Twofold reduction of phosphofructokinase activity in Lactococcus lactis results in strong decreases in growth rate and in glycolytic flux.
Two mutant strains of Lactococcus lactis in which the promoter of the las operon, harboring pfk, pyk, and ldh, were replaced by synthetic promoters were constructed. These las mutants had an approximately twofold decrease in the activity of phosphofructokinase, whereas the activities of pyruvate kinase and lactate dehydrogenase remained closer to the wild-type level. In defined medium supplemented with glucose, the growth rate of the mutants was reduced to 57 to 70% of wild-type levels and the glycolytic flux was reduced to 62 to 76% of wild-type levels. In complex medium growth was even further reduced. Surprisingly, the mutants still showed homolactic fermentation, which indicated that the limitation was different from standard glucose-limited conditions. One explanation could be that the reduced activity of phosphofructokinase resulted in the accumulation of sugar-phosphates. Indeed, when one of the mutants was starved for glucose in glucose-limited chemostat, the growth rate could gradually be increased to 195% of the growth rate observed in glucose-saturated batch culture, suggesting that phosphofructokinase does affect the concentration of upstream metabolites. The pools of glucose-6-phosphate and fructose-6-phosphate were subsequently found to be increased two- to fourfold in the las mutants, which indicates that phosphofructokinase exerts strong control over the concentration of these metabolites.


Mutual expectation compacts: a means to link practice culture and vision.
We describe the development of a mutual expectation compact in an academic department of surgery as a means of reinforcing the department's vision document and promoting cultural change. The compact makes explicit those implicit agreements that exist between a physician and his or her practice. It strengthens the relationship by avoiding the misunderstandings that can arise when agreements are implicit.


Characteristics of patients with Burkholderia cepacia bacteremia.
Burkholderia cepacia has become an important pathogen of infections in immunocompromised and nosocomial patients. The characteristics of 42 episodes of B. cepacia bacteremia in 40 patients admitted to the Taipei Veterans General Hospital between January 1997 and December 1999 were retrospectively analyzed. Factors that adversely influenced the mortality rate included respiratory failure, an unknown infection source, a period in an intensive care unit, and shock. Most of the patients had serious underlying diseases, such as diabetes mellitus, malignancy, congestive heart failure, and chronic obstructive pulmonary disease. The mean time for a positive blood culture was 45 days after admission. The overall mortality rate was 28.6% (12/42), and 44.4% (12/27) of all deaths were directly related to B. cepacia bacteremia. Polymicrobial bacteremia was found in 5 patients. Ceftazidime was the most effective antimicrobial agent in vitro, whereas chloramphenicol, imipenem, and trimethoprim/sulfamethoxazole were less effective alternatives. Appropriate antibiotic therapy was given to 30 patients, most of whom responded to the therapy except for 5 who died despite receiving appropriate treatment. Although B. cepacia infection develops in a relatively small proportion of hospitalized individuals, it has a major impact on morbidity and mortality. In view of the fact that B. cepacia develops resistance to a wide range of antimicrobial agents, ceftazidime and/or trimethoprim/sulfamethoxazole should be the drug of choice for empiric therapy.


Mus spretus SEG/Pas mice resist virulent Yersinia pestis, under multigenic control.
Laboratory mice are well known to be highly susceptible to virulent strains of Yersinia pestis in experimental models of bubonic plague. We have found that Mus spretus-derived SEG/Pas (SEG) mice are exceptionally resistant to virulent CO92 and 6/69 wild type strains. Upon subcutaneous injection of 10(2) colony-forming units (CFU), 90% of females and 68% of males survived, compared with only an 8% survival rate for both male and female C57BL/6 mice. Furthermore, half of the SEG mice survived a challenge of up to 10(7) CFU. The time required for mortality was similar between B6 and SEG, suggesting that survival is dependent on early rather than late processes. The analysis of 322 backcross mice identified three significant quantitative trait loci (QTLs) on chromosomes 3, 4 and 6, with dominant SEG protective alleles. Each QTL increased the survival rate by approximately 20%. The three QTLs function additively, thereby accounting for 67% of the difference between the parental phenotypes. Mice heterozygous for the three QTLs were just as resistant as SEG mice to Y. pestis challenge. The SEG strain therefore offers an invaluable opportunity to unravel mechanisms and underlying genetic factors of resistance against Y. pestis infection.


Intraocular Pressure Changes in Non-Glaucomatous Patients Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Agents.
To study the prevalence of sustained intraocular pressure (IOP) elevation associated with intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents. Prospective comparative study. Non-glaucomatous patients scheduled to receive intravitreal injection of anti-VEGF therapy were recruited from an outpatient eye clinic, Songklanagarind Hospital between April 2013 and March 2014. The IOP was measured by Goldmann applanation tonometer before and at 1 hour, 1 week, 1 month, 3 months, and 6 months after injection. The IOP was compared using the repeated measures analysis. Sustained IOP elevation was defined as either an IOP > 21 mmHg or an increase from baseline ≥ 5 mmHg on two consecutive visits. Seventy eyes of 54 patients met the inclusion criteria. The most common diagnosis was diabetic macular edema (48%). The mean IOP ± standard deviation (SD) before treatment was 13.7 ± 2.8 mmHg. The means ± SDs after treatment at 1 hour, 1 week, 1 month, 3 months, and 6 months were 11.3 ± 2.6, 13.7 ± 3.6, 14.1 ± 3.3, 14.0 ± 2.3, and 13.7 ± 2.4 mmHg, respectively. A mean of IOP difference at 1 hour postinjection and at baseline was -2.36 ± 2.5 mmHg (P < 0.001). Four of 70 treated eyes (5.7%) developed sustained IOP elevation (IOP ≥ 5 mmHg from baseline on two consecutive visits). The IOP returned to baseline levels after 1 month, in three eyes. One eye had sustained IOP elevation at 3 and 6 months follow-up. Thereafter, IOP returned to baseline level. There was no need of anti-glaucoma medication. After receiving intravitreal injection of anti-VEGF agent, a small proportion of non-glaucomatous eyes developed a sustained IOP elevation without requiring IOP-lowering treatment. At 1 hour postinjection, there was a significant reduction of the mean IOP compared with the baseline level.


A genome-wide approach reveals novel imprinted genes expressed in the human placenta.
Genomic imprinting characterizes genes with a monoallelic expression, which is dependent on the parental origin of each allele. Approximately 150 imprinted genes are known to date, in humans and mice but, though computational searches have tried to extract intrinsic characteristics of these genes to identify new ones, the existing list is probably far from being comprehensive. We used a high-throughput strategy by diverting the classical use of genotyping microarrays to compare the genotypes of mRNA/cDNA vs. genomic DNA to identify new genes presenting monoallelic expression, starting from human placental material. After filtering of data, we obtained a list of 1,082 putative candidate monoallelic SNPs located in more than one hundred candidate genes. Among these, we found known imprinted genes, such as IPW, GRB10, INPP5F and ZNF597, which contribute to validate the approach. We also explored some likely candidates of our list and identified seven new imprinted genes, including ZFAT, ZFAT-AS1, GLIS3, NTM, MAGI2, ZC3H12Cand LIN28B, four of which encode zinc finger transcription factors. They are, however, not imprinted in the mouse placenta, except for Magi2. We analyzed in more details the ZFAT gene, which is paternally expressed in the placenta (as ZFAT-AS1, a non-coding antisense RNA) but biallelic in other tissues. The ZFAT protein is expressed in endothelial cells, as well as in syncytiotrophoblasts. The expression of this gene is, moreover, downregulated in placentas from complicated pregnancies. With this work we increase by about 10% the number of known imprinted genes in humans.


Recent developments in the synthesis, properties, and biomedical applications of core/shell superparamagnetic iron oxide nanoparticles with gold.
In the last decade, magnetic nanoparticles (MNPs), especially superparamagnetic iron oxide nanoparticles (SPIONs), have immensely promoted the advancement of diagnostics and theranostics in the biomedical field. The unique properties of the SPIONs-core and the functional gold (Au)-shell together (SPIONS/Au core/shell or CS) have a wide range of biomedical applications including, but not limited to, magnetic resonance imaging (MRI), dual modality MRI/computed tomography (CT), photo-induced and magnetic fluid hyperthermia (MFH), drug delivery, biosensors, and bio-separation. Researchers have made much effort to develop synthesis strategies for size control and surface modifications to achieve the desired properties of these CSs for applications in in vitro and in vivo studies. This review highlights recent developments in the synthesis and biomedical applications of SPIONs/Au CSs, including γ-Fe2O3/Au (maghemite), Fe3O4/Au (magnetite), and MFe2O4/Au (M = divalent metal ions) in the past seven years. More importantly, current trends of SPIONs/Au in relation to the biochemical industry are surveyed. Finally, we outline the developmental needs of SPIONs/Au from the perspective of material synthesis and their novel applications in disease diagnosis and treatment in the near future.


The humanitarian situation in syria: a snapshot in the third year of the crisis.
Between April and June 2014, International Orthodox Christian Charities (IOCC), an International NGO, and the Greek Orthodox Patriarchate of Antioch and All the East (GOPA) conducted a needs assessment of Syrians affected by the crisis with the objective of gaining a better understanding of humanitarian needs and assistance priorities. Findings suggest that interventions that increase access to non-food items, food, medication and education should be prioritized where cost was the primary barrier to accessing goods and services. Cash transfer programs and direct provision of material assistance should be considered, though the most appropriate assistance modality is likely to vary by sector, location and the preferences and prior experience of donors and implementing organizations. Renewed international commitment to funding humanitarian assistance efforts in Syria and neighboring countries where the burden of refugees is greatest is essential from both a human rights perspective and in terms of maintaining stability in the region.


