Risk of environmental transmission of norovirus infection from prior room occupants.

BACKGROUND: Environmental contamination of norovirus (NoV) is believed to be a significant source for further transmission in hospitals. AIM: To investigate the risk of acquiring NoV in a cleaned room previously occupied by a patient with NoV infection. The risk of having a roommate with recent NoV infection was also assessed. METHODS: In a retrospective cohort, comprising 33,788 room stays at five infectious Disease wards in southern Sweden from 2013 to 2018, the risk of acquiring NoV infection after admission to an exposed or non-exposed room was analysed with uni- and multivariable statistical analysis, controlling for age, colonization pressure and any roommate. RNA sequencing of the NoV strains involved in suspected room transmission was also performed. RESULTS: Five of the 1106 patients exposed to a room with a prior occupant with NoV infection and 49 in the non-exposed group acquired NoV infection. An association between NoV acquisition was found in the univariable analysis (odds ratio (OR) 3.3, P=0.01), but not when adjusting for potential confounders (OR 1.9, P=0.2). Sequencing of the NoV samples showed that only two of the five exposed patients with acquired NoV infection were infected by identical strains to the prior room occupant, inferring a room transmission risk of 0.2% (95% confidence interval 0.05-0.78%). None of the 52 patients who shared room with a roommate with NoV symptoms resolved for ≥48 h acquired NoV infection. CONCLUSIONS: In absolute terms, the risk of room transmission of NoV is low. Discontinuation of isolation ≥48 h after resolution of symptoms seems adequate.

A European multicentre evaluation of detection and typing methods for human enteroviruses and parechoviruses using RNA transcripts.

Polymerase chain reaction (PCR) detection has become the gold standard for diagnosis and typing of enterovirus (EV) and human parechovirus (HPeV) infections. Its effectiveness depends critically on using the appropriate sample types and high assay sensitivity as viral loads in cerebrospinal fluid samples from meningitis and sepsis clinical presentation can be extremely low. This study evaluated the sensitivity and specificity of currently used commercial and in-house diagnostic and typing assays. Accurately quantified RNA transcript controls were distributed to 27 diagnostic and 12 reference laboratories in 17 European countries for blinded testing. Transcripts represented the four human EV species (EV-A71, echovirus 30, coxsackie A virus 21, and EV-D68), HPeV3, and specificity controls. Reported results from 48 in-house and 15 commercial assays showed 98% detection frequencies of high copy (1000 RNA copies/5 µL) transcripts. In-house assays showed significantly greater detection frequencies of the low copy (10 copies/5 µL) EV and HPeV transcripts (81% and 86%, respectively) compared with commercial assays (56%, 50%; P = 7 × 10-5 ). EV-specific PCRs showed low cross-reactivity with human rhinovirus C (3 of 42 tests) and infrequent positivity in the negative control (2 of 63 tests). Most or all high copy EV and HPeV controls were successfully typed (88%, 100%) by reference laboratories, but showed reduced effectiveness for low copy controls (41%, 67%). Stabilized RNA transcripts provide an effective, logistically simple and inexpensive reagent for evaluation of diagnostic assay performance. The study provides reassurance of the performance of the many in-house assay formats used across Europe. However, it identified often substantially reduced sensitivities of commercial assays often used as point-of-care tests.

Risk factors for hospital norovirus outbreaks: impact of vomiting, genotype, and multi-occupancy rooms.

