Biliary dyskinesia: a study of more than 200 patients and review of the literature

The aim of this study was to establish, by means of peripheral quantitative computed tomography (pQCT) at the distal radius, the existence of cortical and/or trabecular osteopenia, and to assess the integrity of bone geometry in uremic patients undergoing maintenance hemodialysis. Our results show a clearcut selective reduction in volumetric cortical density, more evident in women (p = -0.0001) than men (p = 0.030), which appears to be independent of age and menopausal status. Trabecular density was not significantly changed in either sex. Cortical density of the patients correlated inversely with age (p = 0.003), duration of dialysis (p = 0.002) and parathyroid hormone (PTH) levels (p = 0.03). Trabecular density correlated only with age. Normally, cortical density is age-dependent and its reduction is accompanied by compensatory geometry changes. Compared with control subjects, in our female patients both cortical area and cortical thickness were reduced (p = 0.02 and 0.008), while cross-sectional area did not change (p = 0.67). Conversely, in the males only cross-sectional area was reduced (p = 0.02). In conclusion, in uremic patients we observed a selective cortical osteopenia, more evident in the female sex, and a sex-specific pattern of geometry impairment, with resultant apparent increased bone fragility in the uremic women. We suggest that the prolonged PTH excess could be responsible, directly and/or interacting with estrogen deficiency.     

Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques

This study investigated the sources of quinolinic acid, a neurotoxic tryptophan-kynurenine pathway metabolite, in the brain and blood of HIV-infected patients and retrovirus-infected macaques. In brain, quinolinic acid concentrations in HIV-infected patients were elevated by > 300-fold to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma. Because nonretrovirus-induced encephalitis confounds the interpretation of human postmortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations and determine the relationships of quinolinic acid to encephalitits and systemic responses. The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses. CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus-induced encephalitis. In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis vs. those without. Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almost all quinolinic acid (>98%) was synthesized locally within the brain. These results demonstrate a role for induction of indoleamine-2,3dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood. Strategies to reduce QUIN production, targeted at intracerebral sites, are potential approaches to therapy.     

HLA-DQ6 and HLA-DQ8 transgenic mice respond to ragweed allergens and recognize a distinct set of epitopes on short and giant ragweed group 5 antigens

We have investigated the genetic and molecular basis of immune responsiveness to short ragweed (SRW) (Ambrosia artemisiifolia) extract, and group 5 allergens from short and giant (Ambrosia trifida) ragweed using transgenic mice expressing DQ6 (HLA-DQA1*0103, HLA-DQB1*0601) and DQ8 (HLA-DQA1*0301, HLA-DQB1*0302) genes in class II knockout (A beta0) mice. Panels of overlapping peptides spanning the Amb a 5 and Amb t 5 Ags were synthesized. Mice were immunized with whole SRW extract or individual peptides s.c. and lymph node cells (LNC) were challenged in vitro. Strong T cell responses to SRW extract were measured in both HLA-DQ transgenic mice, while control, HLA-DQ6-/DQ8-/H-2A beta0, mice were unresponsive. IL-5 and IL-10 were the primary cytokines produced by in vitro challenged LNC of SRW-primed transgenic mice. HLA-DQ6-restricted T cell responses were detected to all three peptides of Amb t 5 and two determinants (residues 1-20 and 11-30) on Amb a 5. In contrast, LNC of HLA-DQ8 mice did not recognize peptide 11-30 of Amb t 5 Ag, but recognized several Amb a 5 determinants. The immune response in transgenic mice was dependent upon CD4+ T cells and was HLA-DQ restricted. Primed with purified Amb t 5, both transgenics recognized peptide 21-40, and an additional DQ6-restricted epitope was found within residue 1-20. SRW-immunized HLA-DQ6 mice respond to peptide 11-30 of Amb a 5, while HLA-DQ8 mice strongly recognize peptide 1-20. These results demonstrate the specificity of HLA class II polymorphism in allergen sensitivity and pave the way for developing antagonistic peptides for desensitization.     

