Alien vs. predator: bacterial challenge alters coral microbiomes unless controlled by Halobacteriovorax predators.
Coral microbiomes are known to play important roles in organismal health, response to environmental stress, and resistance to disease. The coral microbiome contains diverse assemblages of resident bacteria, ranging from defensive and metabolic symbionts to opportunistic bacteria that may turn harmful in compromised hosts. However, little is known about how these bacterial interactions influence the mechanism and controls of overall structure, stability, and function of the microbiome. We sought to test how coral microbiome dynamics were affected by interactions between two bacteria: Vibrio coralliilyticus, a known temperature-dependent pathogen of some corals, and Halobacteriovorax, a unique bacterial predator of Vibrio and other gram-negative bacteria. We challenged reef-building coral with V. coralliilyticus in the presence or absence of Halobacteriovorax predators, and monitored microbial community dynamics with 16S rRNA gene profiling time-series. Vibrio coralliilyticus inoculation increased the mean relative abundance of Vibrios by greater than 35% from the 4 to 8 hour time point, but not in the 24 & 32 hour time points. However, strong secondary effects of the Vibrio challenge were also observed for the rest of the microbiome such as increased richness (observed species), and reduced stability (increased beta-diversity). Moreover, after the transient increase in Vibrios, two lineages of bacteria (Rhodobacterales and Cytophagales) increased in coral tissues, suggesting that V. coralliilyticus challenge opens niche space for these known opportunists. Rhodobacterales increased from 6.99% (±0.05 SEM) to a maximum mean relative abundance of 48.75% (±0.14 SEM) in the final time point and Cytophagales from <0.001% to 3.656%. Halobacteriovorax predators are commonly present at low-abundance on coral surfaces. Based on the keystone role of predators in many ecosystems, we hypothesized that Halobacteriovorax predators might help protect corals by consuming foreign or "alien" gram negative bacteria. Halobacteriovorax inoculation also altered the microbiome but to a lesser degree than V. coralliilyticus, and Halobacteriovorax were never detected after inoculation. Simultaneous challenge with both V. coralliilyticus and predatory Halobacteriovorax eliminated the increase in V. coralliilyticus, ameliorated changes to the rest of the coral microbiome, and prevented the secondary blooms of opportunistic Rhodobacterales and Cytophagales seen in the V. coralliilyticus challenge. These data suggest that, under certain circumstances, host-associated bacterial predators may mitigate the ability of other bacteria to destabilize the microbiome.


ABO blood grouping on dental tissue.
Twenty-five permanent teeth, including eight carious ones whose pulp cavities had been exposed, were used for this research 3-5 weeks after extraction. Phosphate-buffered saline (PBS, at pH 7.2) was employed to extract ABO blood group substance from tooth powder. ABO grouping was performed on blood-stained compresses from the extraction wound (as controls), tooth fragment, tooth powder, and cotton fibers immersed in PBS extract by absorption-elution (AE) technique and on the PBS extracts by the two-dimensional absorption-inhibition (2-D AI) technique. It was found that blood grouping in PBS extracts by 2-D AI yielded reliable results: no false positive results, and a high rate of correct grouping, (24/25), while blood grouping on other dental materials, such as tooth fragments, tooth powders, immersed fibers, by AE gave an unacceptable rate of false positive/negative results.


The immunoglobulin fold. Structural classification, sequence patterns and common core.
Since the first crystal structure of an immunoglobulin revealed a modular architecture, the characteristic beta-sheet fold of the immunoglobulin domain has been found in many other proteins of diverse biological function. Here, a systematic comparison of 23 Ig domain structures with less than 25% pairwise residue identity was performed using automatic structural alignment and analysis of beta-sheet and loop topology. Sequence consensus patterns were identified for nine distinct families with at most marginal similarity to each other. The analysis reveals a common structural core of only four beta-strands (b, c, e and f), embedded in an antiparallel curled beta-sheet sandwich with a total of three to five additional strands (a, c', c'', d, g) and a characteristic intersheet angle. The variation in the position of the edge strands (a, c', c'', d and g) relative to the common core defines four different topological subtypes that correlate with the length of the intervening sequence between strands c and e, the most variable region in sequence. The switch of strand c' from one sheet to the other in seven-stranded domains appears to result from short c-e segments, rather than being a major structural discriminator. The high degree of structural flexibility outside the common core and the extreme variability of side-chain packing inside the core do not support a protein folding pathway common to all members of the structural class. Mutation rates of immunoglobulin-like domains in different proteins vary considerably. Disulfide bridges, thought to contribute to structural stability, are not necessarily invariant in number and location within a subclass.


Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs.
Based on our recent X-ray crystallographic determination of the structure of acetylcholinesterase (AChE) from Torpedo californica, we can see for the first time, at atomic resolution, a protein binding pocket for the neurotransmitter, acetylcholine. It was found that the active site consists of a catalytic triad (S200-H440-E327) which lies close to the bottom of a deep and narrow gorge, which is lined with the rings of 14 aromatic amino acid residues. Despite the complexity of this array of aromatic rings, we suggested, on the basis of modelling which involved docking of the acetylcholine (ACh) molecule in an all-trans configuration, that the quaternary group of the choline moiety makes close contact with the indole ring of W84. In order to study the interaction of AChE with anticholinesterase drugs at the structural level, we have incorporated into the acetylcholinesterase crystals several different inhibitors, and have recently determined the 3-D structure of AChE:edrophonium and AChE:tacrine complexes. The crystal structures of both of these complexes are in good agreement with our model building of the ACh bound in the active site of AChE and indicate the interactions of these two drugs with the enzyme.


Revisiting regression in autism: Heller's dementia infantilis. Includes a translation of Über Dementia Infantilis.
Theodor Heller first described a severe regression of adaptive function in normally developing children, something he termed dementia infantilis, over one 100 years ago. Dementia infantilis is most closely related to the modern diagnosis, childhood disintegrative disorder. We translate Heller's paper, Über Dementia Infantilis, and discuss similarities in presentation between Heller's cases, and a group of children with childhood disintegrative disorder. In particular we discuss a prodromal period of affective dysregulation described by Heller, and also evident in our sample, but not previously described in any detail since the publication of Über Dementia Infantilis.


The importance of the cortical subarachnoid space in understanding hydrocephalus.
In this paper the authors define the role of the cortical subarachnoid space (CSAS) in poorly understood forms of hydrocephalus to cerebrospinal fluid (CSF) dynamics to improve understanding of the importance of the CSAS and its role in selecting patients for endoscopic third ventriculostomy (ETV). The secondary purpose of this work was to define testable hypotheses to explain enigmatic disorders of CSF dynamics and to suggest how these concepts could be tested. The magnitude of the contribution of the CSAS is explored using the solid geometry of concentric spheres. With this starting point, clinical conditions in which CSF dynamics are not easily understood are explored regarding the potential role of the CSAS. Overall, problems of CSF dynamics are easily understood. Insights may be gained when the results of a pathological process or its treatment vary from what has been expected. Acute changes in ventricular volume at the time that hydrocephalus develops, the failure of shunts, and the changes in ventricular volume with shunt repair may occur very rapidly. Changes in the volume of water in the brain, especially in the brain substance itself, are unlikely to occur at this rapid rate and may be interpreted as a simple redistribution of the CSF between the ventricle and CSAS with no initial change in the actual volume of brain parenchyma. Problems such as pseudotumor cerebri, shunt failure with nonresponsive ventricles, and negative-pressure hydrocephalus can be explained by assessing the ability of ventricular CSF to flow to the CSAS and the ability of this fluid to exit this compartment. Ventricular enlargement at the time of shunt failure implies a failure of flow between the ventricles and CSAS, implying that all patients who show this phenomenon are potential candidates for ETV. The important role of the CSAS in the pathophysiology of various forms of hydrocephalus has been largely ignored. Attention to the dynamics of the CSF in this compartment will improve understanding of enigmatic conditions of hydrocephalus and improve selection criteria for treatment paradigms such as ETV. These concepts lead to clearly defined problems that may be solved by the creation of a central database to address these issues.


Intramural activation during early human ventricular fibrillation.
We investigated patterns of intramural activation in early human ventricular fibrillation (VF) and hypothesized that intramural reentry colocalizes to sites with increased intramural fibrosis. Thirteen human Langendorff hearts were used for this study. Twenty-five plunge needles (4 unipoles/needle) were used to map 100 intramural sites. For the global mapping component, 11 20-s episodes of early VF were studied in 6 hearts. Simultaneous activation of all 4 electrodes was the most common pattern observed in 48.7% of needles, followed by an endocardial-to-epicardial activation pattern (9.8% of needles) and epicardial-to-endocardial activation pattern (5.5% of needles); 19.3% of needles had nonuniform multidirectional patterns. In 2 orthogonal planes, 1 parallel and 1 perpendicular to the epicardium and endocardium, reentry was detected in 14.3% of beats at any 1 level, and 5.8% of these were transmural. Simultaneous mapping of the epicardium and endocardium in 5 hearts detected concurrently rotating rotors with similar chirality and cycle length, suggesting the presence of transmural scroll waves (n=6), which was confirmed by high-resolution fixed-space mapping in 2 of those hearts plus 1 additional heart. Transmural optical mapping in 1 additional heart confirmed simultaneous epicardial and endocardial activation. Histopathology revealed greater fibrosis at sites of reentry compared to areas without (53.3±11.9% versus 27.5±2.4%, P=0.02). Intramural activation patterns suggest that early human VF does not organize as multiple reentrant wavefronts but is best explained by transmural scroll wave activation. Intramural reentry localizes to regions of greater intramural fibrosis.