BACKGROUND: Norovirus is frequently introduced to the hospital and is a frequent cause of hospital outbreaks. Recognition of the factors that facilitate or impede norovirus transmission is an important step to effectively prevent hospital outbreaks. AIM: To investigate risk factors for norovirus outbreaks in hospital settings. METHODS: Clinical data, ward setting, and norovirus genotype were collected from all 65 norovirus-positive index cases in outbreaks and all 186 sporadic norovirus cases at 192 wards in southern Sweden during 2010-2012 in a nested case-control study. Uni- and multivariate statistical analyses were conducted. FINDINGS: Outbreak was independently associated with the number of patients sharing a room with the norovirus case (odds ratio (OR): 1.9 per additional patient in the room; P < 0.01), vomiting (OR: 2.6; P = 0.04), age >80 years (OR: 3.2; P < 0.01), comorbidity (OR: 2.3; P = 0.05), and onset of symptoms after admission to the ward (OR: 3.5; P < 0.01) in the multivariate analysis. Infection with genotype GII.4 was found to be strongly associated with outbreak in the univariate analysis (OR: 5.7; P < 0.01). Moreover, associations between GII.4 and vomiting (OR: 2.5; P = 0.01) and old age (OR: 4.3: P < 0.01) were found. CONCLUSION: This is the first study to investigate clinical, ward and genotype risk factors for norovirus hospital outbreaks. Recognition of these factors may help direct and prioritize infection control actions based on the outbreak risk. The results also suggest that the outbreak association with GII.4 partly may be explained by an enhanced ability to induce vomiting.

Fitness effects of mutation: testing genetic redundancy in Arabidopsis thaliana.

Screens of organisms with disruptive mutations in a single gene often fail to detect phenotypic consequences for the majority of mutants. One explanation for this phenomenon is that the presence of paralogous loci provides genetic redundancy. However, it is also possible that the assayed traits are affected by few loci, that effects could be subtle or that phenotypic effects are restricted to certain environments. We assayed a set of T-DNA insertion mutant lines of Arabidopsis thaliana to determine the frequency with which mutation affected fitness-related phenotypes. We found that between 8% and 42% of the assayed lines had altered fitness from the wild type. Furthermore, many of these lines exhibited fitness greater than the wild type. In a second experiment, we grew a subset of the lines in multiple environments and found whether a T-DNA insert increased or decreased fitness traits depended on the assay environment. Overall, our evidence contradicts the hypothesis that genetic redundancy is a common phenomenon in A. thaliana for fitness traits. Evidence for redundancy from prior screens of knockout mutants may often be an artefact of the design of the phenotypic assays which have focused on less complex phenotypes than fitness and have used single environments. Finally, our study adds to evidence that beneficial mutations may represent a significant component of the mutational spectrum of A. thaliana.

Epidermal exfoliation of over 95% after a burn in an 18-month-old boy: Case report and review of the literature.

This report concerns an 18-month-old boy who presented with a 6% total body surface area scald. The subject of this report is unique in that he developed the largest exfoliation described in literature. After 3 days an epidermal exfoliation with the appearance of a deliberately inflicted scald developed. As the exfoliation progressed to over 95% total body surface area the suspicion of child abuse or neglect could be abandoned. The diagnosis Staphylococcal scalded skin syndrome was set, due to the finding of Staphylococcus aureus on swabs, the lack of mucosal engagement, and the patient's age. The boy's skin healed within 3 weeks. The few reports published are all case reports and most frequently described visually infected burns with smaller epidermal exfoliations, and clinically based exfoliation diagnosis. S. aureus often cause burn wound infections that can lead to complications caused by cross-infection. It is important for burn surgeons and intensive care specialists to be aware of the increased possibility of Staphylococcal scalded skin syndrome occurring in patients who have a reduced barrier to infection such as burn patients and also, that the diagnosis can be difficult to make.

Influence of Life Style Factors on Barrett's Oesophagus.

