Structure and function of natural-killer-cell receptors

The function of natural-killer (NK) cells is modulated by the balance between a number of activating and inhibitory receptors. Killer immunoglobulinlike receptors (KIRs) are mostly inhibitory receptors. They play a critical role in recognizing self-class-I major histocompatibility complex (MHC) molecules and thus protect healthy host cells from NK-targeted lysis. In contrast, both NKG2D and CD16 are activating NK receptors that trigger the NK-cell lysis of various tumor and virally infected cells through either direct ligand engagement or antibody-dependent cellular cytotoxicity (ADCC). Through structural studies of members of these distinct receptor families, in particular, the structure and recognition between KIR2DL2 and HLA-Cw3, that between NKG2D and ULBP3, and that between CD16 and IgG Fc, considerable understandings have been achieved about their function and their ligand recognition.     

Premenstrual dysphoric disorder and changes in frontal alpha asymmetry.

OBJECTIVE: Since the clinical picture of premenstrual dysphoric disorder (PMDD) in the Luteal phase of the menstrual cycle is characterized by extreme negative affect, we predicted and obtained a change in frontal cortical EEG alpha asymmetry, which has been shown to be an index of affect. METHOD: We observed two monthly cycles for five women diagnosed as having PMDD and one monthly cycle for five non-PMDD control subjects. RESULTS: Asymmetry percent scores for the five PMDD women, and for the five control subjects before and after the Luteal phase were typically within the normal non-depressed range, however the asymmetry scores for the PMDD group fell into the negative range during the Luteal period while the control subjects remained stable. DISCUSSION: We predicted alpha asymmetry scores would be affected by the luteal phase in PMDD cases. This hypothesis was clearly confirmed.     

Onset of action of pimecrolimus cream 1% in the treatment of atopic eczema in infants

BACKGROUND: Data on the efficacy of pimecrolimus cream 1% within the first days of treatment are scarce, as in previous studies, the first postbaseline assessment was performed only after 1 week. OBJECTIVE: We sought to investigate the onset of action of pimecrolimus cream 1% in infants with mild to very severe atopic eczema. METHODS: We used pimecrolimus cream 1% (n = 129) or vehicle cream (n = 66) administered in a double-blind manner for 4 weeks and then open-label pimecrolimus cream 1% for 12 weeks, with a 4-week follow-up period. RESULTS: Pimecrolimus cream 1% reduced the mean Eczema Area and Severity Index at 4 weeks by 71.5% compared with an increase of 19.4% with vehicle ( P < .001). The reduction in the Eczema Area and Severity Index with pimecrolimus cream 1% was significant at day 4 (38.5% vs 17.6% increase with vehicle). Significant improvements in caregivers' assessments of pruritus and sleep loss were observed with pimecrolimus cream 1% by day 2 ( P < .03) and day 3 ( P = .002), respectively, compared with vehicle. Responses to pimecrolimus cream 1% were sustained during the open-label phase, and pimecrolimus cream 1% was well tolerated. Symptoms of atopic eczema returned gradually after discontinuation. CONCLUSION: Pimecrolimus cream 1% was well tolerated and effective in patients with mild to very severe atopic eczema, with rapid onset of action and no disease rebound after discontinuation.     