Interaction of miconazole, ketoconazole and itraconazole with rat-liver microsomes.
The interaction of the antimycotics miconazole, ketoconazole and itraconazole with liver microsomes from untreated rats or from rats pretreated with phenobarbital or 3-methylcholanthrene, gave rise to type II difference spectra. The interactions of the antimycotics with control, phenobarbital-induced or 3-methylcholanthrene-induced microsomes were biphasic, except for the monophasic binding of ketoconazole to phenobarbital-induced microsomes. The N-demethylation of N,N-dimethylaniline, the O-demethylation of p-nitroanisole and the hydroxylation of aniline in microsomes from untreated and inducer-treated rats were lowered by miconazole and ketoconazole, the former being the more potent inhibitor. Control microsomes were less sensitive than induced microsomes. Itraconazole was almost devoid of inhibitory properties. The three antimycotics were non-competitive (mixed) inhibitors of enzyme activities in phenobarbital-induced microsomes. The Ki values were of the same order of magnitude as the Ks values, except for itraconazole. For the latter drug, Ki values were much greater than could be expected from the spectral studies. It is concluded that the antimycotics affect microsomal enzyme activities via a direct interaction of an azole-nitrogen with the haem group of cytochrome P-450. The interaction with mammalian cytochrome P-450 decreases from miconazole greater than ketoconazole much greater than itraconazole and is much weaker than the interaction of the antimycotics with yeast cytochrome P-450.


Primary afferent terminal function following acrylamide: alterations in the dorsal root potential and reflex.
The dorsal root potential (DRP) and the dorsal root reflex (DRR) were studied in acrylamide (ACR)-induced axonopathy to determine the nature and extent of primary afferent terminal (PAT) dysfunction. Cats were administered 30 mg/kg/day ACR for either 5 (ACR 5D) or 10 (ACR 10D) days. The day after the last injection, the spinal cord as isolated in situ and the DRP and DRR were elicited. It was found that only 21% of the ACR 10D animals exhibited a DRP. Furthermore, in that 21%, the DRP appeared to degrade over distance differently from the control group. There was no change in the DRP evoked in the ACR 5D group. ACR affected the DRR when evoked from the cutaneous sural nerve (SU) to a greater extent than when evoked from the medial gastrocnemius (MG) nerve. A SU-evoked DRR could not be elicited in any of the animals in the ACR 10D group and in only 20% of the ACR 5D group. There was no difference in the ability to elicit a MG-evoked DDR in either ACR-treated group when compared to control. However, the maximum-evoked area under the DRR elicited from the MG nerve was significantly smaller in the ACR-treated groups than in control. These data show that ACR does indeed impair PAT function. ACR preferentially affects the PAT processing of the SU when compared to the MG nerve, which may indicate that the selective vulnerability of the largest diameter fibers to ACR is not necessarily true.


Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation.
AB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC50] = 0.08 to 0.27 μM; EC90 = 0.33 to 1.32 μM) with no significant cytotoxicity (50% cytotoxic concentration > 10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC50s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a de novo infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467 resulted in a trend toward antiviral activity greater than that of either agent alone, consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports its further evaluation for safety, pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.


Characterization of a high throughput approach for large scale retention measurement in liquid chromatography.
Many contemporary challenges in liquid chromatography-such as the need for "smarter" method development tools, and deeper understanding of chromatographic phenomena-could be addressed more efficiently and effectively with larger volumes of experimental retention data than are available. The paucity of publicly accessible, high-quality measurements needed for the development of retention models and simulation tools has largely been due to the high cost in time and resources associated with traditional retention measurement approaches. Recently we described an approach to improve the throughput of such measurements by using very short columns (typically 5 mm), while maintaining measurement accuracy. In this paper we present a perspective on the characteristics of a dataset containing about 13,000 retention measurements obtained using this approach, and describe a different sample introduction method that is better suited to this application than the approach we used in prior work. The dataset comprises results for 35 different small molecules, nine different stationary phases, and several mobile phase compositions for each analyte/phase combination. During the acquisition of these data, we have interspersed repeated measurements of a small number of compounds for quality control purposes. The data from these measurements not only enable detection of outliers but also assessment of the repeatability and reproducibility of retention measurements over time. For retention factors greater than 1, the mean relative standard deviation (RSD) of replicate (typically n=5) measurements is 0.4%, and the standard deviation of RSDs is 0.4%. Most differences between selectivity values measured six months apart for 15 non-ionogenic compounds were in the range of +/- 1%, indicating good reproducibility. A critically important observation from these analyses is that selectivity defined as retention of a given analyte relative to the retention of a reference compound (kx/kref) is a much more consistent measure of retention over a time span of months compared to the retention factor alone. While this work and dataset also highlight the importance of stationary phase stability over time for achieving reliable retention measurements, we are nevertheless optimistic that this approach will enable the compilation of large databases (>> 10,000 measurements) of retention values over long time periods (years), which can in turn be leveraged to address some of the most important contemporary challenges in liquid chromatography. All the data discussed in the manuscript are provided as Supplemental Information.


Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma.
Alveolar soft part sarcoma (ASPS) is a rare, highly vascularized soft tissue sarcoma characterized by a high frequency of metastatic disease and resistance to classical chemotherapy. The purpose of our analysis was to assess long-term sunitinib activity in the treatment of metastatic ASPS. Between 2009 and 2015, 15 patients were diagnosed with metastatic ASPS and received therapy with sunitinib at initial continuous daily dosing of 37.5 mg. Median age was 32 years. The primary tumor sites were lower extremities (8), trunk-retroperitoneum/pelvis (2), upper extremity (3) and other (2). All patients had unresectable disease (primary or relapse in the form of metastases to the lungs ± bones). Five patients received systemic therapy before initiating sunitinib. Median follow-up from start of sunitinib was 38 months (range 5-69 months). At the time of analysis 4 patients continue therapy and 9 are still alive. Six patients had RECIST partial remission as best response, 8 had stable disease, and 1 had disease progression. The median progression-free survival was 19 months, with 86% of patients being free of progression at 6 months. Median overall survival was 56 months; the 5-year overall survival rate was 49%. Five patients were treated with sunitinib longer than 2 years. All patients experienced some side effects: 8 patients (53%) had CTCAE grade 3/4 toxicity, 7 patients required dose reduction. The most common toxicities were neutropenia, thrombocytopenia, hypothyroidism, arterial hypertension, and hand-foot syndrome. Our analysis confirms the long-term efficacy of sunitinib in patients with advanced ASPS.


Visual discrimination transfer and modulation by biogenic amines in honeybees.
For more than a century, visual learning and memory have been studied in the honeybee Apis mellifera using operant appetitive conditioning. Although honeybees show impressive visual learning capacities in this well-established protocol, operant training of free-flying animals cannot be combined with invasive protocols for studying the neurobiological basis of visual learning. In view of this, different attempts have been made to develop new classical conditioning protocols for studying visual learning in harnessed honeybees, though learning performance remains considerably poorer than that for free-flying animals. Here, we investigated the ability of honeybees to use visual information acquired during classical conditioning in a new operant context. We performed differential visual conditioning of the proboscis extension reflex (PER) followed by visual orientation tests in a Y-maze. Classical conditioning and Y-maze retention tests were performed using the same pair of perceptually isoluminant chromatic stimuli, to avoid the influence of phototaxis during free-flying orientation. Visual discrimination transfer was clearly observed, with pre-trained honeybees significantly orienting their flights towards the former positive conditioned stimulus (CS+), thus showing that visual memories acquired by honeybees are resistant to context changes between conditioning and the retention test. We combined this visual discrimination approach with selective pharmacological injections to evaluate the effect of dopamine and octopamine in appetitive visual learning. Both octopaminergic and dopaminergic antagonists impaired visual discrimination performance, suggesting that both these biogenic amines modulate appetitive visual learning in honeybees. Our study brings new insight into cognitive and neurobiological mechanisms underlying visual learning in honeybees.


Comparative metabolomics charts the impact of genotype-dependent methionine accumulation in Arabidopsis thaliana.
Methionine (Met) is an essential amino acid for all organisms. In plants, Met also functions as a precursor of plant hormones, polyamines, and defense metabolites. The regulatory mechanism of Met biosynthesis is highly complex and, despite its great importance, remains unclear. To investigate how accumulation of Met influences metabolism as a whole in Arabidopsis, three methionine over-accumulation (mto) mutants were examined using a gas chromatography-mass spectrometry-based metabolomics approach. Multivariate statistical analyses of the three mto mutants (mto1, mto2, and mto3) revealed distinct metabolomic phenotypes. Orthogonal projection to latent structures-discriminant analysis highlighted discriminative metabolites contributing to the separation of each mutant and the corresponding control samples. Though Met accumulation in mto1 had no dramatic effect on other metabolic pathways except for the aspartate family, metabolite profiles of mto2 and mto3 indicated that several extensive pathways were affected in addition to over-accumulation of Met. The pronounced changes in metabolic pathways in both mto2 and mto3 were associated with polyamines. The findings suggest that our metabolomics approach not only can reveal the impact of Met over-accumulation on metabolism, but also may provide clues to identify crucial pathways for regulation of metabolism in plants.


Pain and ethnicity in the United States: A systematic review.
Evidence suggests that racial and ethnic disparities exist in access to effective pain treatment. To review evidence of these disparities and provide recommendations for care and further research. Systematic review. We conducted a MEDLINE search using the MeSH terms of ethnic groups, minority groups, pain, analgesia, and analgesics. We included studies describing current practice patterns, utilization of available treatments, treatment outcomes, and patient and provider knowledge, attitudes, and behaviors. Our search identified 35 journal articles describing the effect of patient race and ethnicity on pain assessment and management. Three studies on pain assessment revealed that minority patients are more likely to have their pain underestimated by providers and less likely to have pain scores documented in the medical record compared to whites. Eleven of 17 studies found that African Americans and Hispanics are less likely to receive opioid analgesics and more likely to have their pain untreated compared to white patients. Three studies revealed that minority patients are more likely to have negative pain management index (PMI) scores-undertreated pain-compared to whites. Patient-related, provider-related, and pharmacy-related barriers to effective pain management were identified. The majority of studies reveal racial and ethnic disparities in access to effective pain treatment akin to disparities found in other medical services. Quality improvement initiatives that improve treatment of pain for all patients according to established guidelines should decrease disparities by race or ethnicity. Educational interventions should aim to improve patient-provider communication regarding pain and its treatment and should provide support around substance abuse issues. Further research is needed to examine pain treatment outcomes and to determine whether health care system factors lead to these disparities.