To silanate or not to silanate: making a clinical decision.
Etched porcelain-bonded restorations have become the treatment of choice for the esthetic restoration of anterior teeth. The bond strength of composite resin to properly etched and silanated porcelain exceeds the cohesive strength of porcelain. Although bonding to enamel is accomplished by only etching the surface to create micromechanical retention, bonding to porcelain is achieved both mechanically through etching porcelain and chemically through the use of a silane coupling agent. Literature supports silanization of porcelain, which provides a more reliable bond than etching with hydrofluoric acid only, although the combination of both are recommended. This article discusses the importance of proper silanization of porcelain in obtaining a durable and reliable resin composite bond with porcelain.


LTR_retriever: A Highly Accurate and Sensitive Program for Identification of Long Terminal Repeat Retrotransposons.
Long terminal repeat retrotransposons (LTR-RTs) are prevalent in plant genomes. The identification of LTR-RTs is critical for achieving high-quality gene annotation. Based on the well-conserved structure, multiple programs were developed for the de novo identification of LTR-RTs; however, these programs are associated with low specificity and high false discovery rates. Here, we report LTR_retriever, a multithreading-empowered Perl program that identifies LTR-RTs and generates high-quality LTR libraries from genomic sequences. LTR_retriever demonstrated significant improvements by achieving high levels of sensitivity (91%), specificity (97%), accuracy (96%), and precision (90%) in rice (Oryza sativa). LTR_retriever is also compatible with long sequencing reads. With 40k self-corrected PacBio reads equivalent to 4.5× genome coverage in Arabidopsis (Arabidopsis thaliana), the constructed LTR library showed excellent sensitivity and specificity. In addition to canonical LTR-RTs with 5'-TG…CA-3' termini, LTR_retriever also identifies noncanonical LTR-RTs (non-TGCA), which have been largely ignored in genome-wide studies. We identified seven types of noncanonical LTRs from 42 out of 50 plant genomes. The majority of noncanonical LTRs are Copia elements, with which the LTR is four times shorter than that of other Copia elements, which may be a result of their target specificity. Strikingly, non-TGCA Copia elements are often located in genic regions and preferentially insert nearby or within genes, indicating their impact on the evolution of genes and their potential as mutagenesis tools.


A chemical/molecular 4-input/2-output keypad lock with easy resettability based on red-emission carbon dots-Prussian blue composite film electrodes.
In this work, a resettable 4-input/2-output keypad lock system based on red-emission carbon dots (rCDs) and Prussian blue (PB) modified electrodes was developed. Electrochromic PB layers were first electrochemically deposited on the indium tin oxide (ITO) electrode surface. An admixture of rCDs and chitosan (Chi) was then cast on the surface of PB layers, forming rCDs-Chi/PB film electrodes. UV-vis absorption of the films was sensitive to the applied potential since the blue PB constituent of the films would be transformed to nearly colorless Prussian white (PW) at the reduction potential of -0.2 V and then from PW back to PB at the oxidation potential of 0.4 V, and the transformation between PB and PW would also influence the fluorescence emission of the rCD constituent in the films. The addition of cysteine (Cys) in the testing solution could reduce the PB in the films into PW and generate an amperometric electrocatalytic current at 0.4 V. Meanwhile, the addition of Fe3+ in solution could greatly quench the fluorescence from the rCD component in the films. Thus, the responses of UV-vis absorbance, fluorescence emission and amperometric current of the rCDs-Chi/PB film electrode system exhibited potential-, Cys- and Fe3+-responsive switching properties. Based on the aforementioned work, a combinational logic gate circuit with 3 inputs and 3 outputs was established. In particular, on the same platform, a novel chemical/molecular 4-input/2-output keypad lock with easy resettability was elaborately designed with amperometric current and fluorescence peak intensity as two different types of outputs, so that a higher security level could be achieved.


xRic-8 is a GEF for Gsalpha and participates in maintaining meiotic arrest in Xenopus laevis oocytes.
Immature stage VI Xenopus oocytes are arrested at the G(2)/M border of meiosis I until exposed to progesterone, which induces meiotic resumption through a non-genomic mechanism. One of the earliest events produced by this hormone is inhibition of the plasma membrane enzyme adenylyl cyclase (AC), with the concomitant drop in intracellular cAMP levels and reinitiation of the cell cycle. Recently Gsalpha and Gbetagamma have been shown to play an important role as positive regulators of Xenopus oocyte AC, maintaining the oocyte in the arrested state. However, a question that still remains unanswered, is how the activated state of Gsalpha and Gbetagamma is achieved in the immature oocyte, since no receptor or ligand have been found to be required. Here we provide evidence that xRic-8 can act in vitro and in vivo as a GEF for Gsalpha. Overexpression of xRic-8, through mRNA injection, greatly inhibits progesterone induced oocyte maturation and endogenous xRic-8 mRNA depletion, through siRNA microinjection, induces spontaneous oocyte maturation. These results suggest that xRic-8 is participating in the immature oocyte by keeping Gsalpha-Gbetagamma-AC signaling complex in an activated state and therefore maintaining G2 arrest.


Omental fibromatosis treated by laparoscopic wide surgical resection.
The current report presents a case of an omental fibromatosis discovered incidentally in a 46-year-old woman with no particular medical history and few symptoms. A surgical biopsy was performed initially, and microscopic examination revealed myofibroblastic proliferation. After additional immunohistochemical and molecular analyses, omental fibromatosis was diagnosed. Omental fibromatosis, also called intra-abdominal desmoid, is a rare and benign tumour but can be locally aggressive. Majority of cases are asymptomatic, and difficult to diagnose based on clinical presentation and radiological investigation. Final diagnosis is usually made on histopathology and immunohistochemistry studies. Surgical wide excision is currently the treatment of choice.


Serotonin and depression: pathophysiological mechanism or marketing myth?
The notion that impaired serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial. Some have argued that the 5-HT hypothesis has been misused by the pharmaceutical industry to promote a simplistic biological model of depression to market selective serotonin reuptake inhibitors (SSRIs) to medical practitioners and the public. By contrast, there is now substantial evidence that unmedicated depressed patients have abnormalities in brain 5-HT function; however, the relation of these abnormalities to the clinical syndrome is unclear. The best evidence that 5-HT contributes to the pathophysiology of depression comes from studies of tryptophan depletion, which show that lowering brain 5-HT levels can induce acute symptomatic relapse in recovered depressed patients. Clarification of the mechanism of this effect will enable an understanding of how impaired 5-HT activity contributes to the subjective experience of depression.


A clinical perspective of spinal cord injury.
Spinal cord injury (SCI) results in loss of nervous tissue in the spinal cord and consequently loss of motor and sensory function. The impairments are permanent because endogenous repair events fail to restore the damaged axonal circuits that are involved in function. There is no treatment available that restores the injury-induced loss of function. The consequences of SCI are devastating physically and socially. The assessment of functional loss after SCI has been standardized in the larger part of the world. For medical care however there are no standards available. During the early phase, treatments that stabilize the patient's health and attempt to limit further neurological deterioration need to be implemented. During the later phase of SCI, the focus needs to be on prevention and/or treatment of secondary complications such as pain, pressure ulcers, and infections. Neuroprotective, axon growth-promoting and rehabilitative repair approaches are currently being tested but, so far, none of these has emerged as an effective treatment that reverses the consequences of SCI. Promising new repair approaches have emerged from the laboratory during the last years and entered the clinical arena including stem cell transplantation and functional electrical stimulation.


A multifunctional bispecific antibody protects against Pseudomonas aeruginosa.
Widespread drug resistance due to empiric use of broad-spectrum antibiotics has stimulated development of bacteria-specific strategies for prophylaxis and therapy based on modern monoclonal antibody (mAb) technologies. However, single-mechanism mAb approaches have not provided adequate protective activity in the clinic. We constructed multifunctional bispecific antibodies, each conferring three mechanisms of action against the bacterial pathogen Pseudomonas aeruginosa by targeting the serotype-independent type III secretion system (injectisome) virulence factor PcrV and persistence factor Psl exopolysaccharide. A new bispecific antibody platform, BiS4, exhibited superior synergistic protection against P. aeruginosa-induced murine pneumonia compared to parent mAb combinations or other available bispecific antibody structures. BiS4αPa was protective in several mouse infection models against disparate P. aeruginosa strains and unexpectedly further synergized with multiple antibiotic classes even against drug-resistant clinical isolates. In addition to resulting in a multimechanistic clinical candidate (MEDI3902) for the prevention or treatment of P. aeruginosa infections, these antibody studies suggest that multifunctional antibody approaches may be a promising platform for targeting other antibiotic-resistant bacterial pathogens.


Cultural stereotypes die hard: the case of transracial adoption.
Transracial adoption (commonly understood as the adoption of black children by white families) has been the subject of a persistent debate among adoption specialists, legal advocates, mental health professionals, and even civil rights advocates in this country for a long time. This has been so despite cumulative research evidence indicating that transracial adoptees can thrive and develop into confident adults with strong senses of identity and self-esteem. We contend that the evidence undergirding transracial adoption has not been effectively persuasive because of the tenacious and ubiquitous cultural belief that children and their potential adoptive parents should be matched along racial lines. However, the cultural principle of racial matching has also been diluted by judicial decisions that have narrowly allowed the use of race as one factor rather than as the controlling factor in adoption decisions. This article focuses on the use of a third element--federal statutory attempts intended to remove race as a controlling factor in child placement decisions. We will show how as a matter of public policy, the statutory efforts were meant to promote race-neutral approaches to adoption and to support transracial adoptions. However, in practice, the statutory attempts may still leave the door open to continued race-matching, which suggests that the cultural preference for race-matching in the construction of families remains powerfully ingrained and difficult to eradicate. As a consequence, transracial adoption appears to maintain its status as a culturally suspect phenomenon.


