Does the cholecystokinin antagonist proglumide possess antipsychotic activity?

Cholecystokinin (CCK), a neuropeptide which fulfills almost all criteria for neurotransmitter status, has been co-localized with dopamine in midbrain mesolimbic and mesocortical neurons that have been implicated in the pathogenesis of schizophrenia. Preclinical research suggests that CCK may in part act to enhance central dopaminergic activity. In an attempt to evaluate the role of CCK relative to the dopamine hyperactivity hypothesis of schizophrenia, in the present investigation the putative CCK receptor antagonist, proglumide, was administered to four schizophrenic patients in a double-blind, placebo-controlled study. All patients were receiving concurrent neuroleptic medication, but were still significantly symptomatic. Proglumide was without effect on the patients' psychosis ratings. Potential reasons for this negative finding are discussed.     

Peptide-monoamine coexistence: studies of the actions of cholecystokinin-like peptide on the electrical activity of midbrain dopamine neurons

Recent studies have shown that a cholecystokinin-like peptide coexists in a subpopulation of midbrain dopamine-containing neurons. Using extracellular single unit recording techniques we have found that this peptide increases the activity of some, but not all, dopaminergic neurons (identified on the basis of their electrophysiological features). The responsive neurons were found exclusively in areas which were subsequently shown, using immunocytochemical techniques, to contain both cholecystokinin and the enzyme marker for dopaminergic neurons, tyrosine hydroxylase. When administered intravenously, cholecystokinin increased the firing rate of dopaminergic neurons lying in cholecystokinin-rich areas of the substantia nigra. Cells in cholecystokinin-rich ventral tegmental areas showed more variable responses to comparable doses of the peptide. Iontophoretically-applied cholecystokinin consistently activated dopaminergic cells in the substantia nigra and ventral tegmental area, increasing their firing rate and their bursting activity. Cholecystokinin increased the firing rate of some of those neurons to the extent that they were driven into apparent depolarization inactivation. Furthermore, iontophoresis of cholecystokinin resulted in an activation of a population of normally quiescent dopaminergic cells.These results are discussed in light of a possible functional role of cholecystokinin-like peptides in the brain dopaminergic systems. It is suggested that cells in the dopamine-rich areas of the mesencephalon can be characterized both on the basis of their content of peptide and/or catecholamine and of their responsiveness to cholecystokinin-like peptides.     

Soluble kit receptor in human serum

c-kit encodes the transmembrane receptor tyrosine kinase (Kit) for the recently described ligand stem cell factor (SCF). We have developed an enzyme-linked immunosorbent assay for measuring soluble human Kit and we have used the assay to show high levels of soluble Kit in human serum. The distribution of soluble Kit levels was investigated among 112 normal human serum donors. The mean serum level (+/- SD) was found to be 324 +/- 105 ng/mL with the values falling between 163 ng/mL and 788 ng/mL. No correlation between soluble Kit levels and the sexes or ages of the donors was found. Partial purification using immunoaffinity chromatography allowed us to characterize the soluble Kit from pooled human serum. Antibodies generated to a 497-amino acid recombinant human soluble Kit corresponding to the N-terminal extracellular domain of the receptor recognized the serum-derived soluble Kit by immunoblotting. We found that the serum-derived soluble Kit is glycosylated, with mostly N- linked but also O-linked carbohydrate, and with terminal sialic acid residues. When compared with the recombinant human soluble Kit, the serum-derived material was similar both in size and glycosylation pattern. CNBr cleavage of the isolated serum-derived material followed by amino terminal sequencing confirmed the presence of five peptides expected for the extracellular portion of the Kit molecule. The immunoaffinity purified serum-derived soluble Kit inhibited binding of [125I]SCF to membrane-bound receptor in an in vitro assay. These results indicate that soluble Kit could modulate the activity and functions of SCF in vivo.     

