Elucidating the Mechanism(s) Underlying Antipsychotic and Antidepressant-Mediated Fractures.

Mood spectrum disorders and medications used to treat these disorders, such as atypical antipsychotic drugs (AA), are associated with metabolic and endocrine side effects including obesity, dyslipidemia, hyperglycemia and increased risk of fractures. Antidepressant medications, including selective serotonin reuptake inhibitors (SSRI), have also been reported to increase fracture risk in some patients. The pharmacology underlying the increased risk of fractures is currently unknown. Possible mechanisms include alternations in dopaminergic and/or serotonergic signaling pathways. As these medications distribute to the bone marrow as well as to the brain, it is possible that drug-induced fractures are due to both centrally mediated effects as well as direct effects on bone turnover. Given the growing patient population that is prescribed these medications for both on- and off-label indications, understanding the level of risk and the mechanisms underlying drug-induced fractures is important for informing both prescribing and patient monitoring practices.

Evaluation of gene modification strategies for the development of low-alcohol-wine yeasts.

Saccharomyces cerevisiae has evolved a highly efficient strategy for energy generation which maximizes ATP energy production from sugar. This adaptation enables efficient energy generation under anaerobic conditions and limits competition from other microorganisms by producing toxic metabolites, such as ethanol and CO(2). Yeast fermentative and flavor capacity forms the biotechnological basis of a wide range of alcohol-containing beverages. Largely as a result of consumer demand for improved flavor, the alcohol content of some beverages like wine has increased. However, a global trend has recently emerged toward lowering the ethanol content of alcoholic beverages. One option for decreasing ethanol concentration is to use yeast strains able to divert some carbon away from ethanol production. In the case of wine, we have generated and evaluated a large number of gene modifications that were predicted, or known, to impact ethanol formation. Using the same yeast genetic background, 41 modifications were assessed. Enhancing glycerol production by increasing expression of the glyceraldehyde-3-phosphate dehydrogenase gene, GPD1, was the most efficient strategy to lower ethanol concentration. However, additional modifications were needed to avoid negatively affecting wine quality. Two strains carrying several stable, chromosomally integrated modifications showed significantly lower ethanol production in fermenting grape juice. Strain AWRI2531 was able to decrease ethanol concentrations from 15.6% (vol/vol) to 13.2% (vol/vol), whereas AWRI2532 lowered ethanol content from 15.6% (vol/vol) to 12% (vol/vol) in both Chardonnay and Cabernet Sauvignon juices. Both strains, however, produced high concentrations of acetaldehyde and acetoin, which negatively affect wine flavor. Further modifications of these strains allowed reduction of these metabolites.

Vaginal mucosa serves as an inductive site for tolerance.

These data demonstrate that tolerance can be induced by vaginal Ag exposure. In these experiments, mice were given vaginal agarose gel suppositories containing either 5 mg OVA or saline for 6 h. Mice were given suppositories either during the estrous (estrogen dominant) or diestrous (progesterone dominant) stage of the estrous cycle. Mice were restrained during the inoculation period to prevent orovaginal transmission of the Ag. After 1 wk, mice were immunized s. c. with OVA in CFA. After 3 wk, mice were tested for delayed-type hypersensitivity responses by measuring footpad swelling and measuring in vitro proliferation of lymphocytes to Ag. Using ELISA, the magnitude of the serum Ab response was also measured. In some mice, FITC conjugated to OVA was used to track the dissemination of the protein into the systemic tissues. The magnitude of footpad swelling was significantly reduced in mice receiving OVA-containing suppositories during estrus compared with mice receiving saline suppositories. Concomitant decreases in the Ag-specific proliferative response were also observed in lymph node lymphocytes and splenocytes. Conversely, mice inoculated during diestrus did not show a decreased response to Ag by either footpad response or in vitro proliferation. Serum Ab titers in the estrus-inoculated mice did not decrease significantly. These data demonstrate that the reproductive tract can be an inductive site for mucosally induced tolerance. However, unlike other mucosal sites such as the lung and gastrointestinal tract, reproductive tract tolerance induction is hormonally regulated.

Delayed type hypersensitivity: current theories with an historic perspective.

