Disclosure of diagnosis of multiple sclerosis in the workplace positively affects employment status and job tenure.

BACKGROUND: For many employees with multiple sclerosis (MS), disclosure of their diagnosis at work is seen as a high-risk strategy that might lead to diminished perceptions of their capabilities by supervisors and colleagues, if not outright discrimination. The consequence of this mistrust surrounding the disclosure process is that employees with MS may leave it until too late to effectively manage symptoms at work. OBJECTIVE: The objective of this paper is to statistically evaluate the relationship between disclosure of diagnosis at work and maintenance of employment. METHODS: Three annual, large-sample self-report surveys of MS patients prospectively examined the relationship between disclosure of diagnosis at work and employment status. A total of 1438 people responded to all three surveys. Of employed persons in 2010 (n = 946), 673 also responded to the 2012 survey. Of these 673 respondents 564 were still employed. RESULTS: People who had disclosed their MS status to an employer were more likely to remain in employment in Year 3. The effect of disclosure in predicting employment status remained after controlling for age, gender, hours worked and level of disability. CONCLUSION: This study provides the first empirical support for the positive role of disclosure in maintaining employment status, measured both as job retention and tenure in current employment.

Ten-year mortality trends among persons diagnosed with HIV infection in England and Wales in the era of antiretroviral therapy: AIDS remains a silent killer.

OBJECTIVES: We present national trends in death rates and the proportion of deaths attributable to AIDS in the era of effective antiretroviral therapy (ART), and examine risk factors associated with an AIDS-related death. METHODS: Analyses of the national HIV-infected cohort for England and Wales linked to death records from the Office of National Statistics were performed. Annual all-cause mortality rates were calculated by age group and sex for the years 1999-2008 and rates for 2008 were compared with death rates in the general population. Risk factors associated with an AIDS-related death were investigated using a case-control study design. RESULTS: The all-cause mortality rate among persons diagnosed with HIV infection aged 15-59 years fell over the decade: from 217 per 10 000 in 1999 to 82 per 10 000 in 2008, with declines in all age groups and exposure categories except women aged 50-59 years and persons who inject drugs (rate fluctuations in both of these groups were probably a result of small numbers). Compared with the general population (15 per 10 000 in 2008), death rates among persons diagnosed with HIV infection remained high, especially in younger persons (aged 15-29 years) and persons who inject drugs (13 and 20 times higher, respectively). AIDS-related deaths accounted for 43% of all deaths over the decade (24% in 2008). Late diagnosis (CD4 count < 350 cells/µL) was the most important predictor of dying of AIDS [odds ratio (OR) 10.55; 95% confidence interval (CI) 8.22-13.54]. Sixty per cent of all-cause mortality and 81% of all AIDS-related deaths were attributable to late diagnosis. CONCLUSIONS: Despite substantial declines, death rates among persons diagnosed with HIV infection continue to exceed those of the general population in the ART era. Earlier diagnosis could have prevented 1600 AIDS-related deaths over the decade. These findings highlight the need to intensify efforts to offer and recommend an HIV test in a wider range of clinical and community settings.

Effect of repeated oral administration of hypertonic electrolyte solution on equine gastric mucosa.

REASONS FOR PERFORMING STUDY: Electrolyte supplementation is common in horses during endurance competitions, but the effect on the gastric mucosa is unknown. HYPOTHESIS: Repeated oral administration of hypertonic electrolyte solution is associated with exacerbation of gastric ulcers in mature horses. METHODS: The study design was a randomised, blinded, crossover trial. Fourteen horses were divided randomly into equal groups and administered either 60 ml water (placebo) or 56.7 g commercial electrolyte supplement mixed with 60 ml water by dose syringe orally once an hour for 8 h. The minimum concentration of individual constituent electrolytes/28.35 g dry commercial product used was: sodium (5528 mg); chloride (11,886 mg); potassium (3657 mg); calcium (754 mg); and magnesium (153 mg). Gastric lesions were scored prior to and after oral treatments, and analysis of variance procedures were then performed. RESULTS: Administration of hypertonic electrolytes resulted in a significant increase in mean ulcer number (P = 0.0174) and severity (P = 0.0006) scores in the nonglandular stomach. Mean ulcer number score was 3.6 and mean ulcer severity score 2.7 after hypertonic electrolyte treatment. CONCLUSIONS: Oral hypertonic electrolyte administration to horses in this model was associated with exacerbation of gastric ulcers. POTENTIAL RELEVANCE: Our findings suggest that one schedule of electrolyte supplementation used commonly in endurance horses may be harmful to the gastric mucosa.

