Disability, depression and suicide ideation in people with multiple sclerosis.

INTRODUCTION: Depressive symptoms occur frequently in people with Multiple Sclerosis (MS) and rates of suicide ideation are higher than the general population. There is evidence for a direct association between disability and depression, disability and suicide ideation, and depression and suicide ideation in MS. However, the relationship between all three, i.e. the mediating role of depression between disability and suicidal ideation, has not been investigated. Exploring this relationship could highlight risk factors, alerting clinicians to the need for timely intervention. METHOD: Seventy five people with progressive MS attending two out-patient clinics took part in this cross-sectional study. Participants completed the Beck Suicide Scale, Beck Depression Inventory, Multiple Sclerosis Impact Scale and Guy's Neurological Disability Scale. RESULTS: Depressive symptoms mediated the relationship between perceived and actual disability and suicide ideation. Different types of disability were associated with suicidality, including: 'tremors' and 'taking longer to do things'. A small sub-group of participants were identified who reported suicide ideation in the presence of only mild levels of depression. LIMITATIONS: There may be a sample bias in this study as all participants were attending out-patient clinics and receiving support which may not be available to everyone with MS. CONCLUSION: It is important for clinicians to screen regularly for both depression and suicide ideation, to be alert to specific types of disability for which a higher level of suicide ideation might be present and to consider the possibility of suicidal thoughts being present in people who show minimal or no depressive symptoms.

The persistence of foot-and-mouth disease virus on wool.

Five Suffolk sheep, held in a high-security isolation room, were exposed for 2 hours to the aerosol of 3 mature pigs that had been infected with foot-and-mouth disease virus (FMDV), strain O1-BFS. The fleeces of 3 of the sheep were contaminated with FMDV at 2 days post exposure (dpe), while at 5 dpe the fleeces of all 5 sheep were more extensively, and more heavily, contaminated. The persistence of FMDV on contaminated wool was examined in vitro using multiple 0.5 g samples of Merino wool that were each contaminated with one of 3 strains of FMDV in tissue-cultured medium: O1-BFS, O-Morocco (O-MOR 9/91) or an Asia 1 strain (TAI 1/90). Wool samples were held at either 4 degrees C, 18 degrees C or 37 degrees C, and decay curves were established for each virus at each temperature. These curves predicted that O1-BFS, O-MOR 9/91 and TAI 1/90 would fall below detectable levels at 72, 70 and 48 days post contamination (pc), respectively, for wool stored at 4 degrees C; at 11, 12 and 12 days pc, respectively, for wool stored at 18 degrees C; and at 57, 68 and 33 hours pc, respectively, for wool stored at 37 degrees C. For wool contaminated with O1-BFS-infected sheep faeces, urine or blood, or with O1-BFS-infected cattle saliva, decay curves predicted virus to persist for 5 to 11 days pc at 18 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of altered dietary iron intake in Mycobacterium paratuberculosis-infected dairy cattle: sequential observations on growth, iron and copper metabolism and development of paratuberculosis.

Twenty calves were orally inoculated with Mycobacterium paratuberculosis at six weeks old. At six months old, 10 of these, plus four uninfected controls were maintained on limited dietary copper and supplemented iron intake for a further 27 months. During this time all these animals, together with a further four untreated controls, were bred before being killed and examined for evidence of paratuberculosis. Despite significant reduction in weight gain, attributable to both iron supplementation and infection, no significant difference was found in the numbers of iron-supplemented and unsupplemented animals that developed clinical signs nor in the extent and severity of intestinal lesions between groups. Accumulation of iron in paratuberculosis lesions was not affected by iron supplementation but was positively correlated with the frequency of shedding of M paratuberculosis in faeces (P less than 0.05). Dietary iron supplementation alone resulted in serum hyperferraemia, hepatic siderosis and slight hypocuprosis, whereas, in infected animals, this resulted in marked hypocuprosis and anaemia within groups (P less than 0.05). Infection alone resulted in serum hypoferraemia and intestinal and hepatic siderosis which was positively correlated with the severity of infection within groups (P less than 0.05). Susceptibility to paratuberculosis may result from failure ultimately to limit monokine-mediated iron sequestration in intestinal tissue.

