Implementation of Osteoporosis Screening Guidelines in Prostate Cancer Patients on Androgen Ablation

Androgen ablation (AA) therapy is one of the modalities used to treat prostate cancer. It is well known that AA therapy increases the risk of osteoporosis and fractures. In 2004, the British Columbia Cancer Agency published guidelines regarding bone health in these patients. A key recommendation was to arrange for bone mineral density (BMD) testing if AA was to be used for 6 mo or longer. Our objective was to evaluate how well these guidelines were implemented by reviewing the number of BMDs performed in patients who had been treated at one of the 4 cancer centers in British Columbia. We found that the overall number of BMDs documented after the implementation of the guidelines was significantly greater than the number documented before (25% vs 7.5%, p value < 0.0001). There appeared to be regional differences in implementation, with the greatest effect seen at the Vancouver center, which serves as the chief academic center for the province. The greater effect of guidelines at this center suggests a need for more effective dissemination peripherally. The care gap remaining at even the most impacted center indicates a need for greater efforts to both implement guidelines and monitor their implementation over time.     

Personality disorders are important risk factors for disability pensioning

Purpose

To determine whether personality disorders (PDs) are associated with increased risk of disability pensioning in young adults, independent of other common mental disorders.

Methods

2,770 young adults from the general population were assessed for PDs by the Structured Interview for DSM-IV Personality, and for common mental disorders by the Composite of International Diagnostic Interview. These data were linked to the Norwegian National Insurance Administration’s recordings of disability benefits for a 10-year period. Logistic regression analyses were applied to investigate the association between PDs and disability pensioning. The analyses were conducted for three types of PD measures: categorical diagnoses (any PD), dimensional scores of individual PDs and higher order components retrieved by principal component analyses.

Results

Having any PD was strongly associated with disability pensioning, regardless of disability diagnosis. The estimated odds ratio (OR) was substantially higher for PDs [OR 4.69 (95 % confidence interval (CI) 2.6–8.5)] than for mood disorders [OR 1.3 (CI 0.7–2.3)] and anxiety disorders [OR 2.3 (CI 1.3–4.3)]. Measured dimensionally, all PD traits except antisocial traits were significantly associated with disability pensioning. After adjusting for co-occurring traits of other PDs, only schizoid, dependent and borderline PD traits showed a significant positive association with disability pension, while antisocial traits showed a significant negative association. The principal component analyses showed that negative affectivity, psychoticism, and detachment was associated with an increased risk of disability pensioning, while antagonism/disinhibition and obsessivity were not.

Conclusions

PDs are strongly associated with disability pensioning in young adults, and might be more important predictors of work disability than anxiety and depressive disorders. Certain aspects of pathologic personalities are particularly important predictors of disability.     

Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatase-positive osteoclast-like multinucleated giant cells from human monocytes

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of human monocytes into two phenotypically distinct types of macrophages. However, in vivo, not only CSF but also many other cytokines are produced under various conditions. Those cytokines may modulate the differentiation of monocytes by CSFs. In the present study, we showed that CD14+ adherent human monocytes can differentiate into CD1+relB+ dendritic cells (DC) by the combination of GM-CSF plus interleukin-4 (IL-4) and that they differentiate into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like multinucleated giant cells (MGC) by the combination of M-CSF plus IL-4. However, the monocyte-derived DC were not terminally differentiated cells; they could still convert to macrophages in response to M-CSF. Tumor necrosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, cfms mRNA, and aborting the potential to convert to macrophages. In contrast to IL-4, interferon-gamma (IFN-gamma) had no demonstrable effect on the differentiation of monocytes. Rather, IFN- gamma antagonized the effect of IL-4 and suppressed the DC and MGC formation induced by GM-CSF + IL-4 and M-CSF + IL-4, respectively. Taken together, these results provide a new aspect to our knowledge of monocyte differentiation and provide evidence that human monocytes are flexible in their differentiation potential and are precursors not only of macrophages but also of CD1+relB+DC and TRAP-positive MGC. Such a diverse pathway of monocyte differentiation may constitute one of the basic mechanisms of immune regulation.     

