UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.

BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid. Anaplerotic metabolites of triheptanoin have the potential to replace deficient tricarboxylic acid (TCA) cycle intermediates, resulting in net glucose production as a novel energy source for the treatment of LC-FAOD. STUDY DESIGN: A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25-35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks. RESULTS: Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period. CONCLUSIONS: In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.

Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.

Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.

Molecular Beams with Energies above One Electron Volt.

By using as sources supersonic jets of hydrogen or helium containing small concentrations of heavier molecules we have been able to obtain molecular beams with kinetic energies of the heavy molecules well into the range above I electron volt. A variety of molecules have been successfully accelerated. Intensities of 10(16) to 10(17) heavy molecules per steradian-second have been achieved at these high energies.

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms.

The medical and neurodevelopmental characteristics of 14 children with short-chain acyl-CoA dehydrogenase deficiency (SCADD) are described. Eight were detected as neonates by newborn screening. Three children diagnosed on the basis of clinical symptoms had normal newborn screening results while three were born in states that did not screen for SCADD. Treatment included frequent feedings and a low fat diet. All children identified by newborn screening demonstrated medical and neuropsychological development within the normative range on follow-up, although one child had a relative weakness in the motor area and another child exhibited mild speech delay. Of the three clinically identified children with newborn screening results below the cut-off value, two were healthy and performed within the normal range on cognitive and motor tests at follow-up. Four clinically identified children with SCADD experienced persistent symptoms and/or developmental delay. However, in each of these cases, there were supplementary or alternative explanations for medical and neuropsychological deficits. Results indicated no genotype-phenotype correlations. These findings suggest that SCADD might be benign and the clinical symptoms ascribed to SCADD reflective of ascertainment bias or that early identification and treatment prevented complications that may have occurred due to interaction between genetic susceptibility and other genetic factors or environmental stressors.

Diversity oriented synthesis: a challenge for synthetic chemists.

This article covers the diversity-oriented synthesis (DOS) of small molecules in order to generate a collection of pure compounds that are attractive for lead generation in a phenotypic, high-throughput screening approach useful for chemical genetics and drug discovery programmes. Nature synthesizes a rich structural diversity of small molecules, however, unfortunately, there are some disadvantages with using natural product sources for diverse small-molecule discovery. Nevertheless we have a lot to learn from nature. The efficient chemical synthesis of structural diversity (and complexity) is the aim of DOS. Highlights of this article include a discussion of nature's and synthetic chemists' strategies to obtain structural diversity and an analysis of molecular descriptors used to classify compounds. The assessment of how successful one diversity-oriented synthesis is vs another is subjective; therefore we use freely available software (www.cheminformatics.org/diversity) to assess structural diversity in any combinatorial synthesis.

Protocol variations and six-minute walk test performance in stroke survivors: a systematic review with meta-analysis.

Objective. To investigate the use of the six-minute walk test (6MWT) for stroke survivors, including adherence to 6MWT protocol guidelines and distances achieved. Methods. A systematic search was conducted from inception to March 2014. Included studies reported a baseline (intervention studies) or first instance (observational studies) measure for the 6MWT performed by stroke survivors regardless of time after stroke. Results. Of 127 studies (participants n = 6,012) that met the inclusion criteria, 64 were also suitable for meta-analysis. Only 25 studies made reference to the American Thoracic Society (ATS) standards for the 6MWT, and 28 reported using the protocol standard 30 m walkway. Thirty-nine studies modified the protocol walkway, while 60 studies did not specify the walkway used. On average, stroke survivors walked 284 ± 107 m during the 6MWT, which is substantially less than healthy age-matched individuals. The meta-analysis identified that changes to the ATS protocol walkway are associated with reductions in walking distances achieved. Conclusion. The 6MWT is now widely used in stroke studies. The distances achieved by stroke patients indicate substantially compromised walking ability. Variations to the standard 30 m walkway for the 6MWT are common and caution should be used when comparing the values achieved from studies using different walkway lengths.

Diabetes and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS): radiolabeled polymerase chain reaction is necessary for accurate detection of low percentages of mutation.