The effect of different levels of iron intake on the multiplication of Mycobacterium paratuberculosis in C57 and C3H mice.

Two groups of C57 and C3H mice of 5 weeks of age were infected via the intraperitoneal route with 2.0 mg (wet weight) of Mycobacterium paratuberculosis. These were maintained with a similar number of segregated and non-inoculated mice of the same strains under specially controlled conditions of low, medium and high iron intake. Mice were killed and bled at 7 months post-infection and assessments of haematological parameters and the degree of mycobacterial granulomatous involvement of abdominal and other tissues were made. In addition, the total mycobacterial numbers visible in macrophages in standardized histological sections of liver, spleen and bone marrow in the presence or absence of stainable iron storage compounds were assessed using a double staining technique for iron and mycobacteria. Moderate to marked anaemia in both C57 and C3H mice on low iron intake, irrespective of infection, indicated that an effective low iron status was achieved in the animals by dietary manipulation. Medium and high iron intake groups exhibited normal haematological parameters. Iron storage compounds were readily visible in liver microgranulomas of mice on medium and high, but not on low iron intake. In liver, spleen and bone marrow samples, mycobacterial counts in iron-containing microgranulomas were significantly higher than in those without stainable iron. Increased frequencies of residual and progressive infection were associated with increased iron intake. The greater susceptibility of the C57 strain was evident from the significantly higher liver microgranuloma counts, higher mycobacterial numbers and greater progressive infection when compared with the C3H strain. These findings in mice strongly suggest that slow multiplication of M. paratuberculosis is enhanced in iron-replete compared with iron-deficient macrophages. This enhancement occurs despite the capacity of the less susceptible strain of mouse to limit the spread of the organism within the body.

Inhibition of LPS toxicity for macrophages by metallothionein-inducing agents.

Parenteral administration of adrenal corticosteroids or particular transition metal salts are known to protect mice from the lethal effects of bacterial lipopolysaccharides (LPS). To determine if both groups of substances act through similar biologic mechanisms, their capacity to protect macrophages from the direct toxic effects of LPS was examined in vitro. When added simultaneously with LPS at culture initiation, 10 to 100 microM cortisone increased the viability of normal peritoneal macrophages as determined by trypan blue exclusion. Prednisolone and corticosterone protected LPS-treated macrophages at even lower concentrations (0.1 to 1 microM); estradiol and testosterone failed to alter cell viability at any concentration tested. Protection was dependent on de novo synthesis because inclusion of 20 nM actinomycin C1 or 1 microM cycloheximide with 10 microM corticosterone during a 4-hr pretreatment period blocked induction of the protective effect. Murine macrophages were also protected by micromolar concentrations of zinc, cadmium, mercury, and manganese, but not by calcium or lead. As was obtained with corticosteroids, heavy metal-induced protection depended on de novo RNA and protein synthesis. Because all substances that protected against LPS are known inducers of metallothionein in somatic cells, peritoneal macrophages were assayed for the presence of this unique, cytoplasmic protein. Within 2 to 8 hr, 10 microM cadmium caused three to fivefold increases in the incorporation of 35S-cysteine and in the binding of 203Hg into the TCA-soluble fraction of cell lysates that was excluded on centrifugally accelerated Sephadex G-10 columns. These results suggest macrophages may be protected from LPS-mediated cytotoxicity through synthesis of a sulfhydryl-rich, metal-binding protein. Although its mechanism of action remains unknown, it is proposed that metallothionein may function homeostatically by altering intracellular concentrations of zinc or may play a regulatory role by facilitating transfer of heavy metals among metal-requiring apoproteins.

An inhibitor of thymic hormone activity in serum from patients with lymphoblastic leukemia.

Serum from 21 patients with lymphoblastic leukemia, five with myeloblastic leukemia and 30 age matched control subjects tested for thymic hormone activity in an assay that measures the induction of T cell surface antigen. This activity was subnormal in serum from 10 of 16 patients with untreated lymphoblastic leukemia (p less than 0.001) but was within the normal range when the leukemia was in remission. Low inductive activity was associated with an inhibitor of T cell induction which was less than 30,000 daltons in molecular size and interfered with induction by purified thymopoietin plus a high concentration of ubiquitin or by normal serum alone.

