Miracle-dz/UniFAR-FTUs huggingface dataset:
Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment.

OBJECTIVE To assess the benefit of increased follow-up and treatment with ranibizumab between months 24 and 36 in the Ranibizumab for Edema of the Macula in Diabetes (READ-2) Study. DESIGN Prospective, interventional, multicenter follow-up of a randomized clinical trial. METHODS Patients who agreed to participate between months 24 and 36 (ranibizumab, 28 patients; laser, 22; and ranibizumab + laser, 24) returned monthly and received ranibizumab, 0.5 mg, if foveal thickness (FTH, center subfield thickness) was 250 μm or greater. Main outcome measures were improvement in best-corrected visual acuity (BCVA) and reduction in FTH between months 24 and 36. RESULTS Mean improvement from the baseline BCVA in the ranibizumab group was 10.3 letters at month 36 vs 7.2 letters at month 24 (ΔBCVA letters = 3.1, P = .009), and FTH at month 36 was 282 μm vs 352 μm at month 24 (ΔFTH = 70 μm, P = .006). Changes in BCVA and FTH in the laser group (-1.6 letters and -36 μm, respectively) and the ranibizumab + laser group (+2.0 letters and -24 μm) were not statistically significant. The mean number of ranibizumab injections was significantly greater in the ranibizumab group compared with the laser group (5.4 vs 2.3 injections, P = .008) but not compared with the ranibizumab + laser group (3.3, P = .11). CONCLUSIONS More aggressive treatment with ranibizumab during year 3 resulted in a reduction in mean FTH and improvement in BCVA in the ranibizumab group. More extensive focal/grid laser therapy in the other 2 groups may have reduced the need for more frequent ranibizumab injections to control edema. APPLICATION TO CLINICAL PRACTICE Long-term visual outcomes for treatment of diabetic macular edema with ranibizumab are excellent, but many patients require frequent injections to optimally control edema and maximize vision. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00407381
Use of an oral stable isotope label to confirm variation in red blood cell mean age that influences HbA1c interpretation

HbA1c is commonly used to monitor glycemic control. However, there is growing evidence that the relationship between HbA1c and mean blood glucose (MBG) is influenced by variation in red blood cell (RBC) lifespan in hematologically normal individuals. Correction of HbA1c for mean RBC age (MRBC) requires a noninvasive, accurate, and affordable method to measure RBC survival. In this study, we evaluated whether a stable isotope approach would satisfy these requirements. RBC lifespan and MRBC were determined in a group of nine hematologically normal diabetic and nondiabetic subjects using oral 15N‐glycine to label heme in an age cohort of RBC. The MRBC was 58.7 ± 9.1 (2SD) days and RBC lifespan was 106 ± 21 (2SD) days. This degree of variation (±15–20%) is consistent with previous studies using other techniques. In a subset of seven subjects, MRBC determined with the biotin label technique were available from approximately five years prior, and strongly correlated with the stable isotope values (R2 = 0.79). This study suggests that the MRBC is stable over time but varies substantially among individuals, and supports the importance of its variation in HbA1c interpretation. The characteristics of the stable isotope method support its suitability for studies to directly evaluate the impact of variation in MRBC on the interpretation of HbA1c. Am. J. Hematol. 90:50–55, 2015. © 2014 Wiley Periodicals, Inc.
The importance of renal ammonia metabolism to whole body acid-base balance: a reanalysis of the pathophysiology of renal tubular acidosis.

Traditionally, the renal collecting duct has been assigned the dual role of (1) secreting protons derived from dietary metabolism to form luminal NH4+ and titratable acid and (2) generating new HCO3-. This view has recently been challenged. According to current concepts, whole body proton balance is maintained predominantly by the lungs which excrete protons derived from dietary metabolism as the acid anhydride CO2. In the process of excreting CO2, HCO3- is also lost from the body. It is the function of the kidney to generate new HCO3- to replenish this loss. The major site of new HCO3- generation is the proximal tubule rather than the collecting duct. New HCO3- is generated predominantly via the metabolism of organic anions, i.e. alpha-ketoglutarate, citrate, lactate, fatty acids. In the process of generating alpha-ketoglutarate from glutamine, NH4+ is formed. Under normal acid-base conditions, 50% of the NH4+ produced is excreted in the urine, and the remaining 50% is delivered to the renal veins. NH4+ delivered to the renal veins consumes HCO3- during ureagenesis. In the discussion which follows, these new concepts are reviewed and applied to an analysis of the pathophysiology of renal tubular acidosis.
Rasagiline: an anti-Parkinson drug with neuroprotective activity

Mitochondria are now recognized as potent integrators and co-ordinators of cell survival/death and apoptosis. Therefore, they are pharmacological targets for induction or correction of excessive cell death in human pathology, which includes cancer and the neurodegenerative disorders Parkinson’s and Alzheimer’s disease. One such agent is the anti-Parkinson drug, rasagiline, a novel neuroprotective–antiapoptotic second-generation potent irreversible selective inhibitor of monoamine oxidase B. It prevents the neurotoxin-initiated demise of mitochondria via modulation of cell survival/death Bcl-2 family proteins, Bcl-2–Bax, at the mitochondria permeability transition pore, which regulates voltage-dependent anion channels. It may also induce long-term potentiation – a consequence of its protein kinase C-dependent mitogen-activated protein kinase pathway activation. Rasagiline, unlike selegiline, is devoid of sympathomimetic action and is not metabolized to neurotoxic methamphetamine, but to aminoindan. Its neuroprotective activity is attributed to the aminoindan and propargylamine moieties and structural resemblance to certain metabotrophic glutamate 1 receptor antagonists. Ragagiline has been chosen for neuroprotective studies by the National Institutes of Health as a possible disease-modifying agent.
Degradation of p27Kip cdk inhibitor triggered by Kaposi's sarcoma virus cyclin–cdk6 complex

The Kaposi's sarcoma‐associated human herpesvirus 8 (KSHV/HHV8) encodes a protein similar to cellular cyclins. This cyclin is most closely related to cellular D‐type cyclins, but biochemically it behaves atypically in various respects. Complexes formed between the viral cyclin and the cyclin‐dependent kinase subunit, cdk6, can phosphorylate a wider range of substrates and are resistant to cdk inhibitory proteins. We show here that the KSHV‐cyclin–cdk6 complex phosphorylates p27Kip on a C‐terminal threonine that is implicated in destabilization of this cdk inhibitor. Expression of the viral cyclin in tissue culture cells overcomes a cell cycle block by p27Kip. However, full cell‐cycle transit of these cells appears to depend on C‐terminal phosphorylation of p27Kip and seems to involve transactivation of other cellular cyclin‐dependent kinases. A p27Kip‐phosphorylating cdk6 complex exists in cell lines derived from primary effusion lymphoma and in Kaposi's sarcoma, this indicating that virally induced p27Kip degradation may occur in KSHV‐associated tumours.
Radiographic progression of rheumatoid arthritis in patients from the Czech National Registry receiving infliximab treatment.

OBJECTIVE To evaluate the clinical status and radiographic progression in patients with rheumatoid arthritis (RA) being followed by the Czech National Registry of biological treatments. METHODS Patients who failed at least two disease-modifying antirheumatic drugs and had high disease activity (DAS28 > 5.1) were treated with infliximab. Radiographic progression was measured with a modified version of the Sharp score (TSS) after 54 weeks of treatment. RESULTS Ninety-nine patients with an average disease duration of 13.7 years were enrolled. The DAS28 dropped from 6.66 to 4.07 (p < 0.001). Before treatment the mean TSS was 90.1 and the mean estimated yearly disease progression was 8.56. After 54 weeks of infliximab, radiographic progression was 4.15 times slower than the estimated rate before treatment and 63 patients did not show any radiographic progression at all. In the remaining 36 patients, the progression rate slowed to 3.8 +/- 0.9 from the estimated TSS of 10.9 +/- 6.9 before the initiation of treatment (p = 0.011). CONCLUSION Data derived from the Czech National Registry, which reflect general clinical practice, show a significant retardation of radiographic progression in patients treated with anti-TNF and the magnitude of the improvement seen is similar to results from clinical trials.
The Mitochondrial Quality Control Protein Yme1 Is Necessary to Prevent Defective Mitophagy in a Yeast Model of Barth Syndrome*

