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Summary Background The rare inversa subtype of recessive dystrophic epidermolysis bullosa (RDEB-I) is characterized by predominant intertriginous skin blistering and marked mucosal involvement. Specific recessive missense mutations in the collagen VII triple helix are implicated in the disease. To date, otological complications have been reported infrequently in this patient group. Methods We conducted an observational, retrospective, double institution case record review of patients with RDEB-I who presented with otological complications between January 2000 and June 2020. Diagnosis was established on the basis of clinical features, family history and mutation analysis of the COL7A1 gene. Results In total, 11 (44%) of 25 patients with RDEB-I in our database (2 paediatric, 9 adult; mean age 40.9 years, range 8–72 years) experienced otological complications. Of these 11 patients, 10 (90.9%) had recurrent otitis externa, 7 (63.6%) had meatal stenosis and 7 (63.6%) had recurrent blistering of the external auditory canals. All 11 patients reported hearing difficulties, with conductive hearing loss confirmed by audiology testing in 6 (54.5%) of these. Of the 11 patients, 3 (27.3%) went on to have implantable hearing aids [2 bone-anchored hearing aids (BAHA) and 1 middle ear implant (MEI)] fitted with favourable outcome, while a fourth paediatric patient presented with a cholesteatoma that was surgically managed. Discussion We observed a higher prevalence of otological morbidity in RDEB-I than previously reported, and present the first case of cholesteatoma in epidermolysis bullosa (EB). Our data indicate that BAHA and MEI are safe and effective treatment options for hearing loss in EB. Clinicians should be vigilant in screening for ear symptoms in RDEB-I and consider early referral to an Ear, Nose and Throat specialist.

Author(s): Langbroek, GB; Wolkerstorfer, A; Horbach, SER; Spuls, PI; Kelly, KM; Robertson, SJ; van Raath, MI; Al-Niaimi, F; Kono, T; Boixeda, P; Laubach, HJ; Badawi, AM; Troilius Rubin, A; Haedersdal, M; Manuskiatti, W; van der Horst, CMAM; Ubbink, DT; COSCAM study group | Abstract: BackgroundDue to a large variety in treatment outcomes reported in therapeutic trials and lacking patient-relevant outcomes, it is hard to adequately compare and improve current therapies for patients with capillary malformations (CMs). The Core Outcome Set for Capillary Malformations (COSCAM) project aims to develop a core outcome set (COS) for use in future CM trials, in which we will first develop a core outcome (sub)domain set (CDS). Here, we describe the methods for the development of a CDS and present the results of the first development stage.MethodsThe COSCAM project is carried out according to the recommendations of the Cochrane Skin Core OUtcomes Set INitiative (CS-COUSIN) and the Core Outcome Measures in Effectiveness Trials (COMET) initiative. During the first stage, we identified all potentially relevant outcome subdomains based on a systematic review, two focus group sessions and input from patient representatives of Dutch patient organizations and the COSCAM-founding group. In stage two, we will present the subdomains in a three-round e-Delphi study and online consensus meeting, in which CM patients, parents/caregivers and CM experts worldwide rate the importance of the proposed subdomains, hereby finalizing the core outcome (sub)domains of the CDS.ResultsA total of 67 potential outcome subdomains were included; sixteen were previously used in the literature, 20 were proposed by Dutch patients and their parents/caregivers (nn=n13) in focus group sessions and 38 were suggested by the experts of the COSCAM-founding group. Seven were excluded because of overlap.ConclusionThe final CDS may serve as a minimum standard in future CM trials, thereby facilitating adequate comparison of treatment outcomes. After this CDS development, we will select appropriate outcome measurement instruments to measure the core outcome subdomains.

Inflammatory bowel disease (IBD) etiology involves genetic susceptibility, environmental triggers, and the gut microbiome. Antibiotic exposure is associated with IBD, both in early life and adulthood. Here, we investigated whether Nod2-deficiency influenced response of the gut microbiota to antibiotics and subsequent colitis susceptibility. Wild-type and Nod2

Investigating stressed oxidation and scale crystallization kinetics of advanced SiC fibers at elevated temperature in steam is a challenging yet essential undertaking for the assessment of the effects of oxidation on mechanical properties of SiC-SiC ceramic matrix composites (CMCs). Moisture in the oxidizing environment is known to change oxidation rates, reduce scale viscosity and lower temperatures for scale crystallization. In order to study these phenomena, a facility for testing SiC fiber tows in creep at elevated temperatures in air, in steam and in steam saturated with silicic acid was developed. The newly constructed test facility was validated through creep testing of Hi-Nicalon™-S fibers at 800°C in steam saturated with silicic acid. Testing in saturated steam resulted in formation of a uniform oxide scale. Details of the test facility design, development and experimental validation are presented.