A 6-yr-old boy presented with muscle weakness, lactic acidemia, and insulin-dependent diabetes mellitus (IDDM). Using PCR and restriction enzyme analysis, he was found to have the classical A3248G mitochondrial DNA (mtDNA) mutation frequently associated with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). The mutation was confirmed by sequencing muscle mtDNA. The mutation in mtDNA from muscle, lymphoblasts, and blood was clearly demonstrable by standard methods using ethidium bromide staining. His mother also had IDDM, but no A3243G mutation could be detected in her blood or transformed lymphoblasts using the same PCR technique. When PCR was carried out in the presence of [32P]deoxycytidine triphosphate, subsequent autoradiography detected the presence of the mutation at low levels in mtDNA from the mother's lymphoblasts and blood. Study of the mother's muscle showed a mitochondrial myopathy, despite the fact that she was asymptomatic. We emphasize that the increased sensitivity of radiolabeled PCR may be necessary to detect small percentages of heteroplasmic A3243G mtDNA mutation in blood from diabetic subjects. Otherwise the incidence of mtDNA mutations in both IDDM and non-insulin dependent diabetes may be underestimated.

Intense oxidative DNA damage promoted by L-dopa and its metabolites. Implications for neurodegenerative disease.

Oxidative DNA damage can cause mutation and cell death. We show that L-DOPA, dopamine and 3-O-methyl-DOPA cause extensive oxidative DNA damage in the presence of H2O2 and traces of copper ions. 8-Hydroxyguanine is the major product. Iron ions were much less effective and manganese ions did not catalyse DNA damage. We propose that copper ion release, in the presence of L-DOPA and its metabolites, may be an important mechanism of neurotoxicity, e.g. in Parkinson's disease and amyotrophic lateral sclerosis.

Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up.

By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.

1995 survey of physics teaching efforts in radiation oncology residency programs.

A physics teaching survey was constructed and sent to the 83 radiation oncologist training programs. The survey requested program information regarding size, staffing, curriculum, lab/rotation programs, organization, requirements, instructor makeup, teaching materials, and board certification examination results. The surveys were sent to the physicist responsible for the physics program. Forty-nine (59%) institutions returned completed surveys, of which 43 (88%) were university-associated programs, and 27 (55%) were 4-year programs. On average, there were two residents/year. Most programs (39) taught physics exclusively during the first year (PG2). Some programs taught different subjects (or levels) to different year residents. Radiation dosimetry, treatment planning, and brachytherapy constituted nearly half of the teaching hours. On average the total classroom time expended by physicists was 61.4 h/year with a range of 24-118 h. The mean for laboratory/demonstration time was 27 h/year with 18 programs providing none. Physics orientation/rotations ranged from 1 to 480 h with a mean of 170 h for a physics rotation taking place in year 2 (PG3). Mandatory attendance was 80% for first-year residents and decreased in later years. Homework was assigned in 76% of the programs, and 65% of the programs were graded. The primary instructors averaged 18.2 years of experience, and the majority were ABR/ABMP certified. Khan's textbook was the most prevalent resource for most subjects. No correlation could be made between teaching hours and ABR physics percentile scoring. The survey results reveal enormous differences in national teaching efforts.

A survey of radiation oncologists regarding their radiation physics instruction.

The American Association of Physicists in Medicine, Committee on Training of Radiologists conducted a survey of radiation oncologists requesting information regarding their radiation oncology physics training. General questions were asked of the oncologist regarding their radiation oncology practice such as number of oncologists, number of new patients treated, and the size and type of facility in which the practice is located. The oncologist also responded to questions regarding their educational background. The survey requested the radiation oncologists to answer questions regarding the adequacy and importance of their training in specific areas of radiation physics. The responders indicated that the importance of most physics topics in their clinical practice corresponded to the level of their understanding. The survey indicated that for most radiation oncologists their physics instruction was an important and interesting part of their residency program.

Changes in neuronal excitability and synaptic function in a chronic model of temporal lobe epilepsy.

