Loss of p16 (INK4A) expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9p21 in microdissected malignant peripheral nerve sheath tumors.

The p16 is a tumor suppressor gene on the short arm of chromosome 9p21. The product of the p16 acts as a negative cell cycle regulator by inhibiting G1 cyclin-dependent kinases that phosphorylate the retinoblastoma protein. This study was designed to assess the frequency of genetic loss of 9p21 and to determine the role of p16 the pathogenesis of sporadic and neurofibromatosis 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). The authors examined 15 cases for p16 protein expression and 10 cases for allelic imbalance (AI)/loss of heterozygosity (LOH) of chromosome 9p. DNA was microdissected from normal and neoplastic tissues. AI/LOH analysis was performed using six microsatellite markers on the 9p region. On immunohistochemical analysis 80% of cases showed abnormal expression of p16. Similarly, 8 of 10 cases revealed genetic loss with at least one microsatellite marker. The most frequent deletion was that within the coding sequence. Of p16 at me D9S974 locus. These findings emphasize the role of loss of p16 in the development of both sporadic and NF1-associated MPNSTs.     

Inflammatory Markers in Acute Myocardial Infarction Patients: Preliminary Evidence of a Prospective Association With Depressive Symptoms

Inflammatory activity has been associated with both coronary disease and depressive symptoms. We sought to determine whether inflammatory markers in myocardial infarction (MI) patients are prospectively associated with depressive symptomatology. Participants were a convenience sample of MI patients. Depressive symptoms were assessed soon after the MI and again 7 months postdischarge. Inflammatory markers examined were interleukin-6 (IL-6) and interleukin-1β. Results suggest no significant cross-sectional association between inflammatory markers and depressive symptoms at baseline. However, bivariate and multiple regression analyses revealed a significant positive prospective association between baseline IL-6 and depressive symptoms 7 months later ( β  = .57, p  < .01). The results suggest that temporal considerations are important in understanding relationships between inflammation and depressive symptoms following MI.     

Type 2 nitric oxide synthase and protein nitration in chronic lung infection

Inflammation in the lung can lead to increased expression of inducible nitric oxide synthase (iNOS) and enhanced NO production. It has been postulated that the resultant highly reactive NO metabolites may have an important role in host defence, although they might also contribute to tissue damage. However, in a number of inflammatory lung diseases, including bronchiectasis, iNOS expression is increased but no elevation of airway NO can be detected. A potential explanation for this finding is that NO is rapidly scavenged by reaction with superoxide radicals, forming peroxynitrite, which is preferentially metabolized via nitration and nitrosation reactions. To test this hypothesis, anaesthetized, specific pathogen-free rats were inoculated with Pseudomonas aeruginosa incorporated into agar beads (chronically infected group) or sterile agar beads (control group). Ten to 15 days later, the lungs were isolated and fixed. Pseudomonas organisms were isolated from the lungs of the chronically infected group. These lungs showed extensive inflammatory cell infiltration and tissue damage, which were not observed in control lungs. Expression of iNOS was increased in the chronically infected group when compared with the control group. However, the mean number of cells staining for nitrotyrosine in the chronically infected group was not significantly different from that in the controls, nor was there an excess of nitrotyrosine, nitrate, nitrite or nitrosothiol concentrations in the infected lungs. Thus, no evidence was found of increased NO metabolites in chronically infected lungs, including products of the peroxynitrite pathway. These findings suggest that chronic infection does not cause increased iNOS activity in the lung, despite increased expression of iNOS.     

Is there a role for pericytic cells in the vascular bed of infantile hemangioendothelioma of the liver?

Electron microscopic examination of an infantile hemangioendothelioma (IHE) type I of the liver, appearing in a five month old child, showed a high density of pericytes in the walls of the neoplastic vessels. These vessels, in part of the IHE patients, establish an important arteriovenous shunt leading to high output, congestive cardiac failure. It is unclear whether functions ascribed to pericytes, such as participation in microvascular contractility or as suppressors of endothelial cell proliferation are involved in two noteworthy aspects of the present case. The child exhibited no congestive heart failure and the multiple nodular lesions underwent spontaneous regression.     

Activation of lipid metabolism contributes to interleukin-8 production during Chlamydia trachomatis infection of cervical epithelial cells

Chlamydia trachomatis infection is the most common cause of bacterial sexually transmitted diseases. Infection of the urogenital tract by C. trachomatis causes chronic inflammation and related clinical complications. Unlike other invasive bacteria that induce a rapid cytokine/chemokine production, chlamydial infection induces delayed inflammatory response and proinflammatory chemokine production that is dependent on bacterial growth. We present data here to show that the lipid metabolism required for chlamydial growth contributes to Chlamydia-induced proinflammatory chemokine production. By gene microarray profiling, validated with biochemical studies, we found that C. trachomatis LGV2 selectively upregulated PTGS2 (COX2) and PTGER4 (EP4) in cervical epithelial HeLa 229 cells. COX2 is an enzyme that catalyzes the rate-limiting step of arachidonic acid conversion to prostaglandins, including prostaglandin E2 (PGE2) and other eicosanoids, whereas EP4 is a subtype of cell surface receptors for PGE2. We show that Chlamydia infection induced COX2 protein expression in both epithelial cells and peripheral blood mononuclear cells and promoted PGE2 release. Exogenous PGE2 was able to induce interleukin-8 release in HeLa 229 epithelial cells. Finally, we demonstrated that interleukin-8 induction by Chlamydia infection or PGE2 treatment was dependent on extracellular signal-regulated kinase/mitogen-activated protein activity. Together, these data demonstrate that the host lipid remodeling process required for chlamydial growth contributes to proinflammatory chemokine production. This study also highlights the importance of maintaining a balanced habitat for parasitic pathogens as obligate intracellular organisms.     