Herein we detail the cases of three patients transferred on veno-arterial extracorporeal membrane oxygenation (VA ECMO) from a tertiary referral hospital to an ECMO centre. We highlight the benefits of such a transfer and offer this as a model of care for unwell patients likely to require a prolonged period of ECMO support.

The upland water supply from Loch Katrine to Glasgow was unfiltered at the time of investigations reported here. Continuous monitoring of Cryptosporidium oocysts in water treatment works final water entering supply was a regulatory requirement from 2000, using a sampling and analysis protocol for low turbidity water that filtered 1,000 litre samples at site. Cryptosporidium surveillance was extended across the supply by developing a continuous monitoring programme for operational surveillance of raw waters, using the same sampling and analysis protocol. During 2001–2004 six final water samples exceeded 0.1 oocysts per 10 litres, but none exceeded 1 oocyst per 10 litres. Cryptosporidium 90th and 95th percentiles for source waters from three catchments were significantly lower for April–June than each of the other quarters ( p

Type 2 diabetes is characterised by a progressive decline in HbA1c control over time. Early combination therapy, rather than sequential introduction of individual oral glucose-lowering agents, has been proposed to prevent this gradual rise in HbA1c. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naïve patients with type 2 diabetes.This was an observational, open-label, non-randomised study in newly diagnosed patients with type 2 diabetes, aged 35-70 years, with HbA1c levels8.0% at diagnosis or7.0% at the 3-6-month follow-up. Patients were allocated to dietary management alone if the HbA1c level was 7.0-8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA1c was8.0%. Similar treatments were introduced at 3-6 months if the HbA1c was7.0%. Over a 3-year period, HbA1c was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA1c wasor = 7.0%.416 patients were considered eligible for inclusion, with a mean (+/- SD) age of 54.1 +/- 9.2 years, BMI of 33.5 +/- 6.1 kg/m2, and baseline HbA1c of 8.6 +/- 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3-6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA1c values. Amongst those patients treated with the metformin/pioglitazone combination there was an estimated 0.1% increase in HbA1c/year. This was much less pronounced than the rises seen in HbA1c/year of 0.5% with the metformin/gliclazide and metformin/repaglinide combinations.This preliminary analysis of an observational, non-randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3-6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the beta-cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology.

Concern about the neurotoxicity of lead, particularly in infants and young children, has led to a revision of blood lead levels which are considered to involve an acceptable level of human exposure. Drinking water guidelines have also been reviewed in order to reduce this source of population exposure to lead. In the last 20 years, guidelines have been reduced from 100 to 50 to 10 microg/litre. Lead in tap water used to be a major public health problem in Glasgow because of the high prevalence of houses with lead service pipes, the low pH of the public water supply and the resulting high levels of lead in water used for public consumption. Following two separate programmes of water treatment, involving the addition of lime and, a decade later, lime supplemented with orthophosphate, it is considered that maximal measures have been taken to reduce lead exposure by chemical treatment of the water supply. Any residual problem of public exposure would require large scale replacement of lead service pipes. In anticipation of the more stringent limits for lead in drinking water, we set out to measure current lead exposure from tap water in the population of Glasgow served by the Loch Katrine water supply, to compare the current situation with 12 years previously and to assess the public health implications of different limits. The study was based on mothers of young children since maternal blood lead concentrations and the domestic water that mothers use to prepare bottle feeds are the principal sources of foetal and infant lead exposure. An estimated 17% of mothers lived in households with tap water lead concentrations of 10 microg/litre (the [WHO,] guideline) or above in 1993 compared with 49% in 1981. Mean maternal blood lead concentrations fell by 69% in 12 years. For a given water lead concentration, maternal blood lead concentrations were 67% lower. The mean maternal blood lead concentration was 3.7 microg/litre in the population at large, compared with 3.3 microg/litre in households with negligible or absent tap water lead. Nevertheless, between 63% and 76% of cases of mothers with blood lead concentrations of 10 microg/dl or above were attributable to tap water lead. The study found that maternal blood lead concentrations were well within limits currently considered safe for human health. About 15% of infants may be exposed via bottle feeds to tap water lead concentrations that exceed the WHO guideline of 10 microg/litre. In the context of the health and social problems which affect the well-being and development of infants and children in Glasgow, however, current levels of lead exposure are considered to present a relatively minor health problem.

