A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.

Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome.

Emerging challenges of the impacts of pharmaceuticals on aquatic ecosystems: A diatom perspective.

Pharmaceuticals are a ubiquitous group of emerging pollutants of considerable importance due to their biological potency and potential to elicit effects in wildlife and humans. Pharmaceuticals have been quantified in terrestrial, marine, fresh, and transitional waters, as well as the fauna and macro-flora that inhabit them. Pharmaceuticals can enter water ways through different human and veterinary pathways with traditional wastewater treatment, unable to completely remove pharmaceuticals, discharging often unknown quantities to aquatic ecosystems. However, there is a paucity of available information regarding the effects of pharmaceuticals on species at the base of aquatic food webs, especially on phytoplankton, with research typically focussing on fish and aquatic invertebrates. Diatoms are one of the main classes of phytoplankton and are some of the most abundant and important organisms in aquatic systems. As primary producers, diatoms generate ∼40 % of the world's oxygen and are a vital food source for primary consumers. Diatoms can also be used for bioremediation of polluted water bodies but perhaps are best known as bio-indicators for water quality studies. However, this keystone, non-target group is often ignored during ecotoxicological studies to assess the effects of pollutants of concern. Observed effects of pharmaceuticals on diatoms have the potential to be used as an indicator of pharmaceutical-induced impacts on higher trophic level organisms and wider ecosystem effects. The aim of this review is to present a synthesis of research on pharmaceutical exposure to diatoms, considering ecotoxicity, bioremediation and the role of diatoms as bio-indicators. We highlight significant omissions and knowledge gaps which need addressing to realise the potential role of diatoms in future risk assessment approaches and help evaluate the impacts of pharmaceuticals in the aquatic environment at local and global scales.

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population.

Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. (70)DERAA(74), D(70) and I(67) protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1(*)0401∼(*)0404>(*)0101∼(*)1001 ((*)0404>(*)0101: P=0.0003). HLA-DRB1(*)0401/(*)0404 compound heterozygosity conferred a risk similar to (*)0401 homozygosity (P=0.70). Protective effects of D(70) and I(67) were similar. Predictions of the D(70) model fitted the data better than those of the I(67) model. The protective effect of D(70) showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P=5.8 × 10(-4)), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P=0.0012). In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D(70) specifically protected against antibody-positive RA.

Time to Surgery Following Short-Course Radiotherapy in Rectal Cancer and its Impact on Postoperative Outcomes. A Population-Based Study Across the English National Health Service, 2009-2014.

AIMS: Preoperative short-course radiotherapy (SCRT) is an important treatment option for rectal cancer. The length of time between completing SCRT and surgery may influence postoperative outcomes, but the evidence available to determine the optimal interval is limited and often conflicting. MATERIALS AND METHODS: Information was extracted from a colorectal cancer data repository (CORECT-R) on all surgically treated rectal cancer patients who received SCRT in the English National Health Service between April 2009 and December 2014. The time from radiotherapy to surgery was described across the population. Thirty-day postoperative mortality, returns to theatre, length of stay and 1-year survival were investigated in relation to the interval between radiotherapy and surgery. RESULTS: Within the cohort of 3469 patients, the time to surgery was 0-7 days for 76% of patients, 8-14 days for 19% of patients and 15-27 days for 5% of patients. There was a clear variation in relation to different patient characteristics. There was, however, no evidence of differences in postoperative outcomes in relation to interval length. CONCLUSIONS: This study suggests that the time interval between SCRT and surgery does not influence postoperative outcomes up to a year after surgery. The study provides population-level, real-world evidence to complement that from clinical trials.

Prolonged recovery of consciousness in children following symptomatic epileptic seizures.