Background. Since the incidence of adenocarcinoma of the oesophagus is rising, the prognosis is poor, and surveillance programs are expensive and mostly cost ineffective, there is a need to increase the knowledge of risk factors in Barrett's oesophagus and oesophageal cancer in order to be able to give attention to medical prevention and/or surveillance programs. Aim. To study if there is a correlation between the development of Barrett's oesophagus and GOR (gastro oesophageal reflux), family history of GOR, and life style factors, such as alcohol, smoking habits, and mental stress. Methods. Fifty-five consecutively selected patients with Barrett's oesophagus (BO) examined at Linköping University Hospital's Oesophageal Laboratory were matched by sex, age, and duration of reflux symptoms with 55 GOR patients without Barrett's oesophagus at the Oesophageal Laboratory. The medical charts in respective groups were examined for comparison of life style factors, mental stress, medication, duration of gastroesophageal acid reflux at 24 hr-pH-metry, and incidence of antireflux surgery and of adenocarcinoma of the oesophagus (ACO). Also, potential gender differences and diagnosis of ACO were studied. Results. Mean percentage reflux time on 24 hr-pH-metry was higher for the Barrett's oesophagus group, 18% for women and 17% for men compared to 4% for women and 4% for men in the control group (P < 0.05). Family history of GOR was more frequent in Barrett's oesophagus patients (62%) than in the control group (35%) (P < 0.05). Male patients with Barrett's oesophagus had medical therapy for their GOR symptoms to a higher extent (38%) than male controls (65%) (P < 0.05). No difference was found in the number of tobacco users or former tobacco users between Barrett's oesophagus patients and controls. Barrett's oesophagus patients had the same level of alcohol consumption and the same average BMI as the control subjects. Female patients with Barrett's oesophagus rated themselves as more mentally stressed (67%) than the female controls (38%) (P < 0.05). In the five-year medical chart follow-up, five of 55 patients developed adenocarcinoma among the Barrett's oesophagus patients, none in the control group. Conclusions. Long reflux time and family clustering of GOR seem to influence the development of Barrett's oesophagus. Smoking habits, alcohol consumption and BMI do not seem to have any impact on the development of Barrett's oesophagus.

Blood pressure development and hypertensive retinopathy: 20-year follow-up of middle-aged normotensive and hypertensive men.

Screening for hypertensive organ damage is important in assessing cardiovascular risk in hypertensive individuals. In a 20-year follow-up of normotensive and hypertensive men, signs of end-organ damage were examined, focusing on hypertensive retinopathy. In all, 56 of the original 79 men were reexamined for hypertensive organ damage, including by digital fundus photography. The diameters of the central retinal artery equivalent (CRAE) and vein were estimated and the artery-to-vein diameter ratio calculated. Components of metabolic syndrome were assessed. Fifty percent of the normotensive men developed hypertension during follow-up. Significant differences appeared in CRAE between the different blood pressure groups (P=0.025) while no differences were observed for other markers of hypertensive organ damage. There were significant relationships between CRAE and blood pressure at baseline (r=-0.466, P=0.001) and at follow-up (r=-0.508, P<0.001). A linear decrease in CRAE was observed with increasing number of components of the metabolic syndrome (beta=-3.947, R(2)=0.105, P=0.023). Retinal vascular diameters were closely linked to blood pressures and risk factors of the metabolic syndrome. The diversity in the development of hypertensive organ damage, with changes in retinal microvasculature preceding other signs of damage, should encourage more liberal use of fundus photography in assessing cardiovascular risk in hypertensive individuals.

Self-sampling of the vaginal fluid at home combined with high-risk HPV testing.

BACKGROUND: Around 65% of women with cervical carcinoma in Sweden have not attended an organised screening. We therefore investigated the value of using self-sampling at home in combination with a test for high-risk human papilloma virus (HPV) to increase participation. METHODS: A total of 2829 women 30-58 years old, who had not attended the organised screening for > or = 6 years, were recruited. They were offered self-sampling at home (Qvintip) and recommended to send the collected vaginal fluid to a laboratory for analysis of the presence of high-risk HPV (Hybrid Capture 2 method). RESULTS: A total of 39.1% of the women accepted home sampling. These women disclosed a relatively high prevalence of high-risk HPV, which decreased with age, from 11.1% in women 30-39 years old to 2.9% in women > or =50 years . Follow-up disclosed histological cervical intraepithelial neoplasm (CIN) 2-3 lesions in 43.2% of the women with a persistent HPV infection, corresponding to 2.0% of the total number of participating women. The sensitivity of a single smear to detect the histological CIN 2-3 lesions were only 52.6%, even if all abnormal smears (atypical squamous cells of unknown significance (ASCUS)-CIN 3)) were included. CONCLUSION: The use of self-sampling at home in combination with testing for high-risk HPV increases the participation rate of the organised screening and detects almost twice as many women with pre-malignant cell alterations (CIN 2-3) in comparison those with a single cytological smear.