Precision muon momentum measurements at the highest LHC luminosity is a prime objective for the ATLAS experiment. To realise this objective the muon detector is based on a large, superconducting, air-cored toroid magnet system consisting of a long barrel and two end cap toroids. The end-cap toroids are required to produce strong bending powers, 4-8 Tm, over a radial span from 1.5-5 m. This paper presents the final engineering design which includes a number of design optimisation features. The optimisation of the cold mass structure to reduce internal stresses, the developments in resin technology to give greater safety margins in operation and novel techniques for cold mass support systems are described. Final design proposals for quench protection and control are presented with manufacture, assembly and installation plans.

Sordaria brevicollis is a filamentous ascomycete previously considered to be exclusively heterothallic. Here we show that S. brevicollis can exhibit homothallism, and describe the genetic and environmental factors favouring the process. Both mating types can produce perithecia in unmated cultures, but only in the uncrossed perithecia of mtA are ascospores formed (in

Finite element analysis of the end cap toroids for the proposed Atlas Experiment at CERN has shown that the resin bonding and insulation system will be subjected to combined tension and shear forces during magnet operation at 4 K. Little is known of the transverse properties of resin based glass composites at 4 K, and even less about their behaviour in a biaxial shear/tension situation. This paper reports the development of a test procedure to evaluate the through-thickness properties of resin based composites at 4 K in uniaxial tension and in a biaxial tension/shear situation. Results from tests using this procedure on specimens manufactured using differing resins and fibre fractions are reported.

Summary The findings of a survey of the involvement of staff in group activities within a large psychiatric hospital are presented. Over two hundred regular group meetings were being held, excluding ward-rounds and business meetings. There was a wide variation in the type and structure of the groups, the purpose and theoretical underpinning of many of which were unclear to the participants. It is suggested that this lack of clarity reflects the fact that the original therapeutic aims have been subverted in the service of institutionalised defences against anxiety. To be therapeutically effective, groups need clear leadership, good supervision and well-defined aims.

The anthelmintic pyrantel is believed to act as an agonist at acetylcholine receptors on somatic muscle from the parasite Ascaris suum. This study aimed to confirm this mode of action of pyrantel. Single-channel recordings from muscle vesicles formed from the extrasynaptic region of the bag of somatic muscle cells of Ascaris suum were made using the patch-clamp technique. Pyrantel (0.03-100 microM) activated cation-selective channels with at least 2 conductance levels: main conductance 41 +/- 2.04 pS (mean +/- S.E., n = 28), smaller conductance 22.4 +/- 0.34 pS (mean +/- S.E., n = 8). The current/voltage plots showed a linear relationship. Detailed kinetic analysis revealed that activation of the receptor by pyrantel resulted in at least 2 distinct open and burst states and at least 3 distinct closed states. The mean open time of the channel, with 0.1 microM pyrantel, was 1.53 +/- 0.22 ms (mean +/- S.E., n = 7) at -75 mV. We have previously shown that acetylcholine activated channels with similar properties to the pyrantel-activated channels (Pennington, A.J. and R.J. Martin, 1990, J. Exp. Biol. 154, 201) confirming that pyrantel is an acetylcholine agonist. With high concentrations (100 microM) of pyrantel a sequence of rapid openings and closings of the channel was observed, indicating the presence of an open channel block. Previous experiments have shown that the anthelmintic levamisole, which also acts as an acetylcholine agonist on this preparation, induced channel block at hyperpolarised potentials with high concentrations (Robertson, S.J. and R.J. Martin, 1993, Br. J. Pharmacol. 108, 170). A comparison is made of the actions of the 3 agonists pyrantel, levamisole and acetylcholine at the nicotinic receptor in Ascaris muscle, and implications for the therapeutic use of the compounds are discussed.

The patch-clamp technique was used to examine activation by levamisole of nicotinic acetylcholine receptors in muscle vesicle preparations from Ascaris suum. Previous experiments have shown that levamisole, when applied at concentrations greater than 30 μM to the extracellular surface of the membrane, activated channels which showed characteristics of a voltage-sensitive open channel-block and desensitisation. In this study initial experiments were performed where channels were activated with levamisole (2 μM) applied in the patch-pipette. Isolated inside-out patches were used. In addition, levamisole (30-926 μM) was added to the cytoplasmic membrane surface via the bath solution. In eight out of nine experiments, addition of levamisole to the bath solution resulted in an increase in channel activity, a voltage-sensitive open channel-block and desensitisation. The open channel-block occurred at hyperpolarised potentials, an observation consistent with levamisole (a cationic substance) blocking the channel from the extracellular surface. Thus it was concluded that levamisole crossed from the cytoplasmic side of the membrane, via the lipid phase, to the extracellular surface of the patch. In the presence of high cytoplasmic concentrations of levamisole, open channel-block was not observed at depolarised potentials, suggesting channel asymmetry.