INTRODUCTION: There is little published data on the duration of depressed consciousness following epileptic seizures. A prolonged recovery time may be a symptom of underlying brain pathology. This prospective paediatric cohort study investigates whether recovery is prolonged following symptomatic seizures. METHODS: Children aged 1-16 years, who had a witnessed seizure in which consciousness was impaired, were recruited. One hundred and twenty eight children (158 seizures) were studied. Seizure aetiology was classified as febrile, idiopathic, remote symptomatic, acute symptomatic and acute on remote symptomatic. At least hourly Paediatric Coma Scale recordings were used to assess recovery time. RESULTS: Recovery time was longest for children with acute on remote symptomatic seizures (4.0 h, range 0.89-10.5), followed by those with acute symptomatic seizures (1.94 h, range 0-35.27), remote symptomatic seizures (1.5h, range 0.07-85.5) and idiopathic seizures (0.83 h, range 0.07-13.13). Children with febrile seizures recovered the quickest (0.3h, range 0.05-9). Recovery time was significantly longer (p<0.001, CI 1.96-5.38) following seizures for which rescue antiepileptic drugs were administered compared to those for which it was not. Age, sex, type and duration of seizure did not independently affect recovery time. DISCUSSION: Symptomatic seizures take longer to recover than seizures of other aetiologies. It is recommended that a febrile child who presents with a seizure, who has not fully recovered within 30 min, should be investigated for an acute symptomatic aetiology. A high index of suspicion is also needed if children with apparent idiopathic seizures have not fully recovered within 1.5h.

The assessment of diffuse pollution from acid-mine drainage using an updated and revised diatom assessment procedure as an added-value bio-monitoring tool.

Three data sources (physico-chemistry, bio-monitoring and eco-toxicology) are currently used in South Africa to establish environmental water quality conditions. Environmental water quality in turn is key information required for the "ecological reserve determination" of river reaches. Bio-monitoring in South Africa has been limited in recent times mostly to the use of the SASS procedure which relies on invertebrates only. This paper describes the re-introduction of a diatom-based water quality assessment as an added-value bio-monitoring tool. A specific example is discussed citing the response of diatom assemblages to diffuse pollution from acid mine drainage and how effective diatoms are as indicators of ecological integrity and river recovery measured downstream of the area of impact. The advantages of applying this bio-monitoring technique over other biological measures are presented in the context of technological advances in rapid image processing, species identification and software applications of diatom-based water quality indices. The valuable records of the diatom assemblages of the past, held in the South African Diatom Collection at the CSIR (KwaZulu-Natal), can now be accessed and interpreted as historical environmental water quality reference points for several rivers in South Africa.

A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease.

CONTEXT: Autoimmune thyroid diseases (AITD), comprising Graves' disease and autoimmune hypothyroidism, are characterized by loss of immunological self-tolerance to thyroid antigens. These are complex diseases arising from a combination of genetic and environmental factors. An understanding of the genetic susceptibility factors for AITD could help to target treatments more effectively and identify people at risk for these conditions. OBJECTIVE: The objective of this study was to identify regions of genetic linkage to AITD that could potentially harbor genetic susceptibility factors for these conditions. DESIGN: The study design was a genome-wide screen performed on affected relative pairs with AITD. SETTING: Patients were recruited through hospital endocrinology clinics. PARTICIPANTS: Some 1119 Caucasian relative pairs affected with AITD (Graves' disease or autoimmune hypothyroidism) were recruited into the study. INTERVENTION: Blood samples were obtained from each participant for DNA analysis, and clinical questionnaires were completed. MAIN OUTCOME MEASURE: The study aimed to identify regions of genetic linkage to AITD. RESULTS: Three regions of suggestive linkage were obtained on chromosomes 18p11 (maximum LOD score, 2.5), 2q36 (maximum LOD score, 2.2), and 11p15 (maximum LOD score, 2.0). No linkage to human leukocyte antigen was found. CONCLUSIONS: The absence of significant evidence of linkage at any one locus in such a large dataset argues that genetic susceptibility to AITD reflects a number of loci, each with a modest effect. Linkage analysis may be limited in defining such loci, and large-scale association studies may prove to be more useful in identifying genetic susceptibility factors for AITD.

The I gene of bean: a dosage-dependent allele conferring extreme resistance, hypersensitive resistance, or spreading vascular necrosis in response to the potyvirus Bean common mosaic virus.

The resistance to the potyvirus Bean common mosaic virus (BCMV) conferred by the I allele in cultivars of Phaseolus vulgaris has been characterized as dominant, and it has been associated with both immunity and a systemic vascular necrosis in infected bean plants under field, as well as controlled, conditions. In our attempts to understand more fully the nature of the interaction between bean with the I resistance allele and the pathogen BCMV, we carefully varied both I allele dosage and temperature and observed the resulting, varying resistance responses. We report here that the I allele in the bean cultivars we studied is not dominant, but rather incompletely dominant, and that the system can be manipulated to show in plants a continuum of response to BCMV that ranges from immunity or extreme resistance, to hypersensitive resistance, to systemic phloem necrosis (and subsequent plant death). We propose that the particular phenotypic outcome in bean results from a quantitative interaction between viral pathogen and plant host that can be altered to favor one or the other by manipulating I allele dosage, temperature, viral pathogen, or plant cultivar.

Terbutaline and ephedrine in asthmatic children.

The effects of terbutaline, ephedrine, and placebo on the cardiovascular and pulmonary systems have been compared in 24 asthmatic children. Ephedrine and terbutaline were both found to be effective bronchodilators, with onset of action within 30 minutes. The bronchodilator effect of ephedrine was maintained for three hours, while terbutaline was active for five hours. Terbutaline caused significantly greater improvement in pulmonary functions than did ephedrine. Both terbutaline and ephedrine were associated with clinically insignificant changes in blood pressure and pulse rate. The only significant side effect observed was hand tremor in children receiving terbutaline and this appeared only early in the course of drug treatment. There was no evidence of tolerance to the bronchodilator effect of ephedrine or terbutaline after eight weeks of therapy.

Correlations between laser flare measurements and anterior chamber protein concentrations.

The laser flare cell meter quantifies anterior chamber (AC) protein (flare) by measuring light scattering of a helium-neon laser beam in the AC. The relationship between photon count and protein concentration both in vitro and in vivo was assessed. The reproducibility of the in vitro photon count measurements was 7.3%. There was a significant linear relationship between photon count and the concentration of both albumin (r = 1.0, P = 0.0001) and immunoglobulin G (IgG, r = 0.99, P = 0.0001) in vitro, but the linear-regression formulas were different with greater light scattering by IgG than by albumin at the same concentration. Laser flare measurements were done on 22 patients (12 normal eyes, 5 eyes with Fuchs' heterochromic cyclitis, and 5 uveitic eyes) before cataract surgery. Aqueous humor obtained from these patients by paracentesis was analyzed for total protein, albumin, and IgG concentration. There was a significant linear relationship (r = 0.88, P = 0.0001) between the laser flare value (range, 5.8-107.8 photons/msec) and the total aqueous protein concentration (range, 14-388 mg/dl). Use of an in vitro albumin calibration curve to convert photon count into protein concentration was found to overestimate the actual protein concentration. This overestimation was slight in normal eyes and increased with increased blood-aqueous barrier breakdown. The use of such a calibration curve therefore is not appropriate in studies on diseased eyes. The authors recommended that laser flare results be expressed in either photons per milliseconds or converted into an equivalent protein concentration using a calibration curve based on actual AC protein measurements.

Platelet malondialdehyde in cardiovascular disease: effect of prosthetic heart valves and cardioactive drugs on production.

Malondialdehyde (MDA), a product of platelet lipid peroxidation, was measured in human platelet-rich plasma. Levels of 3.19 n moles/10(9) platelets /+- 0.40 S.E. in 11 patients with prosthetic heart valves were elevated (p < 0.25) compared to 17 normal subjects (2.09 /+- 0.13 n moles/10(9) platelets). Reduced production (1.44 /+- 0.28 n moles/10(9) platelets, p < 0.5) was found in 10 patients with unstable angina. Normal levels were found in patients with mitral stenosis, cardiomyopathy or hypertension. Usual serum levels of drugs used in cardiac treatment reduced MDA levels as follows: acetaminophen, 47% (p < .01); aspirin, 58% (p < .05); furosemide, 32.6% (p < .005), and sulfinpyrazone, 41% (p < .05). Digoxin, dipyridamole, heparin, hydrochlorothiazide, lidocaine, nitroglycerin, procainamide, propranolol, quinidine, or warfarin had no significant effect at therapeutic concentrations. None of the drugs explained the enhanced production in patients with prosthetic valves while enhanced production in patients with prosthetic valves while analgesic therapy could explain the decreased levels in other cardiacs. The half-time of platelet survival, measured by suppression of malondialdehyde production, was 3.2 /+- 0.24 days in 9 normal subjects but could not be measured reliably in most patients because of multiple drug therapies. We conclude that the blood platelets of patients with prosthetic heart valves differ from those of normal subjects in their capacity to release malondialdehyde after stimulation with n-ethylmaleimide. Additionally, we find that inhibition of malondialdehyde production by several pharmacologic agents limits the usefulness of this method for the measurement of platelet survival in cardiac patients.

