Ethical issues associated with conducting genetic family studies of complex disease.
To examine subjects' recognition of the risks and ethical issues associated with enrollment in genetic family studies (GFS) and explore how this recognition affects their informed and voluntary participation. A cross-sectional study design including both quantitative and qualitative data was employed. Structured interviews using the Contextual Assessment Approach Questionnaire (CAA-Q) were conducted with 246 Mexican American (MA) participants. To gain in-depth understanding of questionnaire responses, semi-structured interviews with 30 participants were conducted. All participants were interviewed before their enrollment in the Family Investigation of Nephropathy and Diabetes (FIND). Subjects' average age was 56 years; 62% were females. Seventy-eight percent of participants were not formally educated beyond high school and 72% reported an annual household income of < or =20,000 dollars. Eighty-five percent agreed to provide researchers with information on relatives' ages, gender, and education. Sixty-five percent of participants were willing to provide identifiable information such as names, addresses, and phone numbers of relatives. Sixty-three percent of participants indicated that there were direct benefits (i.e., supporting research) to disclosing relatives' information. Seventy-six percent stated that there were no risks associated with participation in GFS (e.g., discrimination or confidentiality of genetic information) compared with 10% who said that there were such risks. While discussing potential risks, subjects did not consider these to influence their decision to participate. Subjects enrolled in GFS did not recognize and tended to underestimate the social and cultural risks associated with their participation in GFS. If subjects do not fully comprehend the risks, this raises questions concerning their ability to provide informed consent and to voluntarily participate. We propose a subject-centered approach that views enrollment as an active process in which subjects and recruiters give and receive information on risks and ethical issues related to participation, which enhances protection of the rights and welfare of subjects participating in GFS.


A comparative biomechanical study of a novel integrated plate spacer for stabilization of cervical spine: an in vitro human cadaveric model.
Integrated plate-spacer may provide adequate construct stability while potentially lowering operative time, decreasing complications, and providing less mechanical obstruction. The purpose of the current study was to compare the biomechanical stability of an anatomically profiled 2-screw integrated plate-spacer to a traditional spacer only and to a spacer and anterior cervical plate construct. In addition, the biomechanical stability of 2-screw integrated plate-spacer was compared to a commercially available 4-screw integrated plate-spacer. Two groups, each of nine cervical cadaver spines (C2-C7), were tested under pure moments of 1.5Nm. Range of motion was recorded at C5-C6 in all loading conditions (flexion, extension, lateral bending, and axial rotation) for the following constructs: 1) Intact; 2) 2-screw or 4-screw integrated plate-spacer; 3) spacer and anterior cervical plate; and 4) spacer only. All fusion constructs significantly reduced motion compared to the intact condition. Within the instrumented constructs, spacer and anterior cervical plate, 2-screw and 4-screw integrated plate-spacer resulted in reduced motion compared to the spacer only construct. No significant differences were found in motion between any of the instrumented conditions in any of the loading conditions. The application of integrated plate-spacer for anterior cervical discectomy and fusion is based on several factors including surgical ease-of-use, biomechanical characteristics, and surgeon preference. The study suggests that integrated plate-spacer provide biomechanical stability comparable to traditional spacer and plate constructs in the cervical spine. Clinical studies on integrated plate spacer devices are necessary to understand the performance of these devices in vivo.