Lagophthalmos is a well known complication in leprosy due to the involvement of seventh cranial nerve resulting in incomplete closure of the eyelids. The real magnitude of ocular morbidity as a consequence of lagophthalmos is unknown, as several ocular complications can occur independently due to involvement of the fifth (trigeminal) nerve or due to secondary infection. Therefore, a study was designed to carefully examine the eyes of 100 consecutive leprosy patients with lagophthalmos seeking treatment at a leprosy referral centre in Delhi. Among the eyes examined, 145 had lagophthalmos. The symptomatology and anterior-posterior chamber morbidity in eyes with lagophthalmos were significantly higher as compared to unaffected eyes. Significantly, higher morbidity was seen regardless of sex or type of leprosy or deformity. Capacity building of the health professionals regarding ocular morbidity and increased emphasis on the importance of self care among patients can significantly reduce ocular morbidity.

The magnetic levitation technique has been used to test for fractional electric charge in sea water, using steel balls coated with sea water residue by evaporation. The objective was to reach concentration levels below 1 g−1 which might result from cosmic ray interactions. Four stages of increasing sensitivity are reported: (1) residue from direct evaporation of unprocessed sea water, (2) residue from sea water samples enriched by ion exchangen, (3) residue reduced by high temperature evaporation, and (4) hypothetical enrichment by dilution and separation of soluble residue. Stages 1–3 are based on the generally accepted preferential retention of fractional charge during evaporation, but stage 4 limits are subject to uncertainties in the enrichment process. No evidence for fractional charge was found in a total of about 130 samples tested in these four stages. Samples containing positive and negative ions were tested separately, and concentration limits are reported for each of the stages. Levels in the region 0.01–0.1g−1 were reached in stage 3, and 0.001 g−1 in stage 4.

The specific activity of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) was found to increase in the ovaries of pregnant and pseudopregnant rabbits. The mean specific activity of cytosolic ovarian PGDH in 14- to 28-day pregnant rabbits was 24.3 +/- 8.1 nmol NADH formed/min/mg protein (n = 16) using PGE1 as substrate whereas in nonpregnant rabbits the specific activity was 1.5 +/- 0.8 nmol NADH formed/min/mg protein (n = 8). The reaction was dependent on NAD+; NADP+ did not support the reaction. In grouping the PGDH activities from pregnant rabbits into second (14-18 days) and third (2-28 days) trimester periods, no significant difference between values was found (26.1 +/- 8.9 vs 23.4 +/- 8.1 nmol NADH formed/min/mg protein, respectively). Western blot analysis of the ovarian cytosol using an antibody which was made to the purified lung PGDH of pregnant rabbits recognized an ovarian protein of identical molecular mass (30 kDa). Ovarian PGDH activities were also examined in rabbits treated with pregnant mare's serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) to induce a state of superovulatory/pseudopregnancy and only on day 11 following hCG treatment was an increase in PGDH specific activity observed. On day 11, the specific activity was 14.8 +/- 4.3 nmol NADH formed/min/mg protein whereas values on days 10 and 12 were only 1.1 +/- 1.1 and 1.0 +/- 0.8, respectively. PGDH activities on days 3, 7 and 16 were also low.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary We describe the challenging case of a patient presenting with extensive, eruptive mid-facial squamous cell carcinomas (SCCs) and keratoacanthomas (KAs) consequent to radiotherapy. Our patient had a personal and family history of multiple KAs and SCCs. Multiple self-healing squamous epithelioma, otherwise known as Ferguson–Smith disease, was diagnosed. This case presented a therapeutic challenge to preserve tissue and avoid severe facial disfigurement. We found oral acitretin to be the treatment of choice.

