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AIMS: Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the pancreatic KATP channel, cause neonatal diabetes. KCNJ11 is also expressed in the brain, and ~ 20% of those affected have neurological features, which may include features suggestive of psychiatric disorder. No previous studies have systematically characterized the psychiatric morbidity in people with KCNJ11 neonatal diabetes. We aimed to characterize the types of psychiatric disorders present in children with KCNJ11 mutations, and explore their impact on families. METHODS: The parents and teachers of 10 children with neonatal diabetes due to KCNJ11 mutations completed the Strengths and Difficulties Questionnaire and the Development and Wellbeing Assessment. Strengths and Difficulties Questionnaire scores were compared with normative data. Diagnoses from the Development and Wellbeing Assessment were compared with known clinical diagnoses. RESULTS: Strengths and Difficulties Questionnaire scores indicated high levels of psychopathology and impact. Psychiatric disorder(s) were present in all six children with the V59M or R201C mutation, and the presence of more than one psychiatric disorder was common. Only two children had received a formal clinical diagnosis, with a further one awaiting assessment, and the coexistence of more than one psychiatric disorder had been missed. Neurodevelopmental (attention deficit hyperactivity disorder and autism) and anxiety disorders predominated. CONCLUSIONS: Systematic assessment using standardized validated questionnaires reveals a range of psychiatric morbidity in children with KCNJ11 neonatal diabetes. This is under-recognized clinically and has a significant impact on affected children and their families. An integrated collaborative approach to clinical care is needed to manage the complex needs of people with KCNJ11 neonatal diabetes.

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OBJECTIVE: The complexity of radiotherapy planning is increasing rapidly. Delivery and planning is subject to detailed quality assurance (QA) checks. The weakest link is often the oncologists' delineation of the clinical target volume (CTV). Weekly departmental meetings for radiotherapy QA (RTQA) were introduced into the Royal Wolverhampton Hospital, Wolverhampton, UK, in October 2011. This article describes the impact of this on patient care. METHODS: CTVs for megavoltage photon radiotherapy courses for all radical, adjuvant and palliative treatments longer than five fractions (with the exception of two field tangential breast treatments not enrolled into clinical trials) were reviewed in the RTQA meeting. Audits were carried out in January 2012 (baseline) and September 2013, each over a 4-week period. Adherence to departmental contouring protocols was assessed and the number of major and minor alterations following peer review were determined. RESULTS: There was no statistically significant difference for major alterations between the two study groups; 8 alterations in 80 patients (10%) for the baseline audit vs 3 alterations from 72 patients (4.2%) in the second audit (p = 0.17). A trend towards a reduction in alterations following peer review was observed. There has, however, been a change in practice resulting in a reduction in variation in CTV definition within our centre and greater adherence to protocols. There is increasing confidence in the quality and constancy of care delivered. CONCLUSION: Introduction of a weekly QA meeting for target volume definition has facilitated consensus and adoption of departmental clinical guidelines within the unit. ADVANCES IN KNOWLEDGE: The weakest areas in radiotherapy are patient selection and definition of the CTV. Engagement in high-quality RTQA is paramount. This article describes the impact of this in one UK cancer centre.

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Primary urethral squamous cell carcinoma is rare. Its management is particularly challenging owing to the paucity of evidence from randomised trials to inform practice. We report two male and female cases of squamous cell carcinoma of the urethra, which were treated with concomitant cisplatin and radiotherapy. These cases add to the body of case reports that have shown benefit for concomitant chemoradiotherapy in urethral squamous cell carcinoma. They also illustrate that single agent chemotherapy, namely, cisplatin, may be used successfully with limited toxicities.

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Extensive CO2 vents have been discovered in the Wagner Basin, northern Gulf of California, where they create large areas with lowered seawater pH. Such areas are suitable for investigations of long-term biological effects of ocean acidification and effects of CO2 leakage from subsea carbon capture storage. Here, we show responses of benthic foraminifera to seawater pH gradients at 74-207m water depth. Living (rose Bengal stained) benthic foraminifera included Nonionella basispinata, Epistominella bradyana and Bulimina marginata. Studies on foraminifera at CO2 vents in the Mediterranean and off Papua New Guinea have shown dramatic long-term effects of acidified seawater. We found living calcareous benthic foraminifera in low pH conditions in the northern Gulf of California, although there was an impoverished species assemblage and evidence of post-mortem test dissolution.