Model of Epstein-Barr virus infection of human thymocytes: expression of viral genome and impact on cellular receptor expression in the T- lymphoblastic cell line, HPB-ALL

Infection of B lymphocytes and epithelial tissue by Epstein-Barr virus (EBV) is associated with malignancy and autoimmunity. The cellular receptor for EBV has been identified as CD21 (CR2). A molecule, which is biochemically and immunologically similar to B-cell CD21, has been identified on a subpopulation of immature thymocytes, suggesting a role for this molecule in the regulation of T-cell development and further suggesting that immature T cells might be susceptible to EBV infection. A growing body of literature now documents the presence of EBV in tumors of T-cell origin. We have evaluated the susceptibility of the human immature T cell line, HPB-ALL, to infection by EBV. Electron microscopy studies showed a rapid internalization of virus by HPB cells. Southern blotting showed the intracellular presence of linear EBV genomes, and components of the virus replicative cycle were identified. Expression of the BamHI Z region of the genome, encoding the nuclear protein, ZEBRA, which is strictly associated with productive infection in B cells, was detected in HPB-ALL cells. A spliced variant of Z, RAZ, was also identified. Cell surface expression of EBV late antigens was observed to occur transiently. Infection of HPB cells was also accompanied by altered expression of T-cell surface molecules involved in antigen recognition, a process critical to normal development of the T-cell repertoire. Delineation of the outcome of T- cell infection by EBV may lead to a better understanding of the role of this virus in autoimmune processes and malignancy.     

Shear-induced platelet aggregation requires von Willebrand factor and platelet membrane glycoproteins Ib and IIb-IIIa

Different types of platelets in various types of plasma were subjected to levels of shear stress that produce irreversible platelet aggregation in normal platelet-rich plasma (PRP). At shear stresses of 90 or 180 dyne/cm2 applied for 30 seconds or five minutes, aggregation was either absent or only transient and reversible using severe von Willebrand's disease (vWD) PRP (less than 1% von Willebrand factor, vWF); Bernard-Soulier syndrome (BSS) PRP (platelets deficient in the membrane glycoprotein Ib, GPIb); normal PRP plus monoclonal antibody (MoAb) to GPIb; thrombasthenic PRP (platelets deficient in membrane glycoprotein IIb-IIIa complex, GPIIb-IIIa); and normal PRP plus MoAb to GPIIb-IIIa. Shear-induced aggregation was inhibited under the above conditions, even though the platelets were activated to release their granular contents. Sheared normal platelets in vWD plasma aggregated in response to added vWF. These studies demonstrate that the formation of stable platelet aggregates under conditions of high shear requires vWF and the availability of both GPIb and GPIIb-IIIa on platelet membranes. The experiments demonstrate that vWF-platelet interactions can occur in the absence of artificial agonists or chemical modification of vWF. They suggest a possible mechanism for platelet aggregation in stenosed or partially obstructed arterial vessels in which the platelets are subjected to relatively high levels of shear stress.     

Serum interleukin-3 levels following autologous or allogeneic bone marrow transplantation: effects of T-cell depletion, blood stem cell infusion, and hematopoietic growth factor treatment

Engraftment of marrow following autologous or allogeneic bone marrow transplantation (BMT) may be influenced by quantity and function of stem cells. T lymphocytes, supporting microenvironmental cells, and hematopoietic growth factors (HGF). To elucidate the physiologic role of interleukin-3 (IL-3) in the engraftment process, serum IL-3 levels were measured in over 400 samples from 77 transplant recipients before and for up to 3 weeks following transplantation using a novel enzyme- linked immunoabsorbent assay (ELISA) with a sensitivity of > or = 78 pg/mL. Thirty-seven patients received two to three log T-cell-depleted allografts. In the remaining 40 patients (18 autologous marrow, 12 allogeneic marrow, and 10 autologous peripheral blood [PB] stem cell), T cells were not depleted (non-TCD) from the grafts. A burst of IL-3 (peak levels, 1,500 to 6,000 pg/mL) was detected in the immediate posttransplant period between day 0 and day 14 in all non-TCD recipients and in 21 of 37 (57%) of TCD recipients. A strong inverse relationship between IL-3 levels and absolute neutrophil count (ANC) was observed in both non-TCD recipients (r = -.796) and in TCD recipients (r = -.897). However, both peak IL-3 levels and mean IL-3 levels from day 0 through 14 were significantly lower in TCD recipients compared with either autologous or unmodified allogeneic marrow recipients (P < .01). The lowest peak or mean day 0 through 14 IL-3 levels were observed in matched related recipients undergoing the most aggressive (2.5 to 3.0 log) T-cell-depleted BMT. Autografted patients receiving blood stem cell transplants alone or posttransplant granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) also had significantly lower peak IL- 3 levels (P < .01). In patients receiving TCD grafts, administration of antithymocyte globulin (ATG) posttransplant significantly increased peak IL-3 levels compared with patients not treated with ATG (P < .04). This study shows that endogenous release of IL-3 is strongly associated with myeloid engraftment and inversely related to ANC. Removal of T lymphocytes from donor marrow or acceleration of engraftment by use of stem cells or growth factors appears to blunt the endogenous release of IL-3 whereas use of ATG posttransplant increases IL-3 release.     