The role of the canonical NF-kappaB pathway in mammary tumorigenesis was investigated using a transgenic (TG) mouse expressing a dominant-negative inhibitor of kappaB (IkappaBalpha(SR (S32A/S36A))) in the mammary gland under the control of the mouse mammary tumor virus promoter (MMTV). TG and control mice were subjected to a chemical carcinogenesis protocol. Hyperkeratinized squamous metaplasias (cytokeratin-6+/p63+) sometimes with a basaloid island component, were found in both TG and control mice whereas luminal (cytokeratin-19+/MUC1+) ErbB2+ papillary and adenomatous lesions developed almost exclusively in control mice. p65/RelA- and NF-kappaB DNA-binding activity were detected in mammary luminal lesions, but rarely in squamous metaplasias. Analysis of NF-kappaB family proteins and target genes using microarray data from a cohort of human mammary tumors revealed the expression of a canonical NF-kappaB pathway, but not non-canonical pathway proteins in HER2+ luminal cancers. HER2+ tumors also showed differential regulation of specific NF-kappaB target genes relative to basal and ER+ luminal cancers. Isolation of mammary cell populations enriched for stem and progenitor cell characteristics from an NF-kappaB-EGFP reporter mouse by fluorescence-activated cell sorting demonstrated that luminal progenitors contain activated NF-kappaB whereas the mammary stem cell-enriched population, does not. Together these data suggest that the canonical NF-kappaB pathway is active in normal luminal progenitor cells before transformation and is required for the formation of mammary luminal-type epithelial neoplasias.

The organization ofAscarismotoneurones and nervous system is summarized. There is an anterior nerve ring and associated ganglia, main dorsal and ventral nerve cords which run longitudinally, and a small set of posterior ganglia. Cell bodies of motoneurones are found in the ventral nerve cord and occur in 5 repeating ‘segments’; each contains 11 motoneurones. Seven morphological types of excitatory or inhibitory motoneurone are recognized.EachAscarissomatic muscle cell is composed of the contractile spindle; the bag region, containing the nucleus; the arm; and the syncytial region, the location of neuromuscular junctions. The resting membrane potential of muscle is approximately — 30 mV and shows regular depolarizing, Ca-dependent ‘spike potentials’ superimposed on smaller Na+- and Ca2+-dependent ‘slow waves’ and even slower ‘modulation waves’. The membrane shows high Cl-permeability. Adjacent cells are electrically coupled so that electrical activity in the cells is synchronized. Acetylcholine (ACh) and γ-aminobutyric acid (GABA) affect the electrical activity. Bath-applied ACh increases membrane cation conductance, depolarizes the cells, alters the frequency and amplitude of spike potentials and produces contraction. Bath-applied GABA increases Cl-conductance, decreases spike activity and causes hyperpolarization and muscle relaxation.The extra-synaptic ACh receptors on the bag region ofAscarismuscle can be regarded as a separate subtype of nicotinic receptor. ACh and anthelmintic agonists (pyrantel, morantel, levamisole) produce a dose-dependent increase in cation conductance and membrane depolarization which is blocked by tubocurarine, mecamylamine but not by hexamethonium. The potency, of GABA agonists, with the exception of sulphonic acid derivatives, correlates with the vertebrate GABAareceptor. The potency of antagonists does not. Thus, bicuculline, securinine, pitrazepine, SR95531 and RU5135 are potent vertebrate GABAaantagonists but have little effect on GABA receptors. The potency order of the arylaminopyridazine GABA antagonists: SR95103, SR95132, SR42666, SR95133, SR95531, SR42627 and SR42640 at theAscarisGABA receptors contrasts with that at vertebrate GABAareceptors. It has been suggested that the receptor is referred to as a GABAnreceptor.Patch-clamp studies show that ACh activates a non-selective cation channel which has a main conductance of 40–50pS and apparent mean open time of 1·3 ms; a smaller channel of 20–30 pS with a similar open-time is also activated. Pyrantel and levamisole also produce openings with similar conductances and open-times. GABA activates a Cl-channel with a main state conductance of 22 pS and an apparent mean open duration of 32 ms; conductance states of 10 and 15 pS are also seen. Piperazine similarly activates this channel but the mean open-time is shorter (14 ms). Ivermectin in high doses, is an antagonist which reduces the GABA channel conductance and Popen; it does, however, open ‘small’ Cl-channels when applied to the outside surface of membrane. These channels have a conductance of 9–15 pS and very long open times (> 100 mS). 5-HT does not have a direct effect on membrane potential or conductance but acts on cAMP levels and glycogen metabolism. Dopamine, octopamine and AF1 may act as neurotransmitters or neuromodulators.

SummaryBackground Although physical irritant contact dermatitis (PICD) is a common occupational dermatosis, it is one of the least well understood because of its multiple types, lack of diagnostic test, and the many mechanisms involved in its production. Objectives To characterize the materials and mechanisms of physical irritation of the skin. Methods We did a retrospective analysis over the past 20 years of all patients with a diagnosis of PICD at St John's Institute of Dermatology Contact Dermatitis Clinic. Results Of the 29 000 patients who attended the clinic over the study period, 392 patients were diagnosed with PICD and of these, 335 files were analysed. Conclusions Our findings show that PICD accounted for 1·15% of all patients attending the contact clinic over the study period. Diverse occupations and materials were implicated. The most common cause of PICD was low humidity due to air-conditioning, which caused dermatitis of the face and neck in office workers due to drying out of the skin.