Optimism and challenge for science-based conservation of migratory species in and out of U.S. National Parks.
Public agencies sometimes seek outside guidance when capacity to achieve their mission is limited. Through a cooperative agreement and collaborations with the U.S. National Park Service (NPS), we developed recommendations for a conservation program for migratory species. Although NPS manages ∼ 36 million hectares of land and water in 401 units, there is no centralized program to conserve wild animals reliant on NPS units that also migrate hundreds to thousands of kilometers beyond parks. Migrations are imperiled by habitat destruction, unsustainable harvest, climate change, and other impediments. A successful program to counter these challenges requires public support, national and international outreach, and flourishing migrant populations. We recommended two initial steps. First, in the short term, launch or build on a suite of projects for high-profile migratory species that can serve as proof to demonstrate the centrality of NPS units to conservation at different scales. Second, over the longer term, build new capacity to conserve migratory species. Capacity building will entail increasing the limited knowledge among park staff about how and where species or populations migrate, conditions that enable migration, and identifying species' needs and resolving them both within and beyond parks. Building capacity will also require ensuring that park superintendents and staff at all levels support conservation beyond statutory borders. Until additional diverse stakeholders and a broader American public realize what can be lost and do more to protect it and engage more with land management agencies to implement actions that facilitate conservation, long distance migrations are increasingly likely to become phenomena of the past.


Probing protein adsorption onto mercaptoundecanoic acid stabilized gold nanoparticles and surfaces by quartz crystal microbalance and zeta-potential measurements.
The adsorption characteristics of three proteins [bovine serum albumin (BSA), myoglobin (Mb), and cytochrome c (CytC)] onto self-assembled monolayers of mercaptoundecanoic acid (MUA) on both gold nanoparticles (AuNP) and gold surfaces (Au) are described. The combination of quartz crystal microbalance measurements with dissipation (QCM-D) and pH titrations of the zeta-potential provide information on layer structure, surface coverage, and potential. All three proteins formed adsorption layers consisting of an irreversibly adsorbed fraction and a reversibly adsorbed fraction. BSA showed the highest affinity for the MUA/Au, forming an irreversibly adsorbed rigid monolayer with a side-down orientation and packing close to that expected in the jamming limit. In addition, BSA showed a large change in the adsorbed mass due to reversibly bound protein. The data indicate that the irreversibly adsorbed fraction of CytC is a monolayer structure, whereas the irreversibly adsorbed Mb is present in form of a bilayer. The observation of stable BSA complexes on MUA/AuNPs at the isoelectric point by zeta-potential measurements demonstrates that BSA can sterically stabilize MUA/AuNP. On the other hand, MUA/AuNP coated with either Mb or CytC formed a reversible flocculated state at the isoelectric point. The colloidal stability differences may be correlated with weaker binding in the reversibly bound overlayer in the case of Mb and CytC as compared to BSA.


Water quality status and trends in agriculture-dominated headwaters; a national monitoring network for assessing the effectiveness of national and European manure legislation in The Netherlands.
Large nutrient losses to groundwater and surface waters are a major drawback of the highly productive agricultural sector in The Netherlands. The resulting high nutrient concentrations in water resources threaten their ecological, industrial, and recreational functions. To mitigate eutrophication problems, legislation on nutrient application in agriculture was enforced in 1986 in The Netherlands. The objective of this study was to evaluate this manure policy by assessing the water quality status and trends in agriculture-dominated headwaters. We used datasets from 5 agricultural test catchments and from 167 existing monitoring locations in agricultural headwaters. Trend analysis for these locations showed a fast reduction of nutrient concentrations after the enforcement of the manure legislation (median slopes of -0.55 mg/l per decade for total nitrogen (N-tot) and -0.020 mg/l per decade for total phosphorus (P-tot)). Still, up to 76 % of the selected locations currently do not comply with either the environmental quality standards (EQSs) for nitrogen (N-tot) or phosphorus (P-tot). This indicates that further improvement of agricultural water quality is needed. We observed that weather-related variations in nutrient concentrations strongly influence the compliance testing results, both for individual locations and for the aggregated results at the national scale. Another important finding is that testing compliance for nutrients based on summer average concentrations may underestimate the agricultural impact on ecosystem health. The focus on summer concentrations does not account for the environmental impact of high winter loads from agricultural headwaters towards downstream water bodies.


Cellular mechanisms of slime gland refilling in Pacific hagfish (Eptatretus stoutii).
Hagfishes use their defensive slime to ward off gill-breathing predators. Slime gland refilling is a surprisingly slow process, and previous research has shown that the composition of the slime exudate changes significantly during refilling, which likely has consequences for the functionality of the slime. This study set out to expand our understanding of slime gland refilling by examining the cellular processes involved in refilling of the glands, as well as determining where in the gland the main slime cells - the gland thread cells and gland mucous cells - arise. Slime glands were electro-stimulated to exhaust their slime stores, left to refill for set periods of time, and harvested for histological and immunohistochemical examination. Whole slime glands, gland thread cell morphometrics and slime cell proportions were examined over the refilling cycle. Slime glands decreased significantly in size after exhaustion, but steadily increased in size over refilling. Gland thread cells were the limiting factor in slime gland refilling, taking longer to replenish and mature than gland mucous cells. Newly produced gland thread cells underwent most of their growth near the edge of the gland, and larger cells were found farthest from the edge of the gland. Immunohistochemical analysis also revealed proliferating cells only within the epithelial lining of the slime gland, suggesting that new slime cells originate from undifferentiated cells lining the gland. Our results provide an in-depth look at the cellular dynamics of slime gland refilling in Pacific hagfish, and provide a model for how slime glands refill at the cellular level.


Prevention of guanylyl cyclase-B dephosphorylation rescues achondroplastic dwarfism.
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase-B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At 2 weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.


Role of low-level laser therapy in neurorehabilitation.
This year marks the 50th anniversary of the discovery of the laser. The development of lasers for medical use, which became known as low-level laser therapy (LLLT) or photobiomodulation, followed in 1967. In recent years, LLLT has become an increasingly mainstream modality, especially in the areas of physical medicine and rehabilitation. At first used mainly for wound healing and pain relief, the medical applications of LLLT have broadened to include diseases such as stroke, myocardial infarction, and degenerative or traumatic brain disorders. This review will cover the mechanisms of LLLT that operate both on a cellular and a tissue level. Mitochondria are thought to be the principal photoreceptors, and increased adenosine triphosphate, reactive oxygen species, intracellular calcium, and release of nitric oxide are the initial events. Activation of transcription factors then leads to expression of many protective, anti-apoptotic, anti-oxidant, and pro-proliferation gene products. Animal studies and human clinical trials of LLLT for indications with relevance to neurology, such as stroke, traumatic brain injury, degenerative brain disease, spinal cord injury, and peripheral nerve regeneration, will be covered.


Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis.
Vitamin E consists of tocopherols and tocotrienols, in which α-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3±3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke.


High-throughput detection of immobilized plasmonic nanoparticles by a hyperspectral imaging system based on Fourier transform spectrometry.
To facilitate the application of plasmonic nanoparticles (PNPs) in high-throughput detection, we develop a hyperspectral imaging system (HSIS) combining dark-filed microscopy and imaging Fourier transform spectrometry to measure scattering spectra from immobilized PNPs. The current setup has acquisition time of 5 seconds and spectral resolution of 21.4 nm at 532.1 nm. We demonstrate the applicability of the HSIS in conjunction with spectral data analysis to quantify multiple types of PNPs and detect small changes in localized surface plasmon resonance wavelengths of PNPs due to changes in the environmental refractive index.


"What matters most:" a cultural mechanism moderating structural vulnerability and moral experience of mental illness stigma.
To understand Chinese immigrants' experiences with mental illness stigma and mental health disparities, we integrate frameworks of 'structural vulnerability' and 'moral experience' to identify how interaction between structural discrimination and cultural engagements might shape stigma. Fifty Chinese immigrants, including 64% Fuzhounese immigrants who experienced particularly harsh socio-economical deprivation, from two Chinese bilingual psychiatric inpatient units in New York City were interviewed from 2006 to 2010 about their experiences of mental illness stigma. Interview questions were derived from 4 stigma measures, covering various life domains. Participants were asked to elaborate their rating of measure items, and thus provided open-ended, narrative data. Analysis of the narrative data followed a deductive approach, guided by frameworks of structural discrimination and "what matters most" - a cultural mechanism signifying meaningful participation in the community. After identifying initial coding classifications, analysis focused on the interface between the two main concepts. Results indicated that experiences with mental illness stigma were contingent on the degree to which immigrants were able to participate in work to achieve "what mattered most" in their cultural context, i.e., accumulation of financial resources. Structural vulnerability - being situated in an inferior position when facing structural discrimination - made access to affordable mental health services challenging. As such, structural discrimination increased healthcare spending and interfered with financial accumulation, often resulting in future treatment nonadherence and enforcing mental health disparities. Study participants' internalizing their structurally-vulnerable position further led to a depreciated sense of self, resulting in a reduced capacity to advocate for healthcare system changes. Paradoxically, the multi-layered structural marginalization experienced by Chinese immigrants with mental illness allowed those who maintained capacity to work to retain social status even while holding a mental illness status. Mental health providers may prioritize work participation to shift service users' positions within the hierarchy of structural vulnerability.


