patients with unexplained subfertility and normal spermiograms. The oocyte penetration ability of sperm may be partially impaired in the not equal to 10/not equal to 10 patients but most of them can be successfully treated with ICSI.