Factor VIII-von Willebrand factor requires calcium for facilitation of platelet adherence

The role of divalent cations in platelet adherence to deendothelialized human arteries in flowing blood was investigated in an annular perfusion chamber. Spreading of platelets on the subendothelium was impaired below 30 microM of free Ca2+ ions (Ca2+). When Ca2+ was replaced by Mg2+, adherence was unchanged in perfusates without exogenous factor VIII-von Willebrand factor (FVIII-vWF), but the ability of FVIII-vWF to support platelet adherence was lost. Binding of FVIII-vWF to the vessel wall was independent of divalent cations, but bound FVIII-vWF was only able to mediate adherence after exposure to Ca2+. Pretreatment of FVIII-vWF with the calcium chelator EGTA (10 mM) resulted in loss of the ability to facilitate platelet adherence, while the ristocetin cofactor activity remained intact. Full restoration of the ability to mediate platelet adherence could only be obtained by prolonged dialysis against Ca2+ in the millimolar range. These data indicate that divalent cations have at least two separate roles to play in supporting platelet adherence: (1) platelet spreading on the subendothelium requires Ca2+ or Mg2+; (2) FVIII-vWF should be exposed to Ca2+ to obtain its optimal biologic activity in supporting platelet adherence.     

Effects of positive and negative pressure ventilation on cerebral blood volume of newborn infants

The effects of intermittent positive airway and continuous negative extrathoracic pressure ventilation on cerebral blood volume in preterm infants were studied using near infrared spectroscopy. In 12 infants continuous negative extrathoracic pressure caused a median decrease in cerebral blood volume of 0.14ml/100ml brain (95% confidence intervals (CI) 0.035–0.280) compared with no respiratory support. Oxygenated and deoxygenated haemoglobin also decreased, implying increased venous drainage as the main effect. In 17 infants intermittent positive pressure ventilation also caused a median reduction in cerebral blood volume of 0.06 ml/100 ml brain (95% CI 0.010–0.115) compared with endotracheal positive airway pressure. Deoxygenated haemoglobin increased by 0.07 ml/100 ml brain (95% CI 0.010–0.100) while oxygenated haemoglobin decreased by O.lOml/lOOml brain (95% CI 0.005–0.175). The increase in deoxygenated haemoglobin implies decreased venous drainage and the decrease in oxygenated haemoglobin implies that other factors may also be significant. Heart rate, blood pressure and oxygen saturation were monitored continuously and remained stable.     

The genetic epidemiology of irrational fears and phobias in men

BACKGROUND: Much of our knowledge of the role of genetic factors in the etiology of phobias comes from one population-based sample of female twins. We examined the sources of individual differences in the risks for phobias and their associated irrational fears in male twins. METHODS: In personal interviews with both members of 1198 male-male twin pairs (707 monozygotic [MZ] and 491 dizygotic [DZ]) ascertained from a population-based registry, we assessed the lifetime history of agoraphobia and social, animal, situational, and blood/injury phobias as well as their associated irrational fears. Twin resemblance was assessed by means of probandwise concordance, odds ratios, tetrachoric correlations, and univariate and multivariate biometrical model fitting. RESULTS: The suggestive results obtained by analysis of phobias only were supported by analyzing both fears and phobias. All 5 phobia subtypes aggregate within twin-pairs. This aggregation is due largely or solely to genetic factors with heritability of liabilities ranging from 25% to 37%. Multivariate analysis revealed a common genetic factor, genetic factors specific to each subtype, and a common familial-environmental factor. CONCLUSIONS: In male subjects, genetic risk factors, which are partially common across all subtypes and partially subtype specific, play a moderate role in the etiology of phobias and their associated irrational fears. Family environment probably has an impact on risk for agoraphobia and social phobia. The genetic liability to blood/injury phobias is not distinct from those of the more typical phobias.     