Tissue Doppler imaging describes diastolic function in men prone to develop hypertension over twenty years.

AIMS: Hypertension is one of several risk factors of cardiovascular disease and is associated with left ventricular (LV) systolic and diastolic dysfunction. A method for reliably detecting the onset of LV dysfunction before transition to irreversible damage of the myocardium would be of crucial importance in subjects with essential hypertension. METHODS AND RESULTS: Subjects with clear differences in BP level, development and duration of the hypertensive disease were examined at the age of 60 yrs: normotensives (n = 17), new hypertensives who developed hypertension over a 20 year period (n = 15) and hypertensives (n = 19). Relationships between conventional echocardiographic and tissue velocities imaging (TVI) parameters compared to LV parameters, and TVI as an estimate of LV function were explored. E'(Lat) (TVI peak early diastolic velocity) (P = 0.006) and E/E'(Lat) (P = 0.002) demonstrated differences in diastolic function between the groups. There were no significant differences regarding systolic myocardial velocities. E'(Lat) correlated to S'(Lat) (TDI peak systolic velocity) (r = 0.32, P = 0.026) and was independently predicted by S'(Lat) (R(2) = 0.24, P = 0.025) in multivariate analysis. E'(Lat) correlated negatively to LV mass index (r = -0.34, P = 0.012), also in multivariate regression analysis (R(2) = 0.12, P = 0.032). CONCLUSIONS: Myocardial diastolic velocities and mitral flow to annulus velocity ratio differentiated LV function between the hypertensive and normotensive groups. The parameters probably reflect changes in relaxation, recoil and contraction and parallel changes in LV mass index.

Access to and use of research by rural nurses.

INTRODUCTION: The use of relevant research findings to inform clinical practice is important for nurses, regardless of setting. Although there have been studies addressing the use of research among various practitioners, little is known about how nurses in rural areas access health information (specifically research findings), nor how such findings are incorporated into daily practice. The purpose of this study was to explore rural nurses' access, use and perceived usefulness of research for rural practice. METHODS: The study was conducted in a sparsely populated state located in the western part of the USA. An ethnographic method was chosen to answer the research questions for this descriptive study. Semi-structured interviews were conducted with 29 rural nurses from nine communities by graduate nursing students enrolled in a rural nursing course following in-class instruction and practice. Field notes taken by the students supplemented the interview data. The students' notes included a windshield survey or description of the context and location within which the participants lived and/or practiced as well as the interviewers' observations, thoughts and impressions about the research project. Interviews were audiotaped and transcribed verbatim. Once transcribed, the interview narratives, windshield data and field notes were analyzed by the students for common themes; the students then wrote and submitted papers to the faculty addressing the themes that emerged from their interviews. The analysis conducted by the faculty members included four sources of data: transcriptions of interviews; field notes; windshield data; and students' papers. The process of identifying themes was facilitated by using the software program NUD*IST (QSR International; Melbourne, VIC, Australia). Demographic information was entered into the Statistical Package for Social Scientists (SPSS Inc; Chicago, IL, USA) to compile descriptive information about the sample. FINDINGS: Twenty-seven female and two male nurses participated in the study. The nurses' ages ranged from 31-72 years and their experience in nursing spanned 3-50 years with a range of 1 to 35 years in rural nursing. The interviews revealed that most of the nurses used the term 'research' to mean 'gathering information'. When asked how often they used 'research' the responses ranged from 2-3 times per day to 2-3 times per month. The preferred means of obtaining information was asking a colleague. Additional resources included work-place journals, books, in-services, conferences and the internet. Twenty-three of the nurses reported having internet access at work; 25 had internet access at home. Supportive supervisors and articles in general nursing journals were identified as helpful. Barriers to using research included: lack of knowledge of research methods; lack of time at work or at home to look up information; and the lack of computers and internet access on the nursing units. When computers were available, the nurses reported that poor computer literacy decreased their ability to quickly find and evaluate information. Additional barriers included diminishing financial support from employers and the long travel distances required to attend conferences. The nurses reported finding little clinical research specifically related to rural practice. CONCLUSIONS: Education and mentorship is needed about how to evaluate the types and strength of evidence, access research using the internet, interpret findings, and incorporate evidence in clinical practice. Interventions that foster the appreciation and use of research by staff nurses and managers are needed in order to build an evidence based culture. Research is needed, specifically as related to rural clinical practice.