Indirubin-3'-monoxime blocks vascular smooth muscle cell proliferation by inhibition of signal transducer and activator of transcription 3 signaling and reduces neointima formation in vivo.
Our goal was to examine the influence of indirubin-3'-monoxime (I3MO), a natural product-derived cyclin-dependent kinase inhibitor, on vascular smooth muscle cell (VSMC) proliferation in vitro, experimentally induced neointima formation in vivo, and related cell signaling pathways. I3MO dose-dependently inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation by arresting cells in the G(0)/G(1) phase of the cell cycle as assessed by 5-bromo-2'-deoxyuridine incorporation and flow cytometry. PDGF-induced activation of the kinases Akt, Erk1/2, and p38(MAPK) was not affected. In contrast, I3MO specifically blocked PDGF-, interferon-γ-, and thrombin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Human endothelial cells (EA.hy926) responded to I3MO with increased endothelial nitric oxide synthase activity as assessed via [(14)C]l-arginine/[(14)C]l-citrulline conversion. The specific STAT3 inhibitor Stattic led to decreased VSMC proliferation, and transient expression of a constitutively active form of STAT3 overcame the I3MO-induced cell cycle arrest in mouse embryonic fibroblasts. In a murine femoral artery cuff model, I3MO prevented neointima formation while reducing STAT3 phosphorylation and the amount of proliferating Ki67-positive cells. I3MO represses PDGF- and thrombin-induced VSMC proliferation and, in vivo, neointima formation, likely because it specifically blocks STAT3 signaling. This profile and its positive effect on endothelial NO production turns I3MO into a promising lead compound to prevent restenosis.


Diversity and complexity of ceramide signalling in apoptosis.
Sphingolipid ceramide has emerged as a lipid messenger of cell functions including differentiation and apoptosis. Diverse kinds of stresses (ultraviolet, irradiation, heat shock and hypoxia) and biological factors (TNF-alpha, IFN-gamma and Fas antibody) require ceramide generation to execute apoptosis. The review summarises the diversity and complexity of up- and downstream of ceramide signalling in apoptosis and clinical implications of ceramide-induced apoptosis.


PCR heads into the field.
Analyzing samples with PCR is routine in the lab. New approaches let researchers do this assay wherever they need.


The evolution of monogenean diversity.
The Monogenea are an ideal group for investigations of the processes behind their past diversification and their present diversity for at least three reasons: they are diverse both in terms of morphology and numbers, they are generally host specific, and their phylogeny is well resolved, at least to the family level. The present investigation takes a broad look at monogenean diversity in order to try to determine whether the diversification of monogeneans is driven by some ecological features of the parasites themselves, or by extrinsic factors associated with their hosts. First, our current knowledge of monogenean diversity appears good enough to warrant investigation into its evolution. The body size of new species correlates negatively with their year of description both generally and within given families, i.e. it decreases over time in a way that suggests that only some of the smallest species are left to be discovered. Second, the occurrence of congeneric monogenean species on the same host species is not associated with host body size, once phylogenetic influences are controlled. This analysis suggests that host size is not one of the factors promoting local diversification of monogenean taxa. Third, the species richness of the different monogenean families does not correlate with the average body size of their members. Thus, this basic parasite life-history trait is not a determinant of diversification rates. Combined, the results of these separate analyses provide preliminary answers to some of the big questions concerning the diversification of monogeneans, but leave many other questions unanswered. The phylogenetic analytical framework adopted here should allow these questions to be tackled once the necessary data become available.


Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists.
Herein, we report the synthesis and structure-activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4 receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.


A simple method for the Schwann cell preparation from newborn rat sciatic nerves.
We have developed a simple and relatively rapid method for obtaining a sufficient number of Schwann cells with a favorable purification ratio from newborn rat sciatic nerves. Perineurium-free nerves were torn into small fascicles of approximately 150-200 microns in diameter and explanted twice on type I collagen gel every 2 days of the culture period in order to reduce the number of contaminant fibroblasts. The last explanted tissues were fed with Dulbecco's modified Eagle medium supplemented with 10% fetal bovine serum and 100 micrograms/ml bovine pituitary extract for 10 days. More than 10 X 10(4) Schwann cells (greater than 95% purity) were obtained from newborn rat sciatic nerves.


Identification of key adipogenic transcription factors for the pork belly parameters via the association weight matrix.
Pork belly, which contains various components of muscle and fat, is one of the most favorable parts of pork. However, pig-breeding has largely focused on improving longissimus thoracis, representing the lean-meat production capacity, and the quality of pork belly has not improved because of the absence of established standards. Previous studies have suggested a standard for the establishment of such standards and relevant genetic parameters, but no key gene has been identified yet. Here, we predicted key genes, including transcription factors, related to pork belly formation. We analyzed 543 Yorkshire pigs and their SNP chip data and identified 3238 genes and 135,025 edges related to pork belly traits by using the association weight matrix. Based on these results, in silico validation was performed. The predicted nine transcription factors, including the key trio, were enriched in adipogenesis-related signaling pathways. The transcription factors and corresponding genetic network identified in this study may be useful in improving pork belly parameters.


[Examination of plasminogen-activators and plasmin-inhibitors in maternal and fetal rat-lung-tissue after administration of DL-carnitine-hydrochloride (author's transl)].
In the formation and resolution of fibrinous pulmonary hyaline membranes of the type occurring in perinatal respiratory distress, the plasminogen activators and plasmin inhibitors contained in the tissue assume central importance. Carnitine does not change plasminogen activator activity and reduces the plasmin inhibitor content in the foetal rat lung. Hence, no inhibiting action on local fibrinolytic processes can be established for carnitine.


Peer effects in adolescent bodyweight: evidence from rural China.
Peer effect is a potential determinant of individual weight gain that has drawn considerable attention recently. The presence of peer effect implies that policies targeted at changing bodyweight can have enhanced effectiveness through a multiplier effect. This study aims to measure the peer effects on adolescent bodyweight in China. Using the small community nature of the rural sample of the wave 2000 of the China Health and Nutrition Survey, we define plausible peer groups and assess the effect of the average BMI of his/her peer group on the BMI of an adolescent. An instrumental variable (IV) approach is applied to control for potential endogeneity of the peer group's BMI. We find evidence supporting peer effect on BMI in general. The peer effect is around 0.3 with slight variation between two alternative peer definitions. Split sample analysis shows that the peer effect is significant for females (0.32-0.37), and insignificant for male adolescents. Furthermore, we find strong influence of same-gender peers (0.34-0.42) for female adolescents. Conditional quantile regressions show that the peer effect in weight gain is mainly present at or below the median in the conditional BMI distribution for girls, and at the higher end of the BMI distribution for boys. Multiple tests show strong identification, and strong instruments in our IV estimation. Placebo tests suggest that our results are reasonably robust to the correlated effect, due to unobserved community- and province-level factors.


Genome characterization of two novel deep-sea sediment fungi, Penicillium pacificagyrus sp. nov. and Penicillium pacificasedimenti sp. nov., from South Pacific Gyre subseafloor sediments, highlights survivability.
Marine deep subsurface sediments were once thought to be devoid of eukaryotic life, but advances in molecular technology have unlocked the presence and activity of well-known closely related terrestrial and marine fungi. Commonly detected fungi in deep marine sediment environments includes Penicillium, Aspergillus, Cladosporium, Fusarium, and Schizophyllum, which could have important implications in carbon and nitrogen cycling in this isolated environment. In order to determine the diversity and unknown metabolic capabilities of fungi in deep-sea sediments, their genomes need to be fully analyzed. In this study, two Penicillium species were isolated from South Pacific Gyre sediment enrichments during Integrated Ocean Drilling Program Expedition 329. The inner gyre has very limited productivity, organic carbon, and nutrients. Here, we present high-quality genomes of two proposed novel Penicillium species using Illumina HiSeq and PacBio sequencing technologies. Single-copy homologues within the genomes were compared to other closely related genomes using OrthoMCL and maximum-likelihood estimation, which showed that these genomes were novel species within the genus Penicillium. We propose to name isolate SPG-F1 as Penicillium pacificasedimenti sp. nov. and SPG-F15 as Penicillium pacificagyrus sp. nov. The resulting genome sizes were 32.6 Mbp and 36.4 Mbp, respectively, and both genomes were greater than 98% complete as determined by the presence of complete single-copy orthologs. The transposable elements for each genome were 4.87% for P. pacificasedimenti and 10.68% for P. pacificagyrus. A total of 12,271 genes were predicted in the P. pacificasedimenti genome and 12,568 genes in P. pacificagyrus. Both isolates contained genes known to be involved in the degradation of recalcitrant carbon, amino acids, and lignin-derived carbon. Our results provide the first constructed genomes of novel Penicillium isolates from deep marine sediments, which will be useful for future studies of marine subsurface fungal diversity and function. Furthermore, these genomes shed light on the potential impact fungi in marine sediments and the subseafloor could have on global carbon and nitrogen biogeochemical cycles and how they may be persisting in the most energy-limited sedimentary biosphere.