Although the delayed type hypersensitivity (DTH) reaction was discovered over 100 years ago, the exact nature of the reaction has been the subject of contentious debate over the years. The reaction was discovered in 1882 by Robert Koch, but it was not until the 1940s that Landsteiner and Chase proved that the reaction was mediated by the cellular and not the humoral arm of the immune system. The first DTH reaction described used only the tuberculin antigen (tuberculin reaction), but the definition was later expanded to include cell mediated reactions to other bacterial and viral antigens, responses to pure protein with adjuvant or haptens, and host responses to allograft. The DTH skin test is used to test if prior exposure to an antigen has occurred. When small quantities of antigen are injected dermally, a hallmark response is elicited which includes induration, swelling and monocytic infiltration into the site of the lesion within 24 to 72 hours. This reaction has been shown to be absolutely dependent on the presence of memory T cells. Both the CD4+ and CD8+ fractions of cells have been shown to modulate a response. Contemporary debate regarding the reaction is focused on the role of the Th1 and Th2 cells originally discovered by Mosmann. It has been postulated that the Th1 cell is the "inducer" of a DTH response since it secretes interferon gamma (IFN ), a potent stimulator of macrophages, while the Th2 cell is either not involved or acting as a downregulator of the cell mediated immune response. Despite the early experimental success of this theory, experiments have shown that Th2 cells may be involved in certain types of proinflammatory cell mediated immunity. This review focuses on the nature of the different forms of DTH that can be elicited and the different experimental evidence that has led to the current theories regarding DTH and its role in cell mediated immunity.

Increased severity of Candida vaginitis in BALB/c nu/nu mice versus the parent strain is not abrogated by adoptive transfer of T cell enriched lymphocytes.

The role of the host immune system in combating candidal infections in the vagina is poorly understood. A murine model of Candida vaginitis was used to elucidate the role of T cells in a candidal infection. Athymic BALB/c nu/nu mice or normal BALB/c mice were induced into estrus and then infected with 1 x 10(6) Candida albicans intravaginally. The infection was monitored over 1 week. Samples from blood, small intestine, tongue, kidney, spleen, liver, uterus and vagina were tested for recoverable C. albicans. Histology of the vagina was assessed for both inflammation and extent of infection. Results indicated that the BALB/c nu/nu mice had similar levels of vaginal yeast load to the normal BALB/c mice. In 25-30% of nude mice Candida was also recovered from extra vaginal sites (kidney, liver, small intestine), however, extra vaginal dissemination was not observed in any normal BALB/c animals. Histologically, both the nu/nu and control BALB/c had similar levels of vaginal inflammation; however, the nu/nu mice had more florid fungal growth in the vaginal epithelium. Adoptive transfer of either immune or non-immune BALB/c T cells into nude mice had no affect on either infection or vaginal inflammation. Immunohistochemical staining of vaginal tissues from normal BALB/c mice or nude mice adoptively transferred with either immune or non-immune T cells with anti-CD3 monoclonal antibody revealed no significant difference between groups in the numbers of CD3+ vaginal T cells. However, in mice receiving either immune or non-immune T cells no yeast was recovered from any tissues except the vagina. These data show that T cells have a limited role in protecting the vagina from C. albicans infection.

Acute neutropenia decreases inflammation associated with murine vaginal candidiasis but has no effect on the course of infection.

We have used a mouse model of vaginal candidiasis to determine the effect of neutrophil depletion on (a) the clearance of Candida albicans and (b) the degree of inflammation associated with infection. No differences in recoverable yeast number or rate of clearance were observed between normal and neutrophil-depleted mice; however, vaginal inflammation was significantly decreased in neutrophil-depleted animals.

Comparative study of risk factors for skin breakdown with cervical orthotic devices: Philadelphia and Aspen.

PURPOSE: To compare risk factors for skin breakdown between Philadelphia and Aspen cervical collars. METHODS: Crossover design. Twenty healthy volunteers wore Philadelphia and Aspen cervical collars in random order. Occipital pressure, relative skin humidity, and skin temperature measured at 0 and 30 minutes. Paired t-tests compared changes between collars from 0 to 30 minutes. FINDINGS: Occipital pressure and skin temperature were not statistically different between collars. Relative skin humidity increased more in Philadelphia (29% +/- 17%) than Aspen (8% +/- 9%), p < 0.001. CONCLUSIONS: Aspen resulted in lower relative skin humidity.

A brief history of the discovery of the immunoglobulins and the origin of the modern immunoglobulin nomenclature.