Inhibition of nitric oxide synthase increases synaptophysin mRNA expression in the hippocampal formation of rats

Synaptophysin is a protein involved in the biogenesis of synaptic vesicles and budding. It has been used as an important tool to investigate plastic effects on synaptic transmission. Nitric oxide (NO) can influence plastic changes in specific brain regions related to cognition and emotion. Experimental evidence suggests that NO and synaptophysin are co-localized in several brain regions and that NO may change synaptophysin expression. Therefore, the aim of the present work was to investigate if inhibition of NO formation would change synaptophysin mRNA expression in the hippocampal formation. Male Wistar rats received single or repeated (once a day for 4 days) i.p. injections of saline or l-nitro-arginine (l-NOARG, 40 mg/kg), a non-selective inhibitor of nitric oxide synthase (NOS). Twenty-four hours after the last injection the animals were sacrificed and their brains removed for ‘in situ’ hybridization study using ³⁵S-labeled oligonucleotide probe complementary to synaptophysin mRNA. The results were analyzed by computerized densitometry. Acute administration of l-NOARG induced a significant (p < 0.05, ANOVA) increase in synaptophysin mRNA expression in the dentate gyrus, CA1 and CA3. The effect disappeared after repeated drug administration. No change was found in the striatum, cingulated cortex, substantia nigra or nucleus accumbens. These results reinforce the proposal that nitric oxide is involved in plastic events in the hippocampus.     

Psychosocial correlates of alcohol intake among women aged 45 to 64 years: The Framingham Study

This study of 749 women, aged 45 to 64 years, investigates the psychological, behavioral, and social correlates of alcohol intake. These data from the Framingham Study are uniquely based on a community sample of women, which results in a normative study of drinking behavior in women. Two measures of alcohol intake were utilized in these analyses: (1) the frequency of alcohol intake over 1 week and (2) drinking vs abstaining from alcohol. Among this sample of women, increased socioeconomic status, worrying about aging, and being easily upset were positively associated with frequency of alcohol intake. The rigid attitude scale was the strongest discriminating variable for drinkers vs nondrinkers. Older women were more likely to be nondrinkers compared to younger women, however, among older women, being a homemaker was significantly associated with increased alcohol intake. Contrarily, younger women who were homemakers were more likely to be abstainers than women employed outside the home. As would be expected, cigarette smoking was associated with drinking alcohol.This research is dedicated in fond remembrance to our friend and colleague Joseph Stokes III, M.D.     

Analysis of human papillomavirus prevalence and TP53 polymorphism in head and neck squamous cell carcinomas

Head and neck squamous cell carcinoma is a disease associated with tobacco and alcohol abuse. There is evidence that the oncogenic human papillomavirus (HPV) may also be a risk for upper aerodigestive tract cancers. High-risk HPVs encode two early proteins, E6 and E7, that can bind to p53 and pRb, respectively, and induce its degradation or inactivation. The TP53 gene has a single polymorphism at codon 72 of exon 4 that encodes either arginine (Arg) or proline (Pro). The purpose of this study was to evaluate the role of HPV infection and TP53 polymorphism in head and neck cancer. We analyzed 50 tumors, as well swabs of oral mucosa from 142 control individuals, with a polymerase chain reaction technique. The prevalence of HPV in controls was 10.6% and in cancer specimens 16%. The frequency distribution of genotypes in controls was 50% Arg/Arg, 43% Arg/Pro and 7% Pro/Pro; in tumors, it was 52% Arg/Arg, 32% Arg/Pro, and 16% Pro/Pro. Contrary to the results of some studies on cervical cancer, no association between any TP53 genotype or allele and the development of head and neck cancer was observed, regardless of HPV status, except for the Pro/Pro genotype, which is associated with the absence of HPV. The arginine allele appears to protect against head and neck cancers. Also, the data showed that HPV infection results in no increased risk of developing head and neck tumors.     

Human brucellosis in the Mid-West 2002-3

Human brucellosis remains a serious public health issue in Ireland. Clinical notifications in the Mid-Western Area (HSE-MWA) underestimate the burden of illness and attendant morbidity in the region. The diagnosis of acute and chronic human brucellosis depends on the clinical evidence and the results from laboratory serological testing or culture on rare occasion. This study examined the clinical evidence behind locally defined serological "positives" in the HSE-MWA from 2002 to 2003. Ninety cases were detected in 2002 and 31 in 2003. While sampling bias is likely to be present, aspects of brucellosis in Ireland were confirmed. Middle-aged males were most commonly affected. The majority of cases were linked to farming or veterinary practice. Symptoms such as sweats, fever and weight loss were commonly associated with acute brucellosis infection while malaise was common in acute and chronic brucellosis. A clear definition of what is notifiable is needed. Surveillance systems must appreciate the importance of both clinical and laboratory evidence to classify confirmed or probable brucellosis as paired sera were not common. Public health authorities must follow-up the clinical aspects for accurate national statistics. General practitioners in the Mid-West appear to be vigilant regarding brucellosis in their patients. Regional zoonoses committees are useful in monitoring disease prevalence in human and animal populations without compromising confidentiality.