De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females.

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X­linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss­of­function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole­exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X­linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.

Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.

First-trimester diagnosis of Meckel-Gruber syndrome by fetal ultrasound with molecular identification of CC2D2A mutations by next-generation sequencing.

We describe a first-trimester ultrasound examination in which the finding of fetal encephalocele and the cystic appearance of the kidneys raised suspicion of Meckel-Gruber syndrome (MKS). On the basis of sonographic findings, the patient elected termination of pregnancy, and post-termination studies using next-generation sequencing of a gene panel revealed two mutations (one previously described and the other novel) in the gene CC2D2A. Mutations in CC2D2A are known to cause MKS and Joubert syndrome, thus providing molecular confirmation of the clinical suspicion of MKS and opening the possibility for future prenatal diagnosis. This case highlights the ability to detect important anomalies in the first trimester using ultrasound, even in low-risk situations. It also demonstrates the growing role of new sequencing technologies in fetal testing.

Ultrasonic displacement measurements from local absorption of ultrasound in thermochromic liquid crystal sensors.

Wavefield imaging can be used for measuring the wavefield produced by an ultrasound transducer for medical and industrial applications, or for the detection and monitoring of defects in non-destructive testing. Typical wavefield imaging methods include interferometry/vibrometry, and the use of microphones and hydrophones. These involve scanning, making them time consuming, and microphones have limited resolution. An alternative method presented here uses thermochromic liquid crystal sensors which react to heat generated due to absorption of ultrasonic waves. The result is a colour scale that varies with temperature, with the temperature change dependent on ultrasonic displacement. Measurements of the resonant modes of a flexural ultrasonic transducer were taken between 320 kHz and 6.77 MHz. Temperature maps were obtained from photographs of the TLC sensor using the true-colour image processing method. The obtained temperature change across the transducer face was compared with displacement measurements taken using interferometry, showing excellent agreement in the position of the mode features and good resolution at lower frequencies. Thermal measurements were also taken to directly observe the heating of the transducer cap, showing the effect of the thermal conductivity of the transducer along with confirming the increased heat generated by the ultrasound absorption when a backing layer is used. The sensors show promise for fast transducer characterisation, with further potential applications in structural health monitoring and defect detection.

Impact of meltwater flow intensity on the spatiotemporal heterogeneity of microbial mats in the McMurdo Dry Valleys, Antarctica.

The meltwater streams of the McMurdo Dry Valleys are hot spots of biological diversity in the climate-sensitive polar desert landscape. Microbial mats, largely comprised of cyanobacteria, dominate the streams which flow for a brief window of time (~10 weeks) over the austral summer. These communities, critical to nutrient and carbon cycling, display previously uncharacterized patterns of rapid destabilization and recovery upon exposure to variable and physiologically detrimental conditions. Here, we characterize changes in biodiversity, transcriptional responses and activity of microbial mats in response to hydrological disturbance over spatiotemporal gradients. While diverse metabolic strategies persist between marginal mats and main channel mats, data collected from 4 time points during the austral summer revealed a homogenization of the mat communities during the mid-season peak meltwater flow, directly influencing the biogeochemical roles of this stream ecosystem. Gene expression pattern analyses identified strong functional sensitivities of nitrogen-fixing marginal mats to changes in hydrological activities. Stress response markers detailed the environmental challenges of each microhabitat and the molecular mechanisms underpinning survival in a polar desert ecosystem at the forefront of climate change. At mid and end points in the flow cycle, mobile genetic elements were upregulated across all mat types indicating high degrees of genome evolvability and transcriptional synchronies. Additionally, we identified novel antifreeze activity in the stream microbial mats indicating the presence of ice-binding proteins (IBPs). Cumulatively, these data provide a new view of active intra-stream diversity, biotic interactions and alterations in ecosystem function over a high-flow hydrological regime.

Iron photoreduction and oxidation in an acidic mountain stream.

In a small mountain stream in Colorado that receives acidic mine drainage, photoreduction of ferric iron results in a well-defined increase in dissolved ferrous iron during the day. To quantify this process, an instream injection of a conservative tracer was used to measure discharge at the time that each sample was collected. Daytime production of ferrous iron by photoreduction was almost four times as great as nighttime oxidation of ferrous iron. The photoreduction process probably involves dissolved or colloidal ferric iron species and limited interaction with organic species because concentrations of organic carbon are low in this stream.

Environmental and Agricultural Relevance of Humic Fractions Extracted by Alkali from Soils and Natural Waters.

To study the structure and function of soil organic matter, soil scientists have performed alkali extractions for soil humic acid (HA) and fulvic acid (FA) fractions for more than 200 years. Over the last few decades aquatic scientists have used similar fractions of dissolved organic matter, extracted by resin adsorption followed by alkali desorption. Critics have claimed that alkali-extractable fractions are laboratory artifacts, hence unsuitable for studying natural organic matter structure and function in field conditions. In response, this review first addresses specific conceptual concerns about humic fractions. Then we discuss several case studies in which HA and FA were extracted from soils, waters, and organic materials to address meaningful problems across diverse research settings. Specifically, one case study demonstrated the importance of humic substances for understanding transport and bioavailability of persistent organic pollutants. An understanding of metal binding sites in FA and HA proved essential to accurately model metal ion behavior in soil and water. In landscape-based studies, pesticides were preferentially bound to HA, reducing their mobility. Compost maturity and acceptability of other organic waste for land application were well evaluated by properties of HA extracted from these materials. A young humic fraction helped understand N cycling in paddy rice ( L.) soils, leading to improved rice management. The HA and FA fractions accurately represent natural organic matter across multiple environments, source materials, and research objectives. Studying them can help resolve important scientific and practical issues.

Relationship between dissolved organic matter quality and microbial community composition across polar glacial environments.

Vast expanses of Earth's surface are covered by ice, with microorganisms in these systems affecting local and global biogeochemical cycles. We examined microbial assemblages from habitats fed by glacial meltwater within the McMurdo Dry Valleys, Antarctica and on the west Greenland Ice Sheet (GrIS), evaluating potential physicochemical factors explaining trends in community structure. Microbial assemblages present in the different Antarctic dry valley habitats were dominated by Sphingobacteria andFlavobacteria, while Gammaproteobacteria and Sphingobacteria prevailed in west GrIS supraglacial environments. Microbial assemblages clustered by location (Canada Glacier, Cotton Glacier and west GrIS) and were separated by habitat type (i.e. ice, cryoconite holes, supraglacial lakes, sediment and stream water). Community dissimilarities were strongly correlated with dissolved organic matter (DOM) quality. Microbial meltwater assemblages were most closely associated with different protein-like components of the DOM pool. Microbes in environments with mineral particles (i.e. stream sediments and cryoconite holes) were linked to DOM containing more humic-like fluorescence. Our results demonstrate the establishment of distinct microbial communities within ephemeral glacial meltwater habitats, with DOM-microbe interactions playing an integral role in shaping communities on local and polar spatial scales.

Treatment of imipramine-resistant recurrent depression, IV: A double-blind crossover study of tranylcypromine for anergic bipolar depression.

OBJECTIVE: Few trials of monoamine oxidase inhibitors (MAOIs) in tricyclic-resistant depression have had double-blind conditions. In the authors' previous double-blind comparison of tranylcypromine and imipramine in anergic bipolar depression, tranylcypromine was significantly more effective. This investigation was a crossover study of nonresponders in the initial study. METHOD: The subjects were 16 outpatients with anergic bipolar depression. Fourteen had not responded to 4 weeks of treatment with at least 30 mg/day of tranylcypromine or 150 mg/day of imipramine, and two patients were crossed over because of intolerable side effects from the initial drug. The crossover medication was prescribed as in the initial double-blind study. RESULTS: Twelve patients were crossed over from imipramine to tranylcypromine; nine of them responded to tranylcypromine. Highly significant improvements were documented on the Hamilton, Beck, and Pittsburgh Reversed Vegetative Symptom Scales. Four patients were switched from tranylcypromine to imipramine, but only one responded. CONCLUSIONS: The high rates of response to tranylcypromine in both the initial and crossover double-blind studies document the efficacy of MAOI treatment for anergic bipolar depression. Moreover, the results further illustrate the utility of MAOIs in tricyclic-resistant depressions.

Hyperglycemia during normothermic cardiopulmonary bypass: the role of the kidney.

BACKGROUND: Hyperglycemia commonly occurs during cardiopulmonary bypass. We studied the quantitative impact of glucose input and its renal excretion on hyperglycemia during cardiopulmonary bypass. METHODS: The quantity of glucose infused and metabolite and hormone concentrations in plasma, as well as oxygen consumption, carbon dioxide production, and renal glucose excretion, were determined before, during, and after cardiopulmonary bypass in 8 patients. RESULTS: Hyperglycemia (14 to 29 mmol/L) was accompanied by an increase in plasma insulin levels. The degree of hyperglycemia was directly related to the amount of glucose infused. The rate of oxygen consumption did not decrease and the rate of urea appearance (gluconeogenesis) did not rise. Despite a very high filtered load of glucose, there was very little glucosuria, indicating a markedly enhanced renal absorption of glucose. CONCLUSIONS: Hormonal and metabolic factors permit the development of hyperglycemia during cardiopulmonary bypass but its severity depends on the quantity of glucose infused and, what appears to be a new finding, a markedly enhanced renal reabsorption of filtered glucose. Thus the kidney plays an important role in the development of severe hyperglycemia during cardiopulmonary bypass.

Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival).

