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Filarial Nematode Parasites Secrete a Homologue of the Human Cytokine Macrophage Migration Inhibitory Factor

Filarial nematode parasites establish long-term chronic infections in the context of an antiparasite immunity that is strongly biased toward a Th2 response. The mechanisms that lead to this Th2 bias toward filarial antigens are not clear, but one possibility is that the parasites produce molecules that have the capacity to proactively modify their immunological environment. Here we report that filarial parasites of humans secrete a homologue of the human proinflammatory cytokine macrophage migration inhibitory factor (MIF) that has the capability of modifying the activity of human monocytes/macrophages. A cDNA clone isolated from a Brugia malayi infective-stage larva expression library encoded a 12.5-kDa protein product (Bm-MIF) with 42% identity to human and murine MIF. MIF homologues were also found to be expressed in the related filarial species Wuchereria bancrofti and Onchocerca volvulus. Bm-mif was transcribed by adult and larval parasites, and the protein product was found in somatic extracts and in the parasite’s excretory-secretory products. Immunohistocytochemistry revealed that Bm-MIF was localized to cells of the hypodermis/lateral chord, the uterine wall, and larvae developing in utero. Unexpectedly, the activities of recombinant Bm-MIF and human MIF on human monocytes/macrophages were found to be similar. When placed with monocytes/macrophages in a cell migration assay, Bm-MIF inhibited random migration. When placed away from cells, Bm-MIF induced an increase in monocyte/macrophage migration that was specifically inhibited by neutralizing anti-Bm-MIF antibodies. Bm-MIF is the first demonstration that helminth parasites produce cytokine homologues that have the potential to modify host immune responses to promote parasite survival.     

Inter-laboratory quality control in neonatal screening for inborn errors of metabolism

Screening of neonates for inborn errors of metabolism has been carried out on a national level since 1969 in the Federal Republic of Germany. To raise the reliability of these routine investigations, we introduced an external quality control in March 1982. Every 2 months ten filter paper samples were sent to the screening centres in West Germany. Some of these samples have a normal and others a slightly raised content of phenylalanine, leucine, methionine and galactose. The success of this external quality control is appraised on the basis of the number of false negative results. In the course of time, screening centres in France, Israel, Italy, Japan, Switzerland, Taiwan, Turkey and Yugoslavia have also practicipated in these inter-laboratory quality controls.Abbreviations QC quality control - BIA bacterial inhibition assay - HPLC high pressure liquid chromatography     

Psychiatric morbidity and low self-attentiveness in patients with environmental illness

Controversy surrounds the origin of symptoms attributed to environmental pollutants or widely used chemicals, and the authors believed that a psychiatric evaluation could advance understanding of this contentious condition. They assessed psychiatric morbidity, somatization, and self-attentiveness in patients seen in their Environmental Clinic. Two hundred ninety-five consecutive patients underwent SCID-I and -II interviews and were investigated with self-rating scales for self-attentiveness and somatization. The authors found a high prevalence of mental disorders (66% had a current SCID diagnosis, and 75% had a lifetime SCID diagnosis) and a low level of self-attentiveness, which was not necessarily associated with psychiatric disease. Among patients visiting an Environmental Clinic, mental disorders were common and needed to be diagnosed and treated by standard interventions. Patients who did not meet diagnostic criteria for a psychiatric disorder had relatively low somatization scores and low private self-attentiveness. These "externalizers" could benefit from an intervention that teaches them to focus on their internal and emotional lives. In these patients, the authors consider low self-attentiveness a major feature that may act as a pathogenic factor for environmental illness.     

