Cdk12 maintains the integrity of adult axons by suppressing actin remodeling.

The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated neurons where its conical role in the cell cycle progression is redundant. We find that in adult neurons Cdk12 acts a negative regulator of actin formation, mitochondrial dynamics and neuronal physiology. Cdk12 maintains the size of the axon at sites proximal to the cell body through the transcription of homeostatic enzymes in the 1-carbon by folate pathway which utilize the amino acid homocysteine. Loss of Cdk12 leads to elevated homocysteine and in turn leads to uncontrolled F-actin formation and axonal swelling. Actin remodeling further induces Drp1-dependent fission of mitochondria and the breakdown of axon-soma filtration barrier allowing soma restricted cargos to enter the axon. We demonstrate that Cdk12 is also an essential gene for long-term neuronal survival and loss of this gene causes age-dependent neurodegeneration. Hyperhomocysteinemia, actin changes, and mitochondrial fragmentation are associated with several neurodegenerative conditions such as Alzheimer's disease and we provide a candidate molecular pathway to link together such pathological events.

Incidence of healthcare-associated infections in patients with fever during the first 48 hours after decannulation from veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: Fevers following decannulation from veno-venous extracorporeal membrane oxygenation often trigger an infectious workup; however, the yield of this workup is unknown. We investigated the incidence of post-veno-venous extracorporeal membrane oxygenation decannulation fever as well as the incidence and nature of healthcare-associated infections in this population within 48 hours of decannulation. METHODS: All patients treated with veno-venous extracorporeal membrane oxygenation for acute respiratory failure who survived to decannulation between August 2014 and November 2018 were retrospectively reviewed. Trauma patients and bridge to lung transplant patients were excluded. The highest temperature and maximum white blood cell count in the 24 hours preceding and the 48 hours following decannulation were obtained. All culture data obtained in the 48 hours following decannulation were reviewed. Healthcare-associated infections included blood stream infections, ventilator-associated pneumonia, and urinary tract infections. RESULTS: A total of 143 patients survived to decannulation from veno-venous extracorporeal membrane oxygenation and were included in the study. In total, 73 patients (51%) were febrile in the 48 hours following decannulation. Among this cohort, seven healthcare-associated infections were found, including five urinary tract infections, one blood stream infection, and one ventilator-associated pneumonia. In the afebrile cohort (70 patients), four healthcare-associated infections were found, including one catheter-associated urinary tract infection, two blood stream infections, and one ventilator-associated pneumonia. In all decannulated patients, the majority of healthcare-associated infections were urinary tract infections (55%). No central line-associated blood stream infections were identified in either cohort. When comparing febrile to non-febrile cohorts, there was a significant difference between pre- and post-decannulation highest temperature (p < 0.001) but not maximum white blood cell count (p = 0.66 and p = 0.714) between the two groups. Among all positive culture data, the most commonly isolated organism was Klebsiella pneumoniae (41.7%) followed by Escherichia coli (33%). Median hospital length of stay and time on extracorporeal membrane oxygenation were shorter in the afebrile group compared to the febrile group; however, this did not reach a statistical difference. CONCLUSION: Fever is common in the 48 hours following decannulation from veno-venous extracorporeal membrane oxygenation. Differentiating infection from non-infectious fever in the post-decannulation veno-venous extracorporeal membrane oxygenation population remains challenging. In our febrile post-decannulation cohort, the incidence of healthcare-associated infections was low. The majority were diagnosed with a urinary tract infection. We believe obtaining cultures in febrile patients in the immediate decannulation period from veno-venous extracorporeal membrane oxygenation has utility, and even in the absence of other clinical suspicion, should be considered. However, based on our data, a urinalysis and urine culture may be sufficient as an initial work up to identify the source of infection.

MLC901 (NeuroAiD II™) for cognition after traumatic brain injury: a pilot randomized clinical trial.

BACKGROUND AND PURPOSE: Treatments to facilitate recovery after traumatic brain injury (TBI) are urgently needed. We conducted a 9-month pilot, randomized placebo-controlled clinical trial to examine the safety and potential effects of the herbal supplement MLC901 (NeuroAiD II™) on cognitive functioning following TBI. METHODS: Adults aged 18-65 years at 1-12 months after mild or moderate TBI were randomized to receive MLC901 (0.8 g capsules 3 times daily) or placebo for 6 months. The primary outcome was cognitive functioning as assessed by the CNS Vital Signs online neuropsychological test. Secondary outcomes included the Cognitive Failures Questionnaire, the Rivermead Post-concussion Symptom Questionnaire (neurobehavioral sequelae), Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale, Modified Fatigue Impact Scale and extended Glasgow Outcome Scale (physical disability). Assessments were completed at baseline and at 3-, 6- and 9-month follow-up. Linear mixed-effects models were conducted, with the primary outcome time-point of 6 months. RESULTS: A total of 78 participants [mean age 37.5 ± 14.8 years, 39 (50%) female] were included in the analysis. Baseline variables were similar between groups (treatment group, n = 36; control group, n = 42). Linear mixed-effects models controlling for time, group allocation, repeated measurements, adherence and baseline assessment scores revealed significant improvements in complex attention (P = 0.04, d = 0.6) and executive functioning (P = 0.04, d = 0.4) at 6 months in the MLC901 group compared with controls. There were no significant differences between the groups for neurobehavioral sequelae, mood, fatigue, physical disability or overall quality of life at 6 months. No serious adverse events were reported. CONCLUSIONS: MLC901 was safe and well tolerated post-TBI. This study provided Class I/II evidence that, for patients with mild to moderate TBI, 6 months of MLC901 improved cognitive functioning.

Pathogenesis of Frog Virus 3 ( Ranavirus, Iridoviridae) Infection in Wood Frogs ( Rana sylvatica).

Wood frogs ( Rana sylvatica) are highly susceptible to infection with Frog virus 3 (FV3, Ranavirus, Iridoviridae), a cause of mass mortality in wild populations. To elucidate the pathogenesis of FV3 infection in wood frogs, 40 wild-caught adults were acclimated to captivity, inoculated orally with a fatal dose of 104.43 pfu/frog, and euthanized at 0.25, 0.5, 1, 2, 4, 9, and 14 days postinfection (dpi). Mild lesions occurred sporadically in the skin (petechiae) and bone marrow (necrosis) during the first 2 dpi. Severe lesions occurred 1 to 2 weeks postinfection and consisted of necrosis of medullary and extramedullary hematopoietic tissue, lymphoid tissue in spleen and throughout the body, and epithelium of skin, mucosae, and renal tubules. Viral DNA was first detected (polymerase chain reaction) in liver at 4 dpi; by dpi 9 and 14, all viscera tested (liver, kidney, and spleen), skin, and feces were positive. Immunohistochemistry (IHC) first detected viral antigen in small areas devoid of histologic lesions in the oral mucosa, lung, and colon at 4 dpi; by 9 and 14 dpi, IHC labeling of viral antigen associated with necrosis was found in multiple tissues. Based on IHC staining intensity and lesion severity, the skin, oral, and gastrointestinal epithelium and renal tubular epithelium were important sites of viral replication and shedding, suggesting that direct contact (skin) and fecal-oral contamination are effective routes of transmission and that skin tissue, oral, and cloacal swabs may be appropriate antemortem diagnostic samples in late stages of disease (>1 week postinfection) but poor samples to detect infection in clinically healthy frogs.

Development, income transfer strategies, and the nutritional transition in Brazilian children from a rural and remote region.

INTRODUCTION: Global development processes have been associated with the nutritional transition, where undernutrition is replaced by overnutrition. Income transfer policies in Brazil have targeted hunger, but may not address the need for balanced nutrition. METHODS: Data was collected from government databanks that document the nutritional status of Brazilians applying for social services. This data was analyzed for descriptive statistics. RESULTS: Development and income transfer processes appear to be associated with an increase in overweight children between the years 2008 and 2012. CONCLUSIONS: Income transfer programs need to incorporate educational programs that address the need to budget for balanced nutrition.

Severe obesity and diabetes self-care attitudes, behaviours and burden: implications for weight management from a matched case-controlled study. Results from Diabetes MILES--Australia.