Toxicity occurs rapidly after overdose with regular-release valproic acid, but there is less experience with enteric-coated formulations. We report a case of delayed onset of toxicity and time to peak levels after ingestion of enteric-coated divalproex sodium (Epival). The patient was a 24-year-old female who ingested an unknown amount of Epival together with ibuprofen, dimenhydrinate, and ethanol. Ninety minutes after ingestion, the patient had only mild toxicity, and valproic acid was undetectable in her blood. By 13 h post-ingestion, valproate levels were 7450 micromol/L (1,075 mg/L), and the patient was comatose and required endotracheal intubation and mechanical ventilation. The toxicity and pharmacokinetics of valproic acid are discussed in the context of this case, and management guidelines are proposed.

Foregoing life-sustaining treatment for adult, developmentally disabled, public wards: a proposed statute.

This Article proposes a procedure for making decisions to forego life-sustaining treatment for adult, developmentally disabled, public wards who are not competent to make health care decisions. Few commentators or cases address the special considerations involved in making life-sustaining treatment decisions for this patient population. The proposal attempts to fill this gap with a patient-centered process that allows decisionmakers, without prior judicial approval, to forego life-sustaining treatment for adult, developmentally disabled, public wards who have been reliably diagnosed with specific medical conditions.

The NARC (nonsteroidal anti-inflammatory in renal colic) trial. Single-dose intravenous ketorolac versus titrated intravenous meperidine in acute renal colic: a randomized clinical trial.

OBJECTIVES: Intravenous (IV) opioid titration is an accepted method of relieving acute renal colic. Studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective in this setting. Our objective was to compare single-dose ketorolac and titrated meperidine, both administered intravenously, with respect to speed and degree of analgesia, adverse effects and functional status. Our primary hypothesis was that these agents provide equivalent analgesia within 60 minutes. Our secondary hypotheses were that ketorolac-treated patients would experience fewer adverse effects and would be better able to resume usual activity. METHODS: This was a multicentre, double-blind randomized equivalence trial in a convenience sample of patients age 18-65 with moderate or severe renal colic, documented by intravenous pyelogram, ultrasound or stone passage. Meperidine-treated patients received 50 mg IV meperidine at 0 minutes, then 25-50 mg every 15 minutes as needed for ongoing pain. Ketorolac-treated patients received 30 mg IV ketorolac at 0 minutes and placebo injections every 15 minutes as needed. Pain levels and adverse effects were assessed every 15 minutes, and functional status was evaluated at 60 minutes. Our primary outcome was the proportion of patients with mild or no pain at 60 minutes. RESULTS: Overall, 49 of 77 meperidine-treated patients (64%; 95% confidence interval [CI], 53%-75%) and 47 of 65 ketorolac-treated patients (72%; 95% CI, 61%-83%) achieved successful pain relief at 60 minutes (p value for equivalence = 0.002). Ten percent of meperidine-treated patients and 44% of ketorolac-treated patients were able to resume usual activity at 60 minutes (p = 0.001). CONCLUSIONS: In the doses studied, single-dose IV ketorolac is as effective as titrated IV meperidine for the relief of acute renal colic and causes less functional impairment.

Nonsteroidal anti-inflammatory drug therapy for neonatal calf diarrhea complex: Effects on calf performance.

The aim of this study was to examine the efficacy of meloxicam (MEL) as supportive therapy for calves with neonatal calf diarrhea complex. For this double-blind controlled trial, 62 Holstein male calves were purchased at birth and transported to a research facility. At the naturally occurring onset of diarrhea, defined as the first occurrence of a fecal score greater than 2 on a 4-point scale, calves were enrolled in the study. Each calf with diarrhea was randomly assigned to receive a single subcutaneous injection of MEL at a rate of 0.5 mg/kg of BW or an equal volume of placebo (PLA) solution. Milk, starter ration, and water intakes were determined daily for each calf from arrival until 56 d of age. The calves were weighed on arrival and each week thereafter. Time to weaning and weaning weight were recorded for each calf. Crude associations between treatment and each outcome variable were examined using t-tests and Pearson chi-squared tests. Subsequently, multivariable regression models were constructed to examine the impact of MEL therapy on meaningful outcome variables. The primary experimental unit in all analyses was the individual calf. In total, 56 calves presented with clinical signs of diarrhea and were enrolled in the study. Two PLA-treated calves died after being enrolled in the study, and there was no calf mortality among the MEL-treated calves. For calves that developed diarrhea after 10 d of age, MEL-treated calves were more likely to consume their entire daily milk allowance (P < 0.05) as compared with PLA-treated calves. Meloxicam-treated calves began consuming starter ration earlier (P < 0.01) and at a greater rate (P < 0.001), and consumed more water (P < 0.001) compared with PLA-treated animals. Over the study period, calves treated with MEL gained BW at a faster rate (P < 0.01) than calves treated with PLA. There was no difference in weaning weight (P > 0.05), but MEL-treated calves tended to wean earlier (P = 0.11) than PLA-treated calves. These results demonstrate that calves receiving a single injection of MEL at the onset of diarrhea had improved appetite and performance compared with PLA-treated calves. Thus, MEL is an effective supportive therapy for neonatal calf diarrhea complex.