Methods to Analyze the Non-Coding RNA Interactome-Recent Advances and Challenges.
Most of the human genome is transcribed to generate a multitude of non-coding RNAs. However, while these transcripts have generated an immense amount of scientific interest, their biological function remains a subject of an intense debate. Understanding mechanisms of action of non-coding RNAs is a key to addressing the issue of biological relevance of these transcripts. Based on some well-understood non-coding RNAs that function inside the cell by interacting with other molecules, it is generally believed many other non-coding transcripts could also function in a similar fashion. Therefore, development of methods that can map RNA interactome is the key to understanding functionality of the extensive cellular non-coding transcriptome. Here, we review the vast progress that has been made in the past decade in technologies that can map RNA interactions with different sites in DNA, proteins or other RNA molecules; the general approaches used to validate the existence of novel interactions; and the challenges posed by interpreting the data obtained using the interactome mapping methods.


Kinematic, strength, and stiffness adaptations after a short-term sled towing training in athletes.
One of the most frequently used methods for training the sprint-specific strength is the sled towing. To date, no studies have been conducted to explore the effects of this method after a training period in well-trained athletes. The purpose of this study was to determine the effects of 4 weeks of resisted sprint training with sled towing. Twenty-two trained athletes experienced in the use of weighted sled (WS) participated in the study. They conducted the same 3-week training to level their initial condition. After that they were distributed in two groups, unresisted (UR) and WS training. They carried out the same 4-week, 2 days/week sprint-specific training, only differing in that the experimental group performed sprints with a (WS) which caused a reduction of 7.5% of their maximum velocity. Pre- and posttest were conducted which included the measurement of sprint kinematics, muscular strength (including isoinertial, isokinetic, and jump measurements), and sprinting stiffness (leg and vertical). Results show different adaptations in the groups although no interaction effect was found. The WS group improved the velocity in the transition phase, while the UR group improved the velocity in the maximum velocity phase. No improvements in the height of the jump tests were found.


Proper microsurgical nerve suture may impede Wallerian degeneration of completely transected nerves. An electron microscopic study.
Electron microscopic findings on the nerve of the biventer cervicis muscle of the chick, which was completely transected and immediately after submitted to an adequate microsurgical nerve suture, confirmed our previous statement that proper microsurgical nerve suture may impede the Wallerian degeneration that normally occurs in the distal segment of a completely transected nerve.


Protective effect of metformin against walker 256 tumor growth is not dependent on metabolism improvement.
The objective of the current work was to test the effect of metformin on the tumor growth in rats with metabolic syndrome. We obtained pre-diabetic hyperinsulinemic rats by neonatal treatment with monosodium L-glutamate (MSG), which were chronically treated every day, from weaning to 100 day old, with dose of metformin (250 mg/kg body weight). After the end of metformin treatment, the control and MSG rats, treated or untreated with metformin, were grafted with Walker 256 carcinoma cells. Tumor weight was evaluated 14 days after cancer cell inoculation. The blood insulin, glucose levels and glucose-induced insulin secretion were evaluated. Chronic metformin treatment improved the glycemic homeostasis in pre-diabetic MSG-rats, glucose intolerance, tissue insulin resistance, hyperinsulinemia and decreased the fat tissue accretion. Meanwhile, the metformin treatment did not interfere with the glucose insulinotropic effect on isolated pancreatic islets. Chronic treatment with metformin was able to decrease the Walker 256 tumor weight by 37% in control and MSG rats. The data demonstrated that the anticancer effect of metformin is not related to its role in correcting metabolism imbalances, such as hyperinsulinemia. However, in morphological assay to apoptosis, metformin treatment increased programmed cell death. Metformin may have a direct effect on cancer growth, and it may programs the rat organism to attenuate the growth of Walker 256 carcinoma.


Precisely constructing hybrid nanogap arrays via wet-transfer of dielectric metasurfaces onto a plasmonic mirror.
We propose a new method for fabricating hybrid metasurfaces by combining Mie and plasmonic resonances. Our approach involves obtaining an ultrasmooth gold film and separately structuring monocrystalline silicon (c-Si) nanoantenna arrays, which are then wet-transferred and finally immobilized onto the gold film. The experimental and simulation analysis reveals the importance of the native oxide layer of Si and demonstrates fascinating dispersion curves with nanogap resonances and bound states in the continuum. The localized field enhancements in the nanogap cavities result from the coupling between multipolar Mie resonances and their mirror images in the gold film. This effective method improves our understanding of hybrid modes and offers opportunities for developing active metasurfaces, such as depositing c-Si nanoantenna arrays onto stretchable polydimethylsiloxane substrates or electro-optic and piezoelectric sensitive lithium niobate films for potential applications in MEMS, LiDAR, and beyond.


Mortality and morbidity from infectious and non-communicable diseases in Greece during Axis/Nazi military occupation (1941-1944).
Greece has been severely damaged by the Second World War and the subsequent military occupation of the country by the Axis forces headed by Nazi Germany. The Greek society and economy were dislocated as a result of plundering of the country's vital resources, as well as enforced payments, instead paid to the occupying forces. The dramatic food shortages and famine appeared plaguing especially large cities. There is very limited information on the trends of mortality and morbidity (1941-1944) at a national level. The morbidity and mortality statistics of the General Statistical Service of Greece were assessed and the incidence morbidity and mortality rates have been calculated. As denominator population we used the population of Greece according to 1940 census. The morbidity due to exanthematic typhus, typhoid fever, dysentery and meningitis has been elevated over the period 1940-1944. An elevated specific mortality due to tuberculosis, malaria and typhoid fever was observed over the period 1940-1941. Regarding non-communicable diseases, the mortality due to hemorrhagic stroke was increased after 1940. In conclusion, we found that the Axis/Nazi military occupation of Greece had considerable health effects on infectious diseases and hemorrhagic stroke mortality. Deaths ostensibly due to infectious diseases (e.g. tuberculosis or malaria), were expedited by the hunger famine of the period under investigation. With regard to the elevated mortality due to hemorrhagic stroke, we believe that the stressful events of occupation and famine have triggered increased psychosocial stress which in turn may have increased the risk of hemorrhagic stroke mortality during the period of Axis/Nazi occupation of Greece.


There is something about BOK we just don't get yet.
Fernández-Marrero and colleagues show in their work that the proapoptotic BCL-2 family member BOK can form large, stable pores in artificial liposomes. This can be enhanced by the proapoptotic protein cBID and is unaffected by the antiapoptotic BCL-XL . Although BOK can bind to isolated mitochondria, it is unable to cause cytochrome c release even with the help of cBID.


Egg yolk can be partially replaced with carboxylated poly-l-lysine (cpll) in extender for nili- ravi buffalo bull sperm.
Egg yolk is inevitably associated with risks of microbial contamination and anti-cryoprotectant agents that necessitate the investigation of some synthetic alternatives. To investigate the potential of carboxylated poly-L-lysine (CPLL) as a replacement for egg yolk during the cryosurvivability of Nili-Ravi buffalo sperm. Semen collected from four Nili-Ravi buffalo bulls (two ejaculates / bull / day; total 40 ejaculates for five replicates) was cryopreserved in different experimental extenders viz: Control (CPLL 0%, egg yolk 20%); E1 (CPLL 5%, egg yolk 15%); E2 (CPLL 10%, egg yolk 10%); E3 (CPLL 15%, egg yolk 5%) and E4 (CPLL 20%, egg yolk 0%). Post-thaw quality was assessed in terms of sperm motility, plasma membrane integrity (PMI), viability, live:dead ratio, lipid peroxidation of sperm and total antioxidant capacity of seminal plasma. Sperm motility improved (P<0.05) in extenders replacing 5%, 10% and 15% egg yolk with CPLL. Sperm PMI, viability and live:dead ratio also improved (P<0.05) in extenders replacing 10%, 15% and whole (20%) egg yolk with CPLL. In contrast, sperm DNA integrity was not different (P>0.05) when CPLL replaced egg yolk at any level. The lipid peroxidation level decreased with a concomitant increase in total antioxidant activity of seminal plasma when CPLL replaced egg yolk at 5%, 10%, 15% and 20%. Replacement of 15% egg yolk in the extender with CPLL improves all sperm quality parameters: motility, PMI, viability, live:dead ratio, lipid peroxidation of sperm and total antioxidant activity of seminal plasma.


Amyotrophic lateral sclerosis and frontal lobe dementia in Alzheimer's disease. Case report and review of the literature.
Clinicopathological data of a woman with a 3-year course of concurrent amyotrophic lateral sclerosis and dementia are presented. Dementia had occurred at time of onset of motor disturbances and presented as typical frontal lobe dementia. Pathology confirmed motor neuron disease of amyotrophic lateral sclerosis and frontal lobe atrophy. Multiple senile plaques were distributed cortically and in the hippocampus, where diffuse spread of neurofibrillary tangles was seen. Hence, this Alzheimer's dementia in a patient with sporadic amyotrophic lateral raises the question of a possible association between the two conditions.


Maternal request cesarean versus planned spontaneous vaginal delivery: maternal morbidity and short term outcomes.
Since no randomized trial evaluates maternal morbidity from planned cesarean versus planned vaginal delivery, the issue must be addressed indirectly from retrospective cohort studies of vertex fetuses by actual or planned delivery route, and retrospective or randomized studies of breech fetuses by planned delivery route. The available data, although limited, suggest that term planned cesarean and planned vaginal delivery have similarly low rates of absolute and relative short-term maternal morbidity. Endometritis and cystitis are more frequent with cesarean, whereas hemorrhage is more frequent with planned vaginal delivery. Much of the morbidity of planned vaginal delivery is the morbidity of unplanned cesarean in labor and operative vaginal delivery, particularly forceps. Thus, the relative risk of short-term maternal morbidity of planned cesarean versus planned vaginal delivery will depend on the proportion of women in each group ultimately delivering in the planned manner and the frequency with which delivery occurs by an alternative unplanned method.