New advances in surface treatments to electrically insulating polymeric films have improved the ability of resins to bond with these materials. This paper evaluates the strength of these bonds at low temperatures in transverse tension and combined shear/tension using a specimen geometry designed to minimise stress raisers from discontinuities in the specimen. Bond strengths of 100 to 150 MPa are reported.

The objective of this study was to correlate the failure pattern of localized prostate carcinoma after radiotherapy (RT) with pretreatment (preTx) PSA and post-RT nadir PSA, using systematic biopsies and serum PSA in the assessment of outcome.From January 1990 to February 1994, 207 patients treated with external beam RT were followed prospectively with systematic transrectal ultrasound-guided biopsies and measurements of serum PSA levels. Three hundred forty-three biopsies were performed, with 4-7 samples taken per session. The distribution of T classification was as follows: 19 patients had T1b, 15 had T1c, 34 had T2a, 79 had T2b/c, 53 had T3, and 7 had T4. Median follow-up was 36 months (range, 12-70 months). Failures were categorized as biochemical (chemF) (PSA2.0 ng/mL and1 ng/ mL over nadir), local (LF) (positive biopsy and PSA2), and distant (DF). The Cox proportional hazards model was used for multivariate analysis (MVA).Overall, failures were seen in 68 of 207 patients: 20 LF, 24 DF, 7 LF + DF, and 17 chemF. In univariate analysis, failures correlated significantly with preTx PSA, post-RT nadir PSA, T classification, and Gleason's score (GS). The total failure rate was 12% for T1b, T1c, and T2a; 39% for T2b and T2c; and 60% for T3 and T4 (P0.0001). By evaluation with preTx PSA, at 36 months the total failure rate was 3% for preTx PSAor = 5 ng/mL 16% for 5.1-10 ng/mL, 32% for 10.1-15 ng/mL, 42% for 15.1-20 ng/mL, 63% for 20.1-50 ng/mL, and 88% for50 ng/mL (P0.0001). By evaluation with post-RT nadir PSA, at 36 months the total failure rate was 4% for nadir PSAor = 0.5 ng/ mL, 26% for 0.6-1 ng/mL, 33% for 1.1-2 ng/mL, and 92% for2 ng/mL (P0.0001). In MVA, nadir PSA (P0.0001) and T classification (P0.0005) were independent predictors for any failure. LF occurred in 13% of patients (27 of 207). For these 27 patients, the categorization of T classification was: T1b/T1c/T2a, 7%; T2b/T2c, 16%; and T3/T4, 15% (P = not significant). In MVA, only nadir PSA (P = 0.0004) predicted for LF. DF occurred in 15% of patients (31 of 207). In MVA, nadir PSA (P0.0001) and T classification (P0.0001) predicted for DF, with pretreatment PSA of borderline significance (P0.05). To assess preTx predictors of outcome, post-RT nadir PSA was removed from the model. PreTx PSA then became the dominant variable to predict any failure (P0.0001), LF (P = 0.05), chemF (P = 0.0001), and DF (P0.003), while T classification also predicted for any failure (P = 0.03), chemF (P = 0.05), and DF (P0.0001).Systematic prostate biopsies, performed as part of the rigorous followup of prostate carcinoma after RT, define the patterns of failure and confirm the prognostic value of preTx PSA, post-RT nadir PSA, and T classification. Prior to treatment, preTx PSA is the overwhelming independent predictor of failure, but it is surpassed by post-RT nadir PSA when this is added to the model.