On the 30th anniversary of the discovery of IgE, the last immunoglobulin identified, the discovery and subsequent naming of the immunoglobulins is recounted. The first immunoglobulin-like protein to be discovered was the Bence Jones protein or light chain in 1845. Over 100 years, later, the final isotype, IgE, was discovered. During this century, there have been various names for what we now know as IgA, IgD, IgE, IgG and IgM. There was also confusion over what constituted a "new' immunoglobulin and how it should be named. As a result the current nomenclature seems arbitrary; however, it reflects both a historical tradition of preserving the original name of the protein as well as a rational system designed in the early 1960s to codify the basic proteins of the humoral response.

Hapten-induced model of murine inflammatory bowel disease: mucosa immune responses and protection by tolerance.

We report here a murine model for experimental chronic colitis where administration of trinitrobenzene sulfonic acid (TNBS) in 50% ethanol induced inflammation of large intestine in susceptible (C3H/HeJ and BALB/c) but not resistant (C57BL/6 and DBA/2) mouse strains. We queried whether mucosal trinitrophenyl (TNP)-specific B cell responses were induced in mice with TNBS-induced colitis, and if induction of tolerance to TNBS by oral administration of this hapten protected mice from development of colitis. Isotypes and subclasses of polyclonal and TNP-specific Ab-forming cells (AFC) were assessed in mucosal and peripheral lymphoid tissues of C3H/HeJ mice with TNBS-induced colitis. Increased numbers of IgA- and IgG-secreting cells were found in the inflamed colon lamina propria. Inflamed colonic tissue also contained high frequencies of IgG anti-TNP AFC (predominantly of IgG1, IgG2a, and IgG2b subclasses); however, anti-TNP responses in noninflamed mucosal tissues of mice with colitis exhibited dominant IgA and IgM with low IgG anti-TNP responses. CD4+ T cells stimulated with TNP-splenocytes produced more IFN-gamma and less IL-4, suggesting a Th1-type response. Oral administration of TNBS before induction of colitis markedly decreased mucosal anti-TNP responses and completely inhibited anti-TNP IgG2a and IgG2b responses. Control mice did not show inhibition of anti-TNP AFC responses or TNBS-induced colitis. Intracolonic sensitization of susceptible C3H/HeJ mice with TNBS induces a localized IgG anti-TNP B cell response in the inflamed tissue, whereas prior oral administration of TNBS results in unresponsiveness to this agent and protects mice from development of TNBS-induced colitis.

Differences in intraepithelial lymphocyte T cell subsets isolated from murine small versus large intestine.

Intraepithelial lymphocytes (IELs) have been extensively studied in the murine small intestine. However, to date no studies have assessed IEL in the large intestine, despite the marked differences in function and lumenal environment. In the present study, we isolated IEL from both small and large intestine of three mouse strains (BALB/c, C3H/HeN, C57BL/6) and determined the frequency of CD2, CD4, and CD8 expression on CD3+ IEL, as well as the frequency of alpha beta and gamma delta TCR usage and V beta distribution. Higher numbers of IEL/unit length were always isolated from the small intestine (20-30 x 10(6)/5 mice) compared with large intestine (1.1-2.5 x 10(6)/5 mice). Interestingly, IEL from the large intestine of all strains were predominantly alpha beta TCR+ whereas gamma delta TCR+ IELs predominated in small intestine. Large intestinal IELs were mainly CD4+, in both BALB/c and C3H/HeN mouse strains. IELs from large intestine of C57BL/6 mice were mainly CD8+; however, the CD4+ subset was fourfold higher when compared with small intestine IEL. Potential functional differences between IEL subsets was assessed by determining the relative levels of mRNA for IL-1, 2, 4, 5, 10, IFN-gamma, TGF-beta, and TNF-gamma. Similar patterns of IL-1, IFN-gamma and TNF-alpha were seen while more IL-2, IL-4, IL-5, and IL-10 mRNA was noted in large intestinal IEL. Stimulation of C3H/HeJ IEL with anti-CD3 also resulted in higher levels of IL-3/GM-CSF, IL-4, and IL-6 by IEL from large intestine. These results show that marked differences occur among the T cell subsets present in IELs from mouse small and large intestine.

Peyer's patch CD8+ memory T cells secrete T helper type 1 and type 2 cytokines and provide help for immunoglobulin secretion.