A novel conserved mechanism for plant NLR protein pairs: the "integrated decoy" hypothesis.
Plant immunity is often triggered by the specific recognition of pathogen effectors by intracellular nucleotide-binding, leucine-rich repeat receptors (NLR). Plant NLRs contain an N-terminal signaling domain that is mostly represented by either a Toll-interleukin1 receptor (TIR) domain or a coiled coil (CC) domain. In many cases, single NLR proteins are sufficient for both effector recognition and signaling activation. However, many paired NLRs have now been identified where both proteins are required to confer resistance to pathogens. Recent detailed studies on the Arabidopsis thaliana TIR-NLR pair RRS1 and RPS4 and on the rice CC-NLR pair RGA4 and RGA5 have revealed for the first time how such protein pairs function together. In both cases, the paired partners interact physically to form a hetero-complex receptor in which each partner plays distinct roles in effector recognition or signaling activation, highlighting a conserved mode of action of NLR pairs across both monocotyledonous and dicotyledonous plants. We also describe an "integrated decoy" model for the function of these receptor complexes. In this model, a plant protein targeted by an effector has been duplicated and fused to one member of the NLR pair, where it acts as a bait to trigger defense signaling by the second NLR upon effector binding. This mechanism may be common to many other plant NLR pairs.


NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers.
The importance of dynamics to biomolecular function is becoming increasingly clear. A description of the structure-function relationship must, therefore, include the role of motion, requiring a shift in paradigm from focus on a single static 3D picture to one where a given biomolecule is considered in terms of an ensemble of interconverting conformers, each with potentially diverse activities. In this Perspective, we describe how recent developments in solution NMR spectroscopy facilitate atomic resolution studies of sparsely populated, transiently formed biomolecular conformations that exchange with the native state. Examples of how this methodology is applied to protein folding and misfolding, ligand binding, and molecular recognition are provided as a means of illustrating both the power of the new techniques and the significant roles that conformationally excited protein states play in biology.


Introducing ICD-resistant mortality as an end point to evaluate the clinical efficacy of an implantable cardioverter-defibrillator in ischaemic cardiomyopathy.
A new end point called ICD-resistant mortality was evaluated to assess the clinical efficacy of ICD implantations. In 302 ICD patients with ischaemic cardiomyopathy, we investigated which clinical parameters predicted useful ICD implantations using cumulative incidence competing risk analysis. Implantation was deemed clinically useful when the ICD provided appropriate therapy and the patient survived implantation by 1 year and the first shock by 30 days. ICD-resistant mortality (ICDRM) was defined as death within 30 days after the first shock, within 1 year of implantation or without previous appropriate ICD therapy. After 5 years, ICDRM occurred in 23% of implantations, while 36% were clinically useful. After multivariable analysis, ICDRM was associated with LVEF <35% (HR: 2.63; p = .005), beta-blocker dose <50% (HR: 2.0; p = .01) and anterior or diffuse infarct location (HR: 3.61; p = .001 and HR: 2.89; p = .02). Useful ICD implantations were associated with beta-blocker dose <50% (HR: 1.64; p = .02) and non-anterior infarct location (HR: 3.22 vs anterior and 1.59 vs diffuse; combined p<.001). Five years after implantation, an ICD could be classified as useful in 1 out of 3, while ICDRM occurred in one out of four patients. At 10 years, up to 80% of implantations could be categorized. Lower LVEF was related with significantly higher incidence of ICDRM. Anterior infarcts were associated with more ICDRM and less useful implantations than non-anterior infarcts. Future risk stratification for ICD should focus more on the discrimination between arrhythmic risk, probably preventable by ICDs and ICD-resistant mortality risk.


An autoradiographic study of the intrarenal localisation and retention of cisplatin, iproplatin and paraplatin.
The intrarenal localisation of platinum following the intravenous administration of platinum-195m-labelled cisplatin, iproplatin and paraplatin was studied using autoradiography. Following injection of cisplatin, platinum was distributed throughout the kidney even up to 14 days after treatment. In the case of iproplatin and paraplatin rapid platinum clearance was noted from the glomeruli, blood vessels and renal medulla within 2 h of administration. Relative cortical and medullary platinum radionuclide concentrations for all three agents were determined by Chalkley grid analysis. This showed greater relative concentrations of platinum in the cortex at increasing times following iproplatin and paraplatin compared with cisplatin. It is suggested that the lower renal toxicity of iproplatin and paraplatin than of cisplatin may be due to reduced platinum retention within the pars recta.


Understanding PROMIS.
Patient reported outcomes (PROs) are becoming increasingly emphasized in health care. Some medical and orthopedic specialties have 1 or 2 primary PROs that are used across the discipline, whereas hand surgery has multiple PROs. The multitude of PROs gives hand surgeons flexibility because each provides slightly different information, but the number of options can present a daunting task when choosing which to use. The latest generation of PROs leverages computer adaptive testing and includes assessments of physical, mental, and social health. The Patient-Reported Outcomes Measurement Information System was funded by the National Institutes of Health to include a comprehensive set of health instruments that are not disease-specific; it has undergone several forms of validation and has been found to be comparable across medical specialties. This article discusses the details of the Patient-Reported Outcomes Measurement Information System, how it compares with other outcomes instruments, and how it can be used in practice.


Multifocal giant cell tumour of bone in a skeletally immature patient--a case report.
Giant cell tumor of bone is usually seen in adults affecting a single bone. Multiple giant cell tumour of bone occurring in skeletally immature patients is extremely rare. Multifocal giant cell tumor of bone in a ten year old boy involving upper end of humerus and tibia is being reported for its extreme paucity in literature.


The role of personal social networks on health inequalities across European regions.
The role of personal social networks on health inequalities is little understood. Theoretically, the characteristics of social network features can contribute to, both, increase and attenuate health inequalities. Few empirical studies that focus on the interaction between socioeconomic position and social networks provide little insight on the topic. Using data from the Survey of Health, Ageing and Retirement in Europe, this study analyses the moderation role of personal social networks on health inequalities in later life among northern, central, and southern European regions. Social advantages of higher socioeconomic individuals are re-enforced by the quality of social connections and the provision of social support. In turn, health inequality is attenuated by marital partnership and participation on social activities that benefits more the health of people at lower socioeconomic positions. Furthermore, results suggest that the influence of social network features on health inequalities is shaped by regions' different policy commitments to familiarization/defamilialization pressures.


Relationship of neurosympathetic responsiveness to early ventricular arrhythmias in ischaemic myocardium.
Myocardial catecholamine overflow has been measured in open-chest anaesthetised dogs after graded stimulation of the left ansa subclavia before and during left anterior descending coronary artery occlusion and on reperfusion. Sequential 1 min periods of ansa stimulation over 3 h resulted in reproducible, frequency dependent regional myocardial noradrenaline (NA) overflow without tachyphylaxis. In seven dogs, two successive 10 min periods of LAD occlusion did not modify peak myocardial NA overflow from the predominantly ischaemic (I) or non-ischaemic (NI) areas at either low (1 Hz) or high (10 Hz) frequency ansa stimulation. In a second group of nine dogs, myocardial catecholamine overflow was related to changes in ischaemic area epicardial activation delay during repeated ansa stimulation on four occasions during 75 min of ischaemia. Stimulation at the period of peak spontaneous arrhythmias 5 and 17 min after coronary occlusion resulted in NA overflow from I of 2.8 +/- 1.3 and 3.0 +/- 1.6 pmol X ml-1 respectively and a significant increase in mean activation delay in I of 12 +/- 4 ms at 5 min and 9 +/- 4 ms at 17 min (p less than 0.05). In contrast, stimulation 30 and 60 min after coronary occlusion, when spontaneous arrhythmias are rare, was not associated with NA overflow from ischaemic areas (0.3 +/- 0.3 and 0.9 +/- 0.5 pmol X ml-1 respectively) and resulted in a minor reduction in mean activation delay in ischaemic areas of 2 +/- 3 ms at 30 min and 3 +/- 4 ms at 60 min. NA overflow from non-ischaemic areas and increases in blood pressure and myocardial lactate release were similar during each period of ansa stimulation. Coronary reperfusion induced massive overflow of NA (11.4 +/- 2.8 pmol X ml-1) and reduced extraction of adrenaline (A) from ischaemic areas with a time course similar to early reperfusion arrhythmias. Stimulation-evoked release of NA in ischaemic myocardium is thus maintained during the early period of enhanced vulnerability to arrhythmias and during reperfusion but is inhibited after 30 min. This temporal variability may be a factor in the time course of spontaneous arrhythmias in this model.


In Vitro Anticancer Activities of B6 Vitamers: A Mini-review.
Vitamin B6 compounds, including pyridoxine, pyridoxal, pyridoxamine, and their phosphorylated forms, have been investigated with regard to their cancer preventive and therapeutic effects through epidemiological, in vivo, and in vitro studies. In particular, in vitro studies in cancer cells have evaluated the effects of several B6 vitamers such as pyridoxine, pyridoxal, pyridoxamine, and pyridoxal-5'-phosphate, which is a bioactive form of vitamin B6 However, the anticancer activity and concentration required to influence cancer cells vary among B6 vitamers. In this review, the various in vitro effects of vitamin B6 compounds on cancer cells are presented and discussed.


Genetic factors in hypertension.
Genetic approaches to hypertension have the potential to identify many of the primary abnormalities that underlie this disorder. Approaches in experimental animals and humans have advanced to the point that this is no longer merely a possibility but is a tangible reality. Successes in the past year include the mapping of a number of relevant loci and the identification of several mutations that contribute to the pathogenesis of hypertension in animals and humans.