Parenting and adult mood, anxiety and substance use disorders in female twins: an epidemiological, multi-informant, retrospective study

BACKGROUND: Although parenting has long been considered an important risk factor for subsequent psychopathology, most investigations of this question have studied a single informant, clinical populations, one or a few disorders and did not consider relevant covariates. METHODS: Three dimensions of parenting (coldness, protectiveness and authoritarianism) were measured by combining the retrospective reports from adult female twins, their co-twins, and their mothers and fathers. We assessed by personal interview, lifetime history in the twins of eight common psychiatric and substance abuse disorders and a range of predictors of parenting. Analyses were performed using logistic regression. RESULTS: Examined individually, high levels of coldness and authoritarianism were modestly but significantly associated with increased risk for nearly all disorders, while the impact of protectiveness was more variable. These associations declined modestly when putative predictors of parenting were added as covariates. Maternal and paternal parenting were equally associated with outcomes in adult daughters. When coldness, protectiveness and authoritarianism were examined together, nearly all significant associations were seen solely with coldness. Few significant interactions were found between maternal and paternal parenting or between coldness, protectiveness and authoritarianism. The shared experience of these three dimensions of parenting predicts a quite small correlation in liability to these disorders in dizygotic twin pairs (e.g. r < 0.04). CONCLUSION: In women, parenting behaviour, especially levels of coldness, is probably causally related to risk for a broad range of adult psychiatric disorders. The impact of parenting on substance use disorders may be largely mediated through their co-morbidity with major depression, phobias and generalized anxiety disorder. In general population samples, the association of poor parenting with psychiatric illness is modest, largely non-specific and explains little of the observed aggregation of these disorders in families.     

Sensitivity of Escherichia coli (MutT) and human (MTH1) 8-oxo-dGTPases to in vitro inhibition by the carcinogenic metals, nickel(II), copper(II), cobalt(II) and cadmium(II)

The toxicity of Ni(II), Co(II) and Cu(II) in animals, and that of Cd(II) in cultured cells, has been associated with generation of the promutagenic lesion 8-oxo-7,8-dihydroguanine (8-oxoguanine) in DNA, among other effects. One possible source of this base may be 8-oxo-7,8- dihydro-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP), a product of oxidative damage to the nucleotide pool, from which it is incorporated into DNA. To promote such incorporation, the metals would have to inhibit specific cellular 8-oxo-dGTPases that eliminate 8-oxo-dGTP from the nucleotide pool. The present study was designed to test such inhibition in vitro on 8-oxo-dGTPases from two different species, the human MTH1 protein and Escherichia coli MutT protein. In the presence of Mg(II), the natural activator of 8-oxo-dGTPases, all four metals were found to inhibit both enzymes. For MTH1, the IC50 values (+/- SE; n = 3-4) were 17 +/- 2 microM for Cu(II), 30 +/- 8 microM for Cd(II), 376 +/- 71 microM for Co(II) and 801 +/- 97 microM for Ni(II). For MutT, they were 60 +/- 6 microM for Cd(II), 102 +/- 8 microM for Cu(II), 1461 +/- 96 microM for Ni(II) and 8788 +/- 1003 microM for Co(II). Thus, Cu(II) and Cd(II) emerged as much stronger inhibitors than Ni(II) and Co(II), and MTH1 appeared to be generally more sensitive to metal inhibition than MutT. Interestingly, in the absence of Mg(II), the activity of the enzymes could be restored by Co(II) to 73% of that with Mg(II) alone for MutT, and 34% for MTH1, the other metals being much less or non-effective. The difference in sensitivity to metal inhibition between the two enzymes may reflect the differences in the amino acid ligands, especially the cysteine ligand, outside their evolutionarily conserved Mg(II)-binding active sites, which might indicate predominantly non-competitive or uncompetitive mechanism of the inhibition. The overall results suggest that inhibition of 8-oxo- dGTPases may be involved in the mechanisms of induction of the 8- oxoguanine lesion in DNA by the metal ions studied, especially the non- redox-active Cd(II) cation.