Very Long-Chain Acyl-CoA Dehydrogenase Deficiency Presenting as Rhabdomyolysis.

Presentation A 20 year old female attended the Emergency Department by ambulance following a collapse at a concert. On arrival she was complaining of generalised muscular pain. She had not eaten for over 12 hours and had been dancing for approximately 6 hours. The patient was known to have Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD). She had a normal exam, and normal vital signs. Diagnosis A diagnosis of rhabdomyolysis was made after her creatinine kinase (CK) was found to be >100000 units/litre (Normal range < 170U/L). Her urine was dark brown with urinalysis positive for blood. Treatment The patient was admitted to the high dependency unit, where she was treated with intravenous fluids. Her urine output and renal function were closely monitored. She made a full recovery and was discharged home four days later. Conclusion (VLCAD) is an inherited, autosomal recessive, metabolic disorder caused by mutations in the ACADVL gene. Management includes treatment of manifestation, primary prevention of manifestation, and prevention of secondary complications.

Site-Specific and Temporal Effects of Apraglutide, a Novel Long-Acting Glucagon-Like Peptide-2 Receptor Agonist, on Intestinal Growth in Mice.

Long-acting glucagon-like peptide-2 receptor (GLP-2R) agonists are well-established to increase intestinal growth in rodents and, most notably, humans with short bowel syndrome. Most of the trophic effects of GLP-2R agonists are reported to be mediated through increased growth of the crypt-villus axis, resulting in enhanced mucosal mass and improved intestinal function. The present study examined the effects of apraglutide, a novel GLP-2R agonist, on the growth of the small intestine and colon after 3, 7, and 10 weeks of treatment in male and female mice. Apraglutide (3 mg/kg; three times per week) significantly increased small intestinal weight (P < 0.001) and length (P < 0.001) after 3 weeks of administration, with a further increase in effectiveness after 10 weeks (P < 0.01). Crypt depth and villus height were both markedly increased after 3 weeks of apraglutide administration (P < 0.001) but did not show any further increase with duration of treatment, whereas crypt number and intestinal circumference were increased after 7 and 10 weeks (P < 0.01) but not after 3 weeks of apraglutide treatment. Both the weight and the length of the colon were also enhanced by apraglutide treatment for 3 weeks (P < 0.001), and these effects were maintained but did not improve further with continued apraglutide administration. The results of this study demonstrate that the novel, long-acting GLP-2R agonist, apraglutide, demonstrates an unexpected marked ability to increase intestinal length as well as exert time- and location-dependent specificity in its intestinotrophic actions. SIGNIFICANCE STATEMENT: The novel long-acting glucagon-like peptide 2 receptor agonist, apraglutide, enhances intestinal weight as well as intestinal length in a time- and site-dependent fashion.

Folic acid levels in some food staples in Ireland are on the decline: implications for passive folic acid intakes?

BACKGROUND: Neural tube defects are largely preventable by the maternal periconceptual consumption of folic acid. The aim of this study was to examine the levels of synthetic folic acid in foods and the range of food stuffs with added folic acid available to consumers in Ireland at the current time. METHODS: Three audits of fortified foods available in supermarkets in the Republic of Ireland were conducted. Researchers visited supermarkets and obtained folic acid levels from nutrition labels in 2004, 2008 and 2013/4. Levels were compared using MS Excel. RESULTS: The profile of foods fortified with folic acid in 2013/4 has changed since 2004. The percentage of foods fortified with folic acid has decreased as has the level of added folic acid in some food staples, such as fat/dairy spreads. CONCLUSION: Bread, milk and spreads no longer contain as much folic acid as previously (2004 and 2008). This may contribute to a decrease in folate intake and therefore may contribute to an increase in NTD rates. Research on current blood concentrations of folate status markers is now warranted.

Ensuring the Health, Safety and Preparedness of U.S. Medical Students Participating in Global Health Electives Overseas.