Prevalence survey of multiple sclerosis in the Australian Capital Territory.

AIM: This study sought to obtain an estimate of the prevalence of multiple sclerosis (MS) in the Australian Capital Territory (ACT), a largely urban region that differs climatically and socioeconomically from other Australian cities examined in previous MS surveys. METHODS: Prevalence day was chosen to coincide with the 1996 National Census. All ACT neurologists' records for the previous 5 years were examined and cases of MS were classified according to the published diagnostic criteria of Rose et al. and Poser et al. RESULTS: By the criteria of Rose et al., as used in previous Australian surveys of MS, prevalence was 79.9/100,000 (95% confidence interval (CI) = 63.4-99.2) for females, 32.8 (22.7-46.2) for males and 56.7 (43.1-74.1) for all people, standardized to the 1996 population. Standardized to the 1981 population for direct comparison with 1981 surveys in New South Wales, the prevalence of MS in the ACT was still unexpectedly high, particularly for females. Using the criteria of Poser et al., the prevalence of MS standardized to the 1996 population was 70.6/ 100,000 (95% CI = 58.4-85.3) for females, 28.0 (20.3-37.8) for males and 49.5 (42.2-58.2) for all people. There was evidence from a relatively short duration of disease in the ACT sample that some persons with long-standing MS had been missed in the survey and therefore that the prevalence of MS observed in the ACT was an underestimate. CONCLUSIONS: The survey found an unexpectedly high prevalence of MS in the ACT. Possible reasons for this are discussed. There was no evidence that the advent of magnetic resonance imaging had increased the numbers of persons diagnosed with MS in the present survey.

CCK peptides with combined features of hexa- and tetrapeptide CCK-A agonists.

Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of tetrapeptides, and most recently a series of benzodiazepines. The SAR of the hexa- and tetrapeptide classes suggests that the Hpa(SO(3)H) and Tac groups may not interact at the CCK-A receptor in the same location. However, the C-terminal dipeptide part of the hexapeptides and tetrapeptides appear to interact at the CCK-A receptor in a similar manner. Compound 7 (Hpa-Nle-Gly-Trp-Lys(Tac)-Asp-MePhe-NH(2)) derived from combining the features of the hexapeptides and the tetrapeptides has subnanomolar affinity and 3500-fold selectivity for CCK-A receptors. Compound 7 administered intraperitoneally produces potent, long-lasting reduction in food intake in rats and a corresponding weight loss when administered over nine consecutive days.

Behavioral effects of AR-R 15849, a highly selective CCK-A agonist.

The behavioral effects of AR-R 15849, a novel cholecystokinin agonist with high affinity and selectivity for the CCK-A receptor subtype, were examined. Initially, using an operant feeding paradigm to test for anorectic activity and specificity, acute administration of AR-R 15849 was found to alter the intake and pattern of feeding in a manner similar to prefeeding. Further, AR-R 15849 did not induce compensatory feeding as did CCK-8, and did not affect performance on running rates of responding, or motor activity on a running wheel, as did fenfluramine. In tests for subchronic anorectic activity, daily intraperitoneal injections of AR-R 15849 significantly reduced food intake in fasted rats over a 9-day test period with greater efficacy compared to its nonselective predecessor AR-R 14294 (formerly FPL 14294). The sustained decrease in food intake with AR-R 15849 treatment resulted in a significant reduction in body weight gain over 9 days. Finally, an experiment designed to determine the effect of caloric deprivation and subchronic drug exposure on the overall efficacy of AR-R 15849 indicated that pharmacological tolerance does not develop following subchronic treatment.

ARL 15849: a selective CCK-A agonist with anorectic activity in the rat and dog.