Cancer-derived extracellular succinate: a driver of cancer metastasis.
Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.


Chitosan/poly (3-hydroxy butyric acid-co-3-hydroxy valeric acid) electrospun nanofibers with cephradine for superficial incisional skin wound infection management.
The belated and compromised incisional skin wound healing caused by the invading of methicillin-resistance staphylococcus aureus is a serious problem in clinic. Designing a new therapeutic strategy to inhibit the growth of invading bacteria at post-surgical site might be helpful in fast healing of post-surgical wounds. In this study, we developed cephradine (Ceph) encapsulated chitosan and poly (3-hydroxy butyric acid-co-3-hydroxy valeric acid, (PHBV)) hybrid nanofibers (Ceph-CHP NFs) employing an electrospinning method to revamp the Ceph bioavailability at the post-surgical wound site to prevent the growth of invading bacteria and trigger the wound healing process. The fabricated nanofibers revealed smooth and uniform surface with a diameter range of 160 ± 25 to 190 ± 55 nm, depending on Ceph concentration. Further, the electrospun hybrid nanofibers exhibited a higher entrapment efficiency (EE) and drug loading capacity (DLC) nearly 72.8 ± 5.2 % and 16.5 ± 3.2 %, respectively. Moreover, the Ceph-CHP NFs showed high swelling rate and biodegradation in presence of lysozyme in contrast to blank CHP NFs. Ceph-CHP NFs exhibited fast drug release in initial few hours followed by slow and controlled drug release drug up to 48 h with a constant rate. In-vitro antimicrobial studies indicated the heightened efficacy of Ceph-CHP NFs against MRSA clinical isolates and exhibited no visible cytotoxicity against keratinocytes, HC11 and L929 cells. Lastly, Ceph-CHP NFs showed the enhanced wound healing and bacterial clearance from post-surgical wound compared to Ceph in C57BL/6 mice skin model. Overall, our results showed that Ceph-CHP NFs might be used as a promising wound dressing material for MRSA-infected post-surgical wounds.


Visual-vestibular interaction studied with stroboscopically illuminated visual patterns.
Horizontal DC-electrooculograms were recorded in subjects rotating on a horizontal turntable sinusoidally at 0.1 Hz and 35 to 40 degrees amplitude. The subjects either fixated a stroboscopically illuminated vertically striped pattern (1.15 to 3.45 degrees period) rotating with the turntable or initiated Sigma-OKN before the rotation began and tried to maintain Sigma-OKN during rotation. In a third paradigm, interaction of vestibulo-ocular reflex (VOR) and Phi-OKN was studied. VOR-suppression by fixation was complete within the limits of EOG-recording precision (+/- 1 degree X s-1) for flash frequencies fs greater than 10 flashes X s-1. VOR-suppression decreased monotonically with fs between 10 and 1 flashes X s-1. A similar dependency on fs was found for VOR-suppression during Sigma- or Phi-OKN. Above 10 flashes X s-1 VOR-suppression remained incomplete; below 5 flashes X s-1 VOR-suppression was stronger with the Sigma-OKN paradigm than during fixation and depended on spatial frequency of the pattern. During sinewave rotation of the subject the perceived speed Vp of Sigma-movement correlated to the movement of gaze in space and not to the movement of the eye in head. In a control experiment with normal optokinetic stimulation, OKN-suppression by fixating a small flashing target was found to depend on fs in a similar way as VOR-suppression in the experiments described above.


Molecular pathogenesis of adult brain tumors and the role of stem cells.
Primary brain tumors consist of neoplasms with varied molecular defects, morphologic phenotypes, and clinical outcomes. The genetic and signaling abnormalities involved in tumor initiation and progression of the most prevalent adult primary brain tumors, including gliomas, meningiomas, and medulloblastomas, are described in this article. The current understanding of the cell-of-origin of these neoplasms is reviewed, which suggests that the malignant phenotype is propelled by cells with stem-like qualities. A comprehensive understanding of the molecular basis of transformation and the cell-of-origin of these neoplasms will enable the formulation of more targeted treatment alternatives that could improve survival and quality of life.


Selective regulation of IKKβ/NF-κB pathway involved in proliferation inhibition of HFLS-RA cells induced by 1,7-dihydroxyl-3,4-dimethoxylxanthone.
Rheumatoid arthritis is a common autoimmune disease, however, available regimes exert little influence on it's long-term prognosis. The aim of the current study is to investigate potential effects of 1,7-dihydroxyl-3,4-dimethoxyl-xanthone (XAN) in HFLS-RA cells and describe the underlying mechanisms of induction of NF-κB activity. Viability of cells was measured by MTT assay. Flow cytometry was employed to assess the pro-apoptotic effects. Modulation on NF-κB signaling was investigated by RT-qPCR, Western-blot and immunofluorescence methods. It was found that XAN induced proliferation inhibition and apoptosis of HFLS-RA cells in the concentration-dependent manner, which were strengthened by pyrrolidinedithiocarbamic acid but antagonized by IKK16. NF-κB signaling was abrogated shortly after the treatment of XAN via various means including mRNA expression, phosphorylation and nuclear translocation, which leaded to up-regulation of p38 and down-regulation of X-linked inhibitor of apoptosis protein. Simultaneous suppressions on p-IKKβ, p-IκB and p-p65 suggested the regulation on NF-κB was IKKβ mediated. Meanwhile, XAN promoted the expression of IKKα, which has a possible connection to pro-apoptotic effects suggested by the up-regulated cleaved PARP. These findings indicated IKKβ/NF-κB mediates the proliferation of HFLS-RA cells inhibited by XAN, and divergent regulations on IKKs could provide synergic effects on the cells' proliferation.


Novel ATAD3A recessive mutation associated to fatal cerebellar hypoplasia with multiorgan involvement and mitochondrial structural abnormalities.
Lethal neonatal encephalopathies are heterogeneous congenital disorders that can be caused by mitochondrial dysfunction. Biallelic large deletions in the contiguous ATAD3B and ATAD3A genes, encoding mitochondrial inner membrane ATPases of unknown function, as well as compound heterozygous nonsense and missense mutations in the ATAD3A gene have been recently associated with fatal neonatal cerebellar hypoplasia. In this work, whole exome sequencing (WES) identified the novel homozygous variant c.1217 T > G in ATAD3A, predicting a p.(Leu406Arg) substitution, in four siblings from a consanguineous family presenting with fatal neonatal cerebellar hypoplasia, seizures, axial hypotonia, hypertrophic cardiomyopathy, hepatomegaly, congenital cataract, and dysmorphic facies. Biochemical phenotypes of the patients included hyperlactatemia and hypocholesterolemia. Healthy siblings and parents were heterozygous for this variant, which is predicted to introduce a polar chain within the catalytic domain of ATAD3A that shortens its beta-sheet structure, presumably affecting protein stability. Accordingly, patient's fibroblasts with the homozygous variant displayed a specific reduction in ATAD3A protein levels associated with profound ultrastructural alterations of mitochondrial cristae and morphology. Our