HPV type-specific risks of high-grade CIN during 4 years of follow-up: a population-based prospective study.

We followed a population-based cohort of 5696 women, 32-38 years of age, by registry linkage with cytology and pathology registries during a mean follow-up time of 4.1 years to assess the importance for CIN2+ development of type-specific HPV DNA positivity at baseline. HPV 16, 31 and 33 conveyed the highest risks and were responsible for 33.1, 18.3 and 7.7% of CIN2+ cases, respectively. Women infected with HPV 18, 35, 39, 45, 51, 52, 56, 58, 59 and 66 had significantly lower risks of CIN2+ than women infected with HPV 16. After adjustment for infection with other HPV types, HPV types 35, 45, 59 and 66 had no detectable association with CIN2+. In summary, the different HPV types found in cervical cancer show distinctly different CIN2+ risks, with high risks being restricted to HPV 16 and its close relatives HPV 31 and HPV 33.

Bacterial vaginosis. Transmission, role in genital tract infection and pregnancy outcome: an enigma.

Whether bacterial vaginosis (BV) is acquired from an endogenous or an exogenous source is subject to controversy. Despite findings of an association between sexual behaviour and BV, some data indicate that BV is not a sexually transmitted infection in the traditional sense, while other data indicate that BV is an exogenous infection. A third aspect of BV is its tendency to go unnoticed by affected women. All of this will have a strong impact on how physicians view the risks of asymptomatic BV. This review focuses on whether or not BV should be regarded as a sexually transmitted infection (STI), its role in postoperative infections and pelvic inflammatory disease (PID), and on whether or not treatment of BV during pregnancy to reduce preterm delivery should be recommended. The reviewed studies do not lend unequivocal support to an endogenous or exogenous transmission of the bacteria present in BV. For women undergoing gynaecological surgery such as therapeutic abortion, the relative risk of postoperative infection is clearly elevated (approx. 2.3-2.8). A weaker association exists between BV and pelvic inflammatory disease. Data on treatment of BV as a way of reducing preterm delivery are inconclusive and do not support recommendations for general treatment of BV during pregnancy. The discrepant associations between BV and preterm birth found in recent studies may be explained by variations in immunological response to BV. Genetic polymorphism in the cytokine response--both regarding the TNF alleles and in interleukin production--could make women more or less susceptible to BV, causing different risks of preterm birth. Thus, studies on the vaginal inflammatory response to microbial colonization should be given priority.

First Report of White Rust Caused by Albugo bliti on Seabeach Amaranth in the United States.