A Global Hypothesis Verification Framework for 3D Object Recognition in Clutter.
Pipelines to recognize 3D objects despite clutter and occlusions usually end up with a final verification stage whereby recognition hypotheses are validated or dismissed based on how well they explain sensor measurements. Unlike previous work, we propose a Global Hypothesis Verification (GHV) approach which regards all hypotheses jointly so as to account for mutual interactions. GHV provides a principled framework to tackle the complexity of our visual world by leveraging on a plurality of recognition paradigms and cues. Accordingly, we present a 3D object recognition pipeline deploying both global and local 3D features as well as shape and color. Thereby, and facilitated by the robustness of the verification process, diverse object hypotheses can be gathered and weak hypotheses need not be suppressed too early to trade sensitivity for specificity. Experiments demonstrate the effectiveness of our proposal, which significantly improves over the state-of-art and attains ideal performance (no false negatives, no false positives) on three out of the six most relevant and challenging benchmark datasets.


Electrophysciological analysis of entrapment neuropathies developed in acute and subacute period in paretic and non-paretic extremities in patients with stroke.
To investigate entrapment neuropathies in stroke patients in a hospital in Turkey with Medical Research Council (MRC) score < or = 2/5 and in those with MRC score > or = 3/5. The study comprising 40 patients from January 2008 to June 2009 in the Stroke Unit of the Department of Neurology, Yuzuncu Yil University in Van, Turkey, entailed electrophysiological analysis of median, ulnar, radial nerves, peroneal, tibial and sural nerves in paretic and nonparetic upper and lower extremities. National Institute of Health Stroke scale was used for the evaluation of neurological deficient, while nerve conduction studies were performed for the diagnosis of entrapment neuropathies (EN). The patients were divided into two groups based on their initial Medical Research Council (MRC) score: < 2/5 and > 3/5. Both groups had 20 patients each. The readings were compared in the control phase 45 to 50 days after the stroke. Paired samples test and t-test using SPSS version 15 were used for statistical analysis. Carpal tunnel syndrome (CTS) at wrist was found in 7 (35%) patients, cubital tunnel syndrome at elbow in 3 (15%) patients, and evident reduction in motor action potential values of peroneal, median and ulnar nerve in 10 (50%) patients in the control studies for conduction on our patients with Medical Research Council (MRC) score of < or = 2/5, unlike the initial findings, in the paretic side. Among the patients, in the other group, 2 (10%) developed bilateral Carpel tunnel syndrome, and it was also detected in the healthy upper extremities in 2 (10%) more patients. In the control studies for conduction in patients with Medical Research Council score of 3/5, Carpel tunnel syndrome was detected in the healthy side in 4 (20%) patients and in the affected side in 3 (15%) patients. In patients with severe paresis, if the affected extremity is not functional, symptoms of entrapment neuropathy are easy to occur.


Ontological definition of population for public health databases.
This paper discusses available definitions of population and criticise them against some basic rules of ontology. None of the found definition satisfies the requirement of an ontology that supports building consistent public heath databases. Most definitions define population on territorial bases or as reproductive communities. The author argues that populations are systems (its members must be in connection to each other) and individuals forming the population must share a common resource. Proper usage of the definitions may help to build consistent ontology for public health indicators and consistent databases.


Carotid Endarterectomy With Simultaneous Proximal Common Carotid Endovascular Intervention is Beneficial for Symptomatic Stenosis and Likely Confers No Advantage for Asymptomatic Lesions.
Carotid bifurcation stenosis may co-exist simultaneously with more proximal common carotid artery (CCA) atherosclerotic plaquing, primarily at the vessel origin in the aortic arch. This scenario is relatively infrequent and its' management does not have quality randomized data to support medical vs surgical treatment. It is logical to treat any high grade common carotid lesions proximal to a carotid bifurcation endarterectomy (CEA) site both to prevent perioperative emboli or thrombosis as well as future embolization. Prior long-term investigations of the combined treatment paradigm have been low volume analysis. Further, prior studies focus on perioperative outcomes with respect to stroke prevention. The only prior VQI study investigating mid-term outcomes following simultaneous CEA with proximal CCA endovascular therapy provided data on less than 10 patients beyond 1.5 years. The long-term follow-up (LFTU) component initiative within VQI has been emphasized in recent years, now allowing for much more robust LTFU analysis. Four cohorts were created for perioperative outcome analysis and Kaplan Meier freedom from event analysis: CEA in isolation for asymptomatic disease; CEA in isolation for symptomatic patients; CEA with proximal CCA endovascular intervention for asymptomatic; and, CEA with proximal CCA intervention for symptomatic patients. Binary logistic multivariable regression was performed for perioperative neurological event and 90-day mortality risk determination and Cox multivariable regression analysis was performed for long term freedom from cumulative ischemic neurological event and long-term mortality analysis. Symptomatology and type of surgery (CEA with or without CCA intervention) were individual variables in the multivariable analysis. Neurological ischemic event in this study encompassed transient ischemic attack (TIA) and stroke combined. We noted a statistically significant (P < .001) escalation in rates of perioperative neurological event, myocardial infarction (MI), carotid re-exploration, 90 day mortality and combined neurological event and 90 day mortality moving from: A) asymptomatic CEA in isolation to B) symptomatic CEA in isolation to C) asymptomatic CEA combined with proximal CCA intervention to D) symptomatic CEA in combination with proximal CCA intervention. The positivity rate for the combined outcome of perioperative ischemic neurological event and 90 day mortality was 2.2% amongst asymptomatic CEA in isolation, 4.1% amongst symptomatic CEA in isolation, 4.4% amongst asymptomatic CEA in combination with proximal CCA intervention; and 8.8% in patients with symptomatic lesions undergoing combined CEA with proximal CCA intervention. On multivariable analysis patients undergoing CEA with proximal CCA endovascular intervention experienced greater risk for perioperative neurological ischemic event (aOR 2.03, 1.43-2.90, P < .001), combined perioperative neurological ischemic event and 90 day mortality (aOR 2.13, 1.62-2.80, P < .001), long term mortality (HR 1.62, 1.12-2.29, P < .001), and cumulative neurological ischemic event in long term follow up (HR 1.62, 1.12-2.29, P = .007). Amongst 4395 cumulative ischemic neurological events in all study patients, 34% were TIA. Carotid bifurcation endarterectomy in combination with proximal endovascular common carotid artery intervention caries an over two fold higher perioperative risk of neurologic ischemic event and 90 day mortality relative to CEA in isolation for asymptomatic and symptomatic cohorts respectively. After surgery, freedom from cerebral ischemia and mortality for patients undergoing dual intervention is closely aligned with patients undergoing CEA in isolation. Despite high adverse perioperative event rates for the combined CEA and CCA treatment, there is likely long term stroke reduction and mortality benefit to this approach in symptomatic patients based on the event free rates seen herein after initial hospital discharge. The benefit of treating asymptomatic tandem ICA and CCA lesions remains vague but the 4.4% perioperative neurologic event and death rate suggests that these patients would be better managed with medical therapy.


Long-term safety and efficacy of olopatadine-mometasone combination nasal spray in patients with perennial allergic rhinitis.
Background: Safety and efficacy of GSP301 nasal spray, an investigational fixed-dose combination of olopatadine hydrochloride and mometasone furoate, was established in three large, 2-week seasonal allergic rhinitis studies. Objective: To evaluate long-term (52 weeks) safety and efficacy of GSP301 in patients with perennial allergic rhinitis (PAR). Methods: In this randomized, double-blind, parallel-group study, 601 patients (ages ≥ 12 years) with PAR were randomized 4:1:1 to twice-daily GSP301 (olopatadine 665 μg and mometasone 25 μg [pH 3.7]) or two GSP301 vehicle formulations (placebo pH 3.7 or 7.0). Safety (primary end point) was monitored through adverse events (AE), laboratory assessments, vital signs, and physical examinations at weeks 30 and 52. The change from baseline in the average A.M. reflective Total Nasal Symptom Score (rTNSS) and instantaneous Total Nasal Symptom Score (iTNSS), Physician-assessed Nasal Symptom Scores (PNSS), and quality of life were assessed for GSP301 versus placebo pH 3.7 (p < 0.05 was considered statistically significant). Results: At week 52, treatment-emergent AEs (TEAE) occurred in 51.7, 41.4, and 53.5% of patients in the GSP301, placebo pH 3.7 and placebo 7.0 groups, respectively. No clinically meaningful differences were observed in TEAE incidences or other safety assessments across treatments. At weeks 6 and 30, GSP301 provided significant and clinically meaningful improvements in average rTNSS and iTNSS versus placebo pH 3.7 (p < 0.01, all comparisons). Similarly, at week 52, GSP301 provided significant and clinically meaningful improvements in rTNSS (least-squares mean difference -0.91 [95% confidence interval {CI}, -1.35 to -0.47]; p < 0.001), and iTNSS (least-squares mean difference -0.75 [95% CI, -1.17 to -0.33]; p < 0.001) versus placebo pH 3.7, with significant improvements in each individual symptom (p < 0.05, all comparisons). PNSS and quality of life were significantly improved versus placebo pH 3.7 at weeks 6 and 30 (p < 0.05, all comparisons), but these greater improvements did not reach statistical significance at week 52 (PNSS, p = 0.552; quality of life, p = 0.790). Conclusion: Twice-daily GSP301 was well tolerated and provided statistically significant and clinically meaningful improvements in PAR nasal symptoms versus placebo over 52 weeks and demonstrated a favorable safety profile and efficacy.Clinical trial NCT02709538, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>.


Configurational Assignment of a Flexible Benzo[g]isochromene Stereodiad from Rubia philippinensis and Inhibition of Soluble Epoxide Hydrolase Activity.
A new benzo[g]isochromene possessing a conformationally mobile moiety was identified from Rubia philippinensis. The 2D structure was established utilizing spectrometric and spectroscopic techniques with variable temperatures. The configurational investigation of the flexible moiety was investigated utilizing contemporary NMR-combined computational tools such as DP4, direct J-DP4, and DP4 Plus. The probabilities computed from DP4 Plus analysis, featuring inclusion of an additional geometry optimization process, demonstrated more conclusive probability scores among the analyses used. The configurational assignment was also supported by compositional and molecular orbital analyses. Compound 1 inhibited soluble epoxide hydrolase (IC50 = 0.6 ± 0.01 μM), an enzyme associated with cardiovascular disorders.


