Vagal mediation of the cholecystokinin satiety effect in rats

Central (intracerebroventricular) and peripheral (intraperitoneal) injections of the octapeptide of cholecystokinin (CCK-8) were compared to determine the most effective route of administration to elicit satiety for food intake in the rat. Subdiaphragmatic bilateral vagotomy and spinal cordotomy (T2-T3) were also performed to investigate the importance of visceral nerves for the satiety effect. CCK-8 suppressed feeding and elicited satiety resting behavior when injected peripherally but it was less effective when injected centrally. The satiety effect of CCK-8 or CCK-33 following peripheral injections was blocked by vagotomy whereas spinal cordotomy had no effect. The results indicate that some component of the vagus is required to mediate the peripherally induced cholecystokinin satiety effect, but the splanchnic nerves are not necessary. The weak effect of CCK-8 following ventricular administration is additional evidence suggesting that cholecystokinin of intestinal origin acts in the periphery rather than directly on the brain to elicit its typically rapid satiety effect in rats.     

Persistence of anti-donor allohelper T cells after neonatal induction of allotolerance in mice

BALB/c mice rendered tolerant to A/J alloantigens by neonatal injection of 10(8) (A/J X BALB/c)F1 spleen cells develop an autoimmune disease associated with a polyclonal activation of donor B cells. To study the mechanisms leading to donor B cell activation in tolerant mice, we prepared mixed lymphocyte cultures (MLC) between splenic T cells from neonatally injected mice and donor-type (A/J X BALB/c)F1 or third-party (C57BL/6 X BALB/c)F1 B cells. T cells from tolerized mice were unable to generate cytotoxic T lymphocytes, to proliferate or to secrete interleukin (IL)2 after stimulation with donor alloantigens in MLC. These T cell responses were present after MLC with third-party antigens, but were of lower intensity than those generated by control BALB/c T cells. In contrast, T cells from tolerized mice stimulated immunoglobulin production by donor-type (A/J X BALB/c)F1 B cells much more powerfully than T cells from control BALB/c mice. The stimulation of donor-type (A/J X BALB/c)F1 B cells was polyclonal, as attested by the levels of anti-hapten and anti-DNA antibodies in the MLC supernatants. IgM was the dominant isotype secreted in vitro, but IgG1 and IgG3 were also produced in significant amounts. Lysis experiments indicated that the T cells responsible for F1 B cell stimulation in MLC were CD4+ host T cells. These T helper cells were alloreactive since they did not stimulate syngeneic BALB/c B cells, and their effect on donor B cells was specifically blocked by anti-donor Ia monoclonal antibodies. Addition of anti-IL 4 monoclonal antibody to MLC between T cells from tolerant mice and (A/J X BALB/c)F1 B cells almost completely abolished the production of IgG1, but not that of IgM or IgG3. Taken together, these findings indicate that neonatal injection of alloantigens in BALB/c mice induces a state of dissociated tolerance, with unresponsiveness of anti-donor T cells secreting IL 2 on the one hand, and persistence of T cells responsible for B cell help and IL 4 secretion on the other hand.     

Phenotypic switching of Cryptococcus neoformans can produce variants that elicit increased intracranial pressure in a rat model of cryptococcal meningoencephalitis

Increased intracranial pressure (ICP) plays an important role in the morbidity and mortality of cryptococcal meningoencephalitis. The microbial and host factors that contribute to the development of increased ICP are poorly understood. We found that phenotypic switch variants of Cryptococcus neoformans (smooth and mucoid) differed in their abilities to promote increased ICP in a rat model of cryptococcal meningitis. Rats infected with the mucoid variant developed increased ICP, whereas rats infected with the smooth parent did not. This trend correlated with a shorter survival time and a higher cerebrospinal fluid (CSF) fungal burden for mucoid variant-infected rats, although brain fungal burdens were comparable between mucoid variant- and smooth parent-infected rats. Magnetic resonance imaging revealed enhanced T2 signal intensity over the surfaces of the brains of mucoid variant-infected rats. In addition, more polysaccharide accumulated in the CSF and brains of mucoid variant-infected rats. The accumulation of glucorunoxylomannan was associated with elevated levels of MCP-1 (CCL2) and, accordingly, a more pronounced but ineffective monocytic inflammatory response in the meninges of mucoid variant-infected rats. In summary, these findings suggest that strain-specific characteristics can influence the development of increased ICP and indicate a manner in which phenotypic switching could influence the outcome of a central nervous system infection.     