Long-term potentiation and depression of glutamatergic synaptic responses are accompanied by an increased firing probability of neurons in response to a given excitatory input. This property, named excitatory postsynaptic potential/spike potentiation, has also been described in epileptic tissue and has pro-epileptic consequences. In this study, we show that excitatory postsynaptic potential/spike potentiation can be reversed in the kainic acid lesioned rat hippocampus, a chronic model of temporal lobe epilepsy. Simultaneous in vitro extracellular recordings in stratum radiatum and stratum pyramidale were performed in the CA1 area of the kainic acid lesioned rat hippocampal slices. Fifteen minutes, application of the K(+) channel blocker tetraethylammonium resulted in excitatory postsynaptic potential/spike potentiation (measured 90min after the start of the washout period) which could be reversed by subsequent low-frequency or tetanic stimuli. Excitatory postsynaptic potential/spike potentiation and its subsequent reversal by an electrical conditioning stimulus were found to have a N-methyl-D-aspartate receptor-independent component. Tetraethylammonium treatment also resulted in excitatory postsynaptic potential/spike potentiation of pharmacologically isolated N-methyl-D-aspartate receptor-mediated responses which could be reversed by subsequent low-frequency or tetanic stimuli. We conclude that excitatory postsynaptic potential/spike potentiation can be reversed in epileptic tissue, even in the absence of synaptic plasticity. These results suggest the presence of endogenous regulatory mechanisms which are able to decrease cell excitability.

Syndrome of hypoparathyroidism, growth hormone deficiency, and multiple minor anomalies.

A 5 1/2-year-old Saudi Arabian girl presented with a syndrome of intrauterine growth retardation, minor anomalies, hypoparathyroidism, and growth hormone deficiency. She was the product of a consanguineous mating. Her minor anomalies and delayed development were similar to findings in a previously reported Saudi Arabian patients with hypoparathyroidism and growth deficiency. There were substantial differences in findings from a series of Kuwaiti children. Parathyroid hormone was undetectable, but the renal response to infused parathyroid hormone was normal, indicating primary hypoparathyroidism. In response to arginine stimulation, her GH rose to 5.8 ng/ml (5.8 micrograms/L) (nl > 10), and to 2.3 ng/ml (2.3 micrograms/L) after L-dopa. Following clonidine it rose to 15 ng/ml (15 micrograms/L) at 120 minutes. She responded normally to infusions of GHRH (GH rose to 22 ng/ml (22 micrograms/L) at 75 minutes) and TRH (TSH rose to 37 mu u/ml, 37 mIU/L). On treatment with recombinant human growth hormone, she showed an increase in height and weight. Hypocalcemia was well controlled with supplemental 1-alpha-cholecalciferol.

Risk factors, falls, and fracture of the distal forearm in Manchester, UK.

OBJECTIVE: To determine the risk factors associated with fracture of the distal forearm, and to evaluate the influence of falls on these risks. DESIGN: This was a case-control study. SETTING: Manchester, UK. PARTICIPANTS: The cases were 62 white women aged 45-82 years who had sustained a fracture of the distal forearm and had attended local hospitals. Two control groups were studied - 50 women who had fallen onto the hand but had not sustained a fracture (recruited from the same source as those with fracture) and 116 women randomly selected from primary care age and sex registers in the catchment area of the hospitals. Both cases and controls were sent a letter inviting them to take part in the study. Data were collected by questionnaire completed by an interviewer. MAIN RESULTS: Compared with the population control group, those with fracture were more likely to walk at a brisk pace (odds ratio (OR) = 3.5; 95% confidence interval (CI) 1.3, 9.6) though they had undertaken less physical activity at home or work on a daily basis throughout life (OR = 0.4; 95% CI 0.2, 0.9). The risk associated with brisk walking was less marked when the cases were compared with fall controls. Other lifestyle factors including calcium intake, smoking, and alcohol consumption were not associated with fracture. Analysis of gynaecological and hormonal factors suggested that compared with population controls, those with fracture of the distal forearm had had fewer fertile years (OR = 0.4; 95% CI 0.1, 0.9) and were less likely to have used oral contraceptives (OR = 0.3; 95% CI 0.1, 0.9). CONCLUSIONS: The data highlight the need for caution when advising middle aged and elderly subjects about exercise. Such advice should be combined with practical information about the prevention of falls. Hormonal factors seem to be additional determinants of fracture. Other lifestyle interventions seem unlikely to play an important part in preventing distal forearm fracture.

Survey response rates: national and regional differences in a European multicentre study of vertebral osteoporosis.

