Neural network analysis of combined conventional and experimental prognostic markers in prostate cancer: a pilot study.

Prostate cancer is the second most common malignancy in men in the UK. The disease is unpredictable in its behaviour and, at present, no single investigative method allows clinicians to differentiate between tumours that will progress and those that will remain quiescent. There is an increasing need for novel means to predict prognosis and outcome of the disease. The aim of this study was to assess the value of artificial neural networks in predicting outcome in prostate cancer in comparison with statistical methods, using a combination of conventional and experimental biological markers. Forty-one patients with different stages and grades of prostate cancer undergoing a variety of treatments were analysed. Artificial neural networks were used as follows: eight input neurons consisting of six conventional factors (age, stage, bone scan findings, grade, serum PSA, treatment) and two experimental markers (immunostaining for bcl-2 and p53, which are both apoptosis-regulating genes). Twenty-one patients were used for training and 20 for testing. A total of 80% of the patients were correctly classified regarding outcome using the combination of factors. When both bcl-2 and p53 immunoreactivity were excluded from the analysis, correct prediction of the outcome was achieved in only 60% of the patients (P = 0.0032). This study was able to demonstrate the value of artificial neural networks in the analysis of prognostic markers in prostate cancer. In addition, the potential for using this technology to evaluate novel markers is highlighted. Further large-scale analyses are required to incorporate this methodology into routine clinical practice.     

Total versus subtotal hysterectomy: a survey of current views and practice among British gynaecologists.

This paper reports the results of a postal questionnaire, with a response rate of 61 per cent. It is clear from the results that subtotal hysterectomy is an unpopular operation in the United Kingdom. Although a majority of consultants felt that subtotal hysterectomy was less likely to affect urinary, bowel and sexual function, this did not seem to affect decision making. Seventy-eight per cent of female gynaecologists would prefer a total hysterectomy for themselves rather than a subtotal procedure.     

Effects of physical training in asthma: a systematic review

OBJECTIVES: To assess the evidence for the effects of physical training on pulmonary function, symptoms, cardiopulmonary fitness, and quality of life in subjects with asthma. METHODS: A search was conducted for randomised controlled trials of subjects with asthma undertaking physical training using the Cochrane Airways Group register of controlled clinical trials, Medline, Embase, Sportdiscus, Science citation index, and Current contents index. Studies were included in the review if the subjects had asthma, were 8 years of age or older, and had undertaken physical training for at least 20 minutes per session, twice a week, for a minimum of four weeks. The eligibility of trials for inclusion in the review and the quality of the trials were independently assessed by two reviewers. RESULTS: Eight studies with a total of 226 subjects met the inclusion criteria for this review. Physical training had no effect on resting lung function but led to an improvement in cardiopulmonary fitness as measured by an increase in maximum oxygen uptake of 5.6 ml/kg/min (95% confidence interval 3.9 to 7.2). None of the studies measured quality of life. CONCLUSIONS: Physical training improves cardiopulmonary fitness without changing lung function. It is not clear if the improvement in fitness translates into a reduction in symptoms or an improvement in the quality of life. There is a need for further randomised controlled trials of the effects of physical training in the management of asthma.     

Audit of a children's epilepsy clinic

A newly established tertiary epilepsy clinic at Guy's Hospital, London was evaluated using a structured questionnaire. Fifty parents of children with epilepsy completed this questionnaire, with some contribution from the children. While a high degree of satisfaction was obtained by the parents and where appropriate the children, specific questions about additional resources implied a large number of unmet needs. This raises methodological issues about the value of open-ended questions in audit questionnaires. In addition, concerns were expressed about many areas, some of which had direct medical implications that were not always raised with the doctors. It is concluded that the service has benefited from both clinical and neuropsychological support. The audit has prompted a number of improvements, including establishing a discussion group for adolescents.     

The use of perioperative Sofradex® eardrops in preventing tympanostomy tube blockage: a prospective double‐blinded randomized‐controlled trial

Around 11–12% of tympanostomy tubes are reported to become blocked by middle ear secretions or blood immediately following surgery, and so no longer function. Many otologists routinely instil an antibiotic and steroid‐containing solution at the time of surgery in the belief that this may reduce this complication. The aim of the study was to investigate the efficacy of instilling the antibiotic and steroid‐containing solution Sofradex^® at the time of grommet insertion in preventing grommet blockage. Double‐blind randomized‐controlled trial, comparing rates of grommet blockage in ears treated with Sofradex^® drops against control (no drops) in patients undergoing bilateral grommet insertion. Sixty‐one pairs of results were obtained. There was a significant difference between the rates of grommet blockage in the two groups. Grommets with Sofradex^® drops instilled perioperatively were nine times less likely to be blocked than controls [1.6%versus 13.1%, odds ratio (Sofradex^®/control) = 9.06, 95% confidence interval (CI): 1.04–78.82, P = 0.05]. There was no association between grommet blockage and perioperative bleeding or the nature and presence of middle ear secretions. Sofradex^® eardrops are effective in reducing the rate of grommet blockage when instilled perioperatively.     

Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes

Transient neonatal diabetes (TND) is a rare type of diabetes that presents soon after birth, resolves by 18 months, and predisposes to diabetes later in life. A total of 30 patients were ascertained and investigated for aberrations of chromosome 6. A genotype/phenotype study was also performed. Genotypically, these patients can be classified into 4 etiologic groups. Group 1 had paternal uniparental isodisomy of chromosome 6 (11 cases, including 1 set of identical twins). Group 2 had a duplication involving chromosome band 6q24, which was paternal in origin where tested (4 sporadic cases and 7 familial cases from 2 families). Group 3 consisted of 1 patient with a loss of methylation at a CpG island within the TND critical region (1 sporadic case). Group 4 had no identifiable rearrangement of chromosome 6 (7 sporadic cases). Most patients were growth retarded at birth, presented at a median age of 3 days, and recovered at a median age of 12 weeks. In group 2, 2 relatives of the TND patients who presented with type 2 diabetes and no early history of TND had inherited an identical duplication. An abnormality of chromosome 6 was identified in approximately 70% of sporadic TND cases and in all familial cases. No significant clinical differences were found between the 4 etiological groups. The study has broadened the clinical spectrum of TND to include type 2 diabetes presenting in later life with no neonatal presentation. The findings are consistent with an imprinted gene for diabetes mapping to 6q24, which we predict will have an important function in normal pancreatic development.     

Transparahippocampal selective amygdalohippocampectomy in children and adolescents: efficacy of the procedure and cognitive morbidity in patients

OBJECT: Unilateral resection of the hippocampus and amygdala can be used to treat medically intractable mesial temporal lobe seizures. To date seizure outcome and the extent of cognitive morbidity have been unknown in children following the transparahippocampal variation of selective amygdalohippocampectomy (TSA), which prompted the present prospective study. METHODS: Preoperative examinations and outcomes in 22 consecutive children and adolescents who underwent TSA were studied. Cognitive and psychological morbidity were assessed using standard neuropsychological instruments. The authors evaluated relationships between seizure control and cognitive morbidity and 13 and nine clinical variables, respectively. Seizure control was achieved in 11 (65%) of 17 patients (>2 years follow up). Among 13 clinical variables, the only preoperative finding that had a significant bearing on seizure control was the presence of unilateral hypometabolism, which could be observed on [18F]fluorodeoxyglucose-positron emission tomography scans (p<0.001). Patients with seizure control showed significant improvements in verbal and full scale intelligence quotients (both p = 0.05). Patients with longer preoperative durations of seizures exhibited more cognitive impairment that persisted postoperatively. Cognitive outcome analysis based on nine clinical factors revealed no significant difference in cognitive parameters postoperatively, except that significant improvement occurred in rote verbal memory scores among patients who underwent right-sided TSA (p = 0.01). Individually, 81% of the children achieved significant improvement in at least one of seven cognitive parameters, and 52% had stable or improved scores in all parameters. CONCLUSIONS: The results indicate that TSA is a safe effective approach for the treatment of medically intractable mesial temporal lobe seizures in children with minimum effect on cognitive morbidity. Given that the literature suggests that children suffer progressive cognitive morbidity from persistent seizures, the results of this study support early surgical intervention for this group of children.     

The role of contextual versus discrete drug-associated cues in promoting the induction of psychomotor sensitization to intravenous amphetamine

The environmental context in which psychostimulant drugs are administered can have a large effect on both their acute psychomotor activating effects and their ability to induce the psychomotor sensitization associated with repeated drug administration. For example, the acute effects of amphetamine and the development of psychomotor sensitization to amphetamine and cocaine are enhanced when they are administered in a distinct and relatively novel test environment, relative to when they are given in the home cage, in the absence of any environmental stimuli predictive of drug administration. The experiments reported here were designed to further examine this phenomenon and to test the hypothesis that the ability of a distinct context to promote robust psychomotor sensitization is due to its ability to reliably signal (cue) drug administration. Specifically, we compared the ability of contextual cues (a distinct test environment) and discrete cues (light, tone and/or odor), which both reliably predict drug administration, to promote the induction of sensitization. The psychomotor stimulant effects (rotational behavior) of repeated intravenous infusions of 0. 5 mg/kg amphetamine were assessed in rats for whom drug treatments were signaled either: (1) by placement into a distinct test environment; (2) by presentation of discrete cues; or (3) rats for whom drug treatments were given in the home environment in the absence of any environmental cues. Amphetamine produced robust sensitization when given in association with placement into a distinct test environment. The same treatment failed to produce sensitization when the drug was given unsignaled in the animal's home cage. Most importantly, signaling drug administration by presenting discrete cues was not sufficient to promote the robust sensitization seen when treatments were given in a distinct test environment. These results confirm that the induction of psychomotor sensitization can be powerfully modulated by environmental context and further establish that, although contextual stimuli associated with a distinct test environment promote robust sensitization, discrete cues that merely predict drug administration do not have this property. Possible reasons for the difference in the ability of contextual versus discrete environmental cues to promote sensitization are discussed.     

PBPK model for radioactive iodide and perchlorate kinetics and perchlorate-induced inhibition of iodide uptake in humans.

Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I-) uptake at the sodium (Na+)-iodide (I-) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I- and cold ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, as well as the subsequent inhibition of thyroid 131I- uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I- in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I- and perchlorate's interaction with free radioactive I- provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I- refers to I- incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins.