Persistence of retinal function after intravitreal melphalan injection for retinoblastoma.

BACKGROUND: The risk/benefit profile of intravitreal melphalan injection for treatment of active vitreous seeds in retinoblastoma remains uncertain. We report clinical and electroretinography results after 6 months of one patient who has shown a favorable initial clinical response to intravitreal melphalan injections for treatment of refractory vitreous seeds. METHODS: Clinical case report. PATIENT: The patient presented at age 17 months with bilateral retinoblastoma [OD: International Classification (ICRB) group E, Reese-Ellsworth (R-E) class Vb; OS: ICRB D, R-E Vb] with no known prior family history. The right eye was enucleated primarily. The patient received systemic chemotherapy and extensive local treatment to the left eye. Ten months later, she presented with recurrent disease, including fine, diffuse vitreous seeds. Tumor control was established with intra-arterial chemotherapy and local treatment. Subsequent recurrence was treated with further intra-arterial chemotherapy, local treatment, and plaque radiotherapy with iodine-125. Persistent free-floating spherical vitreous seeds were treated with 4 cycles of intravitreal melphalan injection via the pars plana, with doses of 30, 30, 30, and 20 μg. RESULTS: After 6 months of follow-up, the left eye remained free of active tumor. Visual acuity was 20/40. Photopic ERGs amplitudes were unchanged compared with those recorded prior to the intravitreal injection treatments. CONCLUSIONS: Intravitreal melphalan injection for refractory spherical vitreous seeds of retinoblastoma with favorable tumor response is compatible with good central visual acuity and preservation of retinal function as indicated by photopic ERG recordings.

A monoclonal antibody which blocks the function of factor D of human complement.

Factor D is an essential enzyme for activation of complement by the alternative pathway (AP). It has been difficult to obtain mouse monoclonal antibodies (Mabs) which block the function of factor D. We have developed a strategy to obtain such Mabs using a double screening procedure of the initial clones. We selected the clone whose supernatant had the lowest level of anti-factor D Ab by ELISA and abolished factor D haemolytic activity. Addition of this Mab to human serum was shown to abolish conversion of C3 by cobra venom factor, haemolysis of rabbit erythrocytes, and activation of C3 and C5 by cuprophane dialysis membranes.

Alteration in neuromuscular function after a 5 km running time trial.

The aim of this study was to characterize the effect of a 5 km running time trial on the neuromuscular properties of the plantar flexors. Eleven well-trained triathletes performed a series of neuromuscular tests before and immediately after the run on a 200 m indoor track. Muscle activation (twitch interpolation) and normalized EMG activity were assessed during maximal voluntary contraction (MVC) of plantar flexors. Maximal soleus H-reflexes and M-waves were evoked at rest (i.e. H (MAX) and M (MAX), respectively) and during MVC (i.e. H (SUP) and M (SUP), respectively). MVC significantly declined (-27%; P < 0.001) after the run, due to decrease in muscle activation (-8%; P < 0.05) and M (MAX)-normalized EMG activity (-13%; P < 0.05). Significant reductions in M-wave amplitudes (M (MAX): -13% and M (SUP): -16%; P < 0.05) as well as H (MAX)/M (MAX) (-37%; P < 0.01) and H (SUP)/M (SUP) (-25%; P < 0.05) ratios occurred with fatigue. Following exercise, the single twitch was characterized by lower peak torque (-16%; P < 0.001) as well as shorter contraction (-19%; P < 0.001) and half-relaxation (-24%; P < 0.001) times. In conclusion, the reduction in plantar flexors strength induced by a 5 km running time trial is caused by peripheral adjustments, which are attributable to a failure of the neuromuscular transmission and excitation-contraction coupling. Fatigue also decreased the magnitude of efferent motor outflow from spinal motor neurons to the plantar flexors and part of this suboptimal neural drive is the result of an inhibition of soleus motoneuron pool reflex excitability.

Skeletal muscle mitochondria in the elderly: effects of physical fitness and exercise training.

