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SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype-genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype-phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction., (© 2021 Wiley Periodicals LLC.)

Meaningful student-instructor interactions during an undergraduate degree course can have important effects on student learning. The format by which those interactions are made possible can vary greatly. We investigated the preferred modality of contact and students' reasons for contact across several modalities in a first-year biology course. We tracked student-instructor contact for two-course instructors who team teach collaboratively (rather than sequentially) across two-course sections. Both instructors had identical scores on student evaluations of approachability. Student-instructor contact was facilitated using five 'student hour' modalities: (a) in office by appointment, (b) 1 h per week, in office drop in, (c) 1 h per week, virtual chat, (d) by email, (e) 10 min immediately after class. Though email was the preferred method of contact, the period immediately following the class instruction was the most popular of the face-to-face options. We note significant differences in the distribution of workload across the two instructors and make recommendations for increasing the accessibility of student-instructor contact and for equity in workload to support student learning., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: Optimising abdominal aortic aneurysm surveillance intervals will improve current surveillance programmes. To the author's knowledge, no known study has exclusively asked patient opinion with regards to their surveillance interval. The aim of this study was to therefore determine a patient's perspective of their optimal intervals, encouraging shared decision-making and creating a patient-focused service., Methods: Fifty patients, currently under abdominal aortic aneurysm surveillance, were interviewed. Patients were asked their opinions before and after seeing a patient decision aid. A patient decision aid presents information of risk in an easy-to-understand format. This specific patient decision aid, designed and created for this study, informed patients of the 'risk of exceeding the 5.5 cm surgical threshold' with regards to various surveillance intervals. The chosen optimal surveillance interval was recorded for each patient, and a median interval was calculated for each abdominal aortic aneurysm group. Groups were categorised based upon maximum aortic diameter (3.0-3.4 cm, 3.5-3.9 cm, 4.0-4.4 cm and 4.5-4.9 cm)., Results: After assessing the patient decision aid, the median surveillance interval calculated for each abdominal aortic aneurysm group was 24 months (3.0-3.4 cm), 12 months (3.5-3.9 cm), 12 months (4.0-4.4 cm) and 6 months (4.5-4.9 cm), respectively. The majority of patients (78%, n  = 39) agreed that the patient decision aid was a useful tool to help make an informed choice., Conclusion: Overall, patients in abdominal aortic aneurysm groups 3.0-3.4 cm and 4.5-4.9 cm would choose to lengthen abdominal aortic aneurysm surveillance intervals. Lengthening the current surveillance intervals to 24 months (currently 12 months) for abdominal aortic aneurysm group 3.0-3.4 cm and to 6 months (currently 3 months) for abdominal aortic aneurysm group 4.5-4.9 cm would not only increase capacity but also reflect the needs and wishes of those using the National Health Service. The use of a patient decision aid is an effective way of communicating, to the patient, the risk of the proposed changes and thus alleviating potential anxiety., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Purpose: Lamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined., Methods: We investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes., Results: Starting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments., Conclusion: We identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B-associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.

Background: The goal of this study was to examine variability across the 92 Indiana counties in missed opportunities for HPV vaccination and to assess county-level correlates of missed opportunities., Methods: The Indiana immunization registry provided county level data on 2017 missed opportunity rates for adolescents ages 11-18. A missed opportunity was an encounter when a patient eligible for HPV vaccination received one or more other recommended vaccines, but not HPV. Potential county-level correlates of missed opportunities included race, income, population density, education, primary care providers per capita, smoking rates, mammography screening, diabetes monitoring, and Pap testing., Results: The missed opportunity rate ranged from 31% to 85% across Indiana counties. Higher population density, mammography screening, income inequality, and diabetes monitoring were associated with fewer missed opportunities., Conclusions: We found wide variability in missed opportunities across counties, which were associated with population density and county-level participation in other health-related behaviors., Sources of Support: This study was supported by the National Cancer Institute under Award Number P30 CA082709-18S4., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gregory Zimet received travel funding from Merck to present research at a scientific conference and received honoraria from Sanofi Pasteur and Merck for consultations related to adolescent vaccination. No other authors have any known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance., Methods: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed., Results: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS., Conclusion: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.