AIMS: To investigate whether diabetes self-care attitudes, behaviours and perceived burden, particularly related to weight management, diet and physical activity, differ between adults with Type 2 diabetes who are severely obese and matched non-severely obese control subjects. METHODS: The 1795 respondents to the Diabetes MILES--Australia national survey had Type 2 diabetes and reported height and weight data, enabling BMI calculation: 530 (30%) were severely obese (BMI ≥ 35 kg/m(2); median BMI = 41.6 kg/m(2)) and these were matched with 530 control subjects (BMI < 35 kg/m(2); median BMI = 28.2 kg/m(2)). Diabetes self-care behaviours, attitudes and burden were measured with the Diabetes Self-Care Inventory-Revised. Within-group and between-group trends were examined. RESULTS: The group with BMI ≥ 35 kg/m(2) was less likely to achieve healthy diet and exercise targets, placed less importance on diet and exercise recommendations, and found the burden of diet and exercise recommendations to be greater than the group with BMI < 35 kg/m(2). The group with BMI ≥ 35 kg/m(2) was more likely to be actively trying to lose weight, but found weight control a greater burden. These issues accentuated with increasing obesity and were greatest in those with BMI > 45 kg/m(2). There were no between-group differences in other aspects of diabetes self-care: self-monitoring of blood glucose, use of medications and smoking. Moderate-to-severe symptoms of depression were independently associated with reduced likelihood of healthy diet and physical activity, and with greater burden associated with diet, physical activity and weight management. CONCLUSIONS: Severely obese people with diabetes demonstrated self-care attitudes, behaviours and burdens that infer barriers to weight loss. However, other important diabetes self-care behaviours are supported equally by severely obese and non-severely obese individuals.

Noiseless optical amplifier operating on hundreds of spatial modes.

We implement a noiseless optical amplifier using a phase-sensitive four-wave mixing process in rubidium vapor. We observe performance near the quantum limit for this type of amplifier over a range of experimental parameters and show that the noise figure is always better than would be obtained with a phase-insensitive amplifier with the same gain. Additionally, we observe that the amplifier supports hundreds of spatial modes, making it possible to amplify complex two-dimensional spatial patterns with less than a 10% degradation of the input signal-to-noise ratio for gains up to 4.6. To confirm the multimode character of the amplifier, we study the noise figure as a function of spatially-varying losses. Additionally, we investigate the spatial resolution of the amplifier and show that it supports a range of spatial frequencies from 1.3 to more than 35 line pairs per millimeter.

Social exclusion and myiasis of the upper lip in a Brazilian rural resident.

CONTEXT: People living in rural or remote Brazil, as in other sub-tropical or tropical nations, are vulnerable to infections that would not normally occur in urban areas or wealthier nations. Brazil is a geographically extensive nation, historically marked by vast socioeconomic inequalities. Approximately 16% of the population live in rural areas. ISSUE: This clinical case report demonstrates the vulnerability of rural residents who are underserved by Brazil's 'universal' public healthcare system, despite social and economic challenges that increase their risk for disease. Myiasis (especially oral myiasis) is a rare health condition in humans caused by fly larvae. Oral myiasis usually appears in periodontal pockets and open wounds, such as after dental extractions. It is associated with poverty, lack of access to health care, and very poor overall health status. While myiasis has a worldwide distribution, it is particularly associated with the tropical and sub-tropical regions of North and South America. LESSONS LEARNED: This article describes a rare case of myiasis in the upper lip of a rural male patient. The case report demonstrate that rural and remote residents can be socially excluded from the benefits of technology and biomedicine, making them vulnerable to rare infections.

Agency perspectives on food safety for the products of animal biotechnology.

Animal biotechnology represents one subset of tools among a larger set of technologies for potential use to meet increasing world demands for food. Assisted reproductive technologies (ART) such as artificial insemination and embryo transfer continue to make positive contributions in food animal production. The US Food and Drug Administration (FDA) performed a comprehensive risk assessment to identify potential food consumption or animal health risks associated with animal cloning, an emerging ART. At that time, FDA concluded that animal cloning posed no unique risks either to animal health or to food consumption, and food from animal clones and their sexually reproduced offspring required no additional federal regulation beyond that applicable to conventionally bred animals of the species examined. At this time, no new information has arisen that would necessitate a change in FDA's conclusions on food from animal clones or their sexually reproduced offspring. Use of recombinant DNA technologies to produce genetically engineered (GE) animals represents another emerging technology with potential to impact food animal production. In its regulation of GE animals, FDA follows a cumulative, risk-based approach to address scientific questions related to the GE animals. FDA evaluates data and information on the safety, effectiveness and stability of the GE event. FDA carries out its review at several levels (e.g. molecular biology, animal safety, food safety, environmental safety and claim validation). GE animal sponsors provide data to address risk questions for each level. This manuscript discusses FDA's role in evaluation of animal cloning and GE animals.