Background: Barth syndrome is an inherited cardiomyopathy due to mutations in the TAZ gene. Results: A screen using taz1Δ yeast cells identified genes whose deletion aggravated its fitness. Conclusion: The protease Yme1 is required for efficient mitophagy in the absence of TAZ1. Significance: This is the first study linking mitochondrial quality control to mitophagy as important in cells lacking TAZ1 function. The Saccharomyces cerevisiae TAZ1 gene is an orthologue of human TAZ; both encode the protein tafazzin. Tafazzin is a transacylase that transfers acyl chains with unsaturated fatty acids from phospholipids to monolysocardiolipin to generate cardiolipin with unsaturated fatty acids. Mutations in human TAZ cause Barth syndrome, a fatal childhood cardiomyopathy biochemically characterized by reduced cardiolipin mass and increased monolysocardiolipin levels. To uncover cellular processes that require tafazzin to maintain cell health, we performed a synthetic genetic array screen using taz1Δ yeast cells to identify genes whose deletion aggravated its fitness. The synthetic genetic array screen uncovered several mitochondrial cellular processes that require tafazzin. Focusing on the i-AAA protease Yme1, a mitochondrial quality control protein that degrades misfolded proteins, we determined that in cells lacking both Yme1 and Taz1 function, there were substantive mitochondrial ultrastructural defects, ineffective superoxide scavenging, and a severe defect in mitophagy. We identify an important role for the mitochondrial protease Yme1 in the ability of cells that lack tafazzin function to maintain mitochondrial structural integrity and mitochondrial quality control and to undergo mitophagy.
Is auditing the new evaluation? Can it be? Should it be?

Purpose The purpose of this paper is to study the changing relationship between auditing and evaluation. Over the past several years, supreme auditing institutions (SAIs) in a number of advanced democracies have evolved from conventional auditing institutions to becoming increasingly concerned with assisting policy change and administrative reform in the public sector; tasks that are traditionally associated with evaluation. The paper discusses the potential consequences of this development for the SAIs themselves as well as for the audited and reforming institutions and for policy-making. Design/methodology/approach The paper uses qualitative method and draws on the extensive literature on auditing and evaluation. The analysis has also benefitted from the authors’ recent comparative research on SAIs. Findings The findings, summarized in six points, are that the growth of auditing in areas previously assigned to evaluators, has led to a shortened time perspective; stronger emphasis on the administration of policies; increased focus on efficiency of the audited entity; greater independence from the evaluated organizations; a shift in receiver of information toward the legislature and/or the public; and improved communication. Practical implications Evaluation as a professional and scholarly field has developed theories and advanced methods to assess the effectiveness of public programs. The growth of auditing may thus change the focus and quality of policy evaluation. Originality/value The paper speaks to both scholars and practitioners. To the best of the knowledge a similar analysis has not been done before.
The Exclusion of High Trauma Fractures May Underestimate the Prevalence of Bone Fragility Fractures in the Community: The Geelong Osteoporosis Study

Fractures associated with severe trauma are generally excluded from estimates of the prevalence of osteoporotic fractures in the community. Because the degree of trauma is difficult to quantitate, low bone mass may contribute to fractures following severe trauma. We ascertained all fractures in a defined population and compared the bone mineral density (BMD) of women who sustained fractures in either “low” or “high” trauma events with the BMD of a random sample of women from the same population. BMD was measured by dual‐energy X‐ray absorptiometry and expressed as a standardized deviation (Z score) adjusted for age. The BMD Z scores (mean ± SEM) were reduced in both the low and high trauma groups, respectively: spine‐posterior‐anterior (−0.50 ± 0.05 and −0.21 ± 0.08), spine‐lateral (−0.28 ± 0.06 and −0.19 ± 0.10), femoral neck (−0.42 ± 0.04 and −0.26 ± 0.09), Ward's triangle (−0.44 ± 0.04 and −0.28 ± 0.08), trochanter (−0.44 ± 0.05 and −0.32 ± 0.08), total body (−0.46 ± 0.06 and −0.32 ± 0.08), ultradistal radius (−0.47 ± 0.05 and −0.42 ± 0.07), and midradius (−0.52 ± 0.06 and −0.33 ± 0.09). Except at the PA spine, the deficits were no smaller in the high trauma group. Compared with the population, the age‐adjusted odds ratio for osteoporosis (t‐score < −2.5) at one or more scanning sites was 3.1 (95% confidence interval 1.9, 5.0) in the high trauma group and 2.7 (1.9, 3.8) in the low trauma group. The data suggest that the exclusion of high trauma fractures in women over 50 years of age may result in underestimation of the contribution of osteoporosis to fractures in the community. Bone density measurement of women over 50 years of age who sustain fractures may be warranted irrespective of the classification of trauma.
Heart-Rate Variability and Blood-Lactate Threshold Interaction During Progressive Resistance Exercise in Healthy Older Men

