Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.

BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.     

Picotamide inhibition of excess in vitro thromboxane B2 release by colorectal mucosa in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease is associated with increased mucosal release of eicosanoids. Among these, thromboxane A2 has been proposed as a possible inflammatory mediator; its suppression may be a useful therapeutic option. METHODS: Using a tissue incubation technique, we compared release of immunoreactive thromboxane B2 by colonic biopsies from patients with ulcerative colitis, Crohn's disease and controls, and assessed the inhibitory effect of picotamide, a thromboxane synthesis inhibitor-receptor antagonist, which has been widely used in Italy for management of ischaemic heart and cerebrovascular disease. RESULTS: Increased amounts of thromboxane B2 were released from biopsies from patients with active ulcerative colitis (median 238 pg/20 min/mg wet weight (interquartile range 147- 325), n = 12) and active Crohn's disease (252 (174-450), 6) compared with those from patients with quiescent ulcerative colitis (95 (61- 140), 12) or Crohn's disease (105 (57-201), 13), or controls (136 (64- 206), 8). Incubation with picotamide at concentrations between 100 microM and 1 mM reduced thromboxane B2 release (IC50 890 microM). CONCLUSION: Since increased thromboxane A2 production may have pathogenetic importance, thromboxane synthesis inhibitor-receptor antagonists such as picotamide merit therapeutic trial in the management of inflammatory bowel disease.     

Follistatin and activin A production by the male reproductive tract

Follistatin is a binding protein for the activin and inhibin family of hormones, regulating their biological activity. In the male reproductive tract, the interaction of these factors is likely to be involved in the regulation of the proliferation of several cell types. We have investigated the presence of follistatin and activin A in seminal plasma using specific immunoassays and have localized follistatin and activin/inhibin subunits in the adult human testis, prostate and seminal vesicle to establish their likely sources. High concentrations of immunoreactive follistatin were present in seminal plasma in normal men (mean 97.9 ng/ml; 1.43 ng/ml in peripheral plasma) and were similar in men with oligo/azoospermia and following vasectomy. Follistatin immunoreactivity was localized to both Leydig and Sertoli cells of the testis, and to epithelial cells of the prostate gland and seminal vesicle, which are likely to be the predominant sources of the hormone in seminal plasma. Activin A was also present in seminal plasma in normal men but was undetectable following vasectomy, thus deriving from the testis. Consistent with this finding, the betaA-subunit was immunolocalized in Sertoli and Leydig cells but was not present in seminal vesicle or prostate gland. The functional significance of the high concentrations of follistatin secreted into seminal plasma by the prostate gland and/or seminal vesicle is uncertain, but they may regulate the biological activity of testis-derived activin A and inhibin B.      

ASSESSING THE IMPACT OF A CHILD WITH SPINA BIFIDA ON THE FAMILY

This study examined the characteristics of families which may be more vulnerable than others to the impact of caring for a child with spina bifida. Morbidity and the use of health services were unexpectedly high. The impact on the family was related less to clinical diagnoses than to the characteristics of the child's functioning in the home and of the family. Major predictors of greater impact on the family were the number of the child's activities of daily living, parental perceptions of the child's health, low maternal educational attainment, low family income, the number of adults in the family, insurance status, the number of visits to a doctor in the month before the interview, and whether the adults in the family were employed. These results reinforce the need for assessments to include the child's function in the home, and for additional resources to help some families care for their child.     

Lymphocyte β-adrenergic receptor binding in panic disorder

Lymphocyte beta adrenergic receptor binding using [¹²⁵I]CNP was determined in patients with panic disorder (N=4) or agoraphobia with panic attacks (N=17) and age- and sex-matched healthy subjects (N=22). The patients showed a significantly lower number of -adrenergic receptor binding sites and a significantly higher affinity of binding than healthy subjects. A past or present history of major depression in the patients did not alter these findings. These results are consistent with a growing body of knowledge implicating noradrenergic dysfunction in the pathophysiology of panic anxiety.     

Significance of Abnormal Rabbit Ileal Histology in the Pathogenesis of Diarrhea

In spite of several macroscopic criteria for predicting the presence of histological abnormalities in rabbit ileum, microscopic ileal abnormalities still can escape detection. The effect of histologically abnormal rabbit ileum was evaluated on basal intestinal absorption, on basal absorption, on basal adenylate cyclase activity, and on cholera toxin-induced secretion and cholera toxin-induced stimulation of adenylate cyclase activity. Compared to histologically normal rabbit ileum, the presence of histological abnormalities was associated with decreased basal intestinal water, Na, Cl, and glucose absorption, absent glucose-dependent water absorption, and elevated basal adenylate cyclase activities. However, histologically abnormal rabbit ileum responded to inoculation of purified cholera toxin with stimulation of intestinal water secretion and adenylate cyclase activity similar to that in histologically normal ileum. These data have implications concerning the design of experiments that attempt to study the pathogenesis of diarrheal diseases by correlating changes in ileal transport with changes in ileal mucosal adenylate cyclase activity. In spite of abnormal ileal histology, studies of intestinal secretory states which attempt to define the role of adenylate cyclase in secretory processes can be performed provided animals are used as their own controls. However, when groups of animals are compared, the presence of an histologically abnormal ileum can cause changes in basal and intestinal secretagogue-stimulated ileal water and electrolyte transport and in basal and intestinal secretagogue-stimulated mucosal adenylate cyclase activity which can lead to erroneous conclusions if the presence of the abnormal ileal histology is not considered.     

Effects of methylprednisolone on electrolyte transport by in vitro rat ileum

Administration of the glucocorticoid methylprednisolone (MP) (30 mg/kg body wt for 3 days) to rats increased intestinal mucosal guanylate cyclase and Na-K-ATPase activities, short-circuit current (Isc), electrical potential difference (PD), net Na absorption, and net Cl secretion and reversed HCO3 transport from secretion to absorption. In the MP-treated animals, removal of HCO3 from both the mucosal and serosal bathing solutions increased Cl secretion but did not alter the Isc, PD, and net Na flux. Removal of Cl abolished the MP-induced increase in Isc but did not affect the MP-induced changes in net Na and HCO3 fluxes. At 6 h, after a single dose of MP, stimulation of guanylate cyclase activity was already maximal, whereas Na-K-ATPase activity was not detectably altered. The changes in intestinal transport properties present 6 h after MP treatment and associated with the increased guanylate cyclase activity were an increase in Isc and PD and a reversal of net Cl absorption to net secretion. These results suggest that an initial response to MP administration is a persistent increase in intestinal guanylate cyclase activity that mediates an electrogenic Cl secretory process, then is followed by a superimposed effect of increased Na-K-ATPase activity that mediates an increase in net Na absorption.