Estrogen-biosynthesis gene CYP17 and its interactions with reproductive, hormonal and lifestyle factors in breast cancer risk: results from the Long Island Breast Cancer Study Project

The genes that are involved in estrogen biosynthesis, cellular binding and metabolism may contribute to breast cancer susceptibility. We examined the effect of the CYP17 promoter T --> C polymorphism and its interactions with the reproductive history, exogenous hormone use and selected lifestyle risk factors on breast cancer risk among 1037 population-based incident cases and 1096 population-based controls in the Long Island Breast Cancer Study Project. Overall, there were no associations between the CYP17 genotype and breast cancer risk. Among postmenopausal women, the joint exposure to higher body mass index (BMI) and the variant C allele was associated with an increased risk of breast cancer [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.15-2.22]. The joint exposure to the variant C allele and long-term use of hormone replacement therapy (HRT) (>51 months) was related to an increased risk of breast cancer (OR, 1.51; 95% CI, 0.99-2.31) especially estrogen receptor-positive, progesterone receptor-positive breast cancer (OR, 1.87; 95% CI, 1.08-3.25). Among the control population, the CYP17 variant C allele was inversely associated with long-term use of postmenopausal HRT and a higher BMI in postmenopausal women. In conclusion, the findings suggest that the CYP17 variant C allele may increase breast cancer risk in conjunction with long-term HRT use and high BMI in postmenopausal women.     

Pertussis is increasing in unimmunized infants: is a change in policy needed?

The proportion and trend in absolute number of pertussis notifications in young infants has increased each year in England and Wales since the accelerated immunization schedule was introduced. We report five infants all less than 3 months of age admitted with life threatening pertussis infection to two paediatric intensive care units. Despite aggressive cardiorespiratory support measures, three of the infants died. Pertussis remains a significant cause of morbidity and mortality in unimmunized infants. In this age group presentation is likely to be atypical and infection more severe. Public health measures to prevent the disease could be strengthened. Chemoprophylaxis should be offered to susceptible contacts and booster vaccinations against pertussis considered.     

Acute management of head injury

Head injury in infants and children is common and the majority of cases have mild/minor injury. After emergency treatment has been given, the clinical priority at the time of assessment includes in the acutely ill, identifying and treating the small proportion that will go on to have serious intracranial complications; in the mild/minor cases, identifying those at risk of physical, emotional and cognitive complications of concussion; and in the young infants, identifying those suffering inflicted or non-accidental injury and initiating appropriate child protection procedures. In all patients, initial assessment should occur within 15 min of arrival at the emergency department. There are now useful decision rules to guide when to undertake cranial imaging as well as management standards to help with emergency support. Subsequent admission should be supervised by a team led by a specialist in the management of head injury. When transfer to a clinical neurosciences unit is required it is important that any communication should use the three separate responses of the Glasgow Coma Scale score to describe the patient. Later, follow-up is required and the family practitioner should be informed of the admission and need for an assessment within one week of discharge. Long-term effects of head injury and postconcussion syndrome will require specialist support.     

The cerebral function analysing monitor in paediatric medical intensive care: Applications and limitations

Practical guidelines for continuous single channel EEG monitoring using the Cerebral Function Analysing Monitor (CFAM) have been outlined based on experience of 54 critically ill comatose and/or paralysed sedated children monitored for up to 9 days during the acute phase of illness. Fall in amplitude and slowing of frequency following either a cerebral insult or barbiturate administration as well as paroxysmal events were readily recognisable in the CFAM traces. Such changes could be used to (1) identify effects of cerebral insults (acute or cumulative), (2) recognise unstable patients exquisitely sensitive to aspects of standard care and (3) evaluate seizure control. Despite these useful contributions to clinical care, significant limitations were apparent. It is recommended that CFAM monitoring should be combined with serial conventional EEG recording in order to check the appropriateness of the cortical areas being monitored, the quality and type of signal being processed as well as the significance of the 1 or 2 channel CFAM findings in relation to global cerebral function.     

