Derivation of internal dose-based thresholds of toxicological concern for occupational inhalation exposure to systemically acting organic chemicals

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61?×?10^?2 and 9?×?10^?4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55?×?10^?1 and 8.5?×?10^?3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r² = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework.     

Respiratory muscle dysfunction in facioscapulohumeral muscular dystrophy

Sleep and Breathing -     

Beta-2 microglobulin and amyloid osteoarthropathy in patients undergoing chronic hemodialysis

The incidence of beta-2 microglobulin amyloidosis was assessed in two populations of chronic hemodialysis patients. Out of 34 patients who underwent biopsy during orthopedic surgery (33 cases) or autopsy (1 case), 26 had amyloid deposits which fixed anti-beta microglobulin serum. Out of 55 unselected patients treated for over months at the dialysis centre, 14 (25%) had clinical symptoms suggesting amyloidosis and out of 43 patients who had a systematic radiological skeletal survey, 23 (53%) had bone deposits. The plasma beta microglobulin concentrations (about 20 times the normal value) we not significantly different whether or not the patients had histological proven amyloidosis, clinically or radiologically probable amyloidosis, no detectable amyloidosis. However, the duration of hemodialysis was longer in those with proven or highly probable amyloidosis. The finding illustrate the indirect role of elevation of beta-2 microglobulin in the genesis of this pathology and also the necessity of lowering its concentration in order to avoid the long term complications of osteoarticular deposits, the functional consequences of which may be very serious.     

The role of medical comorbidity in outcome of major depression in primary care: the PROSPECT study.

OBJECTIVE: The authors described the influence of specific medical conditions on clinical remission and response of major depression (MDD) in a clinical trial evaluating a care-management intervention among older primary-care patients. METHODS: Adults age 60 years and older were randomly selected and screened for depression. Participants were randomly assigned to Usual Care or to an Intervention with a depression care-manager offering algorithm-based care for MDD. In all, 324 adults meeting criteria for MDD were included in these analyses. Remission and response was defined by a score on the Hamilton Rating Scale for Depression <10 and by a decrease from baseline of > or =50%, respectively. Medical comorbidity was ascertained through self-report. Cognitive impairment was defined by a score <24 on the Mini-Mental State Exam (MMSE). RESULTS: In Usual Care, rates of remission were faster in persons who reported atrial fibrillation (AF) than in persons who did not report AF and slower in persons who reported chronic pulmonary disease than in persons who did not report chronic pulmonary disease; rates of response were less stable in persons with MMSE <24 than in those with MMSE > or =24. In the Intervention condition, none of the specific chronic medical conditions were significantly associated with outcomes for MDD. CONCLUSIONS: Because disease-specific findings were observed in persons who received Usual Care but not in persons who received more intensive treatment in the Intervention condition, our results suggest that the association of medical comorbidity and treatment outcomes for MDD may be determined by the intensity of treatment for depression.     

Growth hormone signalling: sprouting links between pathways, human genetics and therapeutic options.

Our molecular understanding of growth hormone-induced signal transduction has improved significantly over the past decades. At the same time, human population genetics and the analysis of genetically engineered animals have led to the discovery of genes that control specific aspects of the overall growth process. Although, currently, growth disorders are still diagnosed and treated on empirical bases, it might soon be possible to stratify patients predominantly by genetic defect, with treatment based on our molecular understanding of the role of the affected gene in the disease.     

Body pain and treatment response in late-life depression.

OBJECTIVE: The authors investigated the influence of body pain on 1) time to treatment response and 2) suicidal ideation, in late-life depression. They hypothesized that higher levels of body pain would predict a longer time to and lower likelihood of response, and increased levels of suicidal ideation. METHODS: Subjects (N=187) were older adult outpatients (age > or =69 years), with current episodes of major depression, who were openly treated with paroxetine up to 40 mg daily and weekly interpersonal psychotherapy. Response was defined as 3 consecutive weeks of Hamilton Rating Scale for Depression at < or =10. Body pain was measured with the Bodily Pain Index of the SF-36 quality-of-life assessment. Authors used survival-analysis models on the responder sample to test the effect of body pain on response, after controlling for severity of depression. RESULTS: Overall response rate was 75.4%. Nonresponders reported more severe pain at baseline. After covarying for severity of baseline depression, no effect was found for physical pain on time-to-response or degree of suicidality. Bodily pain remained stable during acute treatment for responders, independent of depression response to combination psychotherapy and antidepressant treatment. CONCLUSIONS: Older adult patients with higher levels of physical pain can still respond to antidepressant treatment; however, reported bodily pain may be associated with a more difficult-to-treat depression.     

Assessment of myocardial viability in rats: Evaluation of a new method using superparamagnetic iron oxide nanoparticles and Gd-DOTA at high magnetic field.

The aim of this study was to detect salvageable peri-infarction myocardium by MRI in rats after infarction, using with a double contrast agent (CA) protocol at 7 Tesla. Intravascular superparamagnetic iron oxide (SPIO) nanoparticles and an extracellular paramagnetic CA (Gd-DOTA) were used to characterize the peri-infarction zone, which may recover function after reperfusion occurs. Infarcted areas measured from T1-weighted (T1-w) images post Gd-DOTA administration were overestimated compared to histological TTC staining (52% +/- 3% of LV surface area vs. 40% +/- 3%, P=0.03) or to T2-w images post SPIO administration (41% +/- 4%, P=0.04), whereas areas measured from T2-w images post SPIO administration were not significantly different from those measured histologically (P=0.7). Viable and nonviable myocardium portions of ischemically injured myocardium were enhanced after diffusive Gd-DOTA injection. The subsequent injection of vascular SPIO nanoparticles enables the discrimination of viable peri-infarction regions by specifically altering the signal of the still-vascularized myocardium.