Correlated Responses to Selection in FAST and SLOW Mice: Effects of Ethanol on Ataxia, Temperature, Sedation, and Withdrawal

A replicated bidirectional selective breeding program has produced lines of mice that differ in locomotor response to ethanol (EtOH). FAST mice were bred for high locomotor activation, whereas SLOW mice were bred for low or depressed locomotor activity in response to 2.0 g/kg of EtOH. We tested FAST and SLOW mice for differences in sensitivity to the incoordinating (1.5 to 2.5 g/kg), hypothermic (3.0 g/kg), and sedative (4.0 g/kg) effects of EtOH, and for differences in sensitivity to withdrawal after acute and chronic EtOH exposure. SLOW mice were more ataxic in a grid test and developed greater tolerance than FAST mice at 2.0 g/kg of EtOH, were more hypothermic than FAST mice, and were more sensitive to the sedative effects of EtOH than FAST mice, as measured by latency to and duration of loss of righting reflex, and by blood ethanol concentrations at regain of the righting reflex. FAST mice had more severe withdrawal seizures after chronic exposure, but did not differ from SLOW mice in withdrawal severity after an acute injection of EtOH. These data suggest that FAST mice are generally more sensitive to central nervous system excitation, and SLOW mice are generally more sensitive to central nervous system sedation by EtOH, and further suggest genetic overlap with respect to genes that mediate locomotor responses to EtOH and genes determining sensitivity to EtOH-induced ataxia, hypothermia, sedation, and withdrawal severity after chronic exposure. Our current observations are in contrast to observations made earlier in selection, in which few line differences in sensitivity to EtOH effects other than locomotor activity were found. Thus, it seems that continued selection for differences in locomotor response to EtOH has produced genetically correlated differences in other EtOH responses.     

Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening

Background

Malignancy risks in patients with neurofibromatosis 1 (NF1) are increased, but those occurring outside of the nervous system have not been clearly defined.

Aim

To evaluate the risk of breast cancer in women with NF1 in a population‐based study.

Methods

The risk of breast cancer in a cohort of 304 women with NF1 aged ⩾20 years was assessed and compared with population risks over the period 1975–2005 using a person‐years‐at‐risk analysis.

Results

There were 14 cases of breast cancers in the follow‐up period, yielding a standardised incidence ratio (SIR) of 3.5 (95% CI 1.9 to 5.9). However, six breast cancers occurred in women in their 40s, and the SIR of breast cancer in women aged <50 years was 4.9 (95% CI 2.4 to 8.8).

Interpretation

Women with NF1 aged <50 years have a fivefold risk of breast cancer, are in the moderate risk category and should be considered for mammography from 40 years of age.Neurofibromatosis 1 (NF1; MIM 162200) is a common autosomal dominant genetic disorder with an estimated birth incidence of 1 in 2500 and a prevalence of 1 in 5000.¹ NF1 is a fully penetrant condition, with all patients manifesting signs of the disease by the age of 5 years. However, many de novo cases remain undiagnosed well into adult life. All affected individuals will develop at least some of the neurocutaneous features, none of which are life threatening; these include the pigmentary changes (café au lait spots, skin fold freckling and Lisch nodules) and neurofibromas (although these may not be numerous). It is the occurrence of disease complications that causes most of the associated morbidity and mortality. A third of affected individuals will develop at least one of the more severe disease complications in their lifetime; the occurrence of complications cannot be predicted even within families.² The disease is extremely variable, and the individual gene fault is unlikely to determine the total course of the condition.The NF1 gene is a tumour suppressor gene and those with the mutation are at a fourfold increased risk of cancer compared with the general population.^3,4,5 The gene product neurofibromin is thought to deliver much of its function through downregulating the oncogene ras. Patients with NF1 have a greatly increased relative risk of developing gliomas, malignant peripheral nerve sheath tumours, juvenile chronic myelomonocytic leukaemia, rhabdomyosarcoma and phaeochromocytoma; such tumours may have a different natural history from those occurring sporadically, and require a specific approach to their detection and management.Until now no one has reported an overall significantly increased risk of any commonly occurring cancers in patients with NF1, although a recent paper did find a significantly increased risk in women aged <50 years—this was not significant overall.⁶ The fact that several patients develop breast cancer before 50 years of age prompted us to look systematically for an increased risk of breast cancer.     

Methicillin-resistant Staphylococcus aureus as a cause of invasive infections in Central Africa: a case report and review of the literature

Introduction

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) colonization and infection are increasingly being reported worldwide and are associated with severe illness. The vast majority of MRSA infections are skin and soft tissue infections, while invasive disease remains rare. In Western countries, the epidemiology of MRSA is well documented, but from Central Africa, reports on MRSA are very limited.

Methods

Case presentation and review of the literature. The clinical features, epidemiology, and characteristics of MRSA in Central Africa, as well as the treatment options, are discussed. We present a case of severe invasive CA-MRSA infection with pneumonia, pericarditis, and bacteremia in a previously healthy young woman in Gabon. Several virulence factors, like Panton–Valentine leukocidin and type I arginine catabolic mobile element, may play a role in the ability of CA-MRSA to cause severe invasive infections. Based on studies from Gabon and Cameroon (no reports were available from other countries), we find that the prevalence of MRSA is relatively low in this region. Treatment depends primarily on local prevalence and resistance profile of MRSA combined with clinical characteristics.

Conclusion

Severe invasive infection with CA-MRSA is a rare disease presentation in Central Africa, where this pathogen is still relatively uncommon. However, cases of MRSA may be complicated by the human immunodeficiency virus (HIV) and tuberculosis epidemics, and also the limited availability of effective antibiotics.     

DNA testing for fragile X syndrome in schools for learning difficulties

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.