Changes in maternal and newborn lymphocyte reactivity in reciprocal mixed lymphocyte cultures during the postpartum period

Reciprocal one-way mixed mother-newborn lymphocyte cultures (MMNLC) containing alternatively maternal or newborn responding (R) or stimulating (S) cells were investigated in both directions in primiparae at three different times: a few hours after delivery, and at 4 and at 16 weeks. Cultures were grown in the presence of maternal and pooled control serum prepared from the blood of five to eight unrelated healthy donors. Four weeks after delivery in maternal and in control serum a significant increase in MMNLC reactivity could be observed, which disappeared at 16 weeks when a pronounced decline in MMNLC values in both directions was found. The suppressive effect of maternal serum was more pronounced at delivery, still evident 4 weeks later, and insignificant after 16 weeks. The results of this study suggest that 4 weeks after delivery, maternal sensitization to fetal histocompatibility antigens can be detected in primiparae with MMNLC; and that 16 weeks later, this was no longer detectable with the same test.     

Hydrophobic adherence and phase variation in Bordetella pertussis

The hydrophobicity of Bordetella pertussis was assayed by measuring the ability of cells in suspension to adhere to a polystyrene surface. The quantity of adhered bacteria was measured by the binding of enzyme-conjugated anti B. pertussis antibodies. Hydrophobic adherence of non-pathogenic variant strains was about 20% of that exhibited by pathogenic strains. Hydrophobicity was a stable trait as it did not change with passaging or storage. Assays of a series of characterized stable variants suggested that the Filamentous Hemagglutinin (FHA) is the cell surface moiety responsible for hydrophobic adherence in B. pertussis.     

Automated Gamma Knife dose planning using polygon clipping and adaptive simulated annealing

The Gamma Knife (Elekta Instruments, Inc., Norcross, GA), a neurosurgical, highly focused radiation delivery device, is used to eradicate deep-seated anomalous tissue within the human brain by delivering a lethal dose of radiation to target tissue. This dose is the accumulated result of delivering sequential "shots" of radiation to the target, where each shot is approximately three-dimensional (3-D) Gaussian in shape. The size and intensity of each shot can be adjusted by varying the time of radiation exposure and by using one of four collimator sizes ranging from 4-18 mm. Current dose planning requires that the dose plan be developed manually to cover the target, and only the target, with a desired minimum radiation intensity using a minimum number of shots. This is a laborious and subjective process that typically leads to suboptimal conformal target coverage by the dose. We have previously presented a forward-direct-method, which, using adaptive simulated annealing and Nelder-Mead simplex optimizers, automates the selection and placement of generic Gaussian-based kernels or "shots" to form a simulated dose plan. In order to make the computation of the problem tractable, the algorithm exploits 2-D contouring and polygon clipping and takes a 2 1/2-D approach to defining the problem. In the current paper we present the results of four experiments on two historical clinical datasets, where the generic kernels have been replaced by patient specific kernels calculated by Elekta's Leksell Gamma Plan software. For these experiments the user only selects the maximum number of shots to use and the optimizers are then given the freedom to vary the number of shots as well as the weight, collimator size, and 3-D location of each shot. Highly conformal and competitive dose plans were generated for these two difficult cases.     

The economics of alternative payment models for pharmaceuticals

The European Journal of Health Economics - Pharmaceuticals are priced uniformly by convention, but vary in their degree of effectiveness for different disease indications. As more high-cost...     

Clinical and cytogenetic aspects of X-chromosome deletions

Karyotype/phenotype correlations in six non-mosaic patients with dysgenetic ovaries and partial deletions of the X-chromosome (three patients with short arm, and three with long arm deletions) are presented and the pertinent literature is analysed. It would appear that functioning ovarian tissue is present more often in patients with a short arm deletion than in those with a deleted long arm. This may represent a difference in the strength of two sets of controlling factors, but it can also be related to break point position. This in turn may be misinterpreted due to the difficulty in distinguishing between terminal and interstitial deletions in the long arm. Stature may be a heterochromatic effect, but if specific genetic factors influencing stature exist, then they would appear to be situated mostly on the short arm of the X-chromosome, although some 'statural determinants' occur also on the long arm and could be located rather close to the centromere. Deletions of the short arm of the X-chromosome were almost always associated with some features of the Turner phenotype, and could possibly be related to a gene dosage effect.