Further assessment of suspicious lesions found during asymptomatic breast cancer screening is critical and involves mammographic follow up with biopsy. The X-ray procedure is complex and variable in nature and until now there is little information on the radiation dose to the breast or associated risks. A survey of radiation doses from a Siemens MammoTest prone biopsy with the support of a Sectra L30 AIR mammographic unit for workup and post clip images has been completed. Procedure details and outcomes, including radiographic and patient related variables have been collected and analysed using standard dosimetric formulation. The partial irradiation of the breast in biopsy and magnification views was considered. The average mean glandular breast dose was 5.13 mGy, comprising of 3.52 mGy from the biopsy procedure and 1.61 mGy from the workup and post clip images, with an average of 8.4 biopsy images and 5.8 workup and post clip images. The risk from these dose levels are dependent on the age of the woman, however are not considered high for a symptomatic X-ray procedure.

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Steinfeld syndrome (MIM #184705) was first reported in 1982. It is characterised by holoprosencephaly and limb defects, however other anomalies may also be present. Following the initial description, three further cases have been reported in the literature. We report on a 23-year-old girl, with features of microform holoprosencephaly and bilateral congenital elbow dislocation in association with hypoplastic radial heads. She was identified to have a variant in the CDON gene inherited from her father who had ocular hypotelorism, but no other clinical features. We discuss the clinical features of Steinfeld syndrome, and broaden the phenotypic spectrum of this condition. Structural analysis suggests that this variant could lead to destabilisation of binding of CDON with hedgehog proteins. Further work needs to be done to confirm whether mutations in the CDON gene are the cause of Steinfeld syndrome., (© 2016 Wiley Periodicals, Inc.)

In the traditional osmorespiratory compromise, fish increase their effective gill permeability to O2 during exercise or hypoxia, and in consequence suffer unfavorable ionic and osmotic fluxes. However oscars, which live in the frequently hypoxic ion-poor waters of the Amazon, actually decrease ionic fluxes across the gills during acute hypoxia without changing gill paracellular permeability, and exhibit rapid paving over of the mitochondrial-rich cells (MRCs). But what happens during prolonged exercise? Gill paracellular permeability, ionic fluxes, and gill morphology were examined in juvenile oscars at rest and during aerobic swimming. Initial validation tests with urinary catheterized fish quantified drinking, glomerular filtration, and urinary flow rates, and confirmed that measurements of gill paracellular permeability as [(3)H]PEG-4000 clearances were the same in efflux and influx directions, but far lower than previously measured in comparably sized trout. Although the oscars achieved a very similar proportional increase (90%) in oxygen consumption (MO2) to trout during steady-state swimming at 1.2 body lengths sec(-1), there was no increase in gill paracellular permeability, in contrast to trout. However, oscars did exhibit increased unidirectional Na(+) efflux and net K(+) rates during exercise, but no change in drinking rate. There were no changes in MRC numbers or exposure, or other alterations in gill morphology during exercise. A substantial interlamellar cell mass (ILCM) that covered the lamellae to a depth of 30% was unchanged by 4 h of swimming activity. We conclude that a low branchial paracellular permeability which can be dissociated from changes in O2 flux, as well as the presence of the ILCM, may be adaptive in limiting ionoregulatory costs for a species endemic to ion-poor, frequently hypoxic waters.

In the traditional osmorespiratory compromise, as seen in the hypoxia-intolerant freshwater rainbow trout (Oncorhynchus mykiss), the branchial modifications that occur to improve O2 uptake during hypoxia result in unfavorable increases in the fluxes of ions and water. However, at least one hypoxia-tolerant freshwater species, the Amazonian oscar (Astronotus ocellatus), shows exactly the opposite: decreased branchial flux rates of ions, water, and nitrogenous wastes during acute hypoxia. In order to find out whether the two strategies were widespread, we used a standard 2-h normoxia, 2-h hypoxia (20%-30% saturation), 2-h normoxic recovery protocol to survey 10 other phylogenetically diverse tropical and temperate species. Unidirectional influx and efflux rates of Na(+) and net flux rates of K(+), ammonia, and urea-N were measured. The flux reduction strategy was seen only in one additional species, the Amazonian tambaqui (Colossoma macropomum), which is similarly hypoxia tolerant and lives in the same ion-poor waters as the oscar. However, five other species exhibited evidence of the increased flux rates typical of the traditional osmorespiratory compromise in the trout: the rosaceu tetra (Hyphessobrycon bentosi rosaceus), the moenkhausia tetra (Moenkhausia diktyota), the bluegill sunfish (Lepomis macrochirus), the zebra fish (Danio rerio), and the goldfish (Carassius auratus). Four other species exhibited no marked flux changes during hypoxia: the cardinal tetra (Paracheirodon axelrodi), the hemigrammus tetra (Hemigrammus rhodostomus), the pumpkinseed sunfish (Lepomis gibbosus), and the Atlantic killifish (Fundulus heteroclitus). Overall, a diversity of strategies exist; we speculate that these may be linked to differences in habitat and/or lifestyle.

