Delineating the longitudinal structure of depressive illness: beyond clinical subtypes and duration thresholds

Through the use of polysomnographic, epidemiologic, and prospective clinical follow-up studies, the authors document that the course of major depressive disorder (MDD) is expressed by fluctuating symptoms in which depressive subtypes included in official diagnostic systems do not represent discrete disorders, but are stages along a dimensional continuum of symptomatic severity. Depressive symptoms at the major, minor, dysthymic or otherwise sub-threshold levels are all integral components of the longitudinal clinical structure of MDD with each symptom level representing a different phase of illness intensity, activity and severity. Detailed analyses indicate that patients are symptomatic 60 % of the time, much of it at the minor, dysthymic or subthreshold level. The symptomatic phases of illness activity are interspersed sporadically with inactive phases, when patients are asymptomatic. These findings are pertinent to both clinical cohorts and community-based epidemiologic samples. Each level of depressive symptom severity is associated with significant psychosocial impairment; such impairment increases progressively with each stepwise increment in symptom severity. When patients are asymptomatic their psychosocial functioning returns to good or very good levels. Residual subthreshold symptoms in the course of MDD are associated with high risk for early episode relapse and a significantly more chronic course of illness. Asymptomatic recovery from MDD is associated with significant delays in episode relapse and recurrence and a more benign course of illness. We submit that, as in the case of chronic medical conditions, the goal of treating unipolar depressive illness should optimally be to return the patient to as asymptomatic a level as is feasible by all available therapeutic means.     

Blurring the distinctions between on and off the job injuries: similarities and differences in circumstances.

OBJECTIVES: To compare the causes of non-fatal work and non-work injuries and the places or environments where they occur. It has been suggested that many injuries may have similar etiologies on and off the job and thus involve some common prevention strategies. However lack of comparable data on work relatedness has prevented testing this proposition. METHODS: The National Health Interview Survey (NHIS) now collects information on the cause, location, and work relatedness of all medically attended injuries. National US estimates of non-fatal work and non-work injuries were compared by cause and place/location for working age adults (18-64 years). RESULTS: Overall 28.6% of injuries to working age adults were work related (37.5% among employed people). The causes and locations of many work and non-work injuries were similar. Falls, overexertion, and struck/caught by were leading causes for work and non-work injuries. Motor vehicle injuries were less likely to be work related (3.4% at work v 19.5% non-work) and overexertion injuries more likely to be work related (27.1% v 13.8%). Assaults were less than 1% of work injuries and 1.8% of non-work injuries. Both work and non-work injuries occurred in every location examined-including the home where 3.5% of injuries were work related. CONCLUSIONS: Work and non-work injuries share many similarities suggesting opportunities to broaden injury prevention programs commonly restricted to one setting or the other. Comprehensive efforts to prevent both non-work and work injuries may result in considerable cost savings not only to society but also directly to employers, who incur much of the associated costs.     

The changing face of prostate cancer.

Prostate cancer remains the most common noncutaneous human malignancy, and the second most lethal tumor among men. However, the natural history of the disease is often prolonged, and the survival benefits of local therapy for men with low-risk tumors may not be realized for a decade or more, as is increasingly well demonstrated in long-term observational cohorts in both the United States and Europe. A significant proportion of men with prostate cancer may be overdiagnosed, in the sense that diagnosis may not improve their lifespan or quality of life. However, the extent to which overdiagnosis represents a true problem relates to the consistency with which diagnosis leads invariably to active treatment. Prostate cancer is diagnosed at progressively earlier stages and with lower risk features; despite these trends, patients are less likely now than a decade ago to undergo a trial of active surveillance. Rates of brachytherapy and hormonal therapy use, in particular, have risen markedly. Important progress has been made in recent years in prostate cancer risk assessment. These advances, in combination with biomarkers in later stages of development, should be expected in the coming years to yield further improvements in clinicians' ability to diagnose prostate cancer early, and guide appropriately selected patients toward increasingly tailored treatment.     

Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study

Posaconazole is an antifungal with a wide-spectrum of activity against common and emerging fungal pathogens. In this randomised, open-label, two-way crossover study, the potential for drug interactions with posaconazole via the cytochrome P450 (CYP450) enzyme pathway was evaluated. Thirteen subjects received posaconazole tablets (2×100 mg) once daily for 10 days or no treatment; following a 14-day washout period, subjects were crossed over to the alternate treatment. The inhibition spectra of posaconazole were examined using a cocktail of the following probe substrates: caffeine (CYP1A2), tolbutamide (CYP2C8/9), dextromethorphan (CYP2D6 and total CYP3A4), chlorzoxazone (CYP2E1), and midazolam (hepatic CYP3A4). Except for midazolam, which was intravenously infused on Day 10, the cocktail probes were administered simultaneously on Day 9 during both treatment periods. Blood and urine samples were collected at specified times to quantitate probe substrates and/or metabolites. Based on insignificant differences in mean probe ratios, posaconazole did not inhibit CYP1A2, 2C8/9, 2D6, or 2E1. However, the midazolam AUC_(tf) was higher in the posaconazole than no-treatment group (93.4 ng h/ml versus 51.4 ng h/ml, P<0.01), indicating inhibition of hepatic CYP3A4. Drug interactions mediated by various CYP450 are common with the currently available triazole antifungals, however these results suggest that posaconazole may have an improved and more narrow drug interaction profile (CYP3A4 only) compared with other triazoles.     

Hb Manukau [β67(E11)Val → Gly; HBB: c.203T>G]: The Role of Genetic Testing in the Diagnosis of Idiopathic Hemolytic Anemia

The increasing availability of DNA sequencing of globin genes has improved our ability to detect conditions that were presumed to be extremely rare. These conditions may remain undiagnosed due to unfamiliarity with clinical presentation, relative unavailability of advanced diagnostic alternatives, or may defy detection by being electrophoretically silent or extreme instability rendering their presence to be below detection level. Genetic studies were pursued in a mother and daughter with severe hemolytic anemia as initial testing failed to be diagnostic. DNA sequence analysis of the β-globin gene identified Hb Manukau [β67(E11)Val?→?Gly; HBB: c.203T?>?G], an extremely unstable hemoglobin (Hb) variant. This is the second family described with this condition (first in the western hemisphere). An astute clinician may benefit from being persistent and pursuing additional testing including molecular genetic characterization where clinical suspicion remains high.