Cocaine potentiates ethanol-induced excitation of dopaminergic reward neurons in the ventral tegmental area

The coabuse of cocaine and ethanol is one of the most frequently used substance abuse combinations in the United States. The dopamine (DA) neurons in the ventral tegmental area (VTA) are important in the rewarding mechanism of these two substances. Cocaine is known to block the reuptake of DA and serotonin (5-HT). At concentrations below 1 microM, cocaine preferentially blocks the reuptake of 5-HT compared with DA. We have previously shown that ethanol increases the firing rate of DA neurons in the VTA, and that this excitation is enhanced by 5-HT. Extracellular single-unit recordings were made from VTA dopaminergic neurons in coronal brain slices from young adult Fischer 344 rats. Cocaine (1-10 microM) reduced the spontaneous firing rate in VTA dopaminergic neurons in a concentration-related manner. A lower concentration of cocaine (500 nM), which is a concentration that is pharmacologically relevant in addicts, produced only a very small decrease in the firing rate of VTA neurons but potentiated ethanol excitation of these neurons. Higher concentrations of cocaine (1 microM) did not enhance ethanol excitation. Ethanol-induced excitation was potentiated by the higher concentrations of cocaine (1 and 2 microM) in the presence of the D(2) receptor antagonist sulpiride (1 microM). Furthermore, cocaine potentiation of ethanol-induced excitation was reversed by ketanserin (2 microM), a 5-HT(2) antagonist. The enhanced ethanol excitation of VTA dopaminergic neurons caused by cocaine may partially explain the high incidence of the coabuse of these two substances.     

Is the prevalence of pre-eclampsia affected by HIV/AIDS? A retrospective case–control study

Objective

To evaluate the rate of HIV/AIDS (and CD₄ levels) in women with pre-eclampsia compared to that of a control group.

Methods

This was a retrospective case–control study in a tertiary and regional hospital in South Africa. We reviewed the hospital records of women who had delivered in these hospitals between 1 January 2008 and 30 June 2010. The records of women with pre-eclampsia during the study period were analysed. Their HIV infection rate was compared to that of a control group consisting of normotensive healthy pregnant women.

Results

Among 492 cases of pre-eclampsia, 130 (26.4%) were HIV infected. In the control group, 183/500 (36.6%) were HIV infected (p = 0.001, OR = 0.62, 95% CI: 0.47–0.82). After adjustment to match the difference in maternal age and parity, the rate of HIV/AIDS was lower in the pre-eclamptic group than in the control group (p = 0.005, OR = 0.658).

Conclusion

The rate of HIV/AIDS was significantly lower in women with pre-eclampsia than in normotensive healthy pregnant women.     

Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect

Gilbert syndrome is a common genetic disorder associated with mild unconjugated hyperbilirubinemia and no clinical illness. In contrast, Crigler-Najjar syndrome types I and II are rare genetic disorders associated with severe unconjugated hyperbilirubinemia and a life-long risk of kernicterus. Patients with Gilbert syndrome have low levels of a normal form of uridinediphosphoglucuronate glucuronosyltransferase because of a defect in the promoter region of both alleles, whereas patients with Crigler-Najjar syndrome are homozygous for a defect that yields an abnormal form of the enzyme that has limited or no activity. This case report describes a young adult with Crigler-Najjar syndrome type II in whom kernicterus developed after a laparoscopic cholecystectomy. The development of kernicterus was the result of a largely preventable series of events that lead to an increase in the free fraction of his serum bilirubin. Analysis of his genetic defect showed that he was homozygous for the mutation associated with Gilbert syndrome and heterozygous for a second mutation in the open reading frame of one allele of the bilirubin uridinediphosphoglucuronate glucuronosyltransferase gene. The combined defect leads to severe hyperbilirubinemia and shows how seemingly benign genetic defects, when combined, can cause serious clinical disease. (Gastroenterology 1997 Jun;112(6):2099-103)