Evidence for the presence of allatostatin (AST) A-like neuropeptides in the larval midge Chironomus riparius is reported. Immunohistochemical studies on the nervous system and gut revealed the presence of AST A-like immunoreactive (AST-IR) cells and processes. The nerve cord contained AST-IR processes that originated from cells in the brain and travelled the length of nerve cord to the terminal ganglion. Within each ganglion, these processes gave rise to varicosities, suggesting that they formed synapses with neurons in the ganglia. Endocrine cells containing AST-IR were present in three regions of the midgut: near the attachment of the Malpighian tubules, between the anterior and posterior midgut, and in the vicinity of the gastric caecae. The terminal ganglion also contained four AST-IR cells that gave rise to axons that projected onto the hindgut and posterior midgut. Application of a cockroach AST to the semi-isolated hindgut of larval C. riparius led to dose-dependent inhibition of muscle contractions with an EC50 of ~10 nmol l(-1) and a decrease in rectal K(+) reabsorption resulting from reduced rectal Na(+)/K(+)-ATPase and vacuolar type H(+)-ATPase activities. The results suggest the presence of endogenous AST-like neuropeptides in larval C. riparius, where these factors play a role in the function of the gut. Furthermore, regulation of ion reabsorption by ASTs at the rectum could serve as an ideal mechanism of ion regulation in the face of abrupt and acute elevated salt levels., (© 2014. Published by The Company of Biologists Ltd.)

Mechanisms of Na(+) uptake, ammonia excretion, and their potential linkage were investigated in three characids (cardinal, hemigrammus, moenkhausia tetras), using radiotracer flux techniques to study the unidirectional influx (J in), efflux (J out), and net flux rates (J net) of Na(+) and Cl(-), and the net excretion rate of ammonia (J Amm). The fish were collected directly from the Rio Negro, and studied in their native "blackwater" which is acidic (pH 4.5), ion-poor (Na(+), Cl(-) ~20 µM), and rich in dissolved organic matter (DOM 11.5 mg C l(-1)). J in (Na) , J in (Cl) , and J Amm were higher than in previous reports on tetras obtained from the North America aquarium trade and/or studied in low DOM water. In all three species, J in (Na) was unaffected by amiloride (10(-4) M, NHE and Na(+) channel blocker), but both J in (Na) and J in (Cl) were virtually eliminated (85-99 % blockade) by AgNO3 (10(-7) M). A time course study on cardinal tetras demonstrated that J in (Na) blockade by AgNO3 was very rapid (<5 min), suggesting inhibition of branchial carbonic anhydrase (CA), and exposure to the CA-blocker acetazolamide (10(-4) M) caused a 50 % reduction in J in (Na) .. Additionally, J in (Na) was unaffected by phenamil (10(-5) M, Na(+) channel blocker), bumetanide (10(-4) M, NKCC blocker), hydrochlorothiazide (5 × 10(-3) M, NCC blocker), and exposure to an acute 3 unit increase in water pH. None of these treatments, including partial or complete elimination of J in (Na) (by acetazolamide and AgNO3 respectively), had any inhibitory effect on J Amm. Therefore, Na(+) uptake in Rio Negro tetras depends on an internal supply of H(+) from CA, but does not fit any of the currently accepted H(+)-dependent models (NHE, Na(+) channel/V-type H(+)-ATPase), or co-transport schemes (NCC, NKCC), and ammonia excretion does not fit the current "Na(+)/NH4 (+) exchange metabolon" paradigm. Na(+), K(+)-ATPase and V-type H(+)-ATPase activities were present at similar levels in gill homogenates, Acute exposure to high environmental ammonia (NH4Cl, 10(-3) M) significantly increased J in (Na) , and NH4 (+) was equally or more effective than K(+) in activating branchial Na(+),(K(+)) ATPase activity in vitro. We propose that ammonia excretion does not depend on Na(+) uptake, but that Na(+) uptake (by an as yet unknown H(+)-dependent apical mechanism) depends on ammonia excretion, driven by active NH4 (+) entry via basolateral Na(+),(K(+))-ATPase.