Delay in Diagnosis of Two Siblings with Severe Ocular Problems and Autoimmune Polyglandular Syndrome.
Autoimmune polyendocrine syndrome type 1 (APS1) is a scarce polyendocrinopathy with autosomal recessive inheritance results from defects in the human autoimmune regulatory (AIRE) gene. In addition to three major manifestations of APS1 including mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease, ophthalmic problems such as keratoconjunctivitis, dry eye, iridocyclitis, and cataract can be seen in these patients. In this article, we introduced two siblings presented with nail dystrophia, severe photophobia, and keratitis since early childhood which genetic examination revealed single nucleotide T>C translocation in their 2nd exon and heterozygous deletion mutation in their 12th exon.


Reference Correlation for the Viscosity of Carbon Dioxide.
A comprehensive database of experimental and computed data for the viscosity of carbon dioxide (CO2) was compiled and a new reference correlation was developed. Literature results based on an ab initio potential energy surface were the foundation of the correlation of the viscosity in the limit of zero density in the temperature range from 100 K to 2000 K. Guided symbolic regression was employed to obtain a new functional form that extrapolates correctly to T → 0 K and to 10 000 K. Coordinated measurements at low density made it possible to implement the temperature dependence of the Rainwater-Friend theory in the linear-in-density viscosity term. The residual viscosity could be formulated with a scaling term ργ /T the significance of which was confirmed by symbolic regression. The final viscosity correlation covers temperatures from 100 K to 2000 K for gaseous CO2, and from 220 K to 700 K with pressures along the melting line up to 8000 MPa for compressed and supercritical liquid states. The data representation is more accurate than with the previous correlations, and the covered pressure and temperature range is significantly extended. The critical enhancement of the viscosity of CO2 is included in the new correlation.


Predicting amino acid sequences of the antibody human VH chains from its first several residues.
A new method for classification of Ig sequences is suggested. The defining characteristic of a class is presence of particular residues at several class-determining positions. Sequences within a class follow the same amino acid pattern, i.e., residues at identical positions are, in an overwhelming majority of sequences of that class, identical or chemically related. Thus, once the class of a sequence is determined, one can predict the residue(s) at almost any position in the sequence. In this paper, results of analysis of 1,172 human heavy chains are presented. It was shown that a sequence can be assigned to one of six classes depending on which residues are found at its positions 1, 3, 5, 6, 7, 9, 10, 12, and 13. It is important to note that it is possible to achieve same six-class classification of the human heavy chains on the basis of a different set of positions found not at the beginning but near the end of the sequence (around position 80). For every class, an amino acid pattern of an entire sequence (complementarity determining regions excepting) has been determined. Our approach allowed us to reconstruct the incomplete human heavy chains in which residues at certain positions at the beginning or end of the chain are known. We developed a software tool for analysis, classification, and prediction of residues in sequences of the Ig family.


Long-term care under fire: a case for rational enforcement.
Despite reforms to ensure that nursing homes maintain compliance with federal quality standards, one-fourth of all homes nationwide continue to be cited for deficiencies that either caused actual harm to residents or carried the potential for death or serious injury. This pattern has not changed since the July 1995 reforms were implemented. Although the reforms equipped federal and state regulators with many alternatives and tools to help promote sustained compliance with Medicare and Medicaid standards, the way in which states and HCFA have applied them appears to have resulted in little headway against the pattern of serious and repeated noncompliance. Such performance may do little to dispel concerns over the health and safety of frail and dependent nursing home residents.


Response inhibition in preschoolers at familial risk for attention deficit hyperactivity disorder: a behavioral and electrophysiological stop-signal study.
Children participating in the Ben-Gurion Infant Development Study were assessed with a dynamic-tracking version of the stop-signal task at the age of 5 years. The sample consisted of 60 males. Stop-signal reaction time (SSRT) was correlated with concurrent ratings of the child's attention deficit hyperactivity disorder (ADHD) symptoms. Paternal symptoms measured in the child's early infancy predicted the child's performance in the stop-signal task: Paternal inattentiveness predicted SSRT, whereas hyperactivity predicted error proportion. Maternal symptoms were not correlated with the performance of the child in the task. A subsample of children, who were tested while electrophysiological brain activity was measured, showed that having higher ADHD symptomatology, especially hyperactivity, correlated with less activity in the brain areas that are usually recruited by children for successful inhibition.


[Double gloving during orthopaedic procedures--possible discomfort or a right choice].
In the light of the increasing number of infections with hepatitis viruses and HIV, world wide as well as among the health care workers, the prevention of occupationally acquired infections in the operating room environment becomes crucial. Three plausible strategies do not require any knowledge of the exact mechanisms of exposure: vaccination, impenetrable protective barriers and post exposure prophylaxis (PEP). As HIV and HCV vaccine are not currently available, as some of the surgeons avoid the immunisation against hepatitis B as well as PEP in the context of HIV and HBV - appropriate barrier precautions (e.g. gloves, gowns and face shields) remain the last realistic alternative. According to multiple studies the authors present clear arguments for double gloving during surgical procedures. The perforation rates for single gloves or outer gloves are a few times higher than for double-inner gloves. It is concluded that double gloving is an essential element to prevent blood-borne infections at the operating room environment, especially during long-lasting, complex procedures combined with a large amount of blood loss. Possible reduce of sensitivity and manual dexterity may be improved by choosing more suitable combination of inner- and outer-glove size.


Chronobiology of cardiac ventricular fibrillation development in experimental acute coronary failure.
Numerous experiments on simulation of acute coronary failure in initially intact rabbits showed that under the same experimental conditions irreversible ventricular fibrillation developed in some animals and did not develop in other. We hypothesize that the probability of fibrillation development was determined by the time of the day, during which acute coronary failure developed. The study was carried out on 2 groups of rabbits in winter in Moscow. In group 1, the failure was induced by ligation of the left descending coronary artery at the interface between its middle and lower thirds at 11.00-18.00 with 30-min intervals. In group 2, the microcirculatory status of the left-ventricular myocardium was studied by light microscopy and morphometry at 12.00 and 18.00. Induction of coronary failure during the period from 15.30 to 18.00 led to irreversible ventricular fibrillation and death in 100% cases. Modeling of the condition from 11.00 to 15.00 caused no ventricular fibrillation in 89% cases, and the animals survived. The area of left-ventricular myocardial capillaries at 12.00 virtually 2-fold surpassed that at 18.00. Presumably, the electrolyte balance and metabolic characteristics of the myocardium switch over to the nocturnal mode of functioning at 15.30 due to changes in blood filling of the myocardium. The appearance of an ischemic focus in the myocardium during this period inevitably leads to the development of irreversible ventricular fibrillation.


Translation and Validation of the Arrhythmia-Specific Questionnaire in Tachycardia and Arrhythmia (ASTA) to the Brazilian Context: An Instrument Focusing on Arrhythmia Symptoms.
The wide variety of symptoms in patients with cardiac arrhythmias can affect daily living activities. The evaluation of symptoms with patient-reported outcome measures (PROMs), with validated instruments, can provide information that contributes to clinical decisions and treatment. In Brazil, however, there is no available scale that evaluates symptoms in different types of arrhythmias. This study aimed to translate the Arrhythmia-Specific Questionnaire in Tachycardia and Arrhythmia symptom scale (ASTA-symptom scale) and then validate the questionnaire in terms of Brazilian culture. The methodological process of cultural adaptation used was based on international literature guidelines consisting of forward translation, synthesis, back translation, review by an expert committee, and pretest. Psychometric analyses were conducted with 140 patients. These included measuring internal consistency (Cronbach's alpha), construct validity with item-total correlations, and convergent construct validity with correlations with the quality of life questionnaire for patients with atrial fibrillation-version 2 (QVFA-v2). Usability and understandability were evaluated through the usability evaluation of instruments. The translation and adaptation processes were performed by obtaining the Brazilian Portuguese version of the original Swedish instrument. This version presented the internal consistency of items, evaluated through Cronbach's α (0.79). Construct validity was demonstrated by item-total correlations for the nine items, all except one reached the level of >0.30 (0.24). Convergent validity showed a high correlation with QVFA-v2 (0.89). As for the evaluation of usability and understanding, after two small suggested changes, no additional alterations were necessary. The psychometric properties of the Brazilian version of ASTA-symptom scale evaluated in this study were satisfactory, and the scale was proved to be a valid and reliable tool to assess the symptom burden in patients with different forms of tachyarrhythmia. The ASTA-Br-symptom scale questionnaire can be an important addition to PROMs for patients with arrhythmias and could help healthcare professionals in decision-making.


Origin and differentiation of human and murine stroma.
Stromal cells generated in long-term cultures appear to follow a vascular smooth muscle differentiation pathway. Such a pathway, comprising several steps hallmarked by the expression of cytoskeletal and extracellular matrix markers, is found not only for bone marrow stromal cells, but also for stromal cells generated from the different developmental sites of hematopoiesis (yolk sac, aorta-gonad-mesonephros region, fetal liver, and spleen). Factors responsible for this differentiation pathway and its functional significance are discussed. The mesenchymal founder cell might be, at least for bone marrow, a mesenchymal stem cell (MSC), giving rise to stromal cells, endothelial cells, adipocytes, osteoblasts, and chondrocytes. A feature that distinguishes the MSC lineage from that of the hematopoietic stem cell lineage is that differentiation pathways are not strictly delineated, since even apparently fully differentiated cells from a given lineage have the potential to convert into another lineage (phenotype "plasticity") and intermediate cell phenotypes are observed. A stochastic Repression/Induction model that would account for this plasticity is proposed.


The Functional Activity of the Human Serotonin 5-HT1A Receptor Is Controlled by Lipid Bilayer Composition.
Although the properties of the cell plasma membrane lipid bilayer are broadly understood to affect integral membrane proteins, details of these interactions are poorly understood. This is particularly the case for the large family of G protein-coupled receptors (GPCRs). Here, we examine the lipid dependence of the human serotonin 5-HT1A receptor, a GPCR that is central to neuronal function. We incorporate the protein in synthetic bilayers of controlled composition together with a fluorescent reporting system that detects GPCR-catalyzed activation of G protein to measure receptor-catalyzed oligonucleotide exchange. Our results show that increased membrane order induced by sterols and sphingomyelin increases receptor-catalyzed oligonucleotide exchange. Increasing membrane elastic curvature stress also increases this exchange. These results reveal the broad dependence that the 5-HT1A receptor has on plasma membrane properties, demonstrating that membrane lipid composition is a biochemical control parameter and highlighting the possibility that compositional changes related to aging, diet, or disease could impact cell signaling functions.


[A case of recurrent breast cancer responding to combination therapy with mitoxantrone (MIT), 5'-deoxy-5-fluorouridine (5'-DFUR) and medroxyprogesterone acetate (MPA)].
The patient was a 50-year-old woman who had undergone left standard radical mastectomy who had undergone left standard radical mastectomy on June 1, 1986. She showed multiple liver metastases with elevation of CEA level in July, 1991, and 5'-DFUR plus MPA combination therapy was started. The daily dosages were: 800 mg/body and 1,200 mg/body, respectively. After intra-arterial infusion of pirarubicin and Lipiodol, bilateral oophorectomy was performed and an implantable reservoir for intra-arterial infusion chemotherapy was implanted via the proper hepatic artery. Then she was treated by arterial-infusion of mitoxantrone 10mg/body intermittently every two weeks. The metastatic foci responded to this therapy and her CEA level decreased.


Purified human plasma kallikrein aggregates human blood neutrophils.
Exposure of human blood polymorphonuclear leukocytes (PMN) to purified active plasma kallikrein resulted in PMN aggregation when kallikrein was present at concentrations ranging from 0.4 to 0.6 U/ml (0.18-0.27 microM). Kallikrein-induced PMN aggregation was not mediated through C5-derived peptides, because identical responses were observed whether or not kallikrein had been preincubated with an antibody to C5. Moreover, kallikrein was specific for aggregating PMN, because no aggregation was observed with Factor XII active fragments (23 nM), Factor XIa (0.6 U/ml or 15nM), thrombin (1.6 microM), plasmin (2 microM), porcine pancreatic elastase (2 microM), bovine pancreatic chymotrypsin (2 microM), or bradykinin (1 microM). Bovine pancreatic trypsin (2 microM) aggregated PMN, but to a lesser extent than kallikrein (0.18 microM). Kallikrein was a potent aggregant agent for PMN because similar responses were observed with kallikrein (0.5 U/ml or 0.23 microM) and an optimal dose (0.2 microM) of N-formyl-methionyl-leucyl-phenylalanine. In addition, PMN incubation with kallikrein resulted in stimulation of their oxidative metabolism as assessed by an increased oxygen uptake. Neutropenia and leukostasis observed in diseases associated with activation of the contact phase system may be the result of PMN aggregation by plasma kallikrein.


Functional characterization of SOX2 in bovine preimplantation embryos.
To date, efforts to establish pluripotent embryonic stem cells from bovine embryos have failed. The lack of reliable pluripotency markers is an important drawback when attempting to derive these cells. This study aimed to identify genes upregulated in the inner cell mass (ICM) of bovine blastocysts, and we selected SOX2 for further characterization. Spatial and temporal localization of the SOX2 protein revealed that its expression starts at the 16-cell stage and then becomes restricted to the ICMs of blastocysts. To study the role of SOX2 during the early development of bovine embryos, we designed siRNA to target SOX2. We began by injecting this siRNA into zygotes; the rate at which blastocysts developed declined compared to noninjected or scramble-injected controls. When only one blastomere of a two-cell embryo was injected with SOX2 siRNA, we observed development rates similar to those of controls. Daughter cells of the injected blastomere were tracked by TRITC fluorescence and found to contribute to the ICM, as select cells also lacked SOX2. Gene expression analysis revealed a decrease in SOX2 and NANOG gene expression in siRNA-injected embryos, but OCT4 expression remained unchanged. We conclude that SOX2 localizes exclusively in the ICM of bovine blastocysts, and its downregulation negatively impacts preimplantation development; however, it is still unclear as to why downregulation of SOX2 in one cell of a two-cell embryo does not affect the composition of the ICM.


[Insertion of vector sequences in the genome of transgenic plants].
Insertion of vector sequences of different lengths in the genome of transgenic tobacco and carrot plants occurring at a frequency of 35.2% was shown. No significant differences in insertion frequencies between the two species were observed. Integrated fragments of the vector DNA were stably inherited in the following generation resulted from self-pollination of original transformants.


The Delivery of Orthopaedic Care midst COVID-19 and Social Distancing.
In this paper we present the findings of a literature review covering articles published in the last three decades describing the application of telemedicine in orthopaedics. A review of the PubMed Central and Medline provided 75 articles studying the role of telemedicine, the majority directly examining the application of telemedicine in orthopaedic patients. We report the summarized findings of these studies, the financial and HIPAA considerations of using telemedicine, and provide an example of our single urban level-1 trauma center's strategy for incorporating telemedicine into the clinical practice of orthopaedic surgeons during the COVID-19 pandemic.


Electroacupuncture Therapy in Nicotine Dependence: A Double Blind, Sham-Controlled Study.
The number of non-pharmacological controlled studies is insufficient in the treatment of nicotine dependence (ND). Nevertheless, non-pharmacological treatments, such as electroacupuncture (EA), are becoming increasingly popular in the treatment of ND. The aims of this study were to determine the efficacy and safety of "true EA therapy" (TEAT) compared to those of "sham EA therapy" (SEAT) in ND treatment. Eligible patients who met the DSM-IV criteria for ND (n=450) were included in the study. This study was a double-blinded, sham-controlled clinical trial with a 4-week treatment period and 4-week follow-up conducted between June and December 2009 at a psychiatry outpatient clinic. One hundred and sixty four adult (≥18 years; 44 men, 120 women) cigarette smokers out of 450 patients who met the inclusion and exclusion criteria were enrolled in the study in a ratio of 1:1 to receive TEAT (n=84) or SEAT (n=80). Routine biochemical and hematological tests, chest X-Ray, and ECG were carried out; end-expired carbon monoxide (CO) levels were measured too. Clinical characteristics were obtained through the Fagerström Nicotine Dependence Test (FNDT), Hamilton Rating Scale for Depression (HRSD), and Hamilton Anxiety Scale (HAS). EA was carried out by a trademark device, Antismoke 3000®. Efficacy analyses were performed on "intent-to-treat analysis." Primary outcome was the differences from baseline to endpoint in mean FNDT, number of cigarettes smoked per day, and CO levels at week 4. Secondary outcomes were the same variables at week 8. These variables were assessed via analysis of covariance (ANCOVA). Mean baseline FNDT, HRSD, HAS, and CO levels of the groups were statistically similar. TEAT and SEAT groups demonstrated no significant changes in the outcome variables and smoking cessation rates (35.7% and 30%, respectively). Of those remaining outside of the study, 8.3% were from the TEAT group and 8.7% were from the SEAT group; there was no statistical difference between the groups. The rate of treatment discontinuation was similar between the TEAT (44%) and SEAT (43.7%) groups (p>0.05). The rates of adverse events were not similar too. This study showed that both TEAT and SEAT have similar efficacy and safety profiles in patients with ND.


Rhodaelectro-Catalyzed Decarboxylative Cross-Dehydrogenative Coupling of Indole-3-carboxylic Acids and Olefins via Weakly Coordinating Carboxyl Groups.
A rhodaelectro-catalyzed C2-H selectively decarboxylative alkenylation of 3-carboxy-1H-indoles employing electricity as the traceless terminal oxidant has been accomplished. The weakly coordinating carboxyl group serves as the traceless directing groups. External oxidant-free in an undivided cell with constant current in aqueous solution ensures the decarboxylative C-H alkenylation to be viable and sustainable.


Synthesis of Oridonin Derivatives via Mizoroki-Heck Reaction and Click Chemistry for Cytotoxic Activity.
Natural products (NPs) are evolutionarily chosen "privileged structures" that have a profound impact upon the anticancer drug discovery and development progress. However, the search for new drugs based on structure modification of NPs has often been hindered due to the tedious and complicated synthetic pathways. Fortunately, Mizoroki-Heck reaction and copper-catalyzed alkyne-azide cycloaddition (CuAAC) could provide perfect strategies for selective modification on NPs even in the presence of liable functionalities. Here, we used oridonin, an ent-kaurane diterpenoid that showed a wide range of biological activities, as a parent molecule for the generation of analogues with anticancer activity. Derivatives of oridonin were generated based on the structure-activity relationship study of oridonin and synthesized via Mizoroki-Heck reaction and CuAAC. The cytotoxicity of new oridonin derivatives were evaluated on both cancer cells and normal cells. Furthermore, the apoptotic effect and cell cycle arrest effect of the selected potent analogue were evaluated by flow cytometry and western blotting analysis. Two series of novel C-14 and C-17 modified derivatives of oridonin were obtained via Heck reaction and copper-catalyzed alkyne-azide cycloaddition (CuAAC), respectively. In vitro antiproliferative activities showed that the introduction of C-14 (2-triazole)acetoxyl- moiety could retain or enhance cytotoxicity, whereas the introduction of C-17 phenyl ring might exert negative effect. Further studies demonstrated that derivative 23 exhibited broad-spectrum antiproliferative activity, effectively overcame drug-resistance and showed weak cytotoxicity on non-cancer cells. Preliminary mechanistic studies indicated that 23 might cause G2/M phase arrest and induce apoptosis in PC-3 cells. Mizoroki-Heck reaction and CuAAC are perfect strategies for structure modification of complex natural products. The introduction of C-14 (2-triazole)acetoxyl- moiety could retain or enhance the cytotoxicity of oridonin, the introduction of C-17 phenyl group might exert negative effect on its cytotoxicity.