Genomic aberrations and survival in chronic lymphocytic leukemia

BACKGROUND: Fluorescence in situ hybridization has improved the detection of genomic aberrations in chronic lymphocytic leukemia. We used this method to identify chromosomal abnormalities in patients with chronic lymphocytic leukemia and assessed their prognostic implications. METHODS: Mononuclear cells from the blood of 325 patients with chronic lymphocytic leukemia were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 6q21, 11q22-23, 13q14, and 17p13; trisomy of bands 3q26, 8q24, and 12q13; and translocations involving band 14q32. Molecular cytogenetic data were correlated with clinical findings. RESULTS: Chromosomal aberrations were detected in 268 of 325 cases (82 percent). The most frequent changes were a deletion in 13q (55 percent), a deletion in 11q (18 percent), trisomy of 12q (16 percent), a deletion in 17p (7 percent), and a deletion in 6q (7 percent). Five categories were defined with a statistical model: 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality; the median survival times for patients in these groups were 32, 79, 114, 111, and 133 months, respectively. Patients in the 17p- and 11q-deletion groups had more advanced disease than those in the other three groups. Patients with 17p deletions had the shortest median treatment-free interval (9 months), and those with 13q deletions had the longest (92 months). In multivariate analysis, the presence or absence of a 17p deletion, the presence or absence of an 11q deletion, age, Binet stage, the serum lactate dehydrogenase level, and the white-cell count gave significant prognostic information. CONCLUSIONS: Genomic aberrations in chronic lymphocytic leukemia are important independent predictors of disease progression and survival. These findings have implications for the design of risk-adapted treatment strategies.     

Body fat and fat distribution in relation to sex differences in blood pressure

The extent to which the relationship between body fat and blood pressure either differs by sex or explains sex differences in blood pressure is examined. Estimates of the relationship of blood pressure to several measures of adiposity in men and women were obtained from a systematic review of the literature and tests of whether these relationships differ by sex were performed. Analysis of covariance (controlling for age and race) was used for both casual and ambulatory blood pressure in the Cornell Worksite Blood Pressure Study (N = 276). In general, most adiposity measures were significantly related to casual and ambulatory blood pressure in men and women. Subscapular skinfold thickness and body mass index exhibited the strongest associations. The vast majority of adiposity/blood pressure associations were not significantly different for men and women. Finally, sex differences in adiposity did not account for much of the sex difference observed in blood pressure. © 1995 Wiley-Liss, Inc.     

Association analysis of a polymorphism in the G‐protein stimulatory α subunit in patients with major depression*

Growing evidence suggests that G‐proteins may be involved in pathogenesis and treatment of affective disorders. Several studies have reported altered levels and/or activities of stimulatory G‐proteins in depression. The aim of this study was to investigate whether a polymorphism in the stimulatory α subunit of G‐proteins (T/C point mutation in exon 5; ATT → ATC at codon 131) is associated with major depression or response to antidepressant treatment. Therefore, we performed a case‐control association study with 212 depressive patients and 137 healthy, unrelated controls. There was no evidence for an association between the investigated polymorphism in the Gα_s gene and major depression, as well as to treatment response. The results of our study are in concordance with recently published findings which do not support the hypothesis that the gene for the stimulatory α subunit of G‐proteins is a major susceptibility factor in the pathophysiology of major depression. © 2002 Wiley‐Liss, Inc.     

The hypoxia-regulated transcription factor DEC1 (Stra13, SHARP-2) and its expression in human tissues and tumours

DEC1, also known as SHARP-2 or Stra13, is an important molecule in embryonic differentiation and has recently been identified to be strongly inducible by hypoxia. Its distribution in normal human tissues and most tumour types is unknown. In the present study, a polyclonal antiserum to a 10-amino acid peptide from DEC1 has been raised. Using this antiserum, DEC1 was shown to be widely expressed in most normal human tissues, but usually only in a proportion of cells and typically with a nuclear localization. In tumours, expression was either augmented (the commonest pattern) or occasionally decreased. Similarly, in most normal tissues, low or absent expression was observed in endothelial cells, whereas in many tumour samples endothelium was usually strongly positive. In tumours, there was a striking pattern of staining seen in connection with areas of necrosis, with absence of DEC1 expression within a zone of morphologically viable cells immediately adjacent to the necrotic zone. This suggests that while DEC1 may be up-regulated by hypoxia in cancer, in more extreme hypoxia it may have a role in cell death. Its interrelationship with other hypoxically regulated molecules, such as the hypoxia-inducible factors or carbonic anhydrase IX, and differentiation of tumours now requires further investigation.