The physiological regulation of toll-like receptor expression and function in humans

Eleven mammalian toll-like receptors (TLRs 1–11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14⁺ monocytes following activation with specific TLR ligands was greater ( P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34°C). Strenuous exercise resulted in a decrease ( P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14⁺ monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14⁺ monocytes following activation with specific TLR ligands was decreased ( P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.     

Lacunar syndromes due to intracerebral hemorrhage]

Nine cases (seven men and two women, mean age 64.5 years) of classical lacunar syndromes due to intracerebral hemorrhage are reported. Three patients presented with pure motor hemiparesis (two putaminal hematomas with proportional weakness and one cortical hemorrhage with brachio-crural hemiparesis). Four patients presented with sensorimotor stroke due to thalamo-capsular hemorrhage. The last two patients had thalamic hemorrhage causing ataxic hemiparesis or dysarthria-clumsy hand syndrome. Four subjects had arterial hypertension, one was diabetic, and two were treated with anti-vitamin K. Abrupt onset was noted in all instances. Only one patient experienced moderate inaugural headaches. Good recovery occurred in all cases. Lacunar syndromes are a very uncommon presentation of intracerebral bleeding. Hemorrhages are yet the second etiology of such syndromes. Distinguishing hemorrhage from infarction is not clinically possible and needs early unenhanced CT scan.     

Clinical and demographic factors associated with DSM-IV melancholic depression.

BACKGROUND: The purpose of this paper is to use demographic and clinical data from a large diverse group of outpatients diagnosed with non-psychotic major depression to investigate the validity of the DSM-IV concept of melancholic depression. METHODS: Baseline clinical and demographic data were collected on 1500 outpatients (1456 of whom melancholia could be determined) with non-psychotic major depressive disorder (MDD) participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Depressive symptom severity was assessed by clinical telephone interview using the 17-item Hamilton Rating Scale for Depression (HRS-D17) and the 30-item Inventory of Depressive Symptomatology (IDS-C30). The types and degrees of concurrent psychiatric symptoms were measured using a self report, the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items relevant to each diagnostic category endorsed by study participants. RESULTS: Adjusting for severity of depression (as measured by the total HRS-D17 scores), no differences were found in the rate of melancholic depression by race, marital status, education, employment status, family history of depression, primary care versus specialty care, monthly income, and degree of psychiatric and medical co-morbidity. Melancholic depression was significantly more likely in men than women. Melancholic depression after adjustment for severity was associated with a slightly younger age at study entry, as well as with greater illness severity, and slightly shorter duration of current episode. Hispanic ethnicity was associated with lower melancholic depression rates at the .06 level of significance. CONCLUSIONS: Among outpatients with MDD, melancholic features were less likely in Hispanic patients, but more likely in slightly younger patients and in men. Melancholic features were also related to a slightly shorter current episode. These findings are consistent with the notion that external socio-demographic factors do not play an important role in the pathophysiology of melancholic depression.     

Bilateral Duane syndrome and bilateral aniridia.

Duane retraction syndrome has been reported in association with structural abnormalities of the eye, including epibulbar dermoid, keratoconus, iris dysplasia, heterochromia iridis, persistent fetal vasculature, cataract, choroidal coloboma, microphthalmia, and optic nerve dysplasia. A novel association, that of bilateral Duane syndrome with bilateral aniridia, is the subject of this report.     

Psychiatric considerations in pulmonary disease.

Lung disease is a prominent cause of morbidity and mortality worldwide. When a patient has a common lung disease, such as asthma, or a less prevalent one, such as idiopathic pulmonary fibrosis, psychiatric issues should be considered as an integral part of the care plan for each patient. There have been many studies of psychologic factors and psychiatric syndromes in various lung diseases and their treatment. In this article, the authors focus on an evidence-based approach to reviewing this clinical literature.     

Respiratory problems in children with neurological impairment.

Children with severe neurological impairment have a high incidence of respiratory problems which are multifactorial and may be related to or dependent on the underlying disability. In addition, common respiratory conditions such as asthma will be represented in this group as in the general paediatric population. In order to maximise quality of life and reduce morbidity and mortality, each child should be carefully assessed and treated, making adjustments where necessary in the treatment regime to take account of the disability.     

Glatiramer acetate in the treatment of multiple sclerosis

Glatiramer acetate is an immunomodulating drug used in the treatment of multiple sclerosis. It consists of a copolymer of amino acid residues in the same stoichiometric proportions as in myelin basic protein. Its mechanism of action is not entirely known and is probably multifaceted, with deletion of some immune cell populations and stimulation of others in these patients. Some mechanisms involve neuroprotectant effects. There is ample evidence of its efficacy in relapsing-remitting disease, using both clinical and imaging measures of disease activity, and in this paper we review the clinical and basic studies of this drug. Finally we discuss how some of its neuroprotectant effects may be useful in neurodegeneration such as is seen in more advanced cases of multiple sclerosis and other diseases such as amyotrophic lateral sclerosis and Parkinson’s disease.     

Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports.

BACKGROUND: We assessed suicide and suicide attempt risk as well as symptom reduction among 3,282 depressed patients participating in duloxetine and escitalopram clinical trials assigned to either an antidepressant or placebo. METHODS: We reviewed the FDA Summary Basis of Approval reports for data regarding safety and efficacy for duloxetine and escitalopram. Furthermore, we compared suicide risk among antidepressant clinical trials in this study with our two previous analyses on seven antidepressant clinical trials. RESULTS: Suicide and suicide attempt risk varied considerably among the three analyses, showing up to ten fold differences. Interestingly, the variability exists across the three reports, rather than between treatments (antidepressants versus placebo). CONCLUSIONS: These findings suggest caution in generalizing suicide risk even from a relatively large number of participants and thus, firm conclusions can only be drawn if the number of participants is overwhelmingly large (approximately two million patients). We also noted similar magnitude of response to placebo and antidepressants among the three studies.