Seabeach amaranth (Amaranthus pumilus Raf.), a threatened annual marine plant, is a primary colonizer of the windward side of Atlantic coastal dunes. It serves an important ecological role in dune accumulation and stabilization. Because Hurricane Floyd eliminated all native seabeach amaranth in South Carolina in 1999, experimental reestablishment plantings have been attempted. In August 2000, seabeach amaranth on Dewees and Cape Island in Charleston County, Huntington Beach in Georgetown County, and Otter Island in Colleton County, South Carolina were stunted and senesced prematurely. Leaves on affected plants were only one-half of the normal size and internodes were shortened. Most plants (>90%) at each location were affected. Diseased leaves had small, pale green-to-tan spots above hypophyllous pustules that contained numerous, dry, hyaline, subglobose conidia. Conidia measured 13.5 (10 to 17) × 15.0 (11 to 18) µm. Based on morphological characters and the host, the pathogen was identified as Albugo bliti (Biv.-Bern.) Kuntze (1,2). No oospores were observed. Diseased plants were collected from Dewees and Otter Islands and kept frozen for use as a source of inoculum. Six A. pumilus plants each of six Plant Introductions (PI), 553080 through 553085, that had been grown from seed were sprayed with a suspension of 4.7 × 105 conidia per ml. One plant of each PI was sprayed with sterile distilled water as a noninoculated control. All plants were placed in a humidity chamber for 48 h and then moved to a greenhouse bench. Thirteen days after inoculation, all inoculated plants had pustules of white rust. Diseased plants had a mean of 42 pustules per plant and PI's did not differ in susceptibility. Five of six noninoculated plants also had white rust pustules, but only a mean of 2.3 (range 1 to 5) pustules each. White rust likely appeared on noninoculated plants because plants were spaced closely together in the chamber. Pustules and conidia on inoculated plants were identical to those on plants collected originally. Albugo bliti has been reported on 19 other Amaranthus species (1), but to our knowledge, this is the first report of white rust on seabeach amaranth in the United States. White rust reduced the biomass of infected plants and, hence, their ability to trap sand. White rust was not observed on subsequent plantings in 2001 and 2002 at any location. References: (1) D. F. Farr et al. Fungal Databases. Systematic Botany and Mycology Laboratory, On-line publication. ARS USDA, 2002. (2) G. W. Wilson. Bull. Torrey Bot. Club 34:61, 1907.

Aborted genital herpes simplex virus lesions: findings from a randomised controlled trial with valaciclovir.

OBJECTIVES: In prospective trials, episodic valaciclovir significantly increased the chance of preventing or aborting the development of painful vesicular genital herpes simplex virus (HSV) lesions compared with placebo. We explored the clinical outcome of aborted lesions and its association with early treatment in a study designed to compare 3 and 5 days' treatment with valaciclovir. METHODS: In a randomised controlled trial, valaciclovir 500 mg twice daily for 3 or 5 days was initiated at the first symptoms of a genital herpes outbreak. The primary end point was length of episode with pain, HSV shedding, and aborted lesions secondary end points. The effect of time from symptom recognition to treatment initiation on aborted lesions was assessed in a post hoc analysis. RESULTS: In 531 patients, no differences were observed between 3 and 5 days' treatment in episode duration (median 4.7 v 4.6 days), loss of pain/discomfort (2.8 v 3.0 days), or lesion healing (4.9 v 4.5 days). Vesicular lesions were aborted in 27% of patients treated for 3 days v 21% of patients receiving valaciclovir for 5 days. The odds of achieving an aborted episode were 1.93 (95% CI: 1.28 to 2.90) times higher for those initiating treatment with valaciclovir within 6 hours of first sign or symptom. CONCLUSIONS: There was no difference between 3 and 5 days' treatment in reducing episode duration or lesion abortion. Prompt treatment with valaciclovir can abort genital HSV reactivation episodes, preventing a vesicular outbreak. Maximum treatment benefit depends on prompt therapy after recognition of symptoms.

Current treatments and perceptions of genital herpes: a European-wide view.

A European panel of physicians reviewed the current treatments and perceptions of recurrent genital herpes (GH) across the continent. The panel consisted of specialists in dermatology and venereology from France, Finland, Germany, Italy, Norway, Spain, Sweden and the UK. A wide variety of factors that influence GH management were considered, including different health delivery systems, funding and cultural differences. The poor awareness of GH among both the general public and physicians was highlighted. The effectiveness of GH management was then examined from a patient's viewpoint, including the confirmation of the diagnosis, information and counselling about GH, as well as prescriptions for treatment. It was agreed that both physicians and patients often feel uncomfortable about discussing the disease, and that a European-wide effort is needed to re-educate patients and physicians about GH. The panel identified clear and unmet needs to manage a patient with clinical recurrences and to attempt to reduce the risk of GH transmission. Finally, resiquimod, an immune response modifier, was considered as a potential treatment option for GH.

Altered transcription in yeast expressing expanded polyglutamine.