[Cerebral kinetics of brain perfusion agents].
Radiotracers called chemical microsphere are widely accepted as brain perfusion agents. Following the intravenous administration, these drugs are transported via the artery to the brain, cross the intact blood-brain barrier, and enter the brain tissue. Once the tracer flows into the brain, the efflux of the tracer is prevented by some trapping mechanism, resulting in prolonged retention. Because the distribution of the accumulated tracer remains approximately consistent with regional cerebral blood flow for a relatively long period, high-quality SPECT images reflecting the distribution pattern of cerebral blood flow can be acquired. However, unlike true microsphere, cerebral kinetics of the brain perfusion agents is complicated, and various causes may produce discrepancy between the distributions of the tracer and blood flow. In this review, cerebral kinetics of the brain perfusion agents used commonly is discussed. The knowledge of the mechanism of brain accumulation appears to be essential to appropriately determine the tracer of choice and interpret the obtained images.


Vaginal birth after two previous caesarean deliveries in a patient with uterus didelphys and an interuterine septal defect.
Uterus didelphys is a congenital abnormality characterised by double uteri, double cervices and a double or single vagina that affects 0.3% to 11% of the general female population. A 23-year-old woman, gravida 3 para 3003, with uterus didelphys, acquired an iatrogenic interuterine septal defect during an otherwise routine primary caesarean delivery for fetal malpresentation. The defect was repaired but noted to have dehisced during her second pregnancy. A repeat caesarean section was performed due to fetal malpresentation after an unsuccessful external cephalic version. The dehisced defect was left unrepaired. During her third pregnancy, the placenta implanted in the right uterus, but the fetus migrated to the left uterus at approximately 28 weeks gestation. The umbilical cord traversed the interuterine septal defect. With the fetus in the vertex presentation at term gestation, the patient underwent a vaginal birth after two previous caesarean deliveries without any major perinatal complications.


Syntheses and structures of asymmetric Bis(silyl) niobocene hydrides.
This paper deals with the preparation and structural investigation of asymmetric bis(silyl) niobocene hydrides, Cp2Nb(SiHMe2)(H)(SiXMe2) (2; X = F (a), Cl (b), Br (c), I (d)) and Cp2Nb(SiXMe2)(H)(SiYMe2) (X,Y= F-I; X not equal Y). Complexes 2a-d were prepared by selective electrophilic activation of the Si-H bond in Cp2Nb(SiHMe2)2(H). The Cp2Nb(SiXMe2)(H)(SiYMe2) complexes were prepared by electrophilic activation of the Si-H bond in 2a-d and, in some cases, by electrophilic exchange of the X halides in Cp2Nb(SiXMe2)2(H) (1) for other halides, Y. The structures of complexes 2b and 2c have been studied by X-ray and neutron diffraction (ND). The ND results unequivocally established that the hydride ligand in 2c is shifted toward the SiBrMe2 ligand and that in 2b is positioned symmetrically between two nonequivalent silyl groups, with the H...SiClMe2 distance being shorter because of the shorter Nb-SiClMe2 bond length. Analysis of the X-ray structures of complexes 2a-d and complexes Cp2Nb(SiXMe2)(H)(SiYMe2) shows that the largest structural distortions are observed for the silyl groups substituted by heavy halogen atoms. These trends are rationalized in terms of stronger interligand hypervalent interactions (IHI) Nb-H...Si-X for heavy atoms X from Group 7.


Survey of Indian Dental Professionals Regarding the Use of Computer-Aided Design/Computer-Aided Manufacture (CAD/CAM) Technology.
Objective In recent years, digital processes like computer-aided design/computer-aided manufacture (CAD/CAM) have been implemented in dentistry. On the use and reporting of this technology by dentists, there is no published information. The goal of this study was to determine whether CAD/CAM technology had infiltrated Indian dentistry practices and to look into the relationship between various demographic parameters and respondents' answers about using or not using this technology. Materials and methods A sample of Indian dentists, both users and non-users of CAD/CAM, were sent about 500 online surveys. It sought to shed light on the usage style, materials, advantages, and limitations of CAD/CAM dentistry, as well as their perceived advantages and access hurdles. Statistical analysis was conducted to determine the impact of numerous demographic factors, including country of employment, dentist experience, educational attainment, and the nature of the job. Results There were 132 total replies that were finished. The majority of respondents didn't use any aspect of a digital workflow, and the biggest obstacles to using CAD/CAM were the upfront expenses and a lack of perceived advantages over traditional techniques. The likelihood of using CAD/CAM technology was highest among dentists who primarily performed private practice (P<0.0001). A third of users thought that their training was insufficient, even though the majority of users were either self-taught or schooled by firms. The majority of respondents (60.6%) believed that CAD/CAM would have a significant future role. Conclusion Most respondents said they had never used any aspect of a digital process. Although most dentists who responded to the study thought CAD/CAM would play a significant role in the future, the majority were still interested in integrating it into their workflow. Dentists continue to have certain concerns regarding the chairside CAD/CAM restorations' quality.


Infectious rabies viruses from cloned cDNA.
The generation of infectious rabies virus (RV), a non-segmented negative-stranded RNA virus of the Rhabdoviridae family, entirely from cloned cDNA is described. Simultaneous intracellular expression of genetically marked full-length RV antigenome-like T7 RNA polymerase transcripts and RV N, P and L proteins from transfected plasmids resulted in formation of transcriptionally active nucleocapsids and subsequent assembly and budding of infectious rabies virions. In addition to authentic RV, two novel infectious RVs characterized by predicted transcription patterns were recovered from modified cDNA. Deletion of the entire non-translated pseudogene region, which is conserved in all naturally occurring RVs, did not impair propagation of the resulting virus in cell culture. This indicates that non-essential genetic material might be present in the genomes of non-segmented RNA viruses. The introduction of a functional extra cistron border into the genome of another virus resulted in the transcription of an additional polyadenylated mRNA containing pseudogene sequences. The possibility of manipulating the RV genome by recombinant DNA techniques using the described procedure--potentially applicable also for other negative-stranded viruses--greatly facilitates the investigation of RV genetics, virus-host interactions and rabies pathogenesis and provides a tool for the design of new generations of live vaccines.


Effects of sex and gender on adaptation to space: immune system.
This review is focused on sex and gender effects on immunological alterations occurring during space flight. Sex differences in immune function and the outcome of inflammatory, infectious, and autoimmune diseases are well documented. The work of the Immunology Workgroup identified numerous reasons why there could be sex and/or gender differences observed during and after spaceflight, but thus far, there has been very little investigation in this area of research. In most cases, this is due to either a low total number of subjects or the minimal number of female flight crew members available for these studies. Thus, the availability of a sufficient number of female subjects to enable statistical analysis of the data has been a limiting factor. As the inclusion of female crew members has increased in the recent past, such studies should be possible in the future. It is very difficult to obtain immunologic and infectious data in small animals that can be usefully extrapolated to humans undergoing spaceflight. Thus, it is recommended by the Immunology Workgroup that a greater emphasis be placed on studying astronauts themselves, with a focus on long-term evaluations of specific, known infectious risks.


Lymphadenectomy in Primary Fallopian Tube Cancer is Associated with Improved Survival.
Primary fallopian tube cancer (PFTC) shares the same diagnostic and management guidelines with epithelial ovarian cancer (EOC). The LION trail raised concerns regarding the role of systematic pelvic and para-aortic lymphadenectomy during debulking surgery. We aimed to evaluate the significance of lymphadenectomy in PFTC survival. This retrospective study analyzed the clinical features and survival of patients with PFTC who underwent primary surgery in our center between January 2013 and October 2020. Sixty-one patients diagnosed with PFTC were included in the study. Twenty-five (41.0%, 25/61) were diagnosed with FIGO (International Federation of Gynecology and Obstetrics) stages I/II and 36 (59.0%, 36/61) were diagnosed with stage III/IV. Twenty-nine (47.5%, 29/61) underwent pelvic lymphadenectomy with or without para-aortic lymphadenectomy, among which 12 (41.4%, 12/29) had lymph node metastasis confirmed by postoperative pathology. The mean progression-free survival was 60.4 months in the lymphadenectomy group and 37.8 months in the no-lymphadenectomy group (p = 0.042, HR 0.374, 95% CI 0.145-0.966). PFTC is often diagnosed earlier and has a better prognosis than EOC. Most patients with PFTC would benefit from lymphadenectomy. However, the extent to which this association translates to a more diverse population needs to be further identified.


Implementation and barriers to uptake of interactive voice response technology aimed to improve blood pressure control at a large academic medical center.
Blood pressure control among patients with hypertension is a widely recognized quality metric, but many large health systems fail to reach targets set by the Healthcare Effectiveness Data and Information Set. We developed an interactive voice response (IVR) system called the "Mobile You Blood Pressure Program" at a large academic medical center and linked it to the health system's electronic health record (EHR). The goal of the program was to capture home blood pressure readings in the EHR and to alert ambulatory care clinical pharmacists automatically of readings below or above clinical thresholds through direct messaging in the EHR. The goal of this report is to describe implementation of IVR, initial patient participation rates, and pharmacist-identified barriers to patient enrollment. Ambulatory care clinical pharmacist specialists' practice in 14 clinics in family medicine and internal medicine at Michigan Medicine, an academic health system serving more than 24,000 patients with a diagnosis of hypertension. This study describes implementation and initial patient enrollment in IVR linked to the EHR for home blood pressure monitoring. We tracked the number of hypertensive patients enrolled and IVR call completion rates between September 2017 and February 2018. We also assessed pharmacist-identified barriers to patient enrollment during 2 separate 2-week intervals in January and February 2018. Between September 1, 2017, and February 28, 2018, a total of 71 patients were enrolled from 14 clinics. Patients were scheduled for 1-3 IVR calls per week focusing on medication adherence and blood pressure control. A total of 936 IVR phone calls were made, with 488 (52%) calls completed. Access to a validated home blood pressure monitor was the largest pharmacist-identified barrier to patient enrollment. The IVR Mobile You Blood Pressure Program represents a new application of digital technology within our health system. Pharmacist-identified barriers to patient participation included access to a validated home blood pressure monitor.