The scanning ion-selective electrode technique (SIET) was utilized for the first time in Locusta migratoria to characterize K(+) transport along the digestive tract and to determine the effect of two locust FGLamide allatostatins (FGLa/ASTs) on K(+) transport: a previously sequenced FGLa/AST from Schistocerca gregaria (Scg-AST-6; ARPYSFGL-NH2) and a newly sequenced FGLa/AST from L. migratoria (Locmi-FGLa/AST-2; LPVYNFGL-NH2). Regional differences in K(+) fluxes along the gut were evident, where K(+) efflux in vitro (or absorption into the hemolymph in vivo) was greatest at the anterior ileum, and lowest at the colon. Ileal K(+) efflux was inhibited by both Scg-AST-6 and Locmi-FGLa/AST-2, with maximal inhibition at 10(-10) and 10(-11) mol l(-1), respectively. Both FGLa/ASTs also inhibited cAMP-stimulated K(+) efflux from the ileum. Locmi-FGLa/AST-2 also inhibited efflux of water across the ileum. Locusts are terrestrial insects living in dry climates, risking desiccation and making water conservation a necessity. The results suggest that FGLa/ASTs may be acting as diuretics by increasing K(+) excretion and therefore increasing water excretion. Thus it is likely that FGLa/ASTs are involved in the control of hemolymph water and ion levels during feeding and digestion, to help the locust deal with the excess K(+) load (and subsequently fluid) when the meal is processed., (© 2014. Published by The Company of Biologists Ltd.)

Context: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2σ 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3., Objective: The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3., Design: The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1., Results: Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients., Conclusion: The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.

Genetic causes of steroid-resistant nephrotic syndrome are being increasingly recognized. Mutations in NPHS2, which encodes the glomerular protein podocin, account for up to 17% of sporadic and 40% of familial cases, where they display an autosomal-recessive pattern of inheritance. This report describes a non-consanguineous family with three generations of individuals who are either compound heterozygotes for mutations in NPHS2 or who have inherited a mutation and a non-neutral polymorphism (R229Q). As well as providing an aetiological explanation, identifying pathogenic mutations and considering genotype-phenotype correlations can provide prognostic information and lead to changes in genetic counselling and management.

The influence of swimming activity on gill paracellular permeability has not been measured previously in fishes. We critically assessed the use of tritium-labeled polyethylene glycol ([(3)H]PEG-4000) for this purpose, a substance that is also a classic marker for extracellular fluid volume, glomerular filtration rate and drinking rate. Tests (8 h) on resting freshwater trout showed that when measuring [(3)H]PEG-4000 clearance from the plasma in the efflux direction, correction for a large excretion via glomerular filtration was essential, necessitating urinary catheterization. When measuring [(3)H]PEG-4000 clearance from the water in the influx direction, correction for a significant uptake by drinking was essential, necessitating terminal gut removal, whereas glomerular filtration losses were minimal. After correction for these alternate routes of loss and uptake, [(3)H]PEG-4000 clearance rates by efflux from the plasma and by influx from the water were identical, showing that gill paracellular permeability is not rectified, and can be measured in either direction. The influx technique with terminal gut removal was used to assess gill paracellular permeability in trout without urinary catheters freely swimming at 1.2 body lengths s(-1) for 8 h. Branchial [(3)H]PEG-4000 clearance rate (by influx from the water) increased significantly by ~80% in accord with a similar measured increase in O2 consumption rate. Thus in trout, gill paracellular permeability does increase during exercise, in accord with the traditional concept of the osmorespiratory compromise.