Computed tomography in the assessment of raised intracranial pressure in non-traumatic coma

Cranial computed tomography (CT) scans and invasive intracranial pressure (ICP) measurements were reviewed for 34 children with non-traumatic coma from various causes. CT scan features including focal or generalised changes in density were noted and changes in cerebrospinal fluid (CSF) spaces were graded and correlated with the level of maximum ICP in the first 12 hours of treatment and monitoring. Seven patients had normal findings and 27 had abnormal scans. Nineteen of the 27 patients with abnormal scans had generalised abnormalities with varying degrees of loss of CSF space. Seventeen of these 19 patients had pressures greater than 15 mmHg. The highest pressures being found in those with the greatest degree of CSF space obliteration. In the remaining 8 patients, who had focal abnormalities either within the basal ganglia or cerebral hemisphere, there was no relationship between local CSF space obliteration and the level of ICP. In the 7 patients with normal scans three had ICPs of 20 mmHg or greater in the first 12 hours of monitoring and a further two also developed an ICP of this level 13-36 hours after the initiation of monitoring. In non-traumatic coma of various causes there is an association between loss of CSF space and increased ICP. However, there were two important exceptions to this; firstly in patients with focal abnormalities either within the basal ganglia or cerebral hemisphere, in whom the loss of adjacent CSF spaces was not a good indicator of generalised raised ICP; secondly some patients with normal scans, in whom this finding did not indicate normal ICP nor ensure that it remained at this level.     

BRL 20330, an oral prodrug of temocillin: bioavailability studies in man

BRL 20330 is the o-methyl phenyl ester of temocillin which is well absorbed after oral administration and converted to temocillin in the body. BRL 20330 was administered to healthy subjects in a three-part cross-over study with single doses equivalent to 400, 600 and 800 mg of temocillin. Peak serum concentrations of temocillin were 9.8, 12.8 and 15.8 mg/l respectively and concentrations of 3.0-6.0 mg/l were measured at 12 h after dosing. High and prolonged concentrations of temocillin were measured in the urine. The mean urinary recovery was 22-25% and only 0.2% of unhydrolyzed BRL 20330 was detected in the urine. Little difference in the extent of absorption was noted when BRL 20330 was administered with food although the peak levels of temocillin were delayed and reduced slightly. Urinary concentrations of temocillin, even after 24 h, were bactericidal for a number of Gram-negative bacteria including multi-resistant strains. BRL 20330 was well tolerated and there was no evidence of gastro-intestinal adverse effects.     

Activity-dependent release and actions of endocannabinoids in the rat hypothalamic supraoptic nucleus

Exogenous cannabinoids have been shown to significantly alter neuroendocrine output, presaging the emergence of endogenous cannabinoids as important signalling molecules in the neuroendocrine control of homeostatic and reproductive functions, including the stress response, energy metabolism and gonadal regulation. We showed recently that magnocellular and parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus and supraoptic nucleus (SON) respond to glucocorticoids by releasing endocannabinoids as retrograde messengers to modulate the synaptic release of glutamate. Here we show directly for the first time that both of the main endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), are released in an activity-dependent fashion from the soma/dendrites of SON magnocellular neurones and suppress synaptic glutamate release and postsynaptic spiking. Cannabinoid reuptake blockade increases activity-dependent endocannabinoid levels in the region of the SON, and results in the inhibition of synaptically driven spiking activity in magnocellular neurones. Together, these findings demonstrate an activity-dependent release of AEA and 2-AG that leads to the suppression of glutamate release and that is capable of shaping spiking activity in magnocellular neurones. This activity-dependent regulation of excitatory synaptic input by endocannabinoids may play a role in determining spiking patterns characteristic of magnocellular neurones under stimulated conditions.     

Microelectrode techniques in localization of stereotactic targets

Although physiological corroboration of the target is essential in functional stereotactic surgery, the collected data can also be used for the offline study of normal and abnormal brain function. Such studies have the advantage of being made in actual clinical states with the unique opportunity of communicating with the patient. Correlations were made between microelectrode recordings and microstimulation at the same thalamic site with the same microelectrode in 'normal' patients, in those with tremor and in those with central and deafferentation pain. Human somatosensory organization is similar to that of subhuman primates. Five types of tremor cells have been identified-unresponsive nonsynchronous, unresponsive synchronous, kinaesthetic, voluntary, and voluntary with receptive field. While the last two qualify in latency and connectivity as tremor pacemakers, system analysis suggests an important element of long loop feedback as well. In the pain patients, five features were identified-somatotopic reorganization, altered firing in reorganized cells, bursting cells induction of burning widespread in thalamus and reproduction of the patient's pain by microstimulation-possibly a 'central allodynia' found in deafferented somatosensory thalamus particularly in patients with allodynia or hyperpathia. All but the latter effects may be merely the consequence of deafferentation and were seen in a 'control' stroke patient with dystonia, sensory loss but no pain.     

Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment

While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia.