The endophytic fungus Piriformospora indica reprograms barley to salt-stress tolerance, disease resistance, and higher yield

Disease resistance strategies are powerful approaches to sustainable agriculture because they reduce chemical input into the environment. Recently, Piriformospora indica, a plant-root-colonizing basidiomycete fungus, has been discovered in the Indian Thar desert and was shown to provide strong growth-promoting activity during its symbiosis with a broad spectrum of plants. Here, we report on the potential of P. indica to induce resistance to fungal diseases and tolerance to salt stress in the monocotyledonous plant barley. The beneficial effect on the defense status is detected in distal leaves, demonstrating a systemic induction of resistance by a root-endophytic fungus. The systemically altered "defense readiness" is associated with an elevated antioxidative capacity due to an activation of the glutathione-ascorbate cycle and results in an overall increase in grain yield. Because P. indica can be easily propagated in the absence of a host plant, we conclude that the fungus could be exploited to increase disease resistance and yield in crop plants.     

Huntington's Disease (HD): Neurodegeneration of Brodmann's Primary Visual Area 17 (BA17)

Huntington's disease (HD), an autosomal dominantly inherited polyglutamine or CAG repeat disease along with somatomotor, oculomotor, psychiatric and cognitive symptoms, presents clinically with impairments of elementary and complex visual functions as well as altered visual‐evoked potentials (VEPs). Previous volumetric and pathoanatomical post‐mortem investigations pointed to an involvement of Brodmann's primary visual area 17 (BA17) in HD. Because the involvement of BA17 could be interpreted as an early onset brain neurodegeneration, we further characterized this potential primary cortical site of HD‐related neurodegeneration neuropathologically and performed an unbiased estimation of the absolute nerve cell number in thick gallocyanin‐stained frontoparallel tissue sections through the striate area of seven control individuals and seven HD patients using Cavalieri's principle for volume and the optical disector for nerve and glial cell density estimations. This investigation showed a reduction of the estimated absolute nerve cell number of BA17 in the HD patients (71 044 037 ± 12 740 515 nerve cells) of 32% in comparison with the control individuals (104 075 067 ± 9 424 491 nerve cells) (Mann–Whitney U‐test; P < 0.001). Additional pathoanatomical studies showed that nerve cell loss was most prominent in the outer pyramidal layer III, the inner granular layers IVa and IVc as well as in the multiform layer VI of BA17 of the HD patients. Our neuropathological results in BA17 confirm and extend previous post‐mortem, biochemical and in vivo neuroradiological HD findings and offer suitable explanations for the elementary and complex visual dysfunctions, as well as for the altered VEP observed in HD patients.     

Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis

OBJECTIVE: To evaluate bone metabolism in patients with ankylosing spondylitis (AS) and test the hypothesis that osteoprotegerin (OPG) serum concentrations are correlated with the severity of bone loss as assessed by bone mineral density (BMD) and biochemical markers of bone turnover. Osteoporosis occurs frequently in patients with AS and OPG represents a soluble decoy receptor that neutralizes receptor activator of nuclear factor-kB ligand (RANKL), an essential cytokine for osteoclast function. METHODS: Clinical data, radiographs of the spine, BMD of lumbar spine and the femur, biochemical markers of bone turnover, and serum levels of OPG were evaluated in 264 patients with AS (72% men) and 240 age-matched healthy controls (76% men). RESULTS: OPG serum levels were significantly lower in patients with AS compared to controls (1.84 +/- 1.15 vs 3.54 +/- 2.18 pmol/l, p < 0.001), and in contrast to controls, were not positively correlated with age. In addition, BMD of the hip and the femoral neck were significantly lower in patients with AS than in controls. There were positive correlations in patients with AS between BMD of the femoral neck and free testosterone serum levels in men and free estradiol serum levels in women, respectively. Patients with AS and osteoporosis had higher biochemical markers of bone resorption and inflammatory activity. CONCLUSION: Bone loss in patients with AS is associated with low sex steroid hormone serum levels, high biochemical markers of bone resorption and inflammatory activity, low OPG serum levels, and lack of compensatory age-related increase of OPG serum levels.     

Self-expandable metallic stents for malignant duodenal obstruction caused by biliary tract cancer

BACKGROUND: Malignant duodenal obstruction is a common event in patients with advanced biliary tract cancer. Because bypass surgery is accompanied by significant morbidity, self-expandable metallic stents have emerged as a possible alternative for palliation. METHODS: Twenty patients with biliary tract cancer (7 gallbladder, 13 Klatskin tumors) and duodenal obstruction were treated with metallic stents at a single institution between 1999 and 2001. Survival, morbidity, and stent function were studied prospectively. The ability to eat was assessed by using a scoring system. RESULTS: Stent placement was technically successful in all patients. An additional stent was required in 6 cases (4 occlusions, 2 dislocations). Median survival was 20.5 weeks; there was no treatment-related death. Twenty-eight biliary stent exchanges were performed in 13 (65%) patients. Erosive reflux esophagitis improved in 11 of 12 (92%) cases. After 4 weeks, all 17 surviving patients tolerated soft or solid food, whereas 13 of 17 (77%) tolerated a more solid diet (p < 0.001, gastric outlet obstruction scoring system). Twelve of 17 (71%) patients gained a median of 1.5 kg of body weight (p = 0.001). The median Karnofsky scale increased from 50% to 60% in 13 of 17 (77%) patients. CONCLUSIONS: Self-expandable metallic stents are a safe, efficacious, and minimally invasive treatment option for palliation of patients with duodenal obstruction from biliary tract cancer. Technical complications can be managed endoscopically and the bile duct remains accessible for endoluminal treatment.     

MALDI‐TOF Analysis of Halogen Telechelic Poly(methyl methacrylate)s and Poly(methyl acrylate)s Prepared by Atom Transfer Radical Polymerization (ATRP) or Single Electron Transfer‐Living Radical Polymerization (SET‐LRP)

Poly(methyl methacrylate)s (PMMA)s and poly(methyl acrylate)s (PMA)s are prepared by atom transfer radical polymerization (ATRP) or single electron transfer‐living radical polymerization (SET‐LRP) using methyl dichloroacetate (MDCA) and ethyl dibromoacetate (EDBA) as bifunctional initiators. The chain‐end functionality is determined by MALDI‐TOF mass spectrometry. The target PMMA (M_n = 2000 g mol^?1) and PMA (M_n = 2000 g mol^?1) samples obtained by ATRP of MMA and MA with MDCA as initiator have 12 and 81 mol% bis‐chloro end groups, respectively; those prepared by SET‐LRP have 57 and 100 mol% bis‐chloro end groups, respectively. The PMMAs obtained by ATRP or SET‐LRP with EDBA have no bromine end groups.

     

The many weak instruments problem and Mendelian randomization

Instrumental variable estimates of causal effects can be biased when using many instruments that are only weakly associated with the exposure. We describe several techniques to reduce this bias and estimate corrected standard errors. We present our findings using a simulation study and an empirical application. For the latter, we estimate the effect of height on lung function, using genetic variants as instruments for height. Our simulation study demonstrates that, using many weak individual variants, two‐stage least squares (2SLS) is biased, whereas the limited information maximum likelihood (LIML) and the continuously updating estimator (CUE) are unbiased and have accurate rejection frequencies when standard errors are corrected for the presence of many weak instruments. Our illustrative empirical example uses data on 3631 children from England. We used 180 genetic variants as instruments and compared conventional ordinary least squares estimates with results for the 2SLS, LIML, and CUE instrumental variable estimators using the individual height variants. We further compare these with instrumental variable estimates using an unweighted or weighted allele score as single instruments. In conclusion, the allele scores and CUE gave consistent estimates of the causal effect. In our empirical example, estimates using the allele score were more efficient. CUE with corrected standard errors, however, provides a useful additional statistical tool in applications with many weak instruments. The CUE may be preferred over an allele score if the population weights for the allele score are unknown or when the causal effects of multiple risk factors are estimated jointly. © 2014 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.     

Two-stage designs in bioequivalence trials

Purpose

The aim of this study is to assess the current status of non-fixed sample size designs in bioequivalence trials with a focus on two-stage adaptive approaches.

Methods

We searched PubMed and Google Scholar from inception to October 2014. Regulatory guidelines were obtained from the public domain. Different methods were compared by Monte Carlo simulations for their impact on the patient’s and producer’s risks.

Results

Add-on designs, group sequential designs and adaptive two-stage sequential designs are currently accepted to demonstrate bioequivalence in various regulations. All three approaches may inflate the patient’s risk if applied inconsiderately. Direct transfer of methods developed for superiority testing to bioequivalence is not warranted. Published two-stage frameworks maintain the type I error and generally the desired power. Adaptation based on the observed T/R ratio observed in the first stage should be applied with caution. Monte Carlo simulations are an efficient tool to explore the operating characteristics of methods.

Conclusions

Validated two-stage frameworks can be applied without requiring the sponsor to perform own simulations—which could further improve power based on additional assumptions. Two-stage designs are both ethical and economical alternatives to fixed sample designs.

     

Toxic optic neuropathies: an updated review

Toxic optic neuropathy (TON) is caused by the damage to the optic nerve through different toxins, including drugs, metals, organic solvents, methanol and carbon dioxide. A similar clinical picture may also be caused by nutritional deficits, including B vitamins, folic acid and proteins with sulphur‐containing amino acids. This review summarizes the present knowledge on disease‐causing factors, clinical presentation, diagnostics and treatment in TON. It discusses in detail known and hypothesized relations between drugs, including tuberculostatic drugs, antimicrobial agents, antiepileptic drugs, antiarrhythmic drugs, disulfiram, halogenated hydroquinolones, antimetabolites, tamoxifen and phosphodiesterase type 5 inhibitors and optic neuropathy.