To Drive or Not to Drive: Assessment Dilemmas for GPs.

Introduction. Most Australians are dependent on their cars for mobility, thus relinquishing driving licences for medical reasons poses challenges. Aims. To investigate how general practitioners (GPs) recognise and manage patients' fitness to drive, GPs' attitudes and beliefs about their role as assessors, and GPs' experiences in assessing and reporting to driving authorities and identify GPs' educational needs. Methods. Mixed methods: questionnaire mailed to GPs from three rural and two metropolitan Divisons of General Practice in Victoria, Australia. Results. 217/1028 completed questionnaires were returned: 85% recognised a patients' fitness to drive, 54% felt confident in their assessment ability, 21% felt the GP should have primary responsibility for declaring patients' fitness to drive, 79% felt that reporting a patient would negatively impact on the doctor-patient relationship, 74% expressed concern about legal liability, and 74% favoured further education. Discussion. This study provides considerable information including recommendations about GP education, the assessment forms, and legal clarification.

Quantum correlated light beams from non-degenerate four-wave mixing in an atomic vapor: the D1 and D2 lines of 85Rb and 87Rb.

We present experimental results showing that quantum correlated light can be produced using non-degenerate, off-resonant, four-wave mixing (4WM) on both the D1 (795 nm) and D2 (780 nm) lines of (85)Rb and (87)Rb, extending earlier work on the D1 line of (85)Rb. Using this 4WM process in a hot vapor cell to produce bright twin beams, we characterize the degree of intensity-difference noise reduction below the standard quantum limit for each of the four systems. Although each system approximates a double-lambda configuration, differences in details of the actual level structure lead to varying degrees of noise reduction. The observation of quantum correlations on light produced using all four of these systems, regardless of their substructure, suggests that it should be possible to use other systems with similar level structures in order to produce narrow frequency, non-classical beams at a particular wavelength.

Low-noise amplification of a continuous-variable quantum state.

We present an experimental realization of a low-noise, phase-insensitive optical amplifier using a four-wave mixing interaction in hot Rb vapor. Performance near the quantum limit for a range of amplifier gains, including near unity, can be achieved. Such low-noise amplifiers are essential for so-called quantum cloning machines and are useful in quantum information protocols. We demonstrate that amplification and "cloning" of one half of a two-mode squeezed state is possible while preserving entanglement.

First record of Anguillicoloides crassus (Nematoda) in American eels (Anguilla rostrata) in Canadian estuaries, Cape Breton, Nova Scotia.

In the summer of 2007, American eels, Anguilla rostrata, from 2 localities on Cape Breton Island, were found to be infected with the swim bladder nematode Anguillicoloides crassus. This is the first documented report of this highly invasive parasite in Canadian waters. More than half of the yellow eels in Mira River (6 of 10), and 1 eel (of 5) from Sydney Harbour were infected. Parasite intensity ranged from 1 to 11 worms per eel. The occurrence of A. crassus at these 2 localities suggests the need for a more extensive survey on the distribution of this exotic parasite in eel populations throughout Cape Breton Island.

Delocalized correlations in twin light beams with orbital angular momentum.

We generate intensity-difference-squeezed Laguerre-Gauss twin beams of light carrying orbital angular momentum by using four-wave mixing in a hot atomic vapor. The conservation of orbital angular momentum in the four-wave mixing process is studied as well as the spatial distribution of the quantum correlations obtained with different configurations of orbital angular momentum. Intensity-difference squeezing of up to -6.7 dB is demonstrated with beams carrying orbital angular momentum. Delocalized spatial correlations between the twin beams are observed.

Photoassociation of sodium in a Bose-Einstein condensate.

We form ultracold Na2 molecules by single-photon photoassociation of a Bose-Einstein condensate, measuring the photoassociation rate, linewidth, and light shift of the J = 1, v = 135 vibrational level of the A1 Sigma (+)(u) molecular state. The photoassociation rate constant increases linearly with intensity, even where it is predicted that many-body effects might limit the rate. Our observations are in good agreement with a two-body theory having no free parameters.