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OBJECTIVES: Parameters have been derived in head and neck cancer to account for the additional biological effective dose provided by synchronous chemotherapy. The purpose of this study was to establish whether such parameters could be used to predict local control differences in anal cancer. METHODS: In anal cancer two randomised trials of radiotherapy vs chemoradiotherapy and two trials randomising between different synchronous chemotherapy regimens were identified. To predict differences in local control between the arms of the first two studies, a global value of 9.3 Gy for the chemotherapy biologically effective dose was employed. For the last two trials, values specific to differing chemotherapy schedules were derived. These values were added to the calculated biological effective dose for the radiotherapy component in order to predict local control outcomes in anal cancer trials. RESULTS: The predicted difference in local control using the global value of 9.3 Gy for the addition of synchronous chemotherapy in the trials of radiotherapy vs radiotherapy and synchronous chemotherapy was 24.6% compared with the observed difference of 21.4%. Using schedule-specific values for the contribution of chemotherapy, the predicted differences in local control in the two trials of differing synchronous chemotherapy schedules were 7.2% and 12% compared with the observed 18% and 0%. CONCLUSION: The methods initially proposed require modification to result in adequate prediction. If the decreased cisplatin dose intensity employed in anal cancer is modelled, more satisfactory predictions for such trials can be achieved. ADVANCES IN KNOWLEDGE: This revised modelling may be hypothesis generating.

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Thymomas are the most common tumours of the anterior mediastinum; their clinical course is often complicated by accompanying autoimmune and paraneoplastic syndromes. Advanced malignant thymoma is particularly challenging to manage owing to the lack of evidence from randomised trials to guide treatment. Combination first-line chemotherapy has been trialled in several small studies and has been reported to produce a 50-80% response with platinum-containing regimes. Progression following first-line chemotherapy is difficult to manage as most of these patients maintain a good performance status and demand further active palliative treatment. There is no standard second-line treatment. We report a good clinical and radiological response to third-line palliative octreotide therapy in a patient who had a positive octreotide scan.

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Inhalation of nonisotonic solutions can elicit pulmonary obstruction in asthmatic airways. We evaluated the hypothesis that the respiratory epithelium is involved in responses of the airways to nonisotonic solutions using the guinea pig isolated, perfused trachea preparation to restrict applied agents to the mucosal (intraluminal) or serosal (extraluminal) surface of the airway. In methacholine-contracted tracheae, intraluminally applied NaCl or KCl equipotently caused relaxation that was unaffected by the cyclo-oxygenase inhibitor, indomethacin, but was attenuated by removal of the epithelium and Na+ and Cl- channel blockers. Na+-K+-2Cl- cotransporter and nitric oxide synthase blockers caused a slight inhibition of relaxation, whereas Na+,K+-pump inhibition produced a small potentiation. Intraluminal hyperosmolar KCl and NaCl inhibited contractions in response to intra- or extraluminally applied methacholine, as well as neurogenic cholinergic contractions elicited with electric field stimulation (+/- indomethacin). Extraluminally applied NaCl and KCl elicited epithelium-dependent relaxation (which for KCl was followed by contraction). In contrast to the effects of hyperosmolarity, intraluminal hypo-osmolarity caused papaverine-inhibitable contractions (+/- epithelium). These findings suggest that the epithelium is an osmotic sensor which, through the release of epithelium-derived relaxing factor, can regulate airway diameter by modulating smooth muscle responsiveness and excitatory neurotransmission.

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BACKGROUND: Limited data exist on the frequency, circumstances and management of sharp object injuries (SOIs) in pediatric facilities. METHOD: SOIs reported at a large children's hospital during a 2-year period were reviewed. RESULTS: One hundred thirteen SOIs were reported for an average of 6 injuries per 100 employees per year. The greatest number of injuries occurred among nurses (46%) and physicians (23%), but phlebotomists experienced the highest rate (25.5 injuries per 100 full time equivalent employees per year). Most common locations were the patient room (27%), operating room (25%) and intensive care units (17%). Needles accounted for 71% of injuries and procedural devices accounted for 22%. Forty-eight percent of injuries occurred during use of the item, 42% after use or during disposal and 7% after disposal. Twenty percent were associated with loose sharps and 15% with inadvertent patient movement. Only 2 injuries were associated with recapping. Eighty-eight percent of the objects were contaminated with blood or body fluid. Of 88 known source patients 1 tested positive for hepatitis B surface antigen, 2 for hepatitis C virus and none for HIV. One hundred four employees sought treatment: 36 received tetanus vaccine; 14 received hepatitis B vaccine; 9 received hepatitis B immunoglobulin; and 12 received zidovudine. No employee subsequently tested positive for HIV, hepatitis B virus, or hepatitis C virus. CONCLUSIONS: SOIs represent a frequent occurrence among pediatric health care workers. Minimizing the use of sharps, appropriately restraining patients during procedures and promptly disposing of sharp items after use might decrease the frequency of SOIs.