Sequential systematic biopsies after radiotherapy (RT) for prostate carcinoma were evaluated with respect to radiation effect, tumor differentiation, and prostate specific antigen (PSA) staining, and these histopathologic parameters were correlated with local outcome.Since 1990, transrectal ultrasound-guided biopsies have been used to follow patients with localized prostate carcinoma after radical external RT at the General Hospital division of the Ottawa Regional Cancer Centre. Eighty-nine patients with residual tumor in 1 or more biopsies at 10-78 months of follow-up were selected for review. All patients had undergone biopsy on more than one occasion. The 198 biopsies were stained for PSA, high molecular weight keratin, and proliferative cell nuclear antigen (PCNA). Therapy effect was graded by nuclear and cytoplasmic changes.Of these 89 selected patients, 25 progressed to local failure (LF), 38 had delayed tumor clearance, and 26 remained biopsy positive without local or biochemical progression. In the 24- and 36-month biopsies, RT effect correlated with mean nadir serum PSA (Grade 4-6 RT effect: 0.7 ng/mL; Grade 0-3 RT effect: 1.3 ng/mL [P = 0.01]) and with local outcome (Grade 0-2 RT effect: 55% LF; Grade 3-4 RT effect: 30% LF; and Grade 5-6 RT effect: 0% LF [P = 0.003]). Of tumors with minimal RT effect, 61% were PCNA positive, compared with 34% for moderate and 17% for marked RT effect (P0.001). Adjacent areas within biopsies showed varied RT effect in 27 patients, of whom 41% had local failure, compared with 18% of patients with uniform RT effect (P = 0.03). Gleason score was assigned only if RT effect was minimal (36 patients/59 biopsies); 74% had the same Gleason score (+/-1) as the original, whereas 23% were 2 points lower. Only 1 biopsy lost PSA staining completely and 10% stained faintly, whereas 34% stained moderately and 55% strongly.PSA staining is apparently retained in residual tumor after RT, despite obvious RT effect. RT effect correlates with serum PSA nadir, PCNA staining, and local outcome. Varied RT effect is commonly observed in biopsies, and correlates with local failure. There is no convincing evidence for tumor dedifferentiation after RT.

Objective: To assess the relation between tap water lead and maternal blood lead concentrations and assess the exposure of infants to lead in tap water in a water supply area subjected to maximal water treatment to reduce plumbosolvency. Design: Postal questionnaire survey and collection of kettle water from a representative sample of mothers; blood and further water samples were collected in a random sample of households and households with raised water lead concentrations. Setting: Loch Katrine water supply area, Glasgow. Subjects: 1812 mothers with a live infant born between October 1991 and September 1992. Blood lead concentrations were measured in 342 mothers. Main outcome measures: Mean geometric blood lead concentrations and the prevalence of raised tap water lead concentrations. Results: 17% of households had water lead concentrations of 10 μg/l (48.3 nmol/l) or more in 1993 compared with 49% of households in 1981. Tap water lead remained the main correlate of raised maternal blood lead concentrations and accounted for 62% and 76% of cases of maternal blood lead concentrations above 5 and 10 μg/dl (0.24 and 0.48 μmol/l) respectively. The geometric mean maternal blood lead concentration was 3.65 μg/dl (0.18 μmol/l) in a random sample of mothers and 3.16 μg/dl (0.15 μmol/l) in mothers whose tap water lead concentrations were consistently below 2 μg/l (9.7 nmol/l). No mother in the study had a blood lead concentration above 25 μg/dl (1.21 μmol/l). An estimated 13% of infants were exposed via bottle feeds to tap water lead concentrations exceeding the World Health Organisation9s guideline of 10 μg/l (48.3 nmol/l). Conclusions: Tap water lead and maternal blood lead concentrations in the Loch Katrine water supply area have fallen substantially since the early 1980s. Maternal blood lead concentrations are well within limits currently considered safe for human health. Tap water lead is still a public health problem in relation to the lead exposure of bottle fed infants. Key messages For a given tap water lead concentration mater- nal blood lead concentrations are much lower than they were in 1981 Tap water lead remains the main correlate of raised maternal blood lead concentrations An estimated 13% of infants are exposed via bottle feeds to tap water lead concentrations of 10 μg/l (48.3 nmol/l) or more Maternal blood lead concentrations are generally within limits considered safe for human health

The use of glass fibre composites as insulating materials in superconducting magnets is common practice but the trend to larger and more complex structures may require different processing techniques. In order to quantify possible process related effects, three types of glass (E-glass, S2-glass and quartz) were used in the manufacture of composite panels. These panels were exposed to environments which may be experienced by insulating materials during the manufacture and service life of Niobium-Tin magnets. Process variations included heat treatment of fabrics prior to resin impregnation and thermal cycling of the finished composites to the cure temperature and to 77 K. Changes in the mechanical properties at room temperature and at 77 K are reported.