STUDY OBJECTIVE: This analysis aimed to compare the response rates of those invited to attend for screening in a multicentre, multinational study within Europe. DESIGN: This was a population survey. SETTING: Thirty four centres in 16 European countries. SUBJECTS: Men and women aged 50 years and over were recruited from population based sampling frames to participate in a prevalence survey of osteoporosis. Subjects were invited by post to attend for radiological screening and interview, and non-responders were followed up by repeat mailing. RESULTS: There was a substantial variation between centres in response rates: the mean was 49% and the range 5-83%. Adjusting for those known to have died or moved house did not affect the overall ranking. The response rates to each mailing also varied between centres: first mailing 45% (range 5-83%) and second mailing mean 10% (range 0-23%). The response rates varied in relation to age and sex and were higher in women than men. Rates fell gradually with age in women but rose in men until the age of 65 years. Response rates varied regionally. These were highest in countries from northern Europe and lowest in southern European countries, but there was wide variation both within regions and within countries. CONCLUSIONS: Multicentre, multinational studies within Europe will probably become increasingly popular. In this study, despite a standardised approach, the range in response rates between centres both within and between countries was substantial. Attempts at cross national standardisation in survey design can have only a limited effect on yielding uniformity in response.

Contemporary management of primary carcinoma of the vulva.

Over the last 100 years the treatment of vulvar cancer has evolved dramatically. The adoption of radical surgical approaches brought high cure rates, but often with very significant physical and psychosexual morbidity. In the last 20 years, there has been an increasing emphasis on conservative and multimodality treatment. There is, however, good evidence that optimal outcomes are dependent on treatment in specialized multidisciplinary tertiary referral centers.

Optimal management of endometrial hyperplasia.

The optimal management of endometrial hyperplasia is the subject of considerable debate. In this chapter the development of our current classification of endometrial hyperplasias is outlined in some detail in order to give an understanding of the complexity of the problem of determining the malignant potential of the hyperplasia which is the central issue in determining optimal treatment. While hysterectomy is still the definitive treatment for older women with hyperplasia, conservative therapy is perfectly acceptable in a defined group of younger women who are closely monitored.

Gastrointestinal problems in patients with advanced gynaecological malignancy.

Gastrointestinal problems are among the most common problems encountered in the management of women with far advanced gynaecological malignancy. They frequently have a multifactorial aetiology and may require a number of different strategies for effective management. Recognition of the central role of alimentary function in human life is essential to effective treatment. Elucidation of the probable cause of each problem is essential. A thorough knowledge of the natural history of the disease and the patient's current status and future prospects is needed to ensure the highest standard of care for the individual suffering from the problem.

Patterns of referral in patients with medically unexplained motor symptoms.

OBJECTIVE: To investigate the pattern and reasons for referrals in 64 patients with a stable diagnosis of motor conversion symptoms who had been assessed at the National Hospital for Neurology and Neurosurgery (NHNN). METHOD: Patients were interviewed on average 6 years after their original admission to the NHNN. Hospital notes and GP records were consulted. RESULTS: Psychiatrists at the NHNN saw 75% of patients. Treatment was initiated in 60% of these. During the 6-year follow up, many patients continued to be referred to neurologists and other specialists, but subsequent psychiatric referral was rare. Many changed their GP after discharge from the NHNN and a disproportionate number of re-referrals was made by GPs who had known their patients for less than 6 months. Psychological attribution of symptoms was rare and did not appear to be related to the pattern of referrals. CONCLUSION: The pattern of care of these patients was inconsistent and many felt dissatisfied with the treatment they received. This led to further referrals, unnecessary use of valuable resources and unnecessary exposure to iatrogenic damage. Further studies should aim to assist GPs and other clinicians in deciding when referral is likely to be beneficial.

Acute basal ganglia infarction in propionic acidemia.

An 8-year-old girl with propionic acidemia had acute and rapidly fatal symmetric necrosis of the caudate, globus pallidus, and putamen. Clinical presentation was with acute aphasia, generalized hypotonia, and muscle weakness. There was no evidence of metabolic decompensation, and analysis of the organic acids of the urine indicated good metabolic control. Organic acids in the cerebrospinal fluid were unremarkable. These observations indicate that the pathophysiology of "metabolic stroke" is more complicated than previously thought.