Cholecystokinin octapeptide (CCK-8) and the peptide analog ARL 14294, formerly FPL 14294, [Hpa(SO3H)-Met-Gly-Trp-Met-Asp-N(Me)Phe-NH2], have been reported to induce satiety by interaction with the CCK-A receptor subtype. ARL 15849 [Hpa(SO3H)-Nle-Gly-Trp-Nle-N(Me)-Asp-Phe-NH2] is an improved ARL 14294 analog with enhanced CCK-A receptor selectivity, greater stability, and a longer duration of action. The affinity of ARL 15849 for the CCK-A receptor (Ki = 0.034 nM) is 6,600 fold greater than for the CCK-B receptor (Ki = 224 nM), whereas CCK-8 and ARL 14294 are nonselective. Although comparable in potency to contract isolated gallbladder and induce pancreatic phosphatidylinositol hydrolysis, ARL 15849 is 3- and 100-fold more potent than ARL 14294 and CCK-8, respectively, to inhibit 3-h feeding in rats. The duration of feeding inhibition was significantly longer for ARL 15849 (>5 h), compared to equipotent doses of ARL 14294 (3 h), and CCK-8 (1 h). Intranasal administration of ARL 15849 inhibits feeding in beagle dogs with a greater separation between doses that induce emesis and those that inhibit feeding. Therefore, ARL 15849 is a potent, selective, intranasally active anorectic agent which may be useful in the treatment of eating disorders.

Infusion of soluble myelin basic protein protects long-term against induction of experimental autoimmune encephalomyelitis.

Protection against experimental autoimmune encephalomyelitis (EAE) induced by s.c. infusion of myelin basic protein (MBP) alone is dose dependent and long lived. Protection is not effective against passively induced disease nor is it transferable with lymphoid cells. The proliferative response of lymph node cells to MBP following encephalitogenic challenge is decreased in the EAE-protected animals as is the production of IL-2 and IFN-gamma by these cells. Treatment with soluble MBP promed rats for antibody production is evidenced by the early appearance of anti-MBP antibody following encephalitogenic challenge. Determination of antibody isotype following challenge revealed a change in the ratio of IgG1 to IgG2a with a significant increase in the amount of IgG1 produced. These data suggest that infusion of high dose soluble neuroantigen primes the immune response such that subsequent challenge with an encephalitogenic inoculum pushes the response down a non-destructive Th2 autoimmune pathway.

Synthesis and biological evaluation of potent, selective, hexapeptide CCK-A agonist anorectic agents.

Cholecystokinin (CCK) is a 33-amino acid peptide with multiple functions in both the central nervous system (via CCK-B receptors) and the periphery (via CCK-A receptors). CCK mediation of satiety via the A-receptor subtype suggest a role for CCK in the management of obesity. The carboxy terminal octapeptide (CCK-8) is fully active in this regard, but is lacking in receptor selectivity, metabolic stability, and oral bioavailability. Inversion of the chirality of Asp7 in conjunction with N-methylation of Phe8 produces compound 5 which exhibits high affinity and 2100-fold selectivity for CCK-A receptors. Compound 6 (Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2), derived from moving the N-methyl group from Phe to Asp, decreased CCK-B affinity substantially without affecting CCK-A affinity, giving a compound with 6600-fold selectivity for CCK-A receptors. These compounds inhibit food intake with nanomolar potency following intraperitoneal administration in fasted rats. In addition to greater potency, compound 6 produces weight loss in rats when administered over nine consecutive days. Intranasal administration of 6 potently inhibits feeding in beagle dogs. Compound 6 produces potent anorectic activity via the CCK-A receptor system.

Studies on T-cell receptors involved in experimental autoimmune encephalomyelitis using the complementary peptide recognition approach.

Based upon Blalock's complementary recognition approach, a complementary or antisense peptide (CP) was designed to the experimental autoimmune encephalomyelitis (EAE) epitope peptide, rat myelin basic protein (MBP) peptide 72-82. This peptide (EAE CP) was shown to have some sequence similarities to T-cell receptors (TCR) and MHC II molecules in a sequence homology search. Solid-phase binding assays demonstrated specific and high affinity binding (3 and 4 microM) between the EAE CP and the rat and guinea pig EAE epitope peptides (Rt72-82 and Gp69-82), respectively. This EAE CP was also found to be immunogenic in rats in an ear swelling test for delayed type hypersensitivity (DTH) reactions and an ELISA for antibody responses. However, a rabbit antibody generated to EAE CP was shown to be unable to stain the V beta 8+ EAE susceptible T-cells in immunofluorescence analyses. This EAE CP was also used in attempts to down-regulate EAE and the results showed that prior immunization with EAE CP in complete Freund's adjuvant could not prevent the Lewis rats from developing EAE. Although the data on sense-antisense peptide interaction were positive and the EAE CP was immunogenic, the inability of EAE CP to regulate EAE indicates that the CP approach may not be generally applicable.

FPL 14294: a novel CCK-8 agonist with potent intranasal anorectic activity in the rat.

Cholecystokinin octapeptide (CCK-8) induces satiety in many species including man. However, its therapeutic utility is restricted due to its short biological half-life and poor bioavailability. FPL 14294 [4-(sulfoxy)-phenylacetyl(MePhe6)CCK-6] is a CCK analog with enhanced metabolic stability that was comparable to CCK-8 in potency to contract isolated gallbladder and in affinity at the CCK-A and CCK-B receptor. However, FPL 14294 was more than 200 times more potent than CCK-8 in inhibiting 3-h feeding in 21-h fasted rats. FPL 14294 also possessed intranasal anorectic activity at 5 micrograms/kg, while CCK-8 was inactive at doses up to 500 micrograms/kg. Anorectic activity was inhibited by pretreatment with a CCK-A antagonist (MK-329) but not by a CCK-B antagonist (L365,260). The anorectic effects of CCK-8 and FPL 14294 were the result of a direct effect on feeding and not caused indirectly by effects on water intake. These results indicate that FPL 14294 is a potent, intranasally active, anorectic agent whose enhanced in vivo potency over that of CCK-8 may reflect differences in stability, bioavailability, or receptor kinetics.

ICAM-1-dependent pathway is not critically involved in the inflammatory process of autoimmune encephalomyelitis or in cytokine-induced inflammation of the central nervous system.

To determine whether the rat homolog of intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) we examined the effect of anti-ICAM-1 mAb, 1A29, on both active and passive EAE. We also examined its effect on a model of cytokine-induced inflammation in the central nervous system. Treatment of recipients of EAE effector cells with anti-ICAM-1 had no inhibitory activity, and in fact at high doses, treatment enhanced disease as evidenced by an earlier onset of symptoms. Treatment of active EAE with anti-ICAM-1 beginning on the day of sensitization did protect a proportion of animals from development of disease as well as reduce the severity of clinical signs in those which developed symptoms. Lymphocytes from both the draining lymph nodes and spleens of myelin basic protein (MBP)-immunized rats treated with anti-ICAM-1 failed to proliferate in response to MBP in vitro, suggesting that the antibody had prevented the animals from becoming sensitized to the antigen. Microinjection of tumor necrosis factor (TNF)-alpha into the spinal cords of rats led to the expression of ICAM-1 on vascular endothelium, and to the accumulation of leukocytes at sites of injection. The peak expression of ICAM-1 by endothelium and the peak accumulation of leukocytes following TNF alpha injection were not positively correlated. Furthermore, treatment of TNF alpha injected rats with anti-ICAM-1 did not inhibit the accumulation of leukocytes at the site of cytokine injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Sialyl ligands facilitate lymphocyte accumulation during inflammation of the central nervous system.