Global health electives based in resource-poor countries have become extremely popular with medical students from resource rich ones. As the number of such programs and participants increase, so too do the absolute health and safety risks. It is clear from a number of published reports that many institutions provide little or no meaningful preparedness for students and do little to ensure their health and safety. These deficiencies together can affect students, their foreign hosts, and sponsoring institutions. The School of Public Health at the State University of New York, Downstate Medical Center, and its predecessor, the Department of Preventive Medicine and Community Health, have sponsored a 6-8 week global health elective for fourth year medical students since 1980. The purposes of this elective are to provide students with an opportunity to observe the health care and public health systems in resource-poor countries, provide medical service, and have a cross-cultural experience. Over the course of the past 35 years, 386 students have participated in this global health elective in more than 41 resource-poor countries. Recent annual applications for this elective have been as high as 44 out of a class of 200 students. Over the past 10 years, annual acceptance rates have varied, ranging from a low of 32 % in 2007-2008 to a high of 74 % in 2010-2011 and 2013-2014. Careful screening, including a written application, review of academic records and personal interviews, has resulted in the selection of highly mature, adaptable, and dedicated students who have performed well at overseas sites. Appropriately preparing students for an overseas global health experience in resource-poor countries requires the investment of much professional and staff time and effort. At the SUNY Downstate School of Public Health, these resources have underpinned our Global Health in Developing Countries elective for many years. As a result, the elective is characterized by meticulous organization, extensive preparedness measures for students, and continuous monitoring of site and country safety. The health of students is ensured by one-on-one assessment of immunization needs, anti-malarials, and the provision of a five-day supply of post-exposure HIV prophylaxis. Students sign agreements regarding the legal issues, immunizations, and anti-malarials recommended as well as HIV post-exposure prophylaxis. They are also required to obtain medical evacuation insurance provided by the university, and medical care insurance valid overseas. Student travel plans are also approved as is in-country lodging. The focus of our 6-8 week global health elective is not clinical medicine. Rather, it is to enable students to learn about the health care and public health systems in a resource-poor country. Through that focus, they also come to understand the causes of health and health care disparities that exist in the country to which they are assigned. Our students are greatly advantaged with regard to cross-cultural understanding since our school is located in New York City's Borough of Brooklyn, where 40 % of the population was born outside of the U.S. Our comprehensive effort at risk management for this global health elective includes a thorough debriefing for each student upon his/her return. Special attention is given to ascertaining illness or injury while overseas, and, when necessary, immediate referral is made to an appropriate university clinical department where a student can be appropriately case managed. Meticulous oversight, careful selection of safe overseas sites, and attention to preparing students have resulted in significant risk reduction and successful experiences for the majority of our 386 students. This article describes the model we have developed for ensuring the health, safety, and preparedness of students participating in our global health elective.

Environmental endocrine disruptors: Effects on the human male reproductive system.

Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically "endocrine disruptors," that interfere with normal hormonal action. Much research has gone into testing the effects of specific endocrine disrupting chemicals (EDCs) on the development of male reproductive organs and endocrine-related cancers in both in vitro and in vivo models. Efforts have been made to bridge the accruing laboratory findings with the epidemiological data to draw conclusions regarding the relationship between EDCs, altered development and carcinogenesis. The ability of EDCs to predispose target fetal and adult tissues to neoplastic transformation is best explained under the framework of the tissue organization field theory of carcinogenesis (TOFT), which posits that carcinogenesis is development gone awry. Here, we focus on the available evidence, from both empirical and epidemiological studies, regarding the effects of EDCs on male reproductive development and carcinogenesis of endocrine target tissues. We also critique current research methodology utilized in the investigation of EDCs effects and outline what could possibly be done to address these obstacles moving forward.

The Francis Report--implications for oral care of the elderly.

Oral health is an essential, yet often neglected, aspect of care in the elderly population. A mouth free of pain and disease which is functional, comfortable and aesthetic improves quality of life. Following the shocking reports of patient neglect and abuse published in the Francis Report, the dental profession must acknowledge that there are longstanding deficiencies in the provision of oral healthcare for the elderly, whether residing in care homes, hospitals or at home with support. It must be a universal goal to improve the care provision for this population through developing a greater understanding and overcoming the multi-factorial barriers to care. This article will highlight the key features of the Francis Report and its significance in the context of oral healthcare provision for the elderly. Clinical Relevance: To provide insight into the oral healthcare needs of the growing elderly population and the necessity of dealing with the current limitations in service provision.

Exciton dynamics in carbon nanotubes: from the Luttinger liquid to harmonic oscillators.

We show that the absorption spectrum in semiconducting nanotubes can be determined using the bosonization technique combined with mean-field theory and a harmonic approximation. In this framework, a multiple band semiconducting nanotube reduces to a system of weakly coupled harmonic oscillators. We also find that gaps of any size destroy the Luttinger liquid phase in single-walled carbon nanotubes and give rise to electron density fluctuations that resemble excitons built from quasiparticles. Interband processes, such as multiple exciton generation, become progressively weaker as the length to diameter ratio grows larger.

