The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

We have recently reported isolation of the gene responsible for X- linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.      

p53 immunoreactivity in hepatocellular adenoma, focal nodular hyperplasia, cirrhosis and hepatocellular carcinoma

The prolonged half-life of mutant p53 makes feasible its immunocytochemical detection. In order to assess the pathogenetic role of mutant p53 in regenerative and neoplastc liver disease we studied its immunohistochemical expression in cases of hepatic cirrhosis, hepatocellular carcinoma (HCC), cirrhosis with areas of HCC, hepatocellular adenoma and focal nodular hyperplasia. The study included needle and wedge biopsies of 50 cirrhotic livers, 59 HCCs (36 of them with associated cirrhosis), six adenomas and two focal nodular hyperplasias. Sixty-five HCC fineneedle cytology specimens were also included in the study. There was no immunohistochemical evidence of mutant p53 expression in any of the cases of cirrhotic liver (except for one instance associated with HCC) adenoma or focal nodular hyperplasia. In contrast p53 was detected in 8.5% of HCC cases in the biopsy series and 24% of HCC cases in the fine needle aspiration series. In addition, mutant p53 expression in HCC was positively correlated with tumour grade. According to grade, the distribution of p53 positive immunoreactivity among HCCs was as follows: Grade I-II, 0% of cases in the biopsy series and 9% in the fine needle aspirates; Grade III, 18% in the biopsy series and 55% in the fine needle aspirates; and Grade IV, 40% in the biopsy series. Therefore, mutant p53 expression does not seem to be associated with benign liver lesions but seems to correlate with the progression of HCC through various grades of increasing malignancy.     

Predominant type 1 CMV-specific memory T-helper response in humans: evidence for gender differences in cytokine secretion

Cell-mediated memory immune responses to viral antigens are important for protection against viruses causing persistent or acute infections. This study compared the cytokine profile of memory T-helper cells specific for cytomegalovirus (CMV) in healthy CMV-seropositive men and women. The cytokine response reflected T(H)1 bias, with dominant secretion of interferon (IFN)-gamma along with moderate levels of tumor necrosis factor-alpha, interleukin (IL)-10, and IL-2. Analyzed by gender, women had higher and significant spontaneous release of IFN-gamma and CMV-specific IL-2 secretion. Similar analysis with herpes simplex virus-1 showed a trend toward higher cytokine responsiveness in women, but the differences were not statistically significant. In contrast, men had statistically significant higher influenza virus-specific tumor necrosis factor-alpha secretion. IL-4 and IL-5, both T(H)2 cytokines, were low for all three viruses. The results show a predominant T(H)1 antiviral cytokine T-help memory response with significant differences linked to gender. Such differences may have an impact in the design of immunization strategies against CMV.     

A meta-analysis of the effect of HIV prevention interventions on the sex behaviors of drug users in the United States

We examined the effectiveness of 33 U.S.-based HIV intervention studies in reducing the sexual risk behaviors of drug users by reducing unprotected sex or increasing the use of male condoms. The studies, identified as of June 1998, through the HIV/AIDS Prevention Research Synthesis project, were published in 1988 or later, measured behavioral or biologic outcomes, used experimental designs or certain quasi-experimental designs, and reported sufficient data for calculating an effect size for sexual risk reduction. Of the 33 studies, 94% recruited injection drug users; 21% recruited crack users. The mean age of participants was 36 years. Almost all studies were randomized (94%), provided another HIV intervention to the comparison groups (91%), and evaluated behavioral interventions (91%). On average, interventions were conducted in 5 sessions (total, 10 hours) during 4.5 months. Interventions compared with no interventions were strong and significant (k = 3; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.43-0.85). Interventions compared with other HIV interventions showed a modest additional benefit (k = 30; OR, 0.91; 95% CI, 0.81-1.03). When we extrapolated our result (an OR of 0.60) to a population with a 72% prevalence of risk behavior, the proportion of drug users who reduced their risk behaviors was 12.6% greater in the intervention groups than in the comparison groups. Our meta-analysis shows that interventions can lead to sexual risk reduction among drug users and justifies providing interventions to drug users. Developing interventions with stronger effects to further reduce sexual risk behaviors among drug users must remain a high priority.     

Electrolyte Medium Effects on Measurements of Palmar Skin Potential

Two experiments with 12 subjects each compared skin potential recordings taken simultaneously with four different electrolytes. These were polyethylene glycol, hydrated agar (at a site presoaked with water), fresh agar (i.e., not presoaked), and Unibase. The glycol controlled epidermal hydration at a minimal level, while presoaking produced a high level of hydration at the hydrated agar site. Fresh agar and Unibase represented normal recording conditions for these two electrolytes which have been recommended as “standard” for electrodermal measurements. This design permitted a comparison of two standard electrolytes with each other and with recordings from hydrated and unhydrated sites. These comparisons were made for both monophasic negative SPRs and positive SPRs and the prestimulus levels associated with each. The results replicated previous studies in showing a large effect of epidermal hydration on skin potential measurements. Recordings with agar and Unibase did not differ significantly. The effects of hydration were interpreted in terms of a reduction in the resistance of the stratum corneum and of alterations in the functioning of the dermal and epidermal membranes as a result of blockage of the sweat gland pore. In the light of this interpretation, it was suggested that both agar and Unibase substantially alter the functioning of the sweat glands under some conditions, and neither may be entirely suitable for skin potential measurements.     

