ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy.

Typical Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Genetic analysis of 85 unrelated "mutation negative" probands with Martsolf or Martsolf-like syndromes identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). Both probands were from multiplex families with a consistent, lethal and highly distinctive disorder; a Martsolf-like syndrome with infantile-onset dilated cardiomyopathy. Severe ITPase-deficiency has been previously reported with infantile epileptic encephalopathy (MIM 616647). ITPase acts to prevent incorporation of inosine bases (rI/dI) into RNA and DNA. In Itpa-null cells dI was undetectable in genomic DNA. dI could be identified at a low level in mtDNA without detectable mitochondrial genome instability, mtDNA depletion or biochemical dysfunction of the mitochondria. rI accumulation was detectable in proband-derived lymphoblastoid RNA. In Itpa-null mouse embryos rI was detectable in the brain and kidney with the highest level seen in the embryonic heart (rI at 1 in 385 bases). Transcriptome and proteome analysis in mutant cells revealed no major differences with controls. The rate of transcription and the total amount of cellular RNA also appeared normal. rI accumulation in RNA-and by implication rI production-correlates with the severity of organ dysfunction in ITPase deficiency but the basis of the cellulopathy remains cryptic. While we cannot exclude cumulative minor effects, there are no major anomalies in the production, processing, stability and/or translation of mRNA.

Prototype Development of a Temperature-Sensitive High-Adhesion Medical Tape to Reduce Medical-Adhesive-Related Skin Injury and Improve Quality of Care.

Medical adhesives are used to secure wound care dressings and other critical devices to the skin. Without means of safe removal, these stronger adhesives are difficult to painlessly remove from the skin and may cause medical-adhesive-related skin injuries (MARSI), including skin tears and an increased risk of infection. Lower-adhesion medical tapes may be applied to avoid MARSI, leading to device dislodgement and further medical complications. This paper outlines the development of a high-adhesion medical tape designed for low skin trauma upon release. By warming the skin-attached tape for 10-30 s, a significant loss in adhesion was achieved. A C14/C18 copolymer was developed and combined with a selected pressure-sensitive adhesive (PSA) material. The addition of 1% C14/C18 copolymer yielded the largest temperature-responsive drop in surface adhesion. The adhesive film was characterized using AFM, and distinct nanodomains were identified on the exterior surface of the PSA. Our optimized formulation yielded 67% drop in adhesion when warmed to 45 °C, perhaps due to melting nanodomains weakening the adhesive-substrate boundary layer. Pilot clinical testing resulted in a significant decrease in pain when a heat pack was used for removal, giving an average pain reduction of 66%.

The absence of the catalytic domains of Saccharomyces cerevisiae DNA polymerase ϵ strongly reduces DNA replication fidelity.

The four B-family DNA polymerases α, δ, ϵ and ζ cooperate to accurately replicate the eukaryotic nuclear genome. Here, we report that a Saccharomyces cerevisiae strain encoding the pol2-16 mutation that lacks Pol ϵ's polymerase and exonuclease activities has increased dNTP concentrations and an increased mutation rate at the CAN1 locus compared to wild type yeast. About half of this mutagenesis disappears upon deleting the REV3 gene encoding the catalytic subunit of Pol ζ. The remaining, still strong, mutator phenotype is synergistically elevated in an msh6Δ strain and has a mutation spectrum characteristic of mistakes made by Pol δ. The results support a model wherein slow-moving replication forks caused by the lack of Pol ϵ's catalytic domains result in greater involvement of mutagenic DNA synthesis by Pol ζ as well as diminished proofreading by Pol δ during replication.

Severity of Overuse Injury Impacts Self-Efficacy and Quality of Life in Runners: A 2-Year Prospective Cohort Study.

CONTEXT: While 55 million Americans incorporate running into their exercise routines, up to 65% of runners sustain an overuse injury annually. It has been consistently shown that regular physical activity positively impacts quality of life (QOL), an essential public health indicator; however, the impact of running-related injuries on QOL is unknown. This study seeks to determine whether overuse injury severity impacts QOL in recreational runners, and if self-efficacy mediates this relationship. DESIGN: Community-based prospective cohort study of 300 runners who had been running injury free for at least 5 miles/wk in the past 6 months. METHODS: Self-efficacy for running and QOL measures (Short Form-12 Physical Component and Mental Component, Satisfaction with Life, Positive Affect and Negative Affect) were assessed at baseline, time of injury, and follow-up visits. Over 2 years of observation, overuse injuries were diagnosed by an orthopedic surgeon and injured runners were referred to a physical therapist. RESULTS: Injury severity was significantly (P < .01) related with 2 indices of QOL, such that the effect of injury severity was -2.28 units on the Short Form-12 physical component and -0.73 units on positive affect. Self-efficacy accounted for 19% and 48% of the indirect effects on Short Form-12 physical component and positive affect, respectively. CONCLUSIONS: Since self-efficacy is a modifiable factor related to decreased QOL, these findings have important clinical implications for rehabilitation interventions.

A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene.

Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.

Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved. In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome. In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance. The paternally transmitted variant predicted a premature stop mutation (c.2386C>T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G>A; p.D1854N) at a conserved residue within the catalytic domain. Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity. Our results emphasize the importance of phosphoinositide signalling in early brain development.

Functional Scanning Probe Imaging of Nanostructured Solar Energy Materials.

From hybrid perovskites to semiconducting polymer/fullerene blends for organic photovoltaics, many new materials being explored for energy harvesting and storage exhibit performance characteristics that depend sensitively on their nanoscale morphology. At the same time, rapid advances in the capability and accessibility of scanning probe microscopy methods over the past decade have made it possible to study processing/structure/function relationships ranging from photocurrent collection to photocarrier lifetimes with resolutions on the scale of tens of nanometers or better. Importantly, such scanning probe methods offer the potential to combine measurements of local structure with local function, and they can be implemented to study materials in situ or devices in operando to better understand how materials evolve in time in response to an external stimulus or environmental perturbation. This Account highlights recent advances in the development and application of scanning probe microscopy methods that can help address such questions while filling key gaps between the capabilities of conventional electron microscopy and newer super-resolution optical methods. Focusing on semiconductor materials for solar energy applications, we highlight a range of electrical and optoelectronic scanning probe microscopy methods that exploit the local dynamics of an atomic force microscope tip to probe key properties of the solar cell material or device structure. We discuss how it is possible to extract relevant device properties using noncontact scanning probe methods as well as how these properties guide materials development. Specifically, we discuss intensity-modulated scanning Kelvin probe microscopy (IM-SKPM), time-resolved electrostatic force microscopy (trEFM), frequency-modulated electrostatic force microscopy (FM-EFM), and cantilever ringdown imaging. We explain these developments in the context of classic atomic force microscopy (AFM) methods that exploit the physics of cantilever motion and photocarrier generation to provide robust, nanoscale measurements of materials physics that are correlated with device operation. We predict that the multidimensional data sets made possible by these types of methods will become increasingly important as advances in data science expand capabilities and opportunities for image correlation and discovery.

Mixing Temperatures of Bilayers Not Simply Related to Thickness Differences between Lo and Ld Phases.

Micron-scale coexisting Lo and Ld liquid phases can appear in lipid bilayers composed of a ternary mixture of a low-melting temperature lipid, a high-melting temperature lipid, and cholesterol. A priori, temperatures at which membranes demix, Tmix, are not simply related to differences in thicknesses, Δh, between Lo and Ld phases. Here, we use fluorescence microscopy to measure Tmix and we use atomic force microscopy at 22°C to measure Δh for a series of bilayers composed of different ratios of the three components. Our data illustrate cases in which a change in Tmix or Δh does not result in a change in the other parameter. The data provide a context in which to evaluate recent reports of a correlation between Tmix and Δh.

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.

Buprenorphine.

In the crystal structure of a semi-synthetic opioid drug buprenorphine, C29H41NO4 {systematic name: (2S)-2-[(5R,6R,7R,14S)-9α-cyclo-propyl-methyl-3-hy-droxy-6-meth-oxy-4,5-ep-oxy-6,14-ethano-morphinan-7-yl]-3,3-di-methyl-butan-2-ol}, the cyclo-propyl-methyl group is disordered over two sites with an occupancy factor of 0.611 (3) for the major component. One of the hy-droxy groups is involved in intra-molecular O-H⋯O hydrogen bond. The other hy-droxy group acts as a proton donor in an inter-molecular O-H⋯O inter-action that connects mol-ecules into a zigzag chain along the b axis.