Combined models of cytokine-induced inflammation in the skin and spinal cord of the rat were utilised to demonstrate in vivo that circulating lymphocytes depend upon sialylated adhesion molecules on their surface for maximal recruitment into inflammatory sites in both tissues. When radiolabelled normal spleen cells were incubated with sialidase from Vibrio cholerae or Clostridium perfringens, or with the specific sialic acid-binding lectin from Limax flavus, prior to being washed and injected intravenously into rats, they accumulated significantly less than untreated control cells into tumor necrosis factor (TNF)-activated spinal cord and skin. Pretreatment of splenocytes with sialidase plus the competitive inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DDN) partially restored the accumulation of radiolabelled cells at both inflammatory sites, providing evidence for the specificity of sialidase treatment and the importance of sialyl residues. Pretreatment of macrophage-depleted spleen lymphocytes, or ovalbumin-specific W3/25+ (CD4) cell line T lymphocytes with sialidase produced similar decrements in accumulation at inflammatory sites, demonstrating that lymphocytes, including memory T cells, were relying on sialyl ligands for maximal recruitment. Results from this in vivo study are interpreted as providing indirect evidence that inducible sialyl-binding molecules, probably of the 'selectin' type, occur to a functionally significant extent on activated central nervous system (CNS) endothelium. We speculate that such carbohydrate-binding adhesion molecules may play an important role in the recruitment of inflammatory cells during the formation of CNS lesions in diseases such as the encephalomyelitides and multiple sclerosis.

Suppression of active but not passive autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition.

Previous research has shown that the dual cyclo-oxygenase and 5-lipoxygenase inhibitor, BW755c suppresses experimental autoimmune encephalomyelitis (EAE). In the present study, the effects of BW755c on both actively and passively induced EAE in the Lewis rat were examined, and also its effect on the accumulation of radiolabeled spleen cells in response to direct injection of tumor necrosis factor into the spinal cord. It was found that BW755c suppressed actively induced EAE but not passively induced EAE nor cytokine-induced cell accumulation in the central nervous system. It is concluded that arachidonic acid metabolites may be important in the induction phase of EAE, but do not appear to be crucial to the effector phase of EAE.

Lymphocytes utilise sialylated surface molecules to accumulate in developing lesions of autoimmune encephalomyelitis.

The accumulation of desialylated radiolabelled normal spleen cells and non-neuroantigen specific CD4 T-lymphocytes was measured in the lumbosacral spinal cord of Lewis rats with autoimmune encephalomyelitis (EAE) induced with myelin basic protein in Freund's adjuvant. The labelled cells were preincubated with sialidase and thoroughly washed prior to intravenous injection into rats exhibiting early clinical signs of EAE. Four hours later, the rats were killed and blood and spinal cord samples were radioassayed. Compared with untreated cells, desialylation markedly reduced the accumulation of both normal spleen cells and memory T-lymphocytes in the spinal cord, despite similar levels of cells being present in the blood. In another experiment, the accumulation of desialylated, macrophage-depleted spleen lymphocytes was measured during the onset, recovery and short-term "relapse" phases of acute EAE. Again, compared with controls the accumulation of desialylated lymphocytes was always significantly less, despite similar numbers of cells in the circulation. Lastly, intravenous injections of sialidase produced delayed onset of both clinical and histological signs in rats with passively-transferred EAE. These data confirm and extend previous findings, using a different animal model, that sialyl residues on the lymphocyte surface are important to the accumulation of such cells at inflammatory sites in the central nervous system. The possible relevance of these findings to human demyelinating disease is discussed.

Direct injection of cytokines into the spinal cord causes autoimmune encephalomyelitis-like inflammation.

A single micro-injection of Tumour Necrosis Factor alpha (TNF) or gamma Interferon (IFN-gamma) into the lumbosacral spinal cord of the rat produced meningitis and mononuclear cuffs within the cord, an inflammatory response remarkably similar in pattern to that observed during experimental autoimmune encephalomyelitis (EAE), a research analog of multiple sclerosis. Rats injected with saline or heat-inactivated cytokine exhibited no such inflammatory response. In other experiments, the accumulation of radiolabeled spleen cells into spinal cord was measured after the injection of various doses of TNF and IFN-gamma, results indicated that both cytokines elicited accumulation of spleen cells in an additive but not synergistic manner. Potentially, the direct injection model offers a new and simplified way of examining mechanisms of early inflammation in the central nervous system, without the need for immunisation with neuroantigen or passive transfer of sensitised cells.

Nitric oxide mediates iron release from ferritin.