We report two families with a variable presentation in association with a KRIT1 mutation. The index patient in Family 1 was a 9-year old girl who presented with left hemi-dystonia and a cerebral cavernous malformation was identified in the right lentiform nucleus. The maternal grandmother presented with a spinal cavernoma, which was operated at 35-years of age. The mother presented with intractable temporal lobe epilepsy in childhood and underwent temporal lobe resection at 27-years of age. The second family has also presented variably with the youngest member of this family presenting with generalised tonic-clonic seizures at 18-months of age. We report both these families with variable presentation of an autosomal dominant condition and describe the phenotypic presentation in both these families in further detail and review the published literature on this condition., (Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

17α-ethynylestradiol (EE2) is a synthetic estrogen that is an endocrine disruptive toxicant in aquatic environments. The aim of this study was to determine whether metabolic rate influenced EE2 uptake in male killifish (Fundulus heteroclitus), based on the hypothesis that the mechanism of EE2 uptake at the gills is similar to that of oxygen. F. heteroclitus were exposed to 100 ng/L radiolabeled [³H]EE2 for 2 h while swimming at 0, 15, and 40 cm/s. A positive linear correlation between the rates of oxygen consumption (MO₂) and EE2 accumulation was seen (r² = 0.99, p<0.01), with more EE2 taken up at higher swimming speeds, suggesting that oxygen uptake predicts EE2 uptake. EE2 tended to accumulate in the liver (where lipophilic toxicants are metabolized), the gall bladder (where metabolized toxicants enter bile), and the gut (where bile is received). In a subsequent experiment killifish were exposed to both hypoxic and hyperoxic conditions (PO₂=70-80 Torr, and PO₂=400-500 Torr respectively). Despite significant decreases in MO₂ during hypoxia, EE2 uptake rates increased only slightly with hypoxia, but in individual fish there was still a significant correlation between MO₂ and EE2 uptake. This correlation was lost during hyperoxia, and EE2 uptake rates did not change significantly in hyperoxia. Marked influences of salinity on EE2 uptake rate occurred regardless of the oxygen condition, with higher uptake rates in 50% seawater than in freshwater or 100% seawater. Tissue distribution of EE2 in these exposures may have been influenced by changes in tissue blood flow patterns and oxygen supply. These data will be useful in eventually constructing a predictive model to manage the optimal timing for discharge of EE2 from sewage treatment plants into receiving waters., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The regulation of insect gut physiology is complex and involves the interactions of a number of mechanisms, including the neural regulation of gut contraction by altering neural input and the modulation of gut contractions by neuropeptides directly affecting the muscle. The FGLa-type allatostatins (FGLa/ASTs) are known brain/gut peptides with numerous physiological roles, including modulation of gut contraction and neural input. To further investigate the pleiotropic roles of FGLa/AST peptides in Locusta migratoria, we have examined the role of a locust FGLa/AST (Scg-AST-6) in the gut. Proctolin and Scg-AST-6 have opposing effects on gut contraction, where proctolin dose-dependently increases gut muscle tension, while Scg-AST-6 inhibits both muscle tension and spontaneous and neurogenic contractions in a dose-dependent manner. Results from neurophysiological recordings indicate that there may be a central pattern generator (CPG) within the ventricular ganglia regulated by descending inhibition, and the addition of Scg-AST-6 dose-dependently modulates this ventricular ganglion CPG. This work provides a comprehensive picture of how FGLa/ASTs may modulate and coordinate each region of the locust gut, and shows that FGLa/ASTs have both central effects, on the ventricular ganglion CPG, and peripheral effects on the gut muscle. Overall, this study shows how FGLa/ASTs contribute to the complex regulation and fine tuning of gut contraction.

Background: The clinical presentation of Juvenile Huntington's Disease (JHD) can be very different from adult-onset HD with little evidence to guide symptomatic management., Aim: To survey the current use of pharmacological treatments for JHD., Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntington's Disease Network REGISTRY study., Results: The most commonly prescribed agents were anti-psychotics (24/45), anti-depressants (17/45) and anti-parkinsonian medications (15/45). 5 patients were taking more than 8 medications., Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple therapies, highlighting the need to rationalise medications.

Summary Background: The clinical presentation of Juvenile Huntington's Disease (JHD) can be very different from adult-onset HD with little evidence to guide symptomatic management., Aim: To survey the current use of pharmacological treatments for JHD., Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntington's Disease Network REGISTRY study., Results: The most commonly prescribed agents were anti-psychotics (24/45), anti-depressants (17/45) and anti-parkinsonian medications (15/45). 5 patients were taking more than 8 medications., Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple therapies, highlighting the need to rationalise medications.