Evidence of a tissue-restricting DNA regulatory element in the mouse IRBP promoter.

The expression of interphotoreceptor retinoid binding protein (IRBP) is limited to photoreceptor cells of the retina and pinealocytes of the pineal gland. We sought to define cis-elements of the mouse IRBP 5' flanking region that are required for this restricted activity. In vitro transient transfections of retinoblastoma and neuroblastoma cells and in vivo experiments with transgenic Xenopus laevis indicate that -1783/+101 and -156/+101 IRBP gene fragments directed expression predominantly to the retina and pineal, with minor neuronal expression elsewhere. In contrast, a -70/+101 fragment was less restrictive in controlling expression, exhibiting activity not only in retina, but also in forebrain, hindbrain, spinal cord, and motor neurons innervating gills.

Carnitine/acylcarnitine translocase deficiency (neonatal phenotype): successful prenatal and postmortem diagnosis associated with a novel mutation in a single family.

The neonatal phenotype of carnitine-acylcarnitine translocase (CACT) deficiency is one of the most severe and usually lethal mitochondrial fat oxidation disorders characterized by hypoketotic hypoglycemia, hyperammonemia, cardiac abnormalities, and early death. In this study, the proband was the daughter of consanguineous Hispanic parents. At 36 h of life, she had bradycardia and died at 4 days of age without a specific diagnosis. In a subsequent pregnancy, prenatal counseling and amniocentesis were provided. Incubation of the amniocytes from this pregnancy and fibroblasts (from the dead proband) with [16-(2)H(3)]palmitic acid and analysis by tandem mass spectrometry revealed an increasedconcentration of [16-(2)H(3)]palmitoylcarnitine, suggesting the diagnoses of either CACT or carnitine palmitoyltransferase II (CPT-II) deficiency. CACT enzyme activity was absent in both cell lines. Molecular investigation of cDNA from the dead proband and her affected sibling revealed aberrant CACT cDNA species, including exon 3 skipping, both exon 3 and 4 skipping, and a 13-bp insertion at cDNA position 388. Investigation of these cell lines for mutations affecting CACT RNA processing by analysis of CACT gene sequences, including intron and exon boundaries, revealed a single nucleotide G deletion at the donor site in intron 3 which resulted in exon skipping and a 13-bp insertion. The proband and her affected sibling were homozygous for this deletion.

STM studies of 1-D noble metal growth on silicon.

Our scanning tunneling microscopy (STM) studies show that noble metals (Ag, Au) form a wide variety of 1-D structures on the high-index Si(5 5 12) surface. At coverages below 0.25 monolayer (ML), both metals grow as overlayer rows with an inter-row spacing of approximately 5 nm. At higher coverages and annealing temperatures, the underlying Si reconstruction is removed, but periodic row structures persist. Au can also induce faceting to nearby planes, e.g. (7 7 15) and (2 2 5), at temperatures above 500 degrees C. For all coverages and annealing temperatures studied here (0.02-1 ML, 450-800 degrees C), the Si(5 5 12) template initiates 1-D growth of the deposited noble metals.

Filling and voiding symptoms in the American Urological Association symptom index: the value of their distinction in a Veterans Affairs randomized trial of medical therapy in men with a clinical diagnosis of benign prostatic hyperplasia.

PURPOSE: We used data from a large Veterans Affairs trial of medical therapy for men with benign prostatic hyperplasia to evaluate the value of calculating separate filling and voiding subscores of the American Urological Association (AUA) symptom index. MATERIALS AND METHODS: We performed factor analysis to assess the psychometric validity of separating the 7 items of the AUA symptom index into filling and voiding subsets. To assess the clinical usefulness of calculating these subscores we correlated them against baseline measurements of symptom interference as well as urodynamic and anatomical measures of disease severity, and used them for predicting the response to medical therapy. RESULTS: Factor analysis confirmed the psychometric validity of separating the AUA symptom index into a 3-item filling and a 4-item voiding subscale. However, calculating filling and voiding subscores did not result in differential correlations with measures of disease interference or severity. It also did not enable us to predict a better symptomatic or uroflowmetry response to medical therapy. CONCLUSIONS: Calculating separate filling and voiding subscores of the AUA symptom index is psychometrically valid but not clinically useful.