Dysregulation of renal salt and water transport proteins in diabetic Zucker rats

BACKGROUND: Diabetic nephropathy is commonly associated with renal salt and water retention and hypertension. The molecular mechanisms involved and how the kidney responds to this volume expansion, in terms of renal transporter regulation, are not understood. METHODS: Targeted proteomics employing semiquantitative immunoblotting were used to investigate regulation of abundance of the primary salt and water transport proteins of the kidney, in 6-month-old lean and obese Zucker rats, a model for Type II diabetes. RESULTS: Obese rats were significantly heavier, had larger kidneys, increased plasma creatinine and glucose levels and elevated blood pressures. Furthermore, they had a marked decrease in abundance of many pre-macula densa renal sodium transporters. Mean band densities (% lean) were: in cortex, sodium phosphate cotransporter (NaPi-2), 68%, and sodium hydrogen exchanger (NHE3), 66%; and in outer medulla, NHE3, 39%, and the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), 37%. Collecting duct proteins also were markedly reduced. In inner medulla, aquaporins-2, -3, and -4 were reduced to, 46, 48, and 46%, respectively, and the apical urea transporter, UTA1 to 52%. In contrast, post-macula densa sodium transporters were less affected. The thiazide-sensitive Na-Cl cotransporter (NCC) was 106% and the alpha- beta- and gamma-subunits of the epithelial sodium channel (ENaC), 54, 121, and 84% of lean, respectively. CONCLUSIONS: In obese rats, selective decreases for pre-macula densa sodium transporters may reflect decreased glomerular filtration rate and glomerulotubular balance. This potentially could reduce blood pressure by decreasing proximal tubule sodium reabsorption.     

The clock drawing test and questionable dementia: reliability and validity

OBJECTIVES: In order to evaluate the suitability of the clock drawing test (CDT) for the detection of questionable dementia (QD), we assessed the inter-rater reliabilities and intercorrelations of four common scoring methods of the CDT in a sample of non-demented subjects and determined the concurrent validity. METHODS: The study sample consisted of 253 discharged general hospital patients, aged between 65 and 85 years. Subjects were screened for cognitive impairment during their hospital stay. Four to six weeks after discharge each non-demented patient was visited at home and interviewed by a trained psychologist. The interview procedure included a cognitive test battery incorporating the CDT, the Mini-Mental State Examination (MMSE), the Syndrome Short Test (SKT), and a verbal fluency test (VF). The criteria of the Clinical Dementia Rating (CDR) were used to differentiate between cognitively normal subjects and those with QD. Clock drawings were scored independently and blindly by two raters according to four different methods. The agreement between raters was assessed, as well as the agreement between the different scoring methods. The association of gender, education, age, test performance and CDR-rating with CDT scores was examined. Accuracy of the CDT for the detection of QD was calculated. RESULTS: Inter-rater reliabilities were high for all four scoring methods. However, substantial differences among the scoring methods were observed, the proportion of abnormal test results varying between 9% and 50%. The CDT correlated significantly with MMSE, SKT and VF, but correlation coefficients were low (r = 0.13 to r = 0.32). Furthermore, CDT scores were influenced by age, gender, and education. Sensitivity of the CDT for QD was 66%, specificity was 65%; the negative predictive value was 73%, the positive predictive value 58%. CONCLUSION: In a sample of non-demented elderly, the reliability of the CDT was sufficiently high, but the different scoring methods were not equivalent. When established cut-off scores were used, the proportion of abnormal CDTs were significantly different. Concurrent validity with other common cognitive tests was unsatisfactory. The CDT lacks sufficient sensitivity and specificity for the identification of QD and should not be used alone to screen for possible prodromal stages of dementing illnesses. The association of age, gender and level of education with CDT scores should be taken into account by clinicians using the CDT.     

Dermal microdialysis provides evidence for hypersensitivity to noradrenaline in patients with familial dysautonomia

OBJECTIVES: To use the technique of dermal microdialysis to examine sensitivity of skin vessels to noradrenaline (NA) in patients with familial dysautonomia (FD) and in healthy controls. METHODS: In 14 patients with FD and 12 healthy controls, plasma extravasation, local laser Doppler blood flow, and skin blanching were observed before, during, and after application of 10(-6) M NA through a microdialysis membrane, located intradermally in the skin of the lower leg. RESULTS: Maximum local vasoconstriction measured by laser Doppler blood flow did not differ between patients with FD and controls. In contrast, patients with FD had an earlier onset of vasoconstriction (p = 0.02). Moreover, reaction to NA was more prominent and prolonged in FD, shown by a larger zone of skin blanching around the microdialysis membrane (p < 0.001) and delayed reduction of the protein content in the dialysate after termination of NA application (p = 0.03). CONCLUSION: These data support the hypothesis that peripheral blood vessels of patients with FD show a denervation hypersensitivity to catecholamines. This may be one mechanism contributing to the major hypertension that frequently occurs during "dysautonomic crises" in FD.