Evaluation of the bronchodilator properties of Ro 31-6930, a novel potassium channel opener, in the guinea-pig.

1. Ro 31-6930 (0.001-0.3 microM), cromakalim (0.03-3.0 microM), salbutamol (0.001-0.3 microM) and theophylline (0.3-100 microM) evoked dose-related reductions in guinea-pig spontaneous tracheal tone with IC50 values of 0.044, 0.20, 0.021 and 21.0 microM respectively. All four agents also relaxed tone supported by betahistine, carbachol, 5-hydroxytryptamine (5-HT), leukotriene D4 (LTD4), U46619 and prostaglandin D2 (PGD2). The order of potency of tracheal relaxants was always salbutamol greater than Ro 31-6930 greater than cromakalim greater than theophylline. 2. All four agents evoked dose-related reductions in 5-HT- and histamine-induced bronchoconstriction in pithed vagotomised guinea-pigs. The dose of Ro 31-6930 producing 50% inhibition of a 5-HT bronchoconstriction was 11.6 micrograms kg-1 and the dose producing 50% inhibition of a histamine bronchoconstriction was 4.4 micrograms kg-1. Salbutamol was approximately 4-5 times more potent than Ro 31-6930 whilst cromakalim was approximately 10 times less potent than Ro 31-6930 as a bronchodilator. Theophylline was markedly less potent than any of the other agents. 3. Ro 31-6930, cromakalim, salbutamol and theophylline each protected conscious guinea-pigs from histamine-induced respiratory distress. Ro 31-6930 and salbutamol were each effective at oral doses of 1.0 and 3.0 mg kg-1 whilst cromakalim was effective at oral doses of 3.0 and 10.0 mg kg-1. Theophylline showed activity only at 300 mg kg-1 p.o. 4. Ro 31-6930 is a novel potassium channel opener which is a potent relaxant of guinea-pig tracheal smooth muscle in vitro and a bronchodilator in vivo.

Dominant inheritance of a syndrome similar to Rubinstein-Taybi.

Two sibs and their mother were affected with a syndrome like the Rubinstein-Taybi syndrome. All three individuals had broad terminal phalanges of the thumbs and great toes, antimongoloid slant of the palpebral fissures, and characteristic facial appearance with beaked noses. Four sibs of the mother had broad thumbs, suggesting a familial pattern. So far there has been no report of dominant transmission of the Rubinstein-Taybi syndrome. This family bears close resemblance to the Rubinstein-Taybi syndrome, which is transmitted as an autosomal or X-linked dominant trait. Inasmuch as the expressivity of the syndrome may be variable, we propose that a thorough family investigation is indicated in all apparently sporadic cases of Rubinstein-Taybi syndrome. Familial cases may be more common than realized and require appropriate genetic counseling.

Booster response to acellular pertussis vaccine in children primed with acellular or whole cell vaccines.

Few data are available on the effect of a booster dose of acellular pertussis vaccine in children primed as infants with acellular vaccine. We administered acellular pertussis vaccine (ACV) at 19 months to children immunized in infancy with ACV or whole cell vaccine. Forty-one infants had been randomly assigned to receive either ACV or whole cell vaccine at 2, 4 and 6 months of age. Antibody titers to pertussis toxin and filamentous hemagglutinin were significantly higher in ACV than whole cell vaccine recipients at 7 months; at 15 months antibody to filamentous hemagglutinin (but not pertussis toxin) remained significantly higher among those receiving ACV. At 19 months all 41 children received an ACV booster. Local and systemic reactions were few and minor and were equally distributed between the two groups. All children responded to booster with significant increases in antibody; these increases tended to be greater for those having been primed with ACV. ACV booster immunization appears safe and immunogenic, regardless of the vaccine given for primary immunization.

Long-term captopril therapy: evolving hemodynamic effects.