Proteome analysis: biological assay or data archive?

In this review we examine the current state of proteome analysis. There are three main issues discussed: why it is necessary to study proteomes; how proteomes can be analyzed with current technology; and how proteome analysis can be used to enhance biological research. We conclude that proteome analysis is an essential tool in the understanding of regulated biological systems. Current technology, while still mostly limited to the more abundant proteins, enables the use of proteome analysis both to establish databases of proteins present, and to perform biological assays involving measurement of multiple variables. We believe that the utility of proteome analysis in future biological research will continue to be enhanced by further improvements in analytical technology.     

Effect of antisense oligodeoxynucleotides directed to individual calmodulin gene transcripts on the proliferation and differentiation of PC12 cells

Myocarditis has been shown to be a common cause of cardiomyopathy and is believed to account for 25% of all cases in human beings. Unfortunately, the disease is difficult to detect before a myopathic process ensues. Treatment of myocarditis-induced heart failure includes the standard regimen of diuretics, digoxin, angiotensin-converting enzyme inhibitors, and currently, beta-adrenergic blockers. Treatment of myocarditis itself is dependent on the etiology of the illness. Treatments under investigation include immunosuppressants, nonsteroidal antiinflammatory agents, immunoglobulins, immunomodulation, antiadrenergics, calcium-channel blockers, angiotensin-converting enzyme inhibitors, nitric oxide inhibition (e.g., aminoguanidine), and antiviral agents. Despite advances in treatment, more work needs to be done in the early detection of myocarditis. Additionally, better means need to be established for distinguishing between viral and autoimmune forms of the disease, so that appropriate treatment can be instituted.     

Cloning of human p55 gamma, a regulatory subunit of phosphatidylinositol 3-kinase, by a yeast two-hybrid library screen with the insulin-like growth factor-I receptor

The study was performed on 30, 8-year-old children living in an industrial town of the Upper Silesia region. Morning urine samples were collected on 6 consecutive days. Intraindividual variation of urinary 1-hydroxypyrene concentrations, calculated as a coefficient of variance (CV), ranged from 14 to 109% whereas inter-individual variation ranged from 69 to 109%. Three-way analysis of variance disclosed a significant effect of sex, exposure to environmental tobacco smoke and day of examination on 1-hydroxypyrene concentrations not corrected for creatinine. The appropriate sample size for population studies and the minimum number of observations for the individual assessment of environmental exposure to PAHs calculated on the basis of inter- and intraindividual variability of 1-hydroxypyrene concentrations in urine amounted to 164 and 99, respectively. Urinary 1-hydroxypyrene may be considered a good indicator of environmental exposure to PAHs at the group level.     

Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I

Infertility is a common feature of the human disorder ataxia-telangiectasia and Atm-deficient mice are completely infertile. To gain further insight into the role of ATM in meiosis, we examined meiotic cells in Atm-deficient mice during development. Spermatocyte degeneration begins between postnatal days 8 and 16.5, soon after entry into prophase I of meiosis, while oocytes degenerate late in embryogenesis prior to dictyate arrest. Using electron microscopy and immunolocalization of meiotic proteins in mutant adult spermatocytes, we found that male and female gametogenesis is severely disrupted in Atm-deficient mice as early as leptonema of prophase I, resulting in apoptotic degeneration. A small number of mutant cells progress into later stages of meiosis, but no cells proceed beyond prophase I. ATR, a protein related to ATM, DMC1, a RAD51 family member, and RAD51 are mislocalized to chromatin and have reduced localization to developing synaptonemal complexes in spermatocytes from Atm-deficient mice, suggesting dysregulation of the orderly progression of meiotic events. ATM protein is normally present at high levels primarily in ova cytoplasm of developing ovarian follicles, and in the nucleus of spermatogonia and to a lesser extent in spermatoctyes, but without localization to the synaptonemal complex. We propose a model in which ATM acts to monitor meiosis by participation in the regulation or surveillance of meiotic progression, similar to its role as a monitor of mitotic cell cycle progression.     