Differential vasodilation of human placental and myometrial arteries related to myofilament Ca(2+)-desensitization and the expression of Hsp20 but not MYPT1.

Endothelial-dependent regulation of vascular tone occurs in part via protein kinase G1α-mediated changes in smooth muscle myofilament sensitivity to Ca(2+). Tissue-specific differences in PKG-dependent relaxation have been attributed to altered expression of myofilament-associated proteins that are substrates for PKG binding. These include the alternative splicing of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase to yield leucine zipper positive (LZ(+)) and negative (LZ(-)) isovariants, with the former being required for PKG-mediated relaxation, and/or altered expressions of telokin, vasodilator-stimulated phosphoprotein (VASP) or heat shock protein Hsp20. During human pregnancy the uterine and placental circulations remain distinct entities and, as such, their mechanisms of vascular tone regulation may differ. Indeed, the sensitivity of myometrial arteries to endothelial-dependent agonists has been suggested to be greater than that of placental arteries. We tested the hypothesis that this was related to tissue-specific changes in PKG-mediated myofilament Ca(2+)-desensitization and/or the expressions of PKG-interacting myofilament-associated proteins. Permeabilized human placental and myometrial arteries were constricted with maximal activating Ca(2+) (pCa 4.5), or sub-maximal Ca(2+) (pCa 6.7) and the thrombane mimetic U46619, and exposed to 8-Br-cGMP. In each case, relaxation was significantly greater in myometrial arteries (e.g. relaxation in pCa 4.5 to 8-Br-cGMP was 49 ± 9.7%, n = 7) than placental arteries (relaxation of 23 ± 6.6%, n = 6, P < 0.05). MYPT1 protein levels, or MYPT1 LZ(+)/LZ(-) mRNA ratios, were similar for both artery types. Of other proteins examined, only Hsp20 expression was significantly elevated in myometrial arteries than placental arteries. These results demonstrate that the reduced human placental artery relaxation to PKG stimulation lies partly at the level of myofilament (de)activation and may be related to a lower expression of Hsp20 than in myometrial arteries.

Knowledge and use of pre-exposure prophylaxis among an online sample of young men who have sex with men in New York City.

Understanding prior knowledge and experience with pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) is critical to its implementation. In fall 2011, NYC MSM were recruited via banner advertisements on six popular dating websites and asked questions about their knowledge and use of PrEP (n = 329). Overall, 123 (38%) respondents reported knowledge of PrEP, of whom two (1.5%) reported PrEP use in the past 6 months. Knowledge of PrEP was associated with high educational attainment, gay identity and recent HIV testing, suggesting an uneven dissemination of information about PrEP and missed opportunities for education. To avoid disparities in use during scale-up, MSM should be provided with additional information about PrEP.

A tandem duplication in the D-loop of human mitochondrial DNA is associated with deletions in mitochondrial myopathies.

About 40 per cent of patients with mitochondrial myopathies have two populations of mitochondrial DNA (mtDNA) in muscle, one of which is deleted. All patients with single mtDNA deletions and neurological disease are sporadic cases, suggesting that deletions arise as fresh mutational events. We have detected a low abundance heteroplasmic tandem duplication involving the displacement loop of mtDNA in 18 of 58 patients with deletions and 5/5 of their mothers, but not in normal subjects. The location of the duplication to a region that controls both replication and transcription of mtDNA could explain features suggesting mild mitochondrial dysfunction in the muscle biopsies of three patients' mothers, and a predisposition to deletion.

Screening for Autism Spectrum Condition Through Inner City Homeless Services in the Republic of Ireland.

Homeless service users were screened for autism spectrum disorder through one of Ireland's leading not for profit service providers. Keyworkers acted as proxy informants; their caseloads were screened using the DSM-5-Autistic Traits in the Homeless Interview (DATHI). Client current and historical health and behaviour data was collated. A representative sample of 106 eligible keyworkers caseloads were screened, identifying 3% "present" and 9% "possibly present" for autistic traits with the DATHI. These findings suggest a high estimate of autism prevalence and support emerging evidence that, people with autism are overrepresented in the homeless population, compared to housed populations. Autism may be a risk factor for entry into homelessness and a challenge to exiting homeless and engaging with relevant services.