Distribution and magnitude of shear stress after coronary bifurcation lesions stenting with the classical crush technique: a new predictor for in-stent restenosis.
Wall shear stress (SS) plays an important role in the initiation and proliferation of coronary atherosclerosis, especially for bifurcations. Stenting in the coronary artery will cause many different changes in velocity, flow, cross-sectional area, and especially the wall SS. However, it is still unknown how much wall SS distribution varies with stenting in coronary bifurcation. The purpose of this study was to investigate the magnitude and distribution of wall SS after the classical crush stenting for bifurcation lesions. Eleven patients with true coronary bifurcation stenting by the classical crush technique were included. We studied the difference of wall SS between restenosis and nonrestenosis groups in these patients. The differences in SS between preprocedure and postprocedure, as well as between immediately postprocedure and after an 8-month follow-up, were also analyzed. Diameter stenosis or minimal lumen diameter were measured by quantitative coronary analysis. The commercial CD STAR-CCM+ was used to calculate the SS. At baseline, the SS in all the segments of all patients was high. The baseline SS of the restenosis group was 50% lower than the nonrestenosis group. Immediately after percutaneous coronary intervention (PCI), the SS in both areas decreased; however, the SS of the nonrestenosis group decreased to its lowest level possible while the SS of the restenosis group decreased moderately. Eight months later, the SS of all the segments of the nonrestenosis group remained persistently low at the same level of right after PCI. In contrary, the SS in the restenosis group returned to near its baseline level. From our study, after a 2-stent crush technique using drug-eluting stents (DES), the degree of SS reduction appears to predict in-stent restenosis (ISR). A SS decrease to its lowest level and remaining homogenously low is a prime condition to prevent ISR. A baseline low SS, which decreases minimally after PCI and recovers to around its baseline level, appears to be the setting for restenosis. These conditions can be evaluated as predictors of lesions that may need surveillance angiography and proper IVUS evaluation to prevent future in-stent restenosis.


Physical vapor deposition of a polyamorphic system: Triphenyl phosphite.
In situ AC nanocalorimetry and dielectric spectroscopy were used to analyze films of vapor-deposited triphenyl phosphite. The goal of this work was to investigate the properties of vapor-deposited glasses of this known polyamorphic system and to determine which liquid is formed when the glass is heated. We find that triphenyl phosphite forms a kinetically stable glass when prepared at substrate temperatures of 0.75-0.95Tg, where Tg is the glass transition temperature. Regardless of the substrate temperature utilized during deposition of triphenyl phosphite, heating a vapor-deposited glass always forms the ordinary supercooled liquid (liquid 1). The identity of liquid 1 was confirmed by both the calorimetric signal and the shape and position of the dielectric spectra. For the purposes of comparison, the glacial phase of triphenyl phosphite (liquid 2) was prepared by the conventional method of annealing liquid 1. We speculate that these new results and previous work on vapor deposition of other polyamorphic systems can be explained by the free surface structure being similar to one polyamorph even in a temperature regime where the other polyamorph is more thermodynamically stable in the bulk.


Negative self-appraisal: Personal reasons for dying as indicators of suicidality.
Reasons for dying (RFD) are one of the most authentic factors illustrating the lived experience of suicidal individuals. However, the field has been criticized for inadequate evaluation of risk factors and suicidal symptoms, such as RFD, to develop more robust theoretical models and risk assessments. In this study, we aimed to critically examine RFD themes as predictors of suicidal symptoms to improve our understanding of the suicidal mind, test suicide theory validity and improve risk assessment. This cross-sectional mixed-method study included anonymous survey data (N = 713) with a subsample (n = 474; 77% female; age M = 31.48, SD = 13.53) who provided RFD. Participants were asked to write down five RFD (ranked 1st to 5th most important) and completed the Suicidal Affect-Behavior-Cognition Scale (SABCS). Thematic analysis revealed eight valid RFD themes-Negative Self-appraisal, Hopelessness, Desire to Escape, Escape Pain, Relationships, Loneliness, Financial Hardship, and Physical Health. Themes were quantified by rank and total endorsements of the theme. Hierarchical regression modelling, statistically controlling for demographics, showed all RFD themes, except Physical Health, were positive predictors of suicidality, accounting for 26% of variance in suicidal symptoms. Negative Self-appraisal was the strongest predictor. RFD differences were also found by gender, age and education. From these findings, we determined current suicide theories do not fully account for suicidal persons' RFD. There is a pressing need for more critical review of current theories, as current theories only partially represent this key attribute of the suicidal mind, and none of the reviewed theories accurately reflected suicidal participants' RFD. Clinical implications include integrating financial therapies into suicide prevention treatments and incorporating RFD into assessments and treatments. To aid research and risk assessment efforts, we propose a new RFD Index, with eight five-point response items.


Human aortic valve calcification is associated with an osteoblast phenotype.
Calcific aortic stenosis is the third most common cardiovascular disease in the United States. We hypothesized that the mechanism for aortic valve calcification is similar to skeletal bone formation and that this process is mediated by an osteoblast-like phenotype. To test this hypothesis, we examined calcified human aortic valves replaced at surgery (n=22) and normal human valves (n=20) removed at time of cardiac transplantation. Contact microradiography and micro-computerized tomography were used to assess the 2-dimensional and 3-dimensional extent of mineralization. Mineralization borders were identified with von Kossa and Goldner's stains. Electron microscopy and energy-dispersive spectroscopy were performed for identification of bone ultrastructure and CaPO4 composition. To analyze for the osteoblast and bone markers, reverse transcriptase-polymerase chain reaction was performed on calcified versus normal human valves for osteopontin, bone sialoprotein, osteocalcin, alkaline phosphatase, and the osteoblast-specific transcription factor Cbfa1. Microradiography and micro-computerized tomography confirmed the presence of calcification in the valve. Special stains for hydroxyapatite and CaPO4 were positive in calcification margins. Electron microscopy identified mineralization, whereas energy-dispersive spectroscopy confirmed the presence of elemental CaPO4. Reverse transcriptase-polymerase chain reaction revealed increased mRNA levels of osteopontin, bone sialoprotein, osteocalcin, and Cbfa1 in the calcified valves. There was no change in alkaline phosphatase mRNA level but an increase in the protein expression in the diseased valves. These findings support the concept that aortic valve calcification is not a random degenerative process but an active regulated process associated with an osteoblast-like phenotype.


Sensitivity of Early Brain Computed Tomography to Exclude Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis.
Emerging evidence demonstrating the high sensitivity of early brain computed tomography (CT) brings into question the necessity of always performing lumbar puncture after a negative CT in the diagnosis of spontaneous subarachnoid hemorrhage (SAH). Our objective was to determine the sensitivity of brain CT using modern scanners (16-slice technology or greater) when performed within 6 hours of headache onset to exclude SAH in neurologically intact patients. After conducting a comprehensive literature search using Ovid MEDLINE, Ovid EMBASE, Web of Science, and Scopus, we conducted a meta-analysis. We included original research studies of adults presenting with a history concerning for spontaneous SAH and who had noncontrast brain CT scan using a modern generation multidetector CT scanner within 6 hours of symptom onset. Our study adheres to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). A total of 882 titles were reviewed and 5 articles met inclusion criteria, including an estimated 8907 patients. Thirteen had a missed SAH (incidence 1.46 per 1000) on brain CTs within 6 hours. Overall sensitivity of the CT was 0.987 (95% confidence intervals, 0.971-0.994) and specificity was 0.999 (95% confidence intervals, 0.993-1.0). The pooled likelihood ratio of a negative CT was 0.010 (95% confidence intervals, 0.003-0.034). In patients presenting with thunderclap headache and normal neurological examination, normal brain CT within 6 hours of headache is extremely sensitive in ruling out aneurysmal SAH.


Long-term exposure to low concentrations of air pollutants and hospitalisation for respiratory diseases: A prospective cohort study in Australia.
Short- and long-term spatiotemporal variation in exposure to air pollution is associated with respiratory morbidity in areas with moderate-to-high level of air pollution, but very few studies have examined whether these associations also exist in areas with low level exposure. We assessed the association between spatial variation in long-term exposure to PM2.5 and NO2 and hospitalisation for all respiratory diseases, asthma, chronic obstructive pulmonary disease (COPD), and pneumonia, in older adults residing in Sydney, Australia, a city with low-level concentrations. We recorded data on hospitalisations for 100,084 participants, who were aged >45 years at entry in 2006-2009 until June 2014. Annual NO2 and PM2.5 concentrations were estimated for the participants' residential addresses and Cox proportional hazards regression was used to model the association between exposure to air pollutants and first episode of hospitalisation, controlling for personal and area level covariates. We further investigated the shape of the exposure-response association and potential effect modification by age, sex, education level, smoking status, and BMI. NO2 and PM2.5 annual mean exposure estimates were 17.5 μg·m-3 and 4.5 μg·m-3 respectively. NO2 and PM2.5 was positively, although not significantly, associated with asthma. The adjusted hazard ratio for a 1 μg·m-3 increase in PM2.5 was 1.08, 95% confidence interval 0.89-1.30. The adjusted hazard ratio for a 5 μg·m-3 increase in NO2 was 1.03, 95% confidence interval 0.88-1.19. We found no positive statistically significant associations with hospitalisation for all respiratory diseases, and pneumonia while negative associations were observed with COPD. We found weak positive associations of exposure to air pollution with hospitalisation for asthma while there was no evidence of an association for all respiratory diseases.


Technical report: mercury in the environment: implications for pediatricians.
Mercury is a ubiquitous environmental toxin that causes a wide range of adverse health effects in humans. Three forms of mercury (elemental, inorganic, and organic) exist, and each has its own profile of toxicity. Exposure to mercury typically occurs by inhalation or ingestion. Readily absorbed after its inhalation, mercury can be an indoor air pollutant, for example, after spills of elemental mercury in the home; however, industry emissions with resulting ambient air pollution remain the most important source of inhaled mercury. Because fresh-water and ocean fish may contain large amounts of mercury, children and pregnant women can have significant exposure if they consume excessive amounts of fish. The developing fetus and young children are thought to be disproportionately affected by mercury exposure, because many aspects of development, particularly brain maturation, can be disturbed by the presence of mercury. Minimizing mercury exposure is, therefore, essential to optimal child health. This review provides pediatricians with current information on mercury, including environmental sources, toxicity, and treatment and prevention of mercury exposure.