Growth response of human coronary smooth muscle cells to angiotensin II and influence of angiotensin AT1 receptor blockade

BACKGROUND: Adolescents and young adults are four times more likely to be victims of sexual assault than women in all other age groups. In the vast majority of these cases, the perpetrator is an acquaintance of the victim. Date rape is a subset of acquaintance rape where nonconsensual sex occurs between two people who are in a romantic relationship. METHODS: We conducted a MEDLINE and Current Concepts search for articles relating to date rape and then systematically reviewed all relevant articles. RESULTS: Lifetime prevalence of date or acquaintance rape ranges from 13% to 27% among college-age women and 20% to a high of 68% among adolescents. Demographic characteristics that increase vulnerability to date rape include younger age at first date, early sexual activity, earlier age of menarche, a past history of sexual abuse or prior sexual victimization, and being more accepting of rape myths and violence toward women. Other risk factors include date-specific behaviors such as who initiated, who paid expenses, who drove, date location and activity, as well as the use of alcohol or illicit drugs such as flunitrazepam (Rohypnol). Alcohol use that occurs within the context of the date can lead to: the misinterpretation of friendly cues as sexual invitations, diminished coping responses, and the female's inability to ward off a potential attack. CONCLUSIONS: Longitudinal research designs are needed to further our understanding of sexual violence among adolescents and young adults and the most effective ways to eliminate it. Understanding and comparing research findings would be easier if consensus regarding the definitions of date rape, sexual aggression, and sexual assault was obtained. Finally, primary and secondary date and acquaintance rape prevention programs must be developed and systematically evaluated.     

Activity-based cost management. Part II: Applied to a respiratory protection program

The ability of IL-12 and IL-15 to enhance natural killer (NK) activity and antibody-dependent cellular cytotoxicity (ADCC) of mononuclear cells (MNCs) from HIV+ children and their mothers was investigated. MNCs from HIV+ patients were deficient in NK and ADCC activity compared to control MNCs against several target cells. Overnight incubation with IL-15 or IL-12 augmented NK activity of MNCs from both patients and controls, and the combination of IL-12 and IL-15 resulted in the greatest enhancement. ADCC in HIV+ patients against gp120-coated CEM.NKR cells or chicken erythrocytes could also be enhanced by IL-2 or IL-15 in overnight cultures. Culturing MNCs with either IL-2 or IL-15 for 1 week increased the NK activity in patients to levels of controls treated with these cytokines. However, the response to the combination of IL-12 and IL-15 was less than that to IL-15 alone in 1-week cultures. Culturing MNCs with IL-2 and IL-15 for 1 week also increased the percentage of CD16+/CD56+ cells in both patients and controls. Thus, IL-15 can restore the deficient NK activity in patients and may be a candidate for immunomodulative therapy in HIV+ patients.     

Dynamic mechanical compression influences nitric oxide production by articular chondrocytes seeded in agarose

Nitric oxide (NO) has been implicated in the inhibition of cell proliferation in cytokine and lipopolysaccharide (LPS)-stimulated chondrocytes and is known to be influenced by physical forces in several tissues. In this study, a well-characterized model system utilizing bovine chondrocytes embedded in 3% agarose constructs has been used to investigate the effect of dynamic strain at 0.3, 1, or 3 Hz on NO production. LPS induced a significant increase in nitrite levels, which was reversed by both L-NAME and dexamethasone. Dynamic compressive strain produced a significant reduction in nitrite production. The effect was partially blocked by L-NAME but unaffected by dexamethasone. L-NAME also reversed dynamic compression-induced stimulation of [3H]-thymidine incorporation. NO appears to be a constituent of mechanotransduction pathways which influence proliferation of bovine chondrocytes seeded within agarose constructs. The inhibitor experiments also infer that alterations in cNOS activity primarily determine the response.