Improving organ procurement travel practices in the United States: proceedings from the Michigan Donor Travel Forum.

There are significant risks and inefficiencies associated with organ procurement travel. In an effort to identify, quantify, and define opportunities to mitigate these risks and inefficiencies, 25 experts from the transplantation, transportation and insurance fields were convened. The forum concluded that: on procurement travel practices are inadequate, there is wide variation in the quality of aero-medical transportation, current travel practices for organ procurement are inefficient and there is a lack of standards for organ procurement travel liability coverage. The forum concluded that the transplant community should require that air-craft vendors adhere to industry quality standards compatible with the degree of risk in their mission profiles. Within this context, a purchasing collaborative within the transplant community may offer opportunities for improved service and safety with lower costs. In addition, changes in travel practices should be considered with broader sharing of procurement duties across centers. Finally, best practice standards should be instituted for life insurance for transplant personnel and liability insurance for providers. Overall, the aims of these proposals are to raise procurement travel standards and in doing so, to improve the transplantation as a whole.

Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.

BACKGROUND: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The genetic basis of typical cases without CACNA1A point mutations is not fully known. Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1. METHODS: The authors used multiplex ligation dependent probe amplification (MLPA) to screen for intragenic CACNA1A rearrangements. RESULTS: The authors identified five previously unreported large scale deletions in CACNA1A in seven families with episodic ataxia and in one case with hemiplegic migraine. One of the deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four generation family with eight affected individuals previously mapped to 19p13. In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia. CONCLUSIONS: Large scale deletions and duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing alone is not sufficient as a diagnostic screening test.

Counseling clients during New York City's COVID-19 pandemic: observations on fundamental elements of emotions management.

New York City is in the grip of the COVID-19 pandemic. Health care centers are stretched beyond capacity. Daily death rates are staggering. The city's population is hunkered down in fear. Our anxiety treatment center is treating patients via video appointments. We are helping anxious individuals adapt to tumultuous changes that we ourselves are experiencing. Our work in this time has reinforced our core beliefs about managing one's emotions; that difficult times require more active coping and that we all draw heavily from social support and familiarity to create a feeling of well-being. These principles and the experiences of our patients are discussed.

Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients.

BACKGROUND: An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases. METHODS: A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented. RESULTS AND CONCLUSIONS: The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer's cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.

Neocentromere-mediated chromosome movement in maize.

Neocentromere activity is a classic example of nonkinetochore chromosome movement. In maize, neocentromeres are induced by a gene or genes on Abnormal chromosome 10 (Ab10) which causes heterochromatic knobs to move poleward at meiotic anaphase. Here we describe experiments that test how neocentromere activity affects the function of linked centromere/kinetochores (kinetochores) and whether neocentromeres and kinetochores are mobilized on the spindle by the same mechanism. Using a newly developed system for observing meiotic chromosome congression and segregation in living maize cells, we show that neocentromeres are active from prometaphase through anaphase. During mid-anaphase, normal chromosomes move on the spindle at an average rate of 0.79 micron/min. The presence of Ab10 does not affect the rate of normal chromosome movement but propels neocentromeres poleward at rates as high as 1.4 micron/min. Kinetochore-mediated chromosome movement is only marginally affected by the activity of a linked neocentromere. Combined in situ hybridization/immunocytochemistry is used to demonstrate that unlike kinetochores, neocentromeres associate laterally with microtubules and that neocentromere movement is correlated with knob size. These data suggest that microtubule depolymerization is not required for neocentromere motility. We argue that neocentromeres are mobilized on microtubules by the activity of minus end-directed motor proteins that interact either directly or indirectly with knob DNA sequences.

Identification of Porphyromonas levii isolated from clinical cases of bovine interdigital necrobacillosis by 16S rRNA sequencing.

Laboratories use pigmentation, antibiotic susceptibility, and biochemical tests to identify anaerobic organisms that play a role in bovine interdigital necrobacillosis (bovine foot rot). In this study, 16S rRNA gene sequencing was used to identify strains to the species level that were originally classified as Prevotella or Porphyromonas spp by conventional phenotype assessment methods. Of 264 qualified strains from ceftiofur clinical trials, 241 isolates were definitively identified by 16S rRNA sequencing as Porphyromonas levii. Similarly, of 275 qualified strains from tulathromycin clinical trials, 156 isolates were definitively identified by 16S rRNA sequencing as P. levii. The predominance of P. levii in this study supports the role of this organism as an associative agent of bovine foot rot and may have implications for routine laboratory diagnosis.

Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging.

The overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a common underlying mechanism of many neuropathologies, as they have been shown to damage various cellular components, including proteins, lipids and DNA. Free radicals, especially superoxide (O(2)*-), and non-radicals, such as hydrogen peroxide (H(2)O(2)), can be generated in quantities large enough to overwhelm endogenous protective enzyme systems, such as superoxide dismutase (SOD) and reduced glutathione (GSH). Here we review the mechanisms of ROS and RNS production, and their roles in ischemia, traumatic brain injury and aging. In particular, we discuss several acute and chronic pharmacological therapies that have been extensively studied in order to reduce ROS/RNS loads in cells and the subsequent oxidative stress, so-called "free-radical scavengers." Although the overall aim has been to counteract the detrimental effects of ROS/RNS in these pathologies, success has been limited, especially in human clinical studies. This review highlights some of the recent successes and failures in animal and human studies by attempting to link a compound's chemical structure with its efficacy as a free radical scavenger. In particular, we demonstrate how antioxidants derived from natural products, as well as long-term dietary alterations, may prove to be effective scavengers of ROS and RNS.

Characterisation of tone oscillations in placental and myometrial arteries from normal pregnancies and those complicated by pre-eclampsia and growth restriction.

Agonist-induced tone oscillations (rhythmic contractions and relaxations) occur in vascular beds to allow acute regulation of volume flow and thus the delivery of oxygen and nutrients to the tissue. Mechanisms responsible for the control of human placental vasomotor tone and blood flow are poorly characterized. This study aimed to characterise thromboxane-induced tone oscillations in human placental and myometrial arteries. Chorionic plate and myometrial arteries obtained from biopsies at term were mounted for isometric tension measurement. Tone oscillations were observed in chorionic arteries only when exposed to sub-maximal (<1 microM) concentrations of U46619. Slow (mean+/-SEM) frequency (2.6+/-0.5 per hour), large amplitude (39+/-7% of peak contraction) tone oscillations were elicited by 0.03 microM U46619 (n=18). In the presence of the nitric oxide synthase (NOS) inhibitor l-NNA (100 microM) the amplitude was significantly reduced (40+/-13% to 18+/-8%, P<0.05, n=6), frequency was unaltered and the bradykinin-dependent vasodilator response was reduced (68+/-13% to 40+/-19%, P<0.05, n=6). Myometrial arteries exposed to 1 microM U46619 developed tone oscillations within 10 min, which increased in amplitude over 30min occurring at relatively constant frequency. The mean amplitude of oscillations at 30 min (31+/-7%, n=16) was similar to that in chorionic arteries but the occurrence more frequent (42.8+/-9.7 per hour, P<0.001). Inhibition of NOS did not alter tone oscillations in myometrial arteries. Tone oscillations in chorionic arteries from pre-eclamptic and growth restricted (FGR) pregnancies were reduced in amplitude whereas those in myometrial arteries had increased frequency. Inhibition of NOS further reduced oscillation amplitude in chorionic arteries from FGR pregnancies. The alterations may contribute to the vasculopathology of these conditions, or, may represent compensatory mechanisms to maintain a matching of materno-placental blood flow.

Multiple mitochondrial DNA deletions in monozygotic twins with OPMD.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is caused by expansions of the poly (A) binding protein 2 (PABP2) gene. Previous histological analyses have revealed mitochondrial abnormalities in the muscles of OPMD patients but their significance remains uncertain. OBJECTIVE: We had the rare opportunity to study monozygotic twins with identical expansions of the PABP2 gene but with markedly different severities of OPMD. Both had histological features of mitochondrial myopathy. We determined whether mitochondrial DNA abnormalities underlay these changes. METHODS: Clinical information was obtained by history and examination. Muscle biopsies were obtained from each subject and genetic analysis was performed using long-range PCR and Southern blotting. RESULTS: We demonstrate, for the first time, the presence of mitochondrial DNA (mtDNA) deletions by Southern blotting in individuals with OPMD. This correlates with the presence of mitochondrial myopathy in both twins. Moreover, both twins had different mtDNA deletions, which might explain their phenotypic differences. CONCLUSION: We hypothesise that mitochondrial dysfunction may occur as a consequence of PABP2 gene mutations, and that this dysfunction may affect the phenotypic manifestations of OPMD.