CONTEXT: Sarcopenia is thought to be associated with mitochondrial (Mito) loss. It is unclear whether the decrease in Mito content is consequent to aging per se or to decreased physical activity. OBJECTIVES: The objective of the study was to examine the influence of fitness on Mito content and function and to assess whether exercise could improve Mito function in older adults. DESIGN AND SUBJECTS: Three distinct studies were conducted: 1) a cross-sectional observation comparing Mito content and fitness in a large heterogeneous cohort of older adults; 2) a case-control study comparing chronically endurance-trained older adults and sedentary (S) subjects matched for age and gender; and 3) a 4-month exercise intervention in S. SETTING: The study was conducted at a university-based clinical research center. OUTCOMES: Mito volume density (MitoVd) was assessed by electron microscopy from vastus lateralis biopsies, electron transport chain proteins by Western blotting, mRNAs for transcription factors involved in M biogenesis by quantitative RT-PCR, and in vivo oxidative capacity (ATPmax) by (31)P-magnetice resonance spectroscopy. Peak oxygen uptake was measured by graded exercise test. RESULTS: Peak oxygen uptake was strongly correlated with MitoVd in 80 60- to 80-year-old adults. Comparison of chronically endurance-trained older adults vs S revealed differences in MitoVd, ATPmax, and some electron transport chain protein complexes. Finally, exercise intervention confirmed that S subjects are able to recover MitoVd, ATPmax, and specific transcription factors. CONCLUSIONS: These data suggest the following: 1) aging per se is not the primary culprit leading to Mito dysfunction; 2) an aerobic exercise program, even at an older age, can ameliorate the loss in skeletal muscle Mito content and may prevent aging muscle comorbidities; and 3) the improvement of Mito function is all about content.

Disorders of pupillary structure and function.

Neurologists are frequently consulted because of a pupillary abnormality. An unequal size of the pupils, an unusual shape, white colored pupils, or a poorly reactive pupil are common reasons for referral. A directed history and careful observation of the iris and pupil movements can bear out ocular pathology such as congenital or structural anomalies as the cause of abnormal pupils. Thereafter, it is important to evaluate the neurologic causes of anisocoria and poor pupil function. The first part of this article emphasizes pupillary abnormalities frequently encountered in infants and children and discusses some of the more common acquired iris structural defects. The second part focuses on evaluation of lesions in the neural pathways that result in pupillary dysfunction, with particular attention to those conditions having neurologic, systemic, or visual implications.

Cloning and expression of rat pancreatic beta-cell malonyl-CoA decarboxylase.

To gain insight into the function and regulation of malonyl-CoA decarboxylase (MCD) we have cloned rat MCD cDNA from a differentiated insulin-secreting pancreatic beta-cell-line cDNA library. The full-length cDNA sequence shows 69% identity with the cDNA cloned previously from the goose uropygial gland, and predicts a 492 amino acid protein of 54.7 kDa. The open reading frame contains an N-terminal mitochondrial targeting sequence and the C-terminal part of the enzyme ends with a peroxisomal (Ser-Lys-Leu) targeting motif. Since the sequence does not reveal hydrophobic domains, MCD is most likely expressed in the mitochondrial matrix and inside the peroxisomes. A second methionine residue, located 3' of the mitochondrial presequence, might be the first amino acid of a putative cytosolic MCD, since the nucleotide sequence around it fits fairly well with a consensus Kozak site for translation initiation. However, primer extension detects the presence of only one transcript initiating upstream of the first ATG, indicating that the major, if not exclusive, transcript expressed in the pancreatic beta-cell encodes MCD with its mitochondrial presequence. The sequence also shows multiple possible sites of phosphorylation by casein kinase II and protein kinase C. mRNA tissue-distribution analysis indicates a transcript of 2.2 kb, and that the MCD gene is expressed over a wide range of rat tissues. The distribution of the enzyme shows a broad range of activities from very low in the brain to elevated in the liver and heart. The results provide the foundations for further studies of the role of MCD in lipid metabolism and metabolic signalling in various tissues.

Pulmonary artery pressure and cardiac function in children and adolescents after rapid ascent to 3,450 m.

High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high-altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean ± SD; age: 11 ± 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 ± 11 vs. 16 ± 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude-induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 ± 12 vs. 13 ± 8 mmHg; P = 0.004). Even in children with the most severe altitude-induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located.

Obesity in an ageing society implications for health, physical function and health service utilisation.

Key Findings • Based on body mass index (BMI) measurements, 36% of Irish over 50s are obese and a further 43% are overweight. • Based on waist circumference measurements, 52% of Irish over 50s are ‘centrally obese’, i.e., with a ‘substantially increased’ waist circumference, while a further 25% have an ‘increased’ waist circumference. • Using BMI as an indicator of obesity, a higher proportion of men (38%) are obese than women (33%); however, using waist circumference as an indicator of obesity, a higher proportion of women (56%) have a ‘substantially increased’ waist circumference than men (48%). • The prevalence of obesity in Irish men over 50 is comparable with US men over 50 (while English rates are much lower).     .This resource was contributed by The National Documentation Centre on Drug Use.

Biochemical analysis of female mice urine with reference to endocrine function: a key tool for estrus detection.

