Belief in the harmfulness of antidepressants: results from a national survey of the Australian public

BACKGROUND: Surveys of the public in several countries have found that negative attitudes towards antidepressants are common. However, there has been little research into the factors associated with these attitudes. METHODS: A national survey of 999 Australian adults assessed beliefs about the helpfulness or harmfulness of antidepressants for a person with depression and suicidal thoughts. Associated factors investigated were as follows: sociodemographic characteristics, exposure to depression, ability to recognize depression, beliefs about other depression interventions, beliefs about long-term outcomes with and without treatment, beliefs about causes, and stigmatizing attitudes. RESULTS: Around a quarter of Australian adults believe that antidepressants would be harmful for a person who is depressed and suicidal. This group was less educated, had less exposure to depression, showed poorer recognition of depression, was less favorable about other standard interventions including psychological ones, was less pessimistic about the long-term outcome if the person did not have treatment, and was more likely to see depression as due to weakness and to be under the individual's control. LIMITATIONS: The survey did not directly ask about reasons for believing that antidepressants would be harmful. CONCLUSIONS: Belief in the harmfulness of antidepressants is associated with a general lack of exposure to depression, leading to an underestimation of its seriousness and of the necessity for intervention.     

Topical magnetic resonance for the study of muscle metabolism in human myopathy

The role of changes in energy metabolism are obvious in the myopathies with described enzyme defects, but the ability afforded by topical magnetic resonance spectroscopy to study these changes repeatedly and non-invasively helps provide an understanding of the alterations in energy metabolism seen in muscle complaints of which the aetiologies are still unclear. Attention is focused on interpreting the findings with particular regard to Duchenne muscular dystrophy.     

Evaluation of an animal model system for cryptosporidiosis: therapeutic efficacy of paromomycin and hyperimmune bovine colostrum-immunoglobulin.

Several immunodeficient rodent models currently exist in which persistent, largely asymptomatic, Cryptosporidium parvum infections can be established. Piglets, in contrast, develop a self-limiting diarrheal illness. We have consequently developed an animal model system in which scid mice were used to screen drugs for inhibitory activity against C. parvum, after which the drugs' therapeutic potential was evaluated with piglets. Paromomycin and hyperimmune bovine colostrum-immunoglobulin were selected to evaluate this system. C. paravum infections in suckling scid mice tended to be associated with villus surfaces, while in weaned and in older scid mice infections were more commonly localized in abscessed crypts. Rates of oocyst shedding in suckling scid mice were 50 to 200 times higher than in weaned mice and therefore made suckling mice a considerably more sensitive model for drug testing. Paromomycin given in high doses over 9 to 10 days was not toxic to either scid mice (3,000 mg/kg of body weight per day) or piglets (500 mg/kg/day). Paromomycin treatment was very effective against villus surface infections in suckling mice and considerably less effective against infections in inaccessible sites such as abscessed crypts and stomach pits seen in weaned and adult scid mice. The therapeutic efficacy of paromomycin in piglets depended on the severity of the diarrheal illness. Mild to moderate diarrhea and infection were cleared after paromomycin treatment of piglets infected with one C. parvum isolate. However, paromomycin had no impact on severely affected piglets infected with a second isolate, presumably because of a rapid transit time through the gut. In contrast to paromomycin hyperimmune bovine colostrum-immunoglobulin treatment reduced the rate of C. parvum infection moderately in scid mice and only slightly in piglets, again probably because of a rapid transit time through the gut and inactivation in the stomach. It was also clear that the impact of effective drugs against C. parvum can be detected within 5 days after the onset of treatment in either model.     

Noise levels in a clinical chemistry laboratory

An investigation into the noise levels in a clinical chemistry laboratory has been carried out. It was shown that although the levels were insufficient to cause damage to hearing, they exceeded the criteria of acceptability for offices and workshops.     

Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations

The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.     

Cryptosporidium parvum Infection of Human Intestinal Xenografts in SCID Mice Induces Production of Human Tumor Necrosis Factor Alpha and Interleukin-8

The protozoan parasite Cryptosporidium parvum invades intestinal epithelial cells and can cause life-threatening diarrhea in immunocompromised individuals. Despite the clinical importance of this organism, much remains to be learned about the pathogenesis of C. parvum-induced diarrhea. To explore the role of the intestinal inflammatory response in C. parvum disease, using C. parvum oocysts we infected human intestinal xenografts in severe combined immunodeficient (SCID) mice. Seven days after infection, we found levels of human tumor necrosis factor alpha and interleukin-8 in C. parvum-infected human intestinal xenografts that were significantly higher than those seen in uninfected control xenografts. These results demonstrate that human intestinal cells produce proinflammatory cytokines in response to C. parvum infection and establish SCID-HU-INT mice as a model system to study the interactions of C. parvum with the human intestine.     

Genetic control of the antibody response to poly(L Tyr, L Glu)-poly(DL Ala)--poly(L Lys) in mice: analysis of (low responder x low responder)F1 hybrids

The antibody response to the synthetic polypeptide poly (L Tyr, L Glu)-poly (DL Ala)--poly (L Lys) designated (T,G)-A--L, was investigated in inbred, congenic, F1 and F2 hybrid strains of mice. The antibody response was analysed at both low (10 microgram) and high (50 microgram) immunizing doses of (T,G)-A--L. Antibodies were measured using both a modified Farr assay and a plate binding assay. At low immunizing doses it was found that all of the congenic and non-congenic (low responder x low responder) F1 hybrids were low responders. However, the quantitative antibody response of one non-congenic (low responder x low responder) F2 hybrid segregated in a 1:1 ratio of high responders to low responders, suggesting some form of complementation of (T,G)-A--L Ir genes. At high immunizing doses it was found that congenic and non-congenic (low responder x low responder) F1 hybrids were all high responders, indicating a complementation of Ir genes to (T,G)-A--L. This complementation was confirmed using two different routes of immunization, namely footpad and intraperitoneal. Furthermore the quantitative antibody responses of (low responder x low responder) F2 hybrids segregate in a 1:1 ratio of high responders to low responders. The class of antibodies produced to (T,G)-A--L in (low responder x low responder) F1 hybrids was determined by gel filtration on Sephadex G-200, and found to be predominantly IgG, with lesser amounts of IgM.     

Transgenic and Natural Mouse Models of Proteolipid Protein (PLP)-Related Dysmyelination and Demyelination

The X chromosome-linked PLP/DM-20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus-Merzbacher disease, X-linked Spastic Paraplegia). The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death. In most mutants, residual myelin structures have an abnormal ultrastructure and periodicity. Surprisingly, transgenic mice which carry extra copies of the wild type PLP gene show dysmyelination, demonstrating that the PLP gene is dosage sensitive. Pathological changes of transgenic mice vary from the phenotype of natural mutants. Specifically, many Golgi saccules of oligodendrocytes are vacuolated and the cytoplasm contains autophagic vacuoles hinting at a perturbation in protein trafficking. In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment. Surprisingly, transgenic animals which overexpress PLP/DM-20 at a low level appear normal during early development, but later spontaneously demyelinate. The mechanisms underlying this demyelination phenotype is unknown but an immune-mediated process has been suggested. All attempts to correct the phenotype of natural PLP mutants, such as jimpy mice, with a wild type transgene have had little effects, indicating a dominant-negative effect of the mutant gene product. On the other hand, mice with a targeted disruption of the PLP/DM-20 gene have suprisingly minor clinical signs. This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain-of-function effects of a mutant myelin protein.