A pilot study on the utility of a more informative living will.

Most written advance directives are designed to help people prescribe the care they would desire at the very end of their life. They provide little guidance for elderly patients with potentially treatable diseases who may be temporarily incapacitated and thus unable to articulate their wishes. The authors developed an alternative living will format with the intent of better documenting the care wishes of this population. A convenience survey of patients, surrogates and physicians compared the pilot version with the commonly available West Virginia Living Will to determine whether the pilot version was able to provide clearer direction for health care providers and surrogate decision makers. The majority of respondents indicated the pilot version better met their needs when compared to the commonly utilized version. This study suggests there is a need for an alternative living will that addresses the needs of those not at the very end of their life.

Living with type 2 diabetes: A social cognitive perspective on adherence.

OBJECTIVE: This mixed methods study examines the relationship between outcome expectations, self-efficacy, and self-care behaviors in individuals with type 2 diabetes (T2DM). It also explores the personal values motivating these behaviors through in-depth interviews. METHODS: Adults with T2DM (n = 108, M age = 57 years, 58% female, 48% Black) completed questionnaires and participated in in-depth interviews using a laddering technique. RESULTS: Ordinary least squares regression models were used to analyze the relationships between self-efficacy, outcome expectations, and four self-care behaviors (physical activity, dietary choices, blood glucose monitoring, and medication usage). The findings indicate that self-efficacy is significantly and positively associated with diet and physical activity. Both outcome expectations for blood glucose testing and self-efficacy are significantly and positively associated with self-reported monitoring. However, neither outcome expectation nor self-efficacy is associated with medication usage. The in-depth interviews revealed three common values related to self-care behaviors: maintaining health and longevity, agentic values of self-control, achievement, and self-esteem, and a sense of belonging. CONCLUSIONS: This study sheds light on the complexity of diabetes self-management, offering insights into individuals' values, behavioral strategies, and the influence of control perceptions on this relationship, revealing both differences and commonalities in stated values. PRACTICE IMPLICATIONS: By understanding how personal values drive diabetes self-care behaviors, practitioners can assist patients in establishing meaningful connections between their values and the challenges of living with diabetes.

Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome).

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome, is an autosomal-recessively inherited prenatal lethal disorder characterized by hydranencephaly; brain stem, basal ganglia, and spinal cord diffuse clastic ischemic lesions with calcifications; glomeruloid vasculopathy of the central nervous system and retinal vessels; and a fetal akinesia deformation sequence (FADS) with muscular neurogenic atrophy. To identify the molecular basis for Fowler syndrome, we performed autozygosity mapping studies in three consanguineous families. The results of SNP microarrays and microsatellite marker genotyping demonstrated linkage to chromosome 14q24.3. Direct sequencing of candidate genes within the target interval revealed five different germline mutations in FLVCR2 in five families with Fowler syndrome. FLVCR2 encodes a transmembrane transporter of the major facilitator superfamily (MFS) hypothesized to be involved in regulation of growth, calcium exchange, and homeostasis. This is the first gene to be associated with Fowler syndrome, and this finding provides a basis for further studies to elucidate the pathogenetic mechanisms and phenotypic spectrum of associated disorders.

Mutations in GRIP1 cause Fraser syndrome.

BACKGROUND: Fraser syndrome (FS) is a autosomal recessive malformation syndrome characterised by cryptophthalmos, syndactyly and urogenital defects. FS is a genetically heterogeneous condition. Thus far, mutations in FRAS1 and FREM2 have been identified as cause of FS. Both FRAS1 and FREM2 encode extracellular matrix proteins that are essential for the adhesion between epidermal basement membrane and the underlying dermal connective tissues during embryonic development. Mutations in murine Grip1, which encodes a scaffolding protein that interacts with Fras1/Frem proteins, result in FS-like defects in mice. OBJECTIVE: To test GRIP1 for genetic variants in FS families that do not have mutations in FRAS1 and FREM2. METHODS AND RESULTS: In three unrelated families with parental consanguinity, GRIP1 mutations were found to segregate with the disease in an autosomal recessive manner (donor splice site mutation NM_021150.3:c.2113+1G→C in two families and a 4-bp deletion, NM_021150.3:c.1181_1184del in the third). RT-PCR analysis of the GRIP1 mRNA showed that the c.2113+1G→C splice mutation causes skipping of exon 17, leading to a frame shift and a premature stop of translation. CONCLUSION: Mutations in GRIP1 cause classic FS in humans.