Species-specific chemical signals released through urine, sweat, saliva and feces are involved in communication between animals. Urinary biochemical constituents along with pheromones may contribute to variation across reproductive cycles and facilitate to estrus detection. Hence, the present study was designed to analyze such biochemical profiles, such as proteins, carbohydrates, lipids, fatty acids, in response with steroid hormones such as estradiol and progesterone. The experimental groups were normal, prepubertal, ovariectomized, and ovariectomized with estrogentreated female mice. In normal mice, the protein and lipid concentrations in urine were significantly higher in proestrus and estrus phases and the quantity of fatty acids was also comparatively higher in estrus. Furthermore, certain fatty acids, namely tridecanoic, palmitic and oleic acids, were present during proestrus and estrus phases, but were exclusively absent in ovariectomized mice. However, the carbohydrate level was equally maintained throughout the four phases of estrous cycle. For successful communication, higher concentrations of protein and specific fatty acids in estrus are directly involved. The significant increase in estradiol at estrus and progesterone at metestrus seems to be of greater importance in the expression pattern of biochemical constituents and may play a notable role in estrous cycle regulation. Thus, we conclude that the variations observed in the concentration of the biochemical constituents depend on the phase of the reproductive cycle as well as hormonal status of animals. The appearance of protein and specific fatty acids during estrus phase raises the possibility to use these as a urinary indicators for estrus detection.

Autonomic Function Is Impaired in Elderly Stroke Survivors

Impaired autonomic function is common in the acute poststroke phase but little is known about the longer term effects, particularly in older people. This study sought to determine if autonomic function is impaired after stroke recovery in older patients. This is a cross-sectional case-control study comparing autonomic function in 76 nondemented stroke patients with 70 community-living controls aged older than 75 years.

Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment

Physical activity is beneficial for healthy ageing. It may also help maintain good cognitive function in older age. Aerobic activity improves cardiovascular fitness, but it is not known whether this sort of fitness is necessary for improved cognitive function.��Eleven studies of aerobic physical activity programmes for healthy people over the age of 55 years have been included in this review. Eight of these 11 studies reported that aerobic exercise interventions resulted in increased fitness of the trained group and an improvement in at least one aspect of cognitive function. The largest effects were on cognitive speed, auditory and visual attention. However, the cognitive functions which improved were not the same in each study and the majority of comparisons yielded no significant results.��The data are insufficient to show that the improvements in cognitive function which can be attributed to physical exercise are due to improvements in cardiovascular fitness.

The fou2 gain-of-function allele and the wild-type allele of Two Pore Channel 1 contribute to different extents or by different mechanisms to defense gene expression in Arabidopsis.

The fatty acid oxygenation up-regulated 2 (fou2) mutant in Arabidopsis thaliana creates a gain-of-function allele in a non-selective cation channel encoded by the Two Pore Channel 1 (TPC1) gene. This mutant genetically implicates cation fluxes in the control of the positive feedback loop whereby jasmonic acid (JA) stimulates its own synthesis. In this study we observed extensive transcriptome reprogramming in healthy fou2 leaves closely resembling that induced by treatment with methyl jasmonate, biotic stresses and the potassium starvation response. Proteomic analysis of fou2 leaves identified increased levels of seven biotic stress- and JA-inducible proteins. In agreement with these analyses, epistasis studies performed by crossing fou2 with aos indicated that elevated levels of JA in fou2 are the major determinant of the mutant phenotype. In addition, generation of fou2 aba1-5, fou2 etr1-1 and fou2 npr1-1 double mutants showed that the fou2 phenotype was only weakly affected by ABA levels and unaffected by mutations in NPR1 and ETR1. The results now suggest possible mechanisms whereby fou2 could induce JA synthesis/signaling early in the wound response. In contrast to fou2, transcriptome analysis of a loss-of-function allele of TPC1, tpc1-2, revealed no differential expression of JA biosynthesis genes in resting leaves. However, the analysis disclosed reduced mRNA levels of the pathogenesis-related genes PDF1.2a and THI2.1 in healthy and diseased tpc1-2 leaves. The results suggest that wild-type TPC1 contributes to their expression by mechanisms somewhat different from those affecting their expression in fou2.

Role of the transcriptional factor C/EBPbeta in free fatty acid-elicited beta-cell failure.

Fatty acids can favour the development of Type 2 diabetes by reducing insulin secretion and inducing apoptosis of pancreatic beta-cells. Here, we show that sustained exposure of the beta-cell line MIN6 or of isolated pancreatic islets to the most abundant circulating fatty acid palmitate increases the level of C/EBPbeta, an insulin transcriptional repressor. In contrast, two unsaturated fatty acids, oleate and linoleate were without effect. The induction of C/EBPbeta elicited by palmitate was prevented by inhibiting the ERK1/2 MAP kinase pathway or by reducing mitochondrial fatty acid oxidation with an inhibitor of Carnitine Palmitoyl Transferase-1. Overexpression of C/EBPbeta mimicked the detrimental effects of palmitate and resulted in a drastic reduction in insulin promoter activity, impairment in the capacity to respond to secretory stimuli and an increase in apoptosis. Our data suggest a potential involvement of C/EBPbeta as mediator of the deleterious effects of unsaturated free fatty acids on beta-cell function.