Expanded polyglutamine tracts are responsible for at least eight fatal neurodegenerative diseases. In mouse models, proteins with expanded polyglutamine cause transcriptional dysregulation before onset of symptoms, suggesting that this dysregulation may be an early event in polyglutamine pathogenesis. Transcriptional dysregulation and cellular toxicity may be due to interaction between expanded polyglutamine and the histone acetyltransferase CREB-binding protein. To determine whether polyglutamine-mediated transcriptional dysregulation occurs in yeast, we expressed polyglutamine tracts in Saccharomyces cerevisiae. Gene expression profiles were determined for strains expressing either a cytoplasmic or nuclear protein with 23 or 75 glutamines, and these profiles were compared to existing profiles of mutant yeast strains. Transcriptional induction of genes encoding chaperones and heat-shock factors was caused by expression of expanded polyglutamine in either the nucleus or cytoplasm. Transcriptional repression was most prominent in yeast expressing nuclear expanded polyglutamine and was similar to profiles of yeast strains deleted for components of the histone acetyltransferase complex Spt/Ada/Gcn5 acetyltransferase (SAGA). The promoter from one affected gene (PHO84) was repressed by expanded polyglutamine in a reporter gene assay, and this effect was mitigated by the histone deacetylase inhibitor, Trichostatin A. Consistent with an effect on SAGA, nuclear expanded polyglutamine enhanced the toxicity of a deletion in the SAGA component SPT3. Thus, an early component of polyglutamine toxicity, transcriptional dysregulation, is conserved in yeast and is pharmacologically antagonized by a histone deacetylase inhibitor. These results suggest a therapeutic approach for treatment of polyglutamine diseases and provide the potential for yeast-based screens for agents that reverse polyglutamine toxicity.

The significance of p53 codon 72 polymorphism for the development of cervical adenocarcinomas.

Infection with the human papillomavirus is an important co-factor in the development of cervical carcinomas. Accordingly, HPV DNA is recognised in most of these tumours. Polymorphism of the p53 gene, codon 72, is also considered a risk factor in the development of cervical carcinoma. However, this finding is contradicted by several observers. In the present investigation, 111 cases of adenocarcinoma of the cervix collected through the Swedish Cancer Registry and 188 controls (females with normal cytology at organised gynaecological screening) were analysed with regard to p53, codon 72, polymorphism using a PCR- and SSCP-based technique. In the controls, 9% showed pro/pro, 44% pro/arg and 47% arg/arg, whereas in the invasive adenocarcinomas, the corresponding figures were 0%, 29% and 71%, respectively. The difference was statistically significant (P = 0.001). HPV DNA was identified in 86 tumours (HPV 18 in 48, HPV 16 in 31 and HPV of unknown type in 7 cases) and 25 tumours were HPV negative. The p53, codon 72, genotypes observed in HPV-positive and HPV-negative cervical adenocarcinomas were not statistically different (P = 0.690). The results indicate that women homozygotic for arg/arg in codon 72 of the p53 gene are at an increased risk for the development of cervical adenocarcinomas. However, this genetic disposition seems to be unrelated to the HPV infection.

NeuroD2 is necessary for development and survival of central nervous system neurons.

NeuroD2 is sufficient to induce cell cycle arrest and neurogenic differentiation in nonneuronal cells. To determine whether this bHLH transcription factor was necessary for normal brain development, we used homologous recombination to replace the neuroD2 coding region with a beta-galactosidase reporter gene. The neuroD2 gene expressed the reporter in a subset of neurons in the central nervous system, including in neurons of the neocortex and hippocampus and cerebellum. NeuroD2(-/-) mice showed normal development until about day P14, when they began exhibiting ataxia and failure to thrive. Brain areas that expressed neuroD2 were smaller than normal and showed higher rates of apoptosis. Cerebella of neuroD2-null mice expressed reduced levels of genes encoding proteins that support cerebellar granule cell survival, including brain-derived neurotrophic factor (BDNF). Decreased levels of BDNF and higher rates of apoptosis in cerebellar granule cells of neuroD2(-/-) mice indicate that neuroD2 is necessary for the survival of specific populations of central nervous system neurons in addition to its known effects on cell cycle regulation and neuronal differentiation.