Simões, RP, Mendes, RG, Castello, V, Machado, HG, Almeida, LB, Baldissera, V, Catai, AM, Arena, R, and Borghi-Silva, A. Heart-rate variability and blood-lactate threshold interaction during progressive resistance exercise in healthy older men. J Strength Cond Res 24(5): 1313-1320, 2010-The objective of this study was to (a) evaluate the impact of the leg press, at variable percentages of 1 repetition maximum (1RM), on heart rate variability (HRV) and blood lactate and (b) determine the relationship between HRV with blood lactate in a healthy elderly cohort. Ten healthy men (64 ± 4 years) participated in a progressive leg-press protocol to maximal exertion. Initially, 1RM for the leg press was determined for all subjects. The protocol then began at 10% of 1RM, with subsequent increases of 10% until 30% of 1RM, followed by incremental adjustments of 5% until exhaustion. The measurement of instantaneous R-R interval variability from Poincare plots (SD1 and SD2) and time domain indexes (RMSSD and RMSM), blood pressure, and blood lactate were obtained at rest and all leg-press loads. Significant alterations of HRV and blood lactate were observed from 30% of 1RM leg press (p < 0.05). Additionally, significant correlations were found between the lactate threshold (LT) and the RMSSD threshold (r = 0.78; p < 0.01), and between the LT and SD1 threshold (r = 0.81, p < 0.01). We conclude that metabolic and cardiovascular alterations are apparent during relatively low resistance exercise (RE) loads in apparently healthy subjects. In addition, HRV indexes were associated with blood-lactate levels during RE. The practical applications is the possibility of using HRV as a noninvasive measure obtained at a relatively low cost may be used to identify neural and metabolic alterations during RE in older subjects.
Unveiling microbial life in the new deep-sea hypersaline Lake Thetis. Part II: a metagenomic study.

So far only little is known about the microbial ecology of Mediterranean deep-sea hypersaline anoxic lakes (DHALs). These brine lakes were formed by evaporite dissolution/brine seeps and are important model environments to provide insights into possible metabolisms and distributions of microorganisms on the early Earth. Our study on the Lake Thetis, a new thalassohaline DHAL located South-East of the Medriff Corridor, has revealed microbial communities of contrasting compositions with a high number of novel prokaryotic candidate divisions. The major finding of our present work is co-occurrence of at least three autotrophic carbon dioxide fixation pathways in the brine-seawater interface that are likely fuelled by an active ramified sulphur cycle. Genes for the reductive acetyl-CoA and reductive TCA pathways were also found in the brine suggesting that these pathways are operational even at extremely elevated salinities and that autotrophy is more important in hypersaline environments than previously assumed. Surprisingly, genes coding for RuBisCo were found in the highly reduced brine. Three types of sulphide oxidation pathways were found in the interface. The first involves a multienzyme Sox complex catalysing the complete oxidation of reduced sulphur compounds to sulphate, the second type recruits SQR sulphide:quinone reductase for oxidation of sulphide to elemental sulphur, which, in the presence of sulphide, could further be reduced by polysulphide reductases in the third pathway. The presence of the latter two allows a maximal energy yield from the oxidation of sulphide and at the same time prevents the acidification and the accumulation of S(0) deposits. Amino acid composition analysis of deduced proteins revealed a significant overrepresentation of acidic residues in the brine compared with the interface. This trait is typical for halophilic organisms as an adaptation to the brine's extreme hypersalinity. This work presents the first metagenomic survey of the microbial communities of the recently discovered Lake Thetis whose brine constitutes one of saltiest water bodies ever reported.
Dichotomizing continuous predictors in multiple regression: a bad idea