Nitric oxide (NO) synthesis by cytotoxic activated macrophages has been postulated to result in a progressive loss of iron from tumor target cells as well as inhibition of mitochondrial respiration and DNA synthesis. In the present study, the addition of an NO-generating agent, sodium nitroprusside, to the iron storage protein ferritin resulted in the release of iron from ferritin and the released iron-catalyzed lipid peroxidation. Hemoglobin, which binds NO, and superoxide anion, which reacts with NO, inhibited nitroprusside-dependent iron release from ferritin, thereby providing evidence that NO can mobilize iron from ferritin. These results suggest that NO generation in vivo could lead to the mobilization of iron from ferritin disrupting intracellular iron homeostasis and increasing the level of reactive oxygen species.

Immediate, long-lasting suppression of autoimmune encephalomyelitis by cell-bound neuroantigen.

When lymphoid cells from rats recovered from experimental autoimmune encephalomyelitis (EAE) were incubated in vitro for 1 hr with myelin basic protein (BP), then washed and transferred along with anti-BP immune serum to naive recipients, those recipients immediately developed a solid, long-lasting resistance to active induction of EAE. To obtain this high level of suppression, both steps of BP-incubation of cells and transfer of immune serum were found to be essential, i.e., direct transfer of nonincubated cells plus immune serum had no comparable suppressive effect, nor had transfer of BP-incubated cells with nonimmune serum. Specificity of the suppressive effect was indicated by the finding that cells from BP-sensitized donors, incubated with BP, protected against BP-CFA-induced disease but not against disease induced with whole spinal cord homogenate (SCH-CFA). As expected, cells from SCH-CFA-sensitized donors incubated with SCH protected recipients against disease induced with either SCH-CFA or BP-CFA. The suppression appears to act early in the afferent stage of the immune response, since inoculation with incubated cells as little as 24 hr after active challenge was ineffective. There was no suppression of passively induced disease.

Selection of orally active antifungal agents from 3,5-substituted isoxazolidine derivatives based on acute efficacy-safety profiles.

Routine in vitro screening of a new synthetic series of 3,5-substituted 2-methylisoxazolidines revealed that three imidazole analogs (PR 967-248, PR 967-234, and PR 969-566) and, to a lesser extent, a triazole analog (PR 988-399) exerted rather potent antifungal activity against three systemic and four dermatophytic classes of fungi. When tested in vivo for ability to eradicate Candida vaginitis in the rat, the triazole derivative, PR 988-399, was effective after oral administration. In this in vivo test for efficacy, PR 967-234 and PR 969-566 reduced but did not eradicate the infection, while PR 967-248 was inactive. PR 988-399 was, moreover, 4- to 13-fold less potent than the three imidazoles in inhibiting testosterone synthesis in isolated rat Leydig cells. After oral or intravenous administration, PR 988-399 and PR 969-566 elicited the fewest cardiovascular and behavioural side effects in conscious dogs. The rat safety study consisted of oral dosing followed by evaluation of the exploratory motor activity of the naive animals in a novel environment. Motor activity was suppressed least by PR 988-399 and most by PR 969-566. In a battery of mouse behavioural-neuromuscular-drug interaction tests, PR 988-399 and PR 969-566 produced the fewest central-behavioural-neuromuscular signs. These efficacy-safety evaluations were performed with ketoconazole as a positive reference standard. The sequence of drug testing with respect to efficacy-safety considerations appears to be a suitable approach for early detection of orally active antifungal agents such as PR 988-399 for more advanced development.

Methysergide, a serotonin antagonist, does not inhibit the expression of autoimmune encephalomyelitis in the rabbit.

In view of recent interest in the potential role of vasoactive amines in the expression of experimental autoimmune encephalomyelitis (EAE) and neuritis (EAN), we set out to determine the effect of slow-release methysergide, a serotonin antagonist, on the effector phase of EAE/EAN in rabbits immunized with homologous spinal cord in Freund's adjuvant. On day 6 post-immunization (p.i.), slow-release pellets of methysergide maleate were implanted subcutaneously in graded doses 0-400 mg. At the highest dose, blood concentrations of methysergide were approximately 90 ng/ml on day 8 p.i. falling to 20 ng/ml by day 16 p.i. However, even at the highest dose of methysergide, rabbits developed typical clinical and histological signs of EAE/EAN. It is concluded that serotonergic mechanisms do not play a critical role in the effector phase of EAE/EAN in the rabbit.