1. The patch-clamp technique was used to examine levamisole-activated channels in muscle vesicles from Ascaris suum. Cell-attached and isolated inside-out patches were used. 2. Levamisole (1-90 microM), applied to the extracellular surface, activated channels which had apparent mean open-times in the range 0.80-2.85 ms and linear I/V relationships with conductances in the range 19-46 pS. Ion-replacement experiments showed the channels to be cation selective. 3. The kinetics of the channels were analysed. Generally open- and closed-time distributions were best fitted by two, and three exponentials respectively, indicating the presence of at least two open states and at least three closed states. The distributions of burst-times were best-fitted by two exponentials. 4. Channel open- and burst-times were voltage-sensitive: at low levamisole concentrations (1-10 microM), they increased with hyperpolarization. At higher concentrations of levamisole (30 microM and 90 microM) flickering channel-block was observed at hyperpolarized potentials. Using a simple channel-block model, values for the blocking dissociation constant, KB were determined as 123 microM at -50 mV, 46 microM at -75 mV and 9.4 microM at -100 mV. 5. At the higher concentration of levamisole (30 microM and 90 microM) long closed-times separating 'clusters' of bursts were observed, at both hyperpolarized and depolarized membrane potentials and this was interpreted as desensitization.

A fluorescent derivative of the anthelmintic ivermectin (4''-5,7-dimethyl bodipy proprionylivermectin, referred to hereafter as bodipy ivermectin) was synthesized for an investigation of the distribution of avermectins. Injected into adult Ascaris suum at doses greater than 0.1 micron per worm, it produced a dose-dependent immobilization. Fluorescent microscopy of frozen sections revealed the distribution of the probe in the whole nematode. Staining of collagenase-isolated muscle cells was studied using bath application of bodipy ivermectin. The trypan-blue quenching technique showed that the ivermectin probe was located in the outer monolayer of the muscle membrane. The cytoplasm was not stained. The interpretation of these observations is discussed in view of the known lipophilic nature of avermectins. Staining of the muscle membrane and nerve cord is consistent with the view that avermectins act at these sites. The significance of the hypodermal and lateral line staining is also discussed.

Rarefied monatomic gas flow in axisymmetric jet exhaustion into vacuum, noting expansion to low densities at thermodynamic unequilibrium

A three to sevenfold increased risk of Hodgkin's disease has been noted in families of patients. We report the first family in which all four of a four member sibship had Hodgkin's disease. In these four sibling cases, we were able to explore markers of infectious etiologic factors by measuring antibodies to Epstein-Barr virus (EBV) and human T-cell lymphotropic virus (HTLV), and possible genetic risk factors by human leukocyte antigen (HLA) typing and chromosome analysis. All three men were diagnosed within six months of their 30th birthday. HLA typing revealed that all four siblings share the DR5 antigen, and two siblings share HLA-B27. Chromosome analysis on peripheral lymphocytes revealed no abnormalities. A detailed, structured interview failed to elicit evidence of unusual exposures. The EBV antibody titers are probably within the normal range and none of the family had antibodies to HTLV-III. Observations on this family suggest that genetic factors play a greater role than environmental factors in the etiology of familial Hodgkin's disease.

Although the instability of an initially motionless fluid subjected to a Rayleigh-type acceleration is well known, this type of excitation applied to an initially moving fluid has not been studied previously. We have therefore performed numerical analyses for two-dimensional unsteady thermal convection in circular cylinders under variable low-g conditions associated with space flight. When an acceleration vector is applied parallel to the thermal gradient for a fluid at rest, no convection results for the stable direction, and an instability leads to Rayleigh convection for the opposite direction. However, when the acceleration has a component which is orthogonal to the gradient, convection always results at any Rayleigh number; this is the usual situation during space flight. We therefore study the resultant effect on convection when both types of acceleration are applied, concurrently or sequentially, and when the resultant vector varies in direction with time. Our results indicate that for space flight conditions, the Rayleigh accelerations impose significant, but not dominating, alterations in the established convection even when the Rayleigh number is less than critical.

MR studies in eight patients with extraaxial arachnoid cysts in the middle cranial fossa were reviewed in order to identify any associated structural defect in the ipsilateral temporal lobe. The study was prompted by the original theory that agenesis of the temporal lobe is the primary factor in the development of these cysts. Authors of subsequent studies proposed that the cysts are a consequence of embryological malformation of the meninges only and that the adjacent temporal lobe is compressed. Our findings suggest that middle cranial fossa cysts are associated with temporal lobe hypogenesis, and also that compression of the temporal lobe is an infrequent accompaniment.

Eighteen second-grade children initially received feedback in the form of nonredeemable tokens for reducing their disruptive classroom behavior. Four types of tutoring were then introduced in a Latin Square Design: noncontingent tutoring from fifth-grade peers, contingent peer tutoring, noncontingent college tutoring, and contingent college tutoring. No significant difference was found in the level of disruptive behavior of those children tutored by fifth-grade peers or college students, but contingent tutoring was significantly effective in reducing disruptive classroom behavior.

Density field for free molecule flow through circular ducts assuming steady state Maxwellian velocity distribution