In medical research, continuous variables are often converted into categorical variables by grouping values into two or more categories. We consider in detail issues pertaining to creating just two groups, a common approach in clinical research. We argue that the simplicity achieved is gained at a cost; dichotomization may create rather than avoid problems, notably a considerable loss of power and residual confounding. In addition, the use of a data‐derived ‘optimal’ cutpoint leads to serious bias. We illustrate the impact of dichotomization of continuous predictor variables using as a detailed case study a randomized trial in primary biliary cirrhosis. Dichotomization of continuous data is unnecessary for statistical analysis and in particular should not be applied to explanatory variables in regression models. Copyright © 2005 John Wiley & Sons, Ltd.
The biology of normal bone remodelling

&NA; During life, bone undergoes modelling and remodelling in order to grow or change shape. Bone modelling is the process by which bones change shape or size in response to physiologic influences or mechanical forces that are encountered by the skeleton, while bone remodelling takes place so that bone may maintain its strength and mineral homeostasis. During early childhood, both bone modelling (the formation and shaping of bone) and bone remodelling (the replacement or renewal of old bone) occur. The predominant process in childhood is bone modelling, while in adulthood bone remodelling predominates. The exception to this is after a fracture when we see massive increases in bone formation. During childhood and adolescence growth occurs in the bones longitudinally and radially, while in the growth plates it occurs longitudinally, thus promoting growth in size. Cartilage first proliferates in the epiphyseal and metaphyseal areas of long bones before undergoing mineralisation to form new bone.
Personal relative deprivation associated with functional disorders via stress: An examination of fibromyalgia and gastrointestinal symptoms

Background Personal relative deprivation is a negative social comparison process typified by self-comparison, negative appraisal, and resultant negative emotionality. Personal relative deprivation has been associated with poorer physical and mental health in several domains. It has been hypothesized that the deprivation-health link operates through a stress pathway. Stress has been specifically implicated in the onset and maintenance of functional disorders, including fibromyalgia and functional gastrointestinal disorders. Despite the theoretical links between personal deprivation, stress, and functional disorders, researchers have not assessed relationships between these variables. Methods We recruited community participants (n = 517; 54.9% female) to examine whether personal relative deprivation can account for variance in fibromyalgia and functional gastrointestinal symptoms beyond known demographic correlates of physical health. We also examined whether the relationships between personal relative deprivation and functional disorder symptoms are mediated by stress. Results Consistent with our hypotheses, personal relative deprivation accounted for symptom variance in fibromyalgia and functional gastrointestinal disorders beyond that accounted for by demographic variables alone. Further, self-reported stress was found to mediate relationships between personal relative deprivation and fibromyalgia and gastrointestinal symptoms. Conclusions The current results support biopsychosocial models of physical health and suggest that, for patients presenting with functional disorders symptoms, a combination of biological and psychosocial interventions may be warranted.
Improved cross polarization and wideband multilayer wide-slot microstrip antenna with rotated parasitic patch

A single feed, compact and wideband microstrip patch antenna (MSPA) with high gain and low circular polarization is presented. The proposed antenna structure consists of two layers of the substrate. The lower or feeding substrate consists of an elliptical wide-slot and a 50 Ω microstrip line to excite this slot. The elliptical wide-slot generates two resonances, i.e. lower f1 (4.3 GHz) and higher f2 (7 GHz). An elliptical parasitic patch is placed on the upper or antenna substrate to improve the impedance bandwidth (IBW). A low cross-polarization (XP) is achieved by rotating the parasitic patch around its center. Simulation results show that the IBW for 10-dB return loss of 3.84–7.78 GHz (or 91.63%) is obtained. The antenna has the gain ranging from 6 dB to 11 dB. At f1, minimum isolation of 34.63 dB in E-plane and 35 dB in H-plane and 33.69 dB in E-plane and 25.35 dB in H-plane for f2 is achieved. A stable and nearly omnidirectional radiation patterns are obtained for the given operating frequency range.