Myasthenia gravis, thymectomy and serum thymic hormone activity.

Serum thymic hormone activity was measured in 36 patients with myasthenia gravis and in 10 control subjects from each age decade. In all 25 patients under 50 years of age results were within, or close to, the normal range. Activity at levels considered normal for juveniles was detected in 10 of the 11 older patients whereas levels normally decline in older subjects. One week after thymectomy, 13 of 17 patients (76 per cent) had no demonstrable serum thymic hormone activity. However, 10 months or longer after thymectomy only five patients (30 per cent) lacked thymic hormone activity in the serum. There was a significant correlation between clinial improvement and sustained lowering of serum thymic hormone activity after thymectomy.

Age, thymic involution, and circulating thymic hormone activity.

Circulating thymic hormone activity and thymic histology were studied in patients undergoing open heart surgery. Plasma thymic hormone activity was measured using a bioassay based upon thymocyte antigen induction on null mouse lymphocytes. Activity was highest at 15-30 yr of age and declined thereafter, being negligible after the sixth age decade. The age-related decline of circulating thymic hormone activity correlated, in general, with progressive thymic involution. However, hormone activity was detected in plasma from some cases with advanced involution, suggesting that the normal young thymus may have considerable functional reserve.

Rheumatoid factor positive plasma and humoral cytotoxicity to malignant melanoma.

Complement dependent cytotoxicity to malignant melanoma tumor cells was demonstrated in incubations that included rheumatoid factor (RF) positive plasma and normal plasma. Cytotoxicity was not demonstrated to cells from a number of normal tissues. The phenomenon involved coating of tumor cells with immunoglobulins and complement fixation. The activity in RF positive plasma was present in high titer an may not be RF. The activity in normal plasma was present in low titer, was found in plasma from eight out of 11 healthy subjects and may be a naturally occurring antibody. This previously undescribed humoral cytotoxicity system may participate in tumor host interactions, especially after therapy, when the majority of patients become RF seropositive.

Bioassay determinations of thymopoietin and thymic hormone levels in human plasma.

Thymopoietin is a thymic hormone that induces differentiation of thymocytes from precursor cells which arise in hemopoietic tissues. This paper describes a sensitive in vitro assay for the induction of Thy 1.2 antigen on null lymphocytes from germ-free athymic (nu/nu) mice. The sensitivity and specificity of the bioassay were increased by adding high concentrations of ubiquitin (a nonspecific inducer) to the induction incubations. The bioassay was sufficiently sensitive to detect thymopoietin at less than 0.25 ng/ml. A dose-response relationship was shown between thymopoietin concentration and the percentage of cells induced to express Thy 1.2 antigen. When normal human plasma was assayed, induction was registered with activity corresponding to thymopoietin at greater than 1 ng/ml in plasma from infants or young adults. Activities in the thymopoietin range of 0.25 ng/ml were registered with plasma from healthy subjects over 50 years of age. Thymectomy was followed by loss of this inductive activity from the plasma. This bioassay permits clinical studies on T (thymus-derived) cell inducers released by the human thymus into the circulation.

Rheumatoid factor and tumor-host interaction.

In this survey for rheumatoid factor (RF) seropositivity on patients with neoplasms, an 85% rate of positive screening tests was recorded under certain circumstances. This high rate of RF seropositivity occurred after irradiation and/or chemotherapy of breast and lung cancers. Treated patients with breast cancers who had no evidence of residual tumor had an 89% rate of positive RF tests. Conversely, the incidence of RF seropositivity was low among untreated patients with similar tumors and treated patients with glioblastomas or multiple myeloma. The administration of cytotoxic drugs (e.g., azathiprene) was not itself associated with RF production even in renal allograft recipients. The data indicate that RF production occurs frequently after therapy of certain tumors and suggest that in these circumstances RF may be an expression of tumor-host interaction.