Urinothorax: a rare cause of pleural effusion.

There are many benign causes of pleural effusions that can be followed expectantly. This case report will detail a rare cause of pleural effusion. The evaluation of this patient led to a diagnosis of urinothorax. This case will highlight the importance of a thorough history and physical, as well as diagnostic evaluation of effusions of unknown etiology. With the increasing number of urological procedures being performed, it will likely become a more frequent finding.

Fowler syndrome-a clinical, radiological, and pathological study of 14 cases.

We report on 14 fetuses from 10 families with the autosomal recessive syndrome of proliferative vasculopathy and hydranencephaly-hydrocephaly (Fowler syndrome). In four families sibs were affected and in six the parents were consanguineous. Antenatal ultrasonography showed hydrocephaly in all except two fetuses, but hydranencephaly was diagnosed in only one case. Postural abnormalities were seen in 10 fetuses and structural brain abnormalities were suspected in 3. At autopsy the cerebral cortex appeared as a translucent membranous structure (hydranencephaly) in most fetuses. However, in one case, the ventricles were dilated but the cortical mantle was relatively well preserved. Histology of the brain showed the characteristic glomeruloid vascular proliferation of Fowler syndrome in all cases, but with variable extent of involvement of the central nervous system. Dystrophic calcification and necrosis were always present. Extra-cranial anomalies included micrognathia (10 fetuses), cleft palate (1 fetus), cystic hygroma (2 fetuses), joint contractures (12 fetuses), and pterygia (11 fetuses). The typical proliferative vasculopathy was never observed outside the central nervous system and karyotypes were normal in the 10 fetuses studied. Fowler syndrome should be considered in the differential diagnosis of lethal multiple pterygium syndrome, fetal akinesia, and hydrocephalus in addition to classical hydranencephaly. Autopsy and study of the brain are essential to differentiate autosomal recessive Fowler syndrome from other causes of hydrocephaly and hydranencephaly, which may have a lower recurrence risk.

Mosaic trisomy 1q: The longest surviving case.

We present the longest known surviving case of a male infant with a mosaic complete trisomy 1q. Born at 39 weeks of gestation with respiratory distress, his weight was 3,330 g (25th centile); he had micrognathia, a posterior cleft of palate, abnormal ears and left thumb, syndactyly, and an absent corpus callosum. Initial blood karyotype was normal (46,XY). He died at age 5 months. Autopsy suggested aspiration as the primary cause of death and confirmed the antemortem findings of an absent corpus callosum and atrial septal defect. It also identified some central nervous system, cardiac, gastrointestinal, and lung anomalies not previously recognized. Cytogenetic analysis of skin fibroblasts obtained at autopsy showed a de novo unbalanced translocation between chromosomes 1 and 22: 46,XY,+1,der(1;22)(q10;q10)[25]/46,XY[65] in the cells examined. The previously reported cases had a similar phenotype with birth weight above the 50th centile for gestational age, small mouth, micrognathia, abnormal ears, abnormal fingers, microphthalmia, and hydrocephalus. The present case and a review of the literature delineates the phenotype in trisomy 1q, and reinforces the critical importance of effective communication between specialists, and obtaining permission for autopsy and skin biopsy, in the pursuit of a diagnosis.

Reversed twin-to-twin transfusion syndrome following successful laser therapy.

We report a case of severe twin-to-twin transfusion syndrome (TTTS) in which fetoscopic laser ablation was successfully performed at 21 weeks' gestation. Despite successful resolution of signs on ultrasound examination after a period of 7 weeks, the donor developed polyhydramnios whereas the 'initial' recipient maintained normal liquor volume, features suggestive of 'reversed TTTS'. Two live babies were delivered at 31 weeks' gestation with good neonatal outcome. The karyotype of both babies was normal. No significant inter-twin difference in umbilical vein haemoglobin levels was present at delivery and placental injection studies did not identify persistent anastomoses. This case report supports the importance of close monitoring of the pregnancy following apparently successful laser therapy. Further research is needed to understand the pathophysiology of this condition.