S cone pathway sensitivity in eyes with high risk and low risk drusen characteristics.
A method of measuring S cone pathway sensitivity which corrects internally for media absorption, flicker sensitivity variations, and diffuse losses in retinal sensitivity is presented. Foveal S cone pathway sensitivity was measured in elderly subjects who had no ophthalmoscopically detectable retinal abnormality other than the presence of drusen. S cone pathway sensitivity was decreased in the elderly group compared with a group of young normals. The elderly group was subdivided by drusen characteristics present in fundus photographs into a group felt to be at high risk of developing age-related macular degeneration and a group judged to be at low risk. There was a mean difference in age of 7 yr between the groups. There was a weak association between a lower S cone pathway sensitivity and the presence of high risk drusen characteristics not attributable to the age difference. Yellow flicker sensitivity better separated the high risk group from the low risk group, but this was attributable to the mean difference in age between the groups. The limited usefulness of the drusen risk classification in assessing the likelihood of developing severe age-related macular degeneration highlights the need for following a group of drusen patients prospectively to assess the true worth of S cone pathway sensitivity in this disease.


The distribution and clinical significance of sleep time misperceptions among insomniacs.
It is well recognized that sleep time misperceptions are common among insomniacs, but little is known about the distribution and clinical significance of these subjective distortions. The current investigation was conducted to examine the distribution of sleep time misperceptions among a large (n = 173), diverse group of insomniacs and to determine if such misperceptions might relate to the patients' clinical characteristics. Consistent with previous studies, our subjects, as a group, produced sleep estimates that were significantly (p < 0.0001) lower than polysomnographically determined sleep times. However, patients' sleep time perceptions were widely distributed across a broad continuum, which ranged between gross underestimates and remarkable overestimates of actual sleep times. Results also showed that subgroups, formed on the basis of presenting complaints and diagnostic criteria (i.e. International Classification of Sleep Disorders nosology), differed in regard to the magnitude and direction of their sleep distortions. Moreover, these differences appeared consistent with the types of objective sleep disturbances these subgroups commonly experience. Hence, the tendency to underestimate actual sleep time is not a generic attribute of all insomniacs. Furthermore, it appears that the accuracy and nature of sleep time perceptions may relate to the type of sleep pathology underlying insomniacs' presenting complaints.


GABA blocks pathological but not acute TRPV1 pain signals.
Sensitization of the capsaicin receptor TRPV1 is central to the initiation of pathological forms of pain, and multiple signaling cascades are known to enhance TRPV1 activity under inflammatory conditions. How might detrimental escalation of TRPV1 activity be counteracted? Using a genetic-proteomic approach, we identify the GABAB1 receptor subunit as bona fide inhibitor of TRPV1 sensitization in the context of diverse inflammatory settings. We find that the endogenous GABAB agonist, GABA, is released from nociceptive nerve terminals, suggesting an autocrine feedback mechanism limiting TRPV1 sensitization. The effect of GABAB on TRPV1 is independent of canonical G protein signaling and rather relies on close juxtaposition of the GABAB1 receptor subunit and TRPV1. Activating the GABAB1 receptor subunit does not attenuate normal functioning of the capsaicin receptor but exclusively reverts its sensitized state. Thus, harnessing this mechanism for anti-pain therapy may prevent adverse effects associated with currently available TRPV1 blockers.


Technical factors are associated with complications and repeat intervention in neonates undergoing transcatheter right ventricular decompression for pulmonary atresia and intact ventricular septum: results from the congenital catheterisation research collaborative.
Transcatheter right ventricle decompression in neonates with pulmonary atresia and intact ventricular septum is technically challenging, with risk of cardiac perforation and death. Further, despite successful right ventricle decompression, re-intervention on the pulmonary valve is common. The association between technical factors during right ventricle decompression and the risks of complications and re-intervention are not well described. This is a multicentre retrospective study among the participating centres of the Congenital Catheterization Research Collaborative. Between 2005 and 2015, all neonates with pulmonary atresia and intact ventricular septum and attempted transcatheter right ventricle decompression were included. Technical factors evaluated included the use and characteristics of radiofrequency energy, maximal balloon-to-pulmonary valve annulus ratio, infundibular diameter, and right ventricle systolic pressure pre- and post-valvuloplasty (BPV). The primary end point was cardiac perforation or death; the secondary end point was re-intervention. A total of 99 neonates underwent transcatheter right ventricle decompression at a median of 3 days (IQR 2-5) of age, including 63 patients by radiofrequency and 32 by wire perforation of the pulmonary valve. There were 32 complications including 10 (10.5%) cardiac perforations, of which two resulted in death. Cardiac perforation was associated with the use of radiofrequency (p=0.047), longer radiofrequency duration (3.5 versus 2.0 seconds, p=0.02), and higher maximal radiofrequency energy (7.5 versus 5.0 J, p<0.01) but not with patient weight (p=0.09), pulmonary valve diameter (p=0.23), or infundibular diameter (p=0.57). Re-intervention was performed in 36 patients and was associated with higher post-intervention right ventricle pressure (median 60 versus 50 mmHg, p=0.041) and residual valve gradient (median 15 versus 10 mmHg, p=0.046), but not with balloon-to-pulmonary valve annulus ratio, atmospheric pressure used during BPV, or the presence of a residual balloon waist during BPV. Re-intervention was not associated with any right ventricle anatomic characteristics, including pulmonary valve diameter. Technical factors surrounding transcatheter right ventricle decompression in pulmonary atresia and intact ventricular septum influence the risk of procedural complications but not the risk of future re-intervention. Cardiac perforation is associated with the use of radiofrequency energy, as well as radiofrequency application characteristics. Re-intervention after right ventricle decompression for pulmonary atresia and intact ventricular septum is common and relates to haemodynamic measures surrounding initial BPV.


A short history of ideo-motor action.
The ideo-motor theory, which is currently receiving heightened interest in cognitive psychology, looks back on a long history. Essentially two historical roots can be presented. A British one, initiated by Laycock (1845) and Carpenter (1852), which was developed in order to explain ideo-motor phenomena by means of cerebral reflex actions. A second and older root is the German one by Herbart (1816, 1825), Lotze (1852), and Harless (1861), which considered the ideo-motor principle a fundamental mechanism of all intentional human behaviour. Both roots converged in James' (1890) Principles of Psychology before they fell into oblivion due to the dominance of behaviorism in the first half of the 20th century. The few empirical ideo-motor studies of the early 20th century are briefly described. Finally, similarities and differences in the history of the ideo-motor theory are delineated and a perspective is given covering research questions that could be examined in the future.


The prognostic role of serum C-X-C chemokine receptor type 4 in patients with metastatic or recurrent colorectal cancer.
C-X-C chemokine receptor type 4 (CXCR4) is involved in tumor progression including angiogenesis, metastasis, and survival. However, whether serum CXCR4 levels in metastatic or recurrent colorectal cancer have a prognostic role, have not been evaluated. We analyzed serum samples from 55 patients with advanced colorectal cancer diagnosed between March 2008 and July 2011. Serum CXCR4 levels were quantified by a commercially available enzyme-linked immunosorbent assay (ELISA) kit. The median age of the patients was 62 years, and all patients received systemic chemotherapy of two or more lines. The median serum CXCR4 level was 283.47 pg/mL (range: 77.48-846.52). Patients with two or more metastatic sites, liver metastasis, or higher CA 19-9 level (>37 IU/mL) showed significantly higher levels of serum CXCR4 than patients without. The median overall survival (OS) of all patients was 19.53 months. OS was significantly longer in patients with lower CXCR4 levels (≤240.45 pg/mL) compared with those having higher CXCR4 levels (>240.45 pg/mL) (median OS: 26.50 vs 17.03 months, P=0.046). Univariate analysis showed that liver metastasis, no palliative surgery, and higher levels of CXCR4 (>240.45 pg/mL) had a significantly poor prognostic value with regard to OS (P<0.05). Serum CXCR4 level was positively correlated with metastatic sites, liver metastasis, or higher CA 19-9 level. Also, there was a significant difference in OS according to the level of CXCR4 expression. These findings suggest that serum CXCR4 levels may be a useful surrogate marker of clinical outcome in metastatic or recurrent colorectal cancer.


Schistosoma mansoni-Associated Morbidity among Preschool-Aged Children along the Shores of Lake Victoria in Uganda.
Schistosoma mansoni causes morbidity in human beings, with the highest prevalence in rural sub-Saharan Africa. Prolonged S. mansoni infection with egg deposition in intestinal blood vessels leads to liver and spleen enlargement, and thus chronic morbidity. The objective of this study was to assess whether preschool-aged children develop severe S. mansoni-related morbidity. Parasitological, clinical, and ultrasonographic examinations were carried out in 916 preschool-aged children in five schistosomiasis-endemic districts (Bugiri, Buikwe, Jinja, Mayuge, and Namayingo) along the Lake Victoria shoreline in east-central Uganda. Anaemia and anthropometry measurements were also taken. Using the Kato-Katz technique on one stool sample collected on three consecutive days, 74.9% (686/916) were found infected with S. mansoni; the majority were lightly infected (57.9%), while 22.7% and 19.4% were moderately and heavily infected, respectively. The overall geometric mean intensity (GMI) of infected children was 294.2 eggs per gram faeces. Mayuge and Jinja districts had the highest (51.2%) and lowest (2.2%) number of infected children, respectively. Hookworm infection was found in 7.8% (71/916) of the children. Both liver and spleen were significantly more enlarged in the infected children than in the uninfected children (p < 0.0005), as measured by ultrasonography. Physical palpation of the spleen was more often detected in the uninfected children. A significantly (p < 0.0005) higher proportion of S. mansoni-positive children were anaemic (359/686; 52.3%) compared to the children who had no eggs in their stool samples (81/230; 35.2%). Schistosoma mansoni infection did not have any severe effect on the nutrition status of preschool-aged children. Neither infected nor uninfected children were found to be underweight or stunted. Liver fibrosis with distinct Symmer's 'pipe stems' was found in a few heavily-infected children (0.3%). In a linear multivariable regression analysis, age of the child, anaemia, liver fibrosis, and size of the left liver lobe were associated with S. mansoni intensity of infection (adjusted R² = 0.11; p < 0.0005). Our results demonstrate that S. mansoni-related morbidity does develop in children less than six years of age, and that older children (37⁻60 months) are at higher risk (regression coefficient 0.33; p <0.0005) compared to younger ones (12⁻36 months). We recommend that preschool-aged children be included in the target population for schistosomiasis mass treatment so as to prevent the childhood chronic form of schistosomiasis.


Recent transfer of an iron-regulated gene from the plastid to the nuclear genome in an oceanic diatom adapted to chronic iron limitation.
Although the importance and widespread occurrence of iron limitation in the contemporary ocean is well documented, we still know relatively little about genetic adaptation of phytoplankton to these environments. Compared to its coastal relative Thalassiosira pseudonana, the oceanic diatom Thalassiosira oceanica is highly tolerant to iron limitation. The adaptation to low-iron conditions in T. oceanica has been attributed to a decrease in the photosynthetic components that are rich in iron. Genomic information on T. oceanica may shed light on the genetic basis of the physiological differences between the two species. The complete 141790 bp sequence of the T. oceanica chloroplast genome [GenBank: GU323224], assembled from massively parallel pyrosequencing (454) shotgun reads, revealed that the petF gene encoding for ferredoxin, which is localized in the chloroplast genome in T. pseudonana and other diatoms, has been transferred to the nucleus in T. oceanica. The iron-sulfur protein ferredoxin, a key element of the chloroplast electron transport chain, can be replaced by the iron-free flavodoxin under iron-limited growth conditions thereby contributing to a reduction in the cellular iron requirements. From a comparison to the genomic context of the T. pseudonana petF gene, the T. oceanica ortholog can be traced back to its chloroplast origin. The coding potential of the T. oceanica chloroplast genome is comparable to that of T. pseudonana and Phaeodactylum tricornutum, though a novel expressed ORF appears in the genomic region that has been subjected to rearrangements linked to the petF gene transfer event. The transfer of the petF from the cp to the nuclear genome in T. oceanica represents a major difference between the two closely related species. The ability of T. oceanica to tolerate iron limitation suggests that the transfer of petF from the chloroplast to the nuclear genome might have contributed to the ecological success of this species.


Whither the hypercolumn?
Among the crowning achievements of Hubel and Wiesel's highly influential studies on primary visual cortex is the description of the cortical hypercolumn, a set of cortical columns with functional properties spanning a particular parameter space. This fundamental concept laid the groundwork for the notion of a modular sensory cortex, canonical cortical circuits and an understanding of visual field coverage beyond simple retinotopy. Surprisingly, the search for and description of analogous hypercolumnar organizations in other cortical areas to date has been limited. In the present work, we have applied the hypercolumn concept to the functional organization of the second visual area, V2. We found it important to separate out the original definition of the hypercolumn from other associated observations and concepts, not all of which are applicable to V2. We present results indicating that, as in V1, the V2 hypercolumns for orientation and binocular interaction (disparity) run roughly orthogonal to each other. We quantified the 'nearest neighbour' periodicities for the hypercolumns for ocular dominance, orientation, colour and disparity, and found a marked similarity in the periodicities of all of these hypercolumns, both across hypercolumn type and across visual areas V1 and V2. The results support an underlying common mechanism that constrains the anatomical extent of hypercolumn systems, and highlight the original definition of the cortical hypercolumn.


Inhibition of Toxoplasma gondii and Plasmodium falciparum infections in vitro by NSC3852, a redox active antiproliferative and tumor cell differentiation agent.
We searched the National Cancer Institute (NCI) compound library for structures related to the antitumor quinoline NSC3852 (5-nitroso-8-quinolinol) and used a computer algorithm to predict the antiprotozoan activity for each of 13 structures. Half of these compounds inhibited Toxoplasma gondii tachyzoite propagation in human fibroblasts at < or =1 microM. The active compounds comprise a series of low-molecular-weight quinolines bearing nitrogen substituents in the ring-5 position. NSC3852 (EC(50) 80 nM) and NSC74949 (EC(50) 646 nM) were the most potent. NSC3852 also inhibited Plasmodium falciparum growth in human red blood cells (EC(50) 1.3 microM). To investigate the mechanism for NSC3852's anti-T. gondii activity, we used chemiluminescence assays to detect reactive oxygen species (ROS) formation in freshly isolated tachyzoites and in infected host cells; the absence of ROS generation by NSC3852 in these assays indicated NSC3852 does not redox cycle in T. gondii. Inhibitors of enzyme sources of free radicals such as superoxide anion, nitric oxide (NO), and their reaction product peroxynitrite did not interfere with the anti-T. gondii activity of NSC3852. However, inhibition of T. gondii tachyzoite propagation by NSC3852 involved redox reactions because tachyzoites were protected from NSC3852 by inclusion of the cell permeant superoxide dismutase mimetic, MnTMPyP, or N-acetylcysteine in the culture medium. We conclude that the Prediction of Activity Spectra for Substances (PASS) computer program is useful in finding new compounds that inhibit T. gondii tachyzoites in vitro and that NSC3852 is a potent T. gondii inhibitor that acts by indirect generation of oxidative stress in T. gondii.


Quantifying the Intra-Regional Precipitation Variability in Northwestern China over the Past 1,400 Years.
There has been a surge of paleo-climatic/environmental studies of Northwestern China (NW China), a region characterized by a diverse assortment of hydro-climatic systems. Their common approach, however, focuses on "deducing regional resemblance" rather than "exploring regional variance." To date, efforts to produce a quantitative assessment of long-term intra-regional precipitation variability (IRPV) in NW China has been inadequate. In the present study, we base on historical flood/drought records to compile a decadal IRPV index for NW China spanned AD580-1979 and to find its major determinants via wavelet analysis. Results show that our IRPV index captures the footprints of internal hydro-climatic disparity in NW China. In addition, we find distinct ~120-200 year periodicities in the IRPV index over the Little Ice Age, which are attributable to the change of hydro-climatic influence of ocean-atmospheric modes during the period. Also, we offer statistical evidence of El Niño Southern Oscillation (Indo-Pacific warm pool sea surface temperature and China-wide land surface temperature) as the prominent multi-decadal to centennial (centennial to multi-centennial) determinant of the IRPV in NW China. The present study contributes to the quantitative validation of the long-term IRPV in NW China and its driving forces, covering the periods with and without instrumental records. It may help to comprehend the complex hydro-climatic regimes in the region.


Safety and Tolerability of the Anxiolytic and Nootropic Drug Phenibut: A Systematic Review of Clinical Trials and Case Reports.
Phenibut is a nootropic drug that exerts anxiolytic and antinociceptive effects by acting on the GABAB receptor and the α2-δ subunit of voltage-dependent calcium channels. An increased number of reports of dependence to and intoxication by phenibut purchased online on the one hand and the wide prescription of phenibut in Eastern Europe for more than half a century on the other hand have resulted in a number of controversies regarding its use. In this review, we have summarized currently available information from case reports of phenibut dependence and intoxication and safety data from clinical trials. We included 14 dependence and intoxication case reports (16 patients) and reviewed 11 phenibut clinical trials (583 patients). The clinical symptoms in the case reports included cardiovascular effects, insomnia, anxiety and agitation, hallucinations, and depressed level of consciousness. In addition, the doses used (0.5-100 g/day) were much higher than the recommended daily dose (0.25-2 g/day). An analysis of phenibut side effects described in the clinical trials showed adverse events in only 5.66% of patients, and the most reported side effect was somnolence (1.89%). There are discrepancies in the reported side effects of phenibut in clinical trials compared to those reported in cases of online-purchased phenibut dependence and intoxication. The current systematic review provides evidence that, at therapeutic doses, phenibut is safe and well tolerated with minor adverse effects, but questions regarding the quality of phenibut obtained online and the contribution of alcohol and other drug abuse to phenibut dependence and intoxication remain open.


Interleukin-27 acts on hepatic stellate cells and induces signal transducer and activator of transcription 1-dependent responses.
Interleukin (IL)-27 is a cytokine belonging to the IL-6/IL-12 cytokine family that is secreted by activated macrophages and dendritic cells and which strongly acts on T-cells and cells of the innate immune system. Not much is known about possible effects of IL-27 on other cell types. It signals via the common IL-6-type-cytokine receptor chain gp130 and the IL-27-specific chain WSX-1. We previously described that IL-27 also stimulates hepatoma cells and primary hepatocytes. The aim of this study was to investigate whether IL-27 would also act on hepatic stellate cells (HSC), the second most abundant hepatic cell type, which would demonstrate a more general role of this cytokine in the liver. Using a human HSC line and primary rat HSC we investigated the signalling characteristics of IL-27 in these cells. We show that IL-27 activates signal transducer and activator of transcription (STAT) 1 and to a minor extent STAT3 in a human HSC cell line and that it leads to the induction of STAT1 target genes such as interferon response factor-1, myxovirus resistance A and STAT1 itself. Similarly we find that IL-27 also elicits STAT1-dependent responses in primary rat HSC. We provide the first evidence for a function of IL-27 in HSC and show that its responses resemble Interferon-gamma-like functions in these cells. Our data suggests that IL-27 may play an important role in the context of liver inflammation by acting on the different liver cell types.


Predictive Biomarkers for Checkpoint Immunotherapy: Current Status and Challenges for Clinical Application.
Immune-checkpoint blockade (ICB), in particular PD-1 inhibition, has rapidly changed the treatment landscape and altered therapeutic paradigms across many tumor types, with unprecedented rates of durable clinical responses in a number of cancers. Despite this success, only a subset of patients responds to ICB and, as a result, predictive biomarkers would be useful to guide the selection of patients for these therapies. This article highlights currently used biomarkers, as well as several promising novel candidates, and also discusses the challenges involved in establishing their analytic validity and clinical utility. Progress is being evaluated in melanoma and non-small cell lung cancer, for which PD-1 ± CTLA-4 inhibitors have become standard therapy, to other malignancies for which PD-L1 inhibitors remain investigational. Although single biomarkers have substantial limitations, a combination of biomarkers that reflect the interaction of host and tumor will likely be needed to provide a reproducible surrogate for the benefit of checkpoint modulation. Cancer Immunol Res; 6(10); 1122-8. ©2018 AACR.


A comprehensive yoga programs improves pain, anxiety and depression in chronic low back pain patients more than exercise: an RCT.
Previously, outpatient Yoga programs for patients with chronic low back pain (CLBP) lasting several months have been found to reduce pain, analgesic requirement and disability, and improve spinal mobility. This study evaluated changes in pain, anxiety, depression and spinal mobility for CLBP patients on short-term, residential Yoga and physical exercise programs, including comprehensive yoga lifestyle modifications. A seven day randomized control single blind active study in an residential Holistic Health Centre in Bangalore, India, assigned 80 patients (37 female, 43 male) with CLBP to yoga and physical exercise groups. The Yoga program consisted of specific asanas and pranayamas for back pain, meditation, yogic counselling, and lectures on yoga philosophy. The control group program included physical therapy exercises for back pain, and matching counselling and education sessions. Group×time interactions (p<0.05) and between group differences (p<0.05) were significant in all variables. Both groups' scores on the numerical rating scale for pain reduced significantly, 49% in Yoga (p<0.001, ES=1.62), 17.5% in controls (p=0.005, ES=0.67). State anxiety (STAI) reduced 20.4% (p<0.001, ES=0.72) and trait anxiety 16% (p<0.001, ES=1.09) in the yoga group. Depression (BDI) decreased in both groups, 47% in yoga (p<0.001, ES=0.96,) and 19.9% in controls (p<0.001, ES=0.59). Spinal mobility ('Sit and Reach' instrument) improved in both groups, 50%, in yoga (p<0.001, ES=2.99) and 34.6% in controls (p<0.001, ES=0.81). Seven days intensive residential Yoga program reduces pain, anxiety, and depression, and improves spinal mobility in patients with CLBP more effectively than physiotherapy exercises.


Bridging the translational gap: what can synaptopathies tell us about autism?
Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.


Aqueous garlic extract inhibits protamine sulfate-induced bladder damage.
This morphological and biochemical study aims to investigate the antioxidant effects of chronic administration of aqueous garlic extract (AGE) on protamine sulfate (PS)-induced bladder injury. Wistar albino female rats were catheterized and intravesically infused with phosphate-buffered solution (control group) or PS (PS group) dissolved in phosphate-buffered solution. In the PS + AGE group after the PS instillation, AGE (1 ml/kg, i.p., corresponding to 250 mg/kg) was injected intraperitoneally for 3 days. Bladder morphology was investigated by light and scanning electron microscopy. Tissue samples were also obtained to determine bladder malondialdehyde (MDA) and glutathione levels. In the PS group, ulcerated areas, an irregular mucus layer, inflammatory cell infiltration and an increased number of mast cells were observed. In the PS + AGE group a relatively normal urothelial topography, glycosaminoglycan layer and a decreased number of mucosal mast cells and inflammatory cells were observed. Increased MDA levels as a result of PS induction led us to propose that free radicals may have a critical role in this injury. The significant decrease in MDA and increase in glutathione levels in the PS + AGE group was in accordance with morphological findings. Based on the results, AGE treatment significantly prevented PS-induced degenerative morphological and biochemical changes of urinary bladder mucosa.


Automatic photoelastimeter for determining very small dilatations.
A sensitivity of 0.03-mmicro birefringence is achieved by the introduction of a plastic disk (~6-mmicro birefringence) rotated at 30 Hz to modulate the birefringence at 60 Hz and a suitable detector. Two components are found in the detector signal: the one (120 Hz) that depends on the modulator birefringence is rejected; the other (60 Hz) which depends linearly on the compensator birefringence and changes phase at extinction is utilized. An A.E.I. BTH compact mercury are (with interference filter for 546 mmicro) operated on dc is the light source; a photomultiplier 1P21 is the detector. The signal is first fed into a parallel T notch filter which reduces the 120-Hz component five-hundred-fold and then into a three-stage narrow-band (5-Hz) active filter (utilizing three integrated-circuit operational amplifiers) that provides a. possible gain of 151 dB for the 60-Hz component. To obviate tedious manual setting of the compensator for the required traverse of the specimen, a 60-Hz servo motor is linked to the tangent screw of the analyzer and operated by a power amplifier for the active filter-output signal. Potentiometers on the specimen-translation screw and on the analyzer tangent screw permit the data to be plotted on an x-y recorder. For vitreous silica specimens 1 cm deep, 3 mm wide, irradiated with electrons of 1-mm range (0.6 MeV), the effect of a radiation-induced dilatation as small as 3 x 10(-8) can be observed, equivalent to inserting an atomic sheet into a 1-cm long specimen. Alternatively, 1% dilatation of a surface layer 30 A thick can be detected.


Incidence and management of colorectal cancer in liver transplant recipients.
Liver transplant recipients are at an increased risk of developing de novo malignancies because of the prolonged immunosuppression necessary to avoid acute and chronic rejections. Skin cancers and lymphoproliferative diseases are the most common malignancies, but the overall incidence of colon cancer in this patient population does differ from that of the general population. Therefore, colorectal cancer (CRC) is a major health concern in liver transplant recipients. Furthermore, there are unique subsets of liver transplant recipients, such as those with primary sclerosing cholangitis and inflammatory bowel disease, who are at an increased risk for developing CRC after liver transplantation and might require special screening/surveillance strategies. The similar principles for management of colon cancer can be applied to transplant recipients if the adjustment to maintain the need for the long-term immunosuppression is made. Colectomy can be performed safely during the posttransplantation period. Prophylactic colectomy at the time of liver transplantation has been performed in some patients at high risk or with known premalignant conditions. Chemotherapy with 5- fluorouracil and oxaliplatin has been used in transplant recipients for the treatment of metastatic CRC; however, further research is required to examine the safety, tolerability, and efficacy of combination chemotherapy and biologic agents in this patient population. This review summarizes the incidence, risk factors, diagnosis, and management of de novo CRC in liver transplant recipients.


Oncofertility considerations in adolescents and young adults given a diagnosis of melanoma: Fertility risk of Food and Drug Administration-approved systemic therapies.
Melanoma is the most common cancer diagnosed for patients ages 25 to 29 years, the group with the highest birth rates in the United States. Oncofertility is a new field addressing the reproductive needs of patients with cancer facing fertility-threatening treatments. We sought to assess gender-specific fertility risk for Food and Drug Administration (FDA)-approved melanoma therapies with a new risk category system. We conducted a retrospective review of FDA, European Union, and Health Canada regulatory filings, along with previously published reports to grade fertility risk of systemic melanoma therapies. The proposed fertility risk category system is analogous to the FDA's A/B/C/D/X/N pregnancy-risk categories. For female patients, 58% of treatments represent a fertility risk (Category C and D), 33% have unknown risk (Category N), and 1 therapy (vemurafenib) did not show animal ovarian toxicity (Category B). For male patients, 33% represented a fertility risk (Category C and D), 50% of treatments had unknown risk (Category N), and 17% did not show animal testicular toxicity (Category B). Data on fertility risk for melanoma therapies approved after 2009 are limited to preclinical animal studies. Dermatologists have an opportunity to discuss fertility preservation, make appropriate referrals, and steward registries on reproductive outcomes for patients with melanoma.


Penalized feature selection and classification in bioinformatics.
In bioinformatics studies, supervised classification with high-dimensional input variables is frequently encountered. Examples routinely arise in genomic, epigenetic and proteomic studies. Feature selection can be employed along with classifier construction to avoid over-fitting, to generate more reliable classifier and to provide more insights into the underlying causal relationships. In this article, we provide a review of several recently developed penalized feature selection and classification techniques--which belong to the family of embedded feature selection methods--for bioinformatics studies with high-dimensional input. Classification objective functions, penalty functions and computational algorithms are discussed. Our goal is to make interested researchers aware of these feature selection and classification methods that are applicable to high-dimensional bioinformatics data.