Analysis of cytokine gene expression by reverse transcription-polymerase chain reaction (RT-PCR) demonstrated high spontaneous levels of transcripts for multiple cytokines in murine Peyer's patches (PP) compared to spleen and peripheral lymph nodes. This is consistent with the presence of active germinal centers in PP and their continuous exposure to lumenal antigen including bacterial endotoxin. RT-PCR analysis of cytokine transcripts in purified PP T cell populations revealed the presence of transcripts for interleukin-4 (IL-4), IL-5 and IL-10 in addition to interferon-gamma (IFN-gamma) in CD8+ cells purified by flow cytometry. The majority of PP CD8+ T cells were also CD45RBlo (MB23G2-), suggesting that these cells were activated/memory cells. CD8+ cells in spleen and mesenteric lymph nodes (MLN) were predominantly CD45RBhi (MB23G2+) consistent with a resting/naive phenotype. PP and MLN CD8+ T cells also secreted IL-5 and IL-10 when stimulated with anti-CD3 monoclonal antibody and when co-cultured with PP B cells enhanced secretion of both IgG and IgA. These studies suggest that CD8+ T cells at mucosal sites secrete T helper type 2 cytokines and can provide functional help for B cells in these tissues.

The Mycobacterium tuberculosis 71-kDa heat-shock protein induces proliferation and cytokine secretion by murine gut intraepithelial lymphocytes.

Murine intraepithelial lymphocytes (IEL) respond poorly to T cell mitogens and to monoclonal antibody stimulation of T cell receptor (TCR)- and CD3- associated molecules. In contrast, we found that a soluble extract of Mycobacterium tuberculosis (Mtb), but not purified protein derivative of tuberculin, induced significant proliferative responses in IEL cultures. The active component was apparently a heat shock protein (HSP), since recombinant 71-kDa HSP from Mtb induced IEL to proliferate, while 65-kDa HSP from M. bovis and M. leprae did not. Both alpha/beta and gamma/delta TCR-enriched IEL gave proliferative responses to 71-kDa HSP. Further, culture supernatants from IEL stimulated with 71-kDa HSP contained elevated levels of interleukin-(IL)-3/granulocyte-macrophage colony-stimulating factor, interferon-gamma and IL-6, but not IL-2, IL-4, IL-5 or transforming growth factor-beta. Finally, several IEL T cell clones have been maintained for up to 6 weeks, when stimulated with 71-kDa HSP, IL-2 and feeder cells. Our results show that the 71-kDa HSP of Mtb induces IEL T cells to divide and to secrete cytokines and this may offer a model for cloning and study of IEL T cells in vitro.

Sexual abuse in male children and adolescents: indicators, effects, and treatments.

It is believed by many that the sexual abuse of children and adolescents is primarily perpetrated against females. This article presents a review of the literature on the incidence, indicators, effects, and treatment of sexual abuse in males.

Mucocutaneous lymph node syndrome in North Louisiana: review of 15 cases.

Mucocutaneous lymph node syndrome (MLNS) is being more frequently reported in the United States, and it appears to be an important disease of childhood. Fifteen infants and children with MLNS were treated at the Louisiana State University teaching hospitals in Shreveport and Monroe between August 1978 and January 1981. A cluster of nine of the cases (60%) occurred between February and May 1980. In this series the male to female ratio was 2:1, and 53% of the patients were between 11 and 15 months of age. In five of the patients, platelet counts and erythrocyte sedimentation rates were monitored for at least four weeks.

Amphetamine stereotypy is not a homogeneous phenomenon: sniffing and licking show distinct profiles of sensitization and tolerance.

Sniffing and licking components of amphetamine-induced stereotypy were studied separately during chronic drug treatment. Sniffing showed a gradual increase, or sensitization, in intensity and duration. By contrast, licking developed tolerance for approximately the first 21 days, followed by a progressive increase. Stereotypy is therefore not a homogeneous phenomenon, and sniffing and licking are probably subserved by distinct neuroanatomic substrates. The sensitization of sniffing behavior may be related to the induction of amphetamine-induced paranoid psychosis in humans.

Interchangeability of stress and amphetamine in sensitization.

In view of similarities between the behavioral, biochemical, and electrophysiological effects of amphetamine and stress, we tested the hypothesis that presentation of a stressor, mild tail pressure, can sensitize an animal to the later effects of amphetamine, and vice versa. Our findings supported this hypothesis and suggest that amphetamine and at least some stressors may be interchangeable in their ability to induce a sensitization. The data raise the possibility that stress might be a common variable contributing to both amphetamine psychosis and some forms of schizophrenia.