Spectral electroencephalographic correlates of iron status: Tired blood revisited

For some time, clinical reports have described impairment of affective and cognitive functions in iron deficient persons. Recent studies suggest that both brain biochemistry and cognitive performance capacity may be disrupted by inadequate intake of dietary iron, but the relationship of the possible neurophysiological effects to psychological ones is unclear. To examine the relationship of iron status to simultaneous measures of cortical activation and cognitive performance, 8 channels of electroencephalographic (EEG) data were recorded during a resting period and during the performance of several cognitive tasks in two groups of men. The EEG data were spectrally analyzed, and measures of total power and frequency of peak power in each of several bands of the power spectrum for each channel were used as predictors in multiple regression analyses with serum iron and serum ferritin as alternative criteria. Measures of power in the delta frequency in the resting period appeared relevant to iron status in both groups, perhaps indicating alertness or arousal level. Consistently in these regressions, the asymmetry of the EEG appeared relevant to iron and ferritin. These findings suggest that the combination of EEG and performance measures may help characterize the neuropsychological effects of trace element nutrition.     

Allelic exclusion of {alpha} chains in TCRs

Although the ß chains of ß⁺ T cells exhibitallelic exclusion it has recently been shown that 20–30%of such cells express both chain alleles on their surface.Potentially these cells have dual specificity, and it has beensuggested that they may play a role in autoimmunity and alloreactlvtty.The analysis presented in this paper examines critically thepossibility that the observed violation of allelic exclusionof chain expression arises as a natural consequence of a chainrearrangement and intrathymlc positive selection. It is concludedthat, subject to certain identified conditions being satisfied,the observed frequency of T cells expressing two chains iscompatible with such a mechanism. However, It is an essentialassumption of the theory that, of the two ß chaincomplexes on these cells, only one mediates positive selection.It follows that to what extent both receptors are actually functionaldepends on whether an ß chain complex that has failedto satisfy the criterion of positive selection can mediate antigenrecognition in the periphery. In principle the answer to thisquestion may be different if one is considering autoreactlvltyor alloreactlvlty. Finally, attention is drawn to the apparentdiscrepancy between the frequency of peripheral T cells expressingtwo chains and the failure to find T cell clones of this phenotype.Possible explanations are discussed.     

Disease-specific electrophysiological findings in adult ceroid-lipofuscinosis (Kufs disease)

Two adults with mild dementia and a history of memory loss and disequilibrium were seen in the eye clinic following complaints of acuity loss in the 20/30–20/70 (Snellen) range. Results from the fundus examination of one patient were entirely normal; the other showed minimal vascular attenuation and optic atrophy. Electrophysiology was remarkable: (1) Photopic ERG b-waves were reduced, delayed, and showed pronounced oscillations. (2) EOG light-rise potentials were absent or very small. (3) Binocular pattern-VER signals showed addition of the monocular signal. Scotopic ERG signals were normal. Brain biopsy and microscopy showed intercellular, autofluorescent ceroid deposits which provided a clear diagnosis of Kufs disease. Histology of model animal retinal cells show ceroid deposits in cell classes implicated by the human retinal signals. The cluster of electrophysiological results point toward early changes in the pigment epithelium and inner plexiform layer cells as a means of non-invasive diagnosis.     

Mechanisms of central conduction time prolongation in brain-stem auditory evoked potentials

The wave I-wave V delay in the auditory brain-stem response is commonly used as a diagnostic tool in otoneurology. Normative values have been established for different populations and different types of stimuli. This I-V delay has been known for some time as "central conduction time" or "central transmission time." This implies that the measure reflects in normal and in pathologic cases delays due to nerve conduction, synaptic transmission, and neural integration and is not caused by cochlear processes. By virtue of the traveling wave delay in the cochlea, amounting to some 4 ms from the base to the "500-Hz place," it is conceivable that this delay contributes to the I-V delay. From a series of 69 pontine angle tumors in which the auditory brain-stem response was recorded, we selected cases with an apparent peripheral origin of a prolonged I-V delay by comparing the whole-click response to responses derived from high-pass noise masking. It seems that cases with an increased I-V delay in the whole-click response but (almost) normal I-V delays in the narrow-band response are indicative of small intracanalicular acoustic neuroma.