Timing of levosimendan in cardiac surgery.
Levosimendan (LS) is a new inodilator agent that improves cardiac contractility by increasing the sensitivity of troponin C to calcium, which usage in cardiac surgery has been growing in the recent years. We aimed to determine the best timing of the administration of LS in high-risk patients who underwent cardiovascular surgery. Fifteen patients were evaluated retrospectively who have left ventricular dysfunction, underwent open-heart surgery and were applied LS in different phases of operation. Patients were divided into 3 groups according to timing of LS. Levosimendan infusion (0. 1 microg-1kg-1min) was applied after the induction of anaesthesia (n=5) (Group 1), during the pump removal period (n=5) (Group 2) and in postoperative period (n=5) (Group 3). Demographic data, operative characteristics, mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), pulmonary wedge capillary pressure (PWCP), cardiac index (CI), inotropic agent consumption, postoperative urine output, lactate levels of groups were compared between before and after LS treatment. Data were evaluated by Fisher exact, Kruskal-Wallis, Mann-Whitney U and Wilcoxon rank tests. In all patients, urine output was satisfactory 24 hours after LS application. There was a significant increase in CI of all 3 groups (p=0.04). Also, there was a significant decrease in PCWP of all 3 groups before and after LS (p=0.04). There was a significant decrease in MPAP in Group 2 and 3 (p=0.04). Twenty- four hours after LS application, whereas all inotropic agents could be stopped in Group 1 and 2, in Group 3 inotropic infusion (dopamine [10 microg-1kg-1min (5-17.5)], dobutamine [15 microg-1kg-1min (5-20)] and adrenaline [0.4 microg-1kg-1min (0.15-0.65)]) couldn't be stopped (p=0.007). During postoperative period, in Groups 1 and 2 one case from each required intraaortic balloon pump, while in Group 3 four patients were applied intraaortic balloon pump (p=0.08). According to our experience, LS is effective in high-risk cases during cardiac surgery, especially during the intra-operative and pump removal periods;however, no successful outcomes were observed during the post-operative period. As a result, case selection and timing should be performed well when using LS.


Evaluation of the Group Lifestyle Balance Program in a Military Setting: An Investment Worth Expanding.
The Diabetes Prevention Program (DPP) demonstrated that lifestyle intervention programs were effective in preventing or delaying the onset of diabetes. The Group Lifestyle Balance (GLB) program translated the DPP curriculum into a 12-wk group intervention for those at risk for diabetes. This retrospective evaluation examined clinical outcomes for patients in the Diabetes Center of Excellence GLB program located at Wilford Hall Ambulatory Surgical Center from 2009 to 2013. Objectives included determining rates of retention, demographic characteristics of program completers, and changes in metabolic surrogates of disease prevalence. Adults with prediabetes or metabolic syndrome (MetS) were referred to the GLB program. Updated participant metabolic data were collected at regular intervals during their participation. During the 5-yr study, 704 patients attended the initial class. Overall, 52% of all participants completed the program with the greatest decline in participation occurring by the fourth week (30%). Baseline prevalence of conditions of interest for those who completed the program was prediabetes (93.2%), obesity (56.1%), and MetS (31.5%). GLB completers were older and retired (p < 0.05). A significant number of active duty military members (44.9%, p < 0.01, n = 53) dropped out of the program before the fourth week. Furthermore, those who completed the program saw a 2.0% reduction in prediabetes prevalence (p < 0.001), obesity decreased by 8.7% (p < 0.001), and MetS decreased by 6.8% (p < 0.01). Significant differences were found for central obesity, triglycerides, and fasting blood sugar (p < 0.001). The GLB program is a valuable DPP and was effective at improving clinical outcomes and reducing the incidence of prediabetes, obesity, and MetS for participants who completed the program. Every effort should be made to support and encourage GLB participants to complete the program.


The acoustical Klein-Gordon equation: the wave-mechanical step and barrier potential functions.
The transformed form of the Webster equation is investigated. Usually described as analogous to the Schrödinger equation of quantum mechanics, it is noted that the second-order time dependency defines a Klein-Gordon problem. This "acoustical Klein-Gordon equation" is analyzed with particular reference to the acoustical properties of wave-mechanical potential functions, U(x), that give rise to geometry-dependent dispersions at rapid variations in tract cross section. Such dispersions are not elucidated by other one-dimensional--cylindrical or conical--duct models. Since Sturm-Liouville analysis is not appropriate for inhomogeneous boundary conditions, the exact solution of the Klein-Gordon equation is achieved through a Green's-function methodology referring to the transfer matrix of an arbitrary string of square potential functions, including a square barrier equivalent to a radiation impedance. The general conclusion of the paper is that, in the absence of precise knowledge of initial conditions on the area function, any given potential function will map to a multiplicity of area functions of identical relative resonance characteristics. Since the potential function maps uniquely to the acoustical output, it is suggested that the one-dimensional wave physics is both most accurately and most compactly described within the Klein-Gordon framework.


An allelic series at the KARRIKIN INSENSITIVE 2 locus of Arabidopsis thaliana decouples ligand hydrolysis and receptor degradation from downstream signalling.
Karrikins are butenolide compounds present in post-fire environments that can stimulate seed germination in many species, including Arabidopsis thaliana. Plants also produce endogenous butenolide compounds that serve as hormones, namely strigolactones (SLs). The receptor for karrikins (KARRIKIN INSENSITIVE 2; KAI2) and the receptor for SLs (DWARF14; D14) are homologous proteins that share many similarities. The mode of action of D14 as a dual enzyme receptor protein is well established, but the nature of KAI2-dependent signalling and its function as a receptor are not fully understood. To expand our knowledge of how KAI2 operates, we screened ethyl methanesulphonate (EMS)-mutagenized populations of A. thaliana for mutants with kai2-like phenotypes and isolated 13 new kai2 alleles. Among these alleles, kai2-10 encoded a D184N protein variant that was stable in planta. Differential scanning fluorimetry assays indicated that the KAI2 D184N protein could interact normally with bioactive ligands. We developed a KAI2-active version of the fluorescent strigolactone analogue Yoshimulactone Green to show that KAI2 D184N exhibits normal rates of ligand hydrolysis. KAI2 D184N degraded in response to treatment with exogenous ligands, suggesting that receptor degradation is a consequence of ligand binding and hydrolysis, but is insufficient for signalling activity. Remarkably, KAI2 D184N degradation was hypersensitive to karrikins, but showed a normal response to strigolactone analogues, implying that these butenolides may interact differently with KAI2. These results demonstrate that the enzymatic and signalling functions of KAI2 can be decoupled, and provide important insights into the mechanistic events that underpin butenolide signalling in plants.


[History of injections. Pictures from the history of otorhinolaryngology highlighted by exhibits of the German History of Medicine Museum in Ingolstadt].
Injections are part of the arsenal of all medical disciplines. In addition to this common ground, each specialty has its own particular aspects; the historical development of these are presented here with respect to otorhinolaryngology. The first experiments with intravenous injections were carried out in 1642 by a gentleman's hunting servant in eastern Germany. Similar experiments were done in 1656 by Christopher Wren, the astronomer, mathematician, and architect in Oxford, England, and a group of scientists around the physicist Robert Boyle. These experiments were prompted by new knowledge about blood circulation provided by William Harvey in 1628. The first books on the applications of intravenous infusions in humans were published in Germany by Major 1664 (Chirurgia Infusoria) and Elsholtz 1667 (Clysmatica Nova). Bladders of animals or enema syringes were used as instruments. Because of lethal accidents the infusions soon fell from favour. Köhler in Germany in 1776 eliminated a large bolus impacted in a patient's esophagus by an intravenous infusion of tartar emetic thus inducing violent vomiting. After this crucial experiment, foreign bodies in the esophagus were the most important indication for applying intravenous injections until Killian introduced extraction by esophagoscopy in 1990. The French surgeon C. Pravaz in Lyon in 1853 invented a small syringe, the piston of which could be driven by a screw thus allowing exact dosage. A sharp needle with a pointed trocar could be introduced into the vessel making a dissection unnessessary. Pravaz used his syringe for obliteration of arterial aneurysms by injection of ferric sesquichlorate. Pravaz's syringe initiated the invention of a great number of various calibrated syringes made of glass or metal combined with glass. The calibrated syringes were commonly used in the treatment of syphilis by mercurialization. In otorhinolaryngology, they had and still have their primary application in local anaesthesia, which was introduced by Carl Ludwig Schleich in Berlin in 1892. PARAFFIN-INJECTIONS: Around 1900 the injection of liquid paraffin for closing defects in subcutaneous tissues came into use (Gersuny in Vienna, Delangre in Tournai). This technique was immediately applied to rhinological indications such as a saddle nose (Stein 1901). This gave rise to the invention of special syringes and modifications of paraffin with different hardness and melting points. Around the middle of this century, paraffin was abandoned for this application because of serious complications, and new substances were introduced such like teflon, silicone and collagen. The historical development of these techniques of injections is described in details with many literature citations and figures.


Celiac Disease Symptom Resolution: Effectiveness of the Gluten-free Diet.
The aim of the study was to evaluate the efficacy of the gluten-free diet (GFD) on gastrointestinal (GI) and extra-intestinal (EI) symptom resolution and identify predictors for persistence of symptoms in all celiac patients at the University of Chicago. We conducted a retrospective chart review from 2002 to 2015. GI symptoms included abdominal pain, bloating, constipation, diarrhea, failure to thrive/weight loss, nausea, reflux, and vomiting. EI symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility. A total of 554 patients (227 children) with celiac disease (CeD) were included. Abdominal pain, diarrhea and failure to thrive were the most common GI symptoms in children whereas diarrhea, bloating, and abdominal pain were most common in adults. Short stature, fatigue, and headache were the most common EI symptoms in children whereas iron deficiency anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children had significantly higher rates of EI and GI symptom resolution as compared to adults, with greater rates of improvements in GI versus EI symptoms at more than 24 months. Long duration of symptoms, female sex, and non-adherence to a GFD were the most important significant predictors of failure to clinically improve. On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution.