Shrinkage-based similarity metric for cluster analysis of microarray data

The current standard correlation coefficient used in the analysis of microarray data was introduced by M. B. Eisen, P. T. Spellman, P. O. Brown, and D. Botstein [(1998) Proc. Natl. Acad. Sci. USA 95, 14863-14868]. Its formulation is rather arbitrary. We give a mathematically rigorous correlation coefficient of two data vectors based on James-Stein shrinkage estimators. We use the assumptions described by Eisen et al., also using the fact that the data can be treated as transformed into normal distributions. While Eisen et al. use zero as an estimator for the expression vector mean mu, we start with the assumption that for each gene, mu is itself a zero-mean normal random variable [with a priori distribution N(0,tau 2)], and use Bayesian analysis to obtain a posteriori distribution of mu in terms of the data. The shrunk estimator for mu differs from the mean of the data vectors and ultimately leads to a statistically robust estimator for correlation coefficients. To evaluate the effectiveness of shrinkage, we conducted in silico experiments and also compared similarity metrics on a biological example by using the data set from Eisen et al. For the latter, we classified genes involved in the regulation of yeast cell-cycle functions by computing clusters based on various definitions of correlation coefficients and contrasting them against clusters based on the activators known in the literature. The estimated false positives and false negatives from this study indicate that using the shrinkage metric improves the accuracy of the analysis.     

Ginkgo biloba does not benefit patients with tinnitus: a randomized placebo-controlled double-blind trial and meta-analysis of randomized trials

The objective was to ascertain if Ginkgo biloba benefits patients with tinnitus. The study design was: 1. Randomized double blind trial of Ginkgo biloba versus placebo; 2. A meta-analysis of randomized placebo controlled double blind trials. Participants included 66 adult patients with tinnitus and six (including our study) randomized placebo controlled double blind trials were meta-analysed.The main outcome measures were the Tinnitus Handicap Inventory (THI), Glasgow Health Status Inventory (GHSI) and average of hearing threshold at 0.5, 1, 2, 4 kHz. In the meta-analysis the proportion of patients gaining benefit and an overall odds ratio were determined. The results showed the mean difference in change of the THI, GHSI and hearing between Ginkgo biloba (n = 31) and placebo group (n = 29) was 2.51 (CI -10.1, 5.1, P = 0.51), 0.58 (CI-4.8, 3.6, P = 0.38) and 0.68 db (CI -4.13, 2.8, P = 0.69). Meta-analysis revealed 21.6% of Ginkgo biloba treated patients (n = 107/552) gained benefit versus 18.4% (n = 87/504) of placebo treated patients with an odds ratio of 1.24 (CI 0.89, 1.71). In conclusion, Ginkgo biloba does not benefit patients with tinnitus.     

Prenatal nicotine exposure increases heart susceptibility to ischemia/reperfusion injury in adult offspring

In the present study we tested the hypothesis that prenatal nicotine exposure increases heart susceptibility to ischemia/reperfusion (I/R) injury in adult offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps throughout gestation. Nicotine treatment resulted in a rapid and transient decrease in food-intake and a moderate decrease in maternal body weight gain. Hearts were isolated from adult male and female offspring and subjected to I/R in a Langendorff preparation. Nicotine significantly attenuated left ventricle (LV) developed pressure, heart rate, and coronary flow rate in female but not male hearts at baseline. Additionally, nicotine significantly increased LV infarct size and attenuated postischemic recovery of LV function in both male and female offspring with more pronounced effects in females. In female but not male hearts, nicotine significantly decreased the postischemic coronary flow rate. However, coronary nitric oxide release was decreased in male but not female hearts. Caspase-3, -8, and -9 levels were not significantly changed in either female or male hearts. However, nicotine caused a significant decrease in protein levels of protein kinase (PK) Cepsilon in both male and female hearts and a decrease in PKCdelta levels in female hearts only. Control studies of maternal food restriction showed that a moderate decrease in maternal body weight gain had no effect on female hearts but significantly improved postischemic recovery of LV function in male hearts. The results suggest that prenatal nicotine exposure causes in utero programming of the PKC isozyme gene expression pattern in the developing heart and increases heart susceptibility to I/R injury in adult offspring.     

Serum selenium level and other risk factors for breast cancer among patients in a Malaysian hospital

Objective The aim of this study is to investigate the association between breast cancer and serum selenium level as well as other risk factors for breast cancer. Methods A matched case-control study was conducted in a hospital in Malaysia from July 2000 to January 2001 and from May 2001 to June 2001. Sixty-two newly diagnosed breast cancer patients were selected as the cases. Each control, selected from the same hospital population was matched to each case according to age, ethnic group, and menopausal status. Results The mean selenium concentration among the cases was significantly lower than that among the control. There was a significant association (p<0.05) between breast cancer and low selenium serum level, nulliparity (OR=5.5,95% CI=1.22 to 24.81), exposure to cigarette smoke (OR=2.2, 95% CI=1.04 to 4.65) and use of oral contraceptives (OR=3.0, 95% CI=1.09 to 8.25) as determined by the McNemar test. Multivariate analysis showed that nulliparity (OR=10.08, 95% CI=1.48 to 68.52) and use of oral contraceptives (OR=3.66, 95% CI=1.36 to 9.87) were associated with increased breast cancer risk. An increased selenium concentration contributes to a reduced risk of breast cancer (OR=0.89, 95% CI=0.84 to 0.94). Conclusion The results suggest that use of oral contraceptive pills, being nulliparous, and a low serum selenium level are associated with breast cancer.     

The in vitro Effect of Oxidized LDL and PHA on Proliferation and Gene Expression of Regulatory T Cells in Patients with Atherosclerosis

Atherosclerosis is a chronic inflammatory condition that affects the arterial wall. Oxidized low-density lipoprotein (ox-LDL) seems to have an important role in atherosclerotic plaque formation.This study was performed to investigate the effects of ox-LDL as well as PHA on proliferation and gene expression of peripheral blood mononuclear cells (PBMCs) in patients with atherosclerosis compared to healthy controls. Proliferation of PBMCs was assessed by BrdU assay, while gene expression was assessed by real-time PCR.Both PHA and ox-LDL significantly induced proliferation of PBMCs of patients and controls. PBMCs from controls showed significantly higher proliferation when stimulated with ox-LDL compared to patients. Expression of TGF-β was significantly lower in PBMCs from patients compared to healthy controls (p<0.001). Following simulation with PHA, TGF-β and Foxp3 gene expression levels in patients and controls were significantly decreased (p<0.001). Expression of Foxp3 in PBMCs treated with ox-LDL was significantly decreased in patients and controls.Decreased expression of TGF-β and Foxp3 genes after ox-LDL stimulation may be due to more sensitivity of Treg cells than effector T cells to ox-LDL. Presence of ox-LDL within atheroma could be associated with the diminished population of Treg cells in the atherosclerotic patients.     

Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons

Spiral ganglion neurons often degenerate in the deaf ear, compromising the function of cochlear implants. Cochlear implant function can be improved by good preservation of the spiral ganglion neurons, which are the target of electrical stimulation by the implant. Brain derived neurotrophic factor (BDNF) has previously been shown to enhance spiral ganglion survival in experimentally deafened ears. Providing enhanced levels of BDNF in human ears may be accomplished by one of several different methods. The goal of these experiments was to test a modified design of the cochlear implant electrode that includes a coating of fibroblast cells transduced by a viral vector with a BDNF gene insert. To accomplish this type of ex vivo gene transfer, we transduced guinea pig fibroblasts with an adenovirus with a BDNF gene cassette insert, and determined that these cells secreted BDNF. We then attached BDNF-secreting cells to the cochlear implant electrode via an agarose gel, and implanted the electrode in the scala tympani. We determined that the BDNF expressing electrodes were able to preserve significantly more spiral ganglion neurons in the basal turns of the cochlea after 48 days of implantation when compared to control electrodes. This protective effect decreased in the higher cochlear turns. The data demonstrate the feasibility of combining cochlear implant therapy with ex vivo gene transfer for enhancing spiral ganglion neuron survival.     

GJB2 c.−23+1G&gt;A mutation is second most common mutation among Iranian individuals with autosomal recessive hearing loss

GJB2 mutation analysis is used routinely as a first step in genetic testing for autosomal recessive non-syndromic sensorineural hearing loss. Although most GJB2 mutations can be detected by sequencing of the exon 2 of this gene, a prevalent splice mutation, c.?23+1G>A (IVS1+1G>A), is not usually included in the analyzed region. In this study, we have developed an ARMS-PCR strategy for detection of this mutation among Iranian deaf individuals. A total of 418 Iranian individuals with hearing loss consistent with autosomal recessive non-syndromic sensorineural hearing loss based on audiological test result, medical history, physical examination and pedigree of the family, were included in this study. c.35delG and c.?23+1G>A mutations were detected by using ARMS-PCR. Direct sequencing of the exon 2 of the GJB2 gene was performed for mutation analysis of the coding region of this gene. Among 418 investigated cases, a total of 81 patients (~19.4 %) with biallelic pathogenic mutations in the GJB2 gene and 13 cases with only one pathogenic mutant allele were identified. The total allele frequencies of the two most frequent mutations, c.35delG and c.?23+1G>A, among mutated alleles were found to be around 59 and 15.7 %, respectively. High frequency of the c.35delG and c.?23+1G>A mutations among Iranian deaf individuals shows the importance of developing rapid and cost-effective methods for primary mutation screening methods before performing direct sequencing.     

Acquired immune deficiency syndrome (AIDS) presenting as a nasal septal perforation.

Patients infected with the Human Immunodeficiency Virus (HIV) and those with AIDS may present with many head and neck manifestations. We report a case of an undiagnosed HIV positive male who presented with symptoms due to a nasal septal perforation, and rapidly developed AIDS. The histopathology of the perforation margins revealed active chronic inflammation with no evidence of neoplasia or granuloma. No viral or fungal infection was demonstrable on immunological testing and fungal stain. This is the first reported case of a patient developing AIDS presenting with a nasal septal perforation.     

Suspending tonsillectomy: the effects on primary and secondary acute care in Scotland

For the first six months of 2001, tonsillectomy operations were effectively suspended in Scotland. This was due to concern regarding the potential transmission of vCJD prions by surgical instruments, and the subsequent gradual introduction of disposable instruments. The number of patients awaiting tonsillectomy therefore increased and theoretically there should have been an increase in the number of tonsillitis episodes in the community, or even in the number of tonsillitis-related complications seen in secondary care. We examined for these effects using available national data sources which record primary and secondary care activity. No increases in the incidences of acute tonsillitis or tonsillitis-related complications were found for this period. The reasons and implications are discussed.     

Mucocele mimicking a Warthin's tumour recurrence

We report an unusual case of an extravasation mucocele complicating superficial parotidectomy. The tumour excised was a Warthin's tumour. Three months following the primary surgery a cystic lesion appeared in the parotid bed. It was initially thought to represent a recurrence. The area was re-explored and a mucocele excised. The pathogenesis of mucoceles and the difficulties encountered when dealing with parotid tumour recurrence are discussed.