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Results are reported from a potentiometric and spectroscopic (UV-visible, CD, and ESR) of the protonation constants and Cu(II)-complex stability constants of leucine enkephalin amide (H-Tyr-Gly-Gly-Phe-Leu-NH2, Leu-EN-amide) and two nitro analogs having 4-nitro substituent on the phenyl ring of the Phe residue, (H-Tyr-Gly-Gly-Phe(NO2)-LeuNH2, Leu-EN(nitro)- amide) and the other one with a sarcosine residue replacing the Gly3 residue (Leu-ENSar-amide). Over the pH range of 6-8.5, Leu-EN-amide interacts more strongly with Cu(II) than does the methionine analog, forming a more stable complex with three nitrogens coordinated. The Sar residue acts as a "breakpoint" to the formation of 3N or 4N complexes and, as a result, causes the formation of dimeric complexes bonded through the amino-N, a deprotonated peptide-N- and deprotonated Tyr-O- donors.

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A total of 169 patients undergoing colorectal surgery were randomly allocated to receive either gentamicin plus metronidazole or oral ciprofloxacin plus metronidazole as prophylaxis; they were also allocated to receive cover for 1 or 3 days. Twenty-eight patients (17 per cent) developed postoperative wound infections. The proportion of patients with wound infections and other infective complications was significantly less (P < 0.02) in those receiving oral ciprofloxacin. Cover for 3 days was no better than that for only 1 day. Oral ciprofloxacin for prophylaxis may offer advantages in efficacy and ease of administration compared with parenteral antibiotics.

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One hundred and fifty patients undergoing gastroduodenal surgery were randomly allocated to receive intravenous (iv) cefuroxime, iv ciprofloxacin or oral ciprofloxacin as prophylaxis. There were no differences in the incidence of postoperative infection complications or duration of stay among the three groups. Oral ciprofloxacin offers obvious advantages in terms of ease of administration and cost.

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Potentiometric and spectroscopic (EPR, CD, and absorption spectra) data obtained for digalactosamine and di- and trigalacturonic acid with Cu(II) have shown that the di-sugar binding is usually less efficient than that of monomeric units while the tri-sugar can probably simultaneously use two terminal subunits to coordinate a metal ion. The latter result may have some relevance for metal binding by polysaccharides. All sugar ligands use amino or carboxylate functions as an anchor site, as in monomeric units. Bulky oligomeric ligands protect formation of the bis complexes. This causes the hydrolysis to be a dominant process at higher pH.

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The extent of complex formation between Cu(II) and many biologically active oligopeptides has been shown to change significantly in the presence of SDS micelles, a recognized model for cell lipid membranes. Protonation constants of peptides can be increased by up to 2 log unit, especially when they contain hydrophobic side chains. Metal complex formation is generally less extensive and the conformations of peptides can be altered dramatically when compared to those in simple aqueous solution.

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The pentapeptide fragment of ANF, Asn-Ser-Phe-Arg-Tyr-NH2, coordinates to Cu(II) using the same four nitrogen donor centers as simple pentapeptides such as pentaalanine yet the complexes are of much higher stability as a result of a highly organized side-chain structure which is present in the complex but absent from the free ligand.

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The results are reported of a potentiometric and spectroscopic study of the H+ and Cu2+ complexes of Ala-Arg8-vasopressin (Ala-AVP) and oxytocin at 25 degrees C and an ionic strength of 0.10 mol dm-3 (KNO3). The coordination chemistry of oxytocin and Cu(II) has been shown to be virtually identical to that of Arg8-vasotocin, forming unusually stable complexes with four nitrogen coordination (4N complexes) below pH 7. Spectroscopic evidence suggests weak interaction between Cu(II) and the sulphur atom of the -Cys6- residue in the 2N species (pH congruent to 6) but this is absent in the 4N complex. Evidence is also presented for perturbation of electronic transitions within the aromatic ring of the Tyr residue by Cu(II). While the physiological potency of Ala-AVP is very high, its coordination chemistry differs significantly from that of Arg8-vasopressin. With Cu(II) it forms complexes of similar stability to those with tetraglycine, demonstrating that the addition of an alanyl residue to the amino-terminal of the peptide destroys the conformation which is particularly favorable for rapid 4N coordination.

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Results are reported of a pH-metric and spectroscopic (CD and ESR) study of the complexes formed between the pseudo-peptide 1-hydroxy-4-(Gly-His-Lys)-anthraquinone (Q-GHK) since, when complexed to copper ions, Q-GHK has been shown to be very effective in promoting the formation of free radicals and inducing DNA cleavage. Q-GHK forms very stable complexes with copper, the major species being bonded to three nitrogen donors in the coordination plane: an imidazole-N of the His residue and the peptide nitrogens of the Gly and His residues. This species is probably stabilized through bonding of the fourth planar coordination site of Cu(II) to the 9-anthraquinone oxygen. At high Q-GHK:copper ratios a second Q-GHK molecule is coordinated through its imidazole-N donor.

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