Background: The clinical presentation of Juvenile Huntington's Disease (JHD) can be very different from adult-onset HD with little evidence to guide symptomatic management., Aim: To survey the current use of pharmacological treatments for JHD., Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntington's Disease Network REGISTRY study., Results: The most commonly prescribed agents were anti-psychotics (24/45), anti-depressants (17/45) and anti-parkinsonian medications (15/45). 5 patients were taking more than 8 medications., Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple therapies, highlighting the need to rationalise medications.

Allatostatin-like immunoreactivity (ALI) is widely distributed in processes and varicosities on the fore-, mid-, and hindgut of the locust, and within midgut open-type endocrine-like cells. ALI is also observed in cells and processes in all ganglia of the central nervous system (CNS) and the stomatogastric nervous system (SNS). Ventral unpaired median neurons (VUMs) contained ALI within abdominal ganglia IV-VII. Neurobiotin retrograde fills of the branches of the 11th sternal nerve that innervate the hindgut revealed 2-4 VUMs in abdominal ganglia IV-VIIth, which also contain ALI. The VIIIth abdominal ganglion contained three ventral medial groups of neurons that filled with neurobiotin and contained ALI. The co-localization of ALI in the identified neurons suggests that these cells are the source of ALI on the hindgut. A retrograde fill of the nerves of the ingluvial ganglia that innervate the foregut revealed numerous neurons within the frontal ganglion and an extensive neuropile in the hypocerebral ganglion, but there seems to be no apparent co-localization of neurobiotin and ALI in these neurons, indicating the source of ALI on the foregut comes via the brain, through the SNS., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

The etiology of mental retardation remains elusive in the majority of cases. Microdeletions within chromosomal bands 5q14.3q15 were recently identified as a recurrent cause of severe mental retardation, epilepsy, muscular hypotonia, and variable minor anomalies. By molecular karyotyping we identified two novel 2.4- and 1.5-Mb microdeletions of this region in patients with a similar phenotype. Both deletions contained the MEF2C gene, which is located proximally to the previously defined smallest region of overlap. Nevertheless, due to its known role in neurogenesis, we considered MEF2C as a phenocritical candidate gene for the 5q14.3q15 microdeletion phenotype. We therefore performed mutational analysis in 362 patients with severe mental retardation and found two truncating and two missense de novo mutations in MEF2C, establishing defects in this transcription factor as a novel relatively frequent autosomal dominant cause of severe mental retardation accounting for as much as 1.1% of patients. In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. We therefore conclude that the phenotypic overlap of patients with MEF2C mutations and atypical Rett syndrome is due to the involvement of a common pathway.

Though initially identified as necessary for neural migration, Disconnected and its partially redundant paralog, Disco-related, are required for proper head segment identity during Drosophila embryogenesis. Here, we present evidence that these genes are also required for proper ventral appendage development during development of the adult fly, where they specify medial to distal appendage development. Cells lacking the disco genes cannot contribute to the medial and distal portions of ventral appendages. Further, ectopic disco transforms dorsal appendages toward ventral fates; in wing discs, the medial and distal leg development pathways are activated. Interestingly, this appendage role is conserved in the red flour beetle, Tribolium (where legs develop during embryogenesis), yet in the beetle we found no evidence for a head segmentation role. The lack of an embryonic head specification role in Tribolium could be interpreted as a loss of the head segmentation function in Tribolium or gain of this function during evolution of flies. However, we suggest an alternative explanation. We propose that the disco genes always function as appendage factors, but their appendage nature is masked during Drosophila embryogenesis due to the reduction of limb fields in the maggot style Drosophila larva.

During animal development, the HOM-C/HOX proteins direct axial patterning by regulating region-specific expression of downstream target genes. Though much is known about these pathways, significant questions remain regarding the mechanisms of specific target gene recognition and regulation, and the role of co-factors. From our studies of the gnathal and trunk-specification proteins Disconnected (DISCO) and Teashirt (TSH), respectively, we present evidence for a network of zinc-finger transcription factors that regionalize the Drosophila embryo. Not only do these proteins establish specific regions within the embryo, but their distribution also establishes where specific HOM-C proteins can function. In this manner, these factors function in parallel to the HOM-C proteins during axial specification. We also show that in tsh mutants, disco is expressed in the trunk segments, probably explaining the partial trunk to head transformation reported in these mutants, but more importantly demonstrating interactions between members of this regionalization network. We conclude that a combination of regionalizing factors, in concert with the HOM-C proteins, promotes the specification of individual segment identity.