Effects of maternal tobacco smoking,sleeping position,and sleep state on arousal in healthy term infants

OBJECTIVES: To investigate whether a history of maternal tobacco smoking affected the maturation of arousal responses and whether sleeping position and infant age alters these relations. DESIGN: Healthy term infants (13 born to mothers who did not smoke and 11 to mothers who smoked during pregnancy) were studied using daytime polysomnography on three occasions: (a) two to three weeks after birth, (b) two to three months after birth, and (c) five to six months after birth. Multiple measurements of arousal threshold in response to air jet stimulation were made in both active sleep (AS) and quiet sleep (QS) when infants slept both prone and supine. RESULTS: Maternal smoking significantly elevated arousal threshold in QS when infants slept supine at 2-3 months of age (p<0.05). Infants of smoking mothers also had fewer spontaneous arousals from QS at 2-3 months in both prone (p<0.05) and supine (p<0.001) sleeping positions. In infants of non-smoking mothers, arousal thresholds were elevated in the prone position in AS at 2-3 months (p<0.01) and QS at 2-3 weeks (p<0.05) and 2-3 months (p<0.001). CONCLUSIONS: Maternal tobacco smoking significantly impairs both stimulus induced and spontaneous arousal from QS when infants sleep in the supine position, at the age when the incidence of sudden infant death syndrome is highest.     

Double ectopic thyroid

Ectopic thyroid gland is a well-known developmental anomaly. We present a child with a unique anatomical variant of this anomaly, namely double ectopic thyroid. The purpose of this report is to demonstrate the scintigraphic findings and to emphasize the importance of performing a thyroid scan in every case of thyroid ectopia to accurately identify all sites of functioning thyroid tissue.     

Proconvulsant-induced seizures in alpha(4) nicotinic acetylcholine receptor subunit knockout mice

The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby these mutations produce seizures is unknown. Three mutations of the alpha(4) subunit of the neuronal nicotinic acetylcholine receptor (nAChR) have been identified in autosomal dominant nocturnal frontal lobe epilepsy. In vitro studies of two mutations suggest an alteration of receptor function resulting in decreased ion channel current flow. We investigated the response of alpha(4) nAChR subunit knockout mice to the gamma-aminobutyric acid (GABA) receptor antagonists; pentylenetetrazole (PTZ) and bicuculline (BIC), the glutamate receptor agonist kainic acid (KA), the glycine receptor antagonist strychnine and the K(+) channel blocker 4-aminopyridine (4-AP). Mutant (Mt) mice had a greater sensitivity to PTZ and BIC, with an increase in major motor seizures and seizure-related deaths. Furthermore, Mt mice were more sensitive to KA and strychnine, but the effects were much smaller compared to those seen with the GABA receptor antagonists. Paradoxically, Mt mice appeared to be relatively protected from 4-AP-induced major motor seizures and death.The results show that a functional deletion of the alpha(4) nAChR subunit in vivo is associated with a major increase in sensitivity to GABA receptor blockers.     

Parameters of coagulant and fibrinolytic capacity and activity in postmenopausal women: within-subject variability

We have analyzed the within-subject variability of a battery of parameters of coagulant and fibrinolytic capacity and activity in postmenopausal women. We observed large differences in within-subject variability among the tests and have demonstrated how such data can be used to estimate the number of times a parameter must be measured to produce a statistically adequate sample.     

Glial responses associated with dopaminergic striatal reinnervation following lesions of the rat substantia nigra

Lesioning of dopaminergic substantia nigra pars compacta (SNpc) neurons leads to depletion of dopamine (DA) and dopaminergic axons in the dorsal striatum, followed by subsequent compensatory sprouting of dopaminergic fibers and striatal reinnervation. In this study, the response of striatal glia (microglia and astroglia) was compared with the degeneration and regeneration of dopaminergic axons following SNpc lesions. Following partial SNpc lesions, density of dopamine transporter (DAT) immunoreactive (-ir) terminals in the dorsal striatum returned to normal within 16 weeks of injury, suggesting that dopaminergic reinnervation of the striatum was complete. In conjunction, the glial responses in the dorsal striatum consisted of two peaks. The first peak in glial density occurred immediately after lesioning, peaking at 7 days, implying that it was likely to be associated with removal of debris from degenerating terminals. The second glial response commenced 8 weeks after lesioning and peaked some time after 16 weeks. The time of onset of the second peak suggests that it may be associated with the establishment of synapses rather than with axonal guidance.     

Catastrophic thinking about pain increases discomfort during internal atrial cardioversion

OBJECTIVES: This study investigated whether pain catastrophizing is associated with distress and perceived disability in patients with atrial fibrillation, whether pain catastrophizing predicts pain and fear during a medical procedure of atrial cardioversion, and whether pain catastrophizing influences the effects of an opioid analgesic during internal cardioversion. METHODS: A secondary analysis is performed upon data from a double-blind placebo-controlled trial during which the effect of intranasal butorphanol tartrate (INB) was evaluated in patients with atrial fibrillation using a step-up internal atrial cardioversion protocol. Before the procedure, patients completed measures of pain catastrophizing, mood, distress and perceived disability. After each shock, patients completed measures of pain and fear. RESULTS: We found that pain catastrophizing predicted the affective pain rating of the first shock, and the fear increase during subsequent shocks. There was no effect of INB. However, when controlling for the differences in pain catastrophizing, INB significantly reduced fear as compared to placebo. This suggests that the effects of INB during atrial cardioversion were overshadowed by the effects of pain catastrophizing. CONCLUSIONS: It is recommended that in future atrial cardioversion trials, stratification based on pain catastrophizing be performed. Reducing catastrophizing thinking about pain through cognitive-behavioral techniques are likely to reduce levels of fear during internal atrial cardioversion and may increase the effectiveness of concomitant analgesics.     

Alcohol continues to affect sleepiness related driving impairment, when breath alcohol levels have fallen to near-zero

Epidemiological findings point to very low blood alcohol levels heightening the risk of sleep-related fatal road crashes. This was further assessed using a full sized interactive car simulator. Twenty, sleep restricted, healthy young men underwent a 2 h simulated afternoon monotonous drive, having previously consumed nil alcohol or 3 units >90 min previously, and having near-zero breath alcohol (BrACs) at the start of the drive. In a repeated measures, double-blind, balanced design, driving performance, subjective sleepiness and EEG were monitored throughout. Compared with nil alcohol, the alcohol condition initially increased sleepiness-related driving impairment. However, this was not mirrored by subjective sleepiness or EEG. An unexpected reversal (i.e. improvement) in driving impairment occurred with the alcohol group, in the second hour of the drive. This was supported by a trend for improved subjective alertness. Alcohol continued to interact with sleepiness-related driving impairment after BrACs had reached zero. However, a lack of subjective perception of increased sleepiness, at this time, further points to the dangerous combination of even modest alcohol intake and sleepiness, and confirms the road crash findings. BrACs are a poor guide to driver impairment.     

Patients' use of GPs and community pharmacists in minor illness: a cross-sectional questionnaire-based study

BACKGROUND: Despite pharmacists having increased involvement in managing minor illness, many patients continue to attend their GP with problems that could be managed by community pharmacists. OBJECTIVE: Our aim was to investigate the prevalence of visits to the GP that GPs felt could be managed by a pharmacist, and to explore patients' reasons for such visits. METHODS: This cross-sectional questionnaire study was conducted at 13 general practices in West Sussex, UK. A questionnaire was given to all patients attending appointments with their GP in these practices over a 1-week period, asking what the presenting problem was and whether the advice of a pharmacist had been sought. If patients had not sought the advice of a pharmacist, they were asked why not. The GP was then asked to indicate whether, in their opinion, the patient's problem could have been managed by a community pharmacist. RESULTS: The response rate was 94% (3984), representing 87% of all patients consulting their doctor during the week of the study. GPs felt that only 7% (260) of these visits could have been managed by a community pharmacist. The proportion of 'unnecessary' visits was significantly higher (P < 0.001) amongst young adults, those presenting with new medical problems and those consulting about a child's health. Skin and musculoskeletal problems were the most common causes of 'unnecessary' visits to the GP. The majority of patients making 'unnecessary' visits (59%) disagreed with the GP and felt that the pharmacist would not have been appropriate for their problem. CONCLUSIONS: GPs and patients were, on the whole, in agreement over which conditions were appropriate for GP attention. There is, however, a need for education to increase awareness of the roles of pharmacists, aimed particularly at young adults and at those with children.     

A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells

GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.