Nine patients with resistant hypertension received captopril for 12 months. Five received captopril alone, four required additional therapy. In the former, mean blood pressure fell from 109 +/- 4.2 mm Hg to 84 +/- 7.5 mm Hg (P less than 0.025) after seven days. A rise to 101 +/- 19 mm Hg was noted at six and 12 months. Total peripheral resistance fell at seven days but returned to levels above control at six and 12 months. Cardiac index was 3.21 +/- 0.55 liters/min/m2 before treatment, 3.27 +/- 0.56 liters/min/m2 at seven days, and 2.17 +/- 4.0 liters/min/m2 (P less than 0.025) at 12 months. However, forearm blood flow rose from subnormal levels during the 12 months of observation, suggesting a persistent effect on the arterioles of the extremities. Plasma converting enzyme activity was significantly reduced at seven days but was above control levels at six and 12 months. However, plasma renin activity remained elevated, and plasma aldosterone concentration was significantly reduced. The fall in mean blood pressure was not related to the change in plasma converting enzyme activity in patients receiving captopril alone (five patients) or with diuretic (two patients). In the presence of beta-adrenergic blockade and volume depletion (two patients), changes in mean blood pressure appeared to be related to changes in converting enzyme activity. The data suggest that patients with essential hypertension whose blood pressure was not adequately controlled by previous medications may initially respond to captopril with a fall in blood pressure and total peripheral resistance. However, in certain individuals, these effects diminish with time despite addition of diuretics and beta-adrenergic receptor blocking agents.

Familial temperature sensitive alpha 1 protease inhibitor (M1Anaheim).

An alpha 1 protease inhibitor which is sensitive to increased temperatures and which migrates in the same position as the normal M1 phenotype, has been identified. The sensitivity of the trypsin inhibitory capacity is an inherited characteristic, which is enhanced by acid conditions, as well as conditions during isoelectric focusing. Loss of the serum trypsin inhibitory capacity is not parallel to that of the serum elastase capacity, suggesting that the inhibitory sites for these proteases are oriented differently within the alpha 1 protease inhibitor molecule.

Primary intranasal encephalocele. Report of four cases.

Four cases of primary intranasal encephalocele are presented. Three of the patients had been treated for nasal polyps. One of these three patients presented with persistent cerebrospinal fluid (CSF) rhinorrhea after fourth a polypectomy, another with recurrent CSF rhinorrhea and bacterial meningitis following a second polypectomy, and the third case with recurrence of meningitis, also following polypectomy. Recurrent bacterial meningitis was the mode of presentation in the fourth case. Encephalocele was the isolated abnormality in three, but the fourth had a degree of associated hypertelorism. The diagnosis of encephalocele should be considered in any patient with a nasal polyp, especially in children and in patients with recurrent bacterial meningitis, with or without rhinorrhea, in the absence of cranial trauma or surgery, or in the absence of external craniospinal anatomical defects.

Reinforcement with gauze wrapping for ruptured aneurysms of the middle cerebral artery.

A 2- to 15-year follow-up study is presented of a series of 35 consecutive patients treated for ruptured aneurysms of the middle cerebral artery by reinforcement with gauze wrapping. Only one patient suffered early recurrent hemorrhage in the postoperative period, and none had a late hemorrhage. The procedure carried a relatively low mortality rate (8.6%). Morbidity was the direct sequel of preoperative conditions. Wrapping is an effective and safe treatment of these aneurysms, with a low mortality and morbidity, and freedom from occlusive infarcts.

Treatment of open fractures of the tibial shaft with the use of interlocking nailing without reaming.

Fifty open fractures of the tibial shaft that were treated with débridement and interlocking nailing without reaming were followed for an average of twelve months. Most of the fractures were the result of high-energy trauma, and 68 per cent of the fracture wounds were grade III. Forty-eight (96 per cent) of the fifty fractures united at an average of seven months; there were no malunions. There were four infections (8 per cent), all at the sites of grade-III fractures. Locking screws broke in five tibiae (10 per cent), but the breakage did not result in a loss of reduction. Three nails broke, two at the sites of ununited fractures and one at the site of a healed fracture. These results are comparable with, or better than, those obtained with other forms of fixation, including immobilization with a cast, unlocked intramedullary nailing, and external fixation.

Escape behavior in task situations: task versus social antecedents.

We designed an investigation to differentiate two types of challenging behaviors occurring in teaching situations: those evoked by task stimuli (i.e., task avoidance), and those evoked by social stimuli present in teaching situations (i.e., social avoidance). Four students with developmental disabilities who exhibited challenging behaviors in teaching situations were exposed to social interaction in a play situation and task demands in a teaching situation. Results indicated that the students exhibited two distinct behavior patterns. Two of the students exhibited a behavior pattern consistent with task avoidance and the other two students exhibited a behavior pattern consistent with social avoidance. Implications concerning task versus social avoidance and the need for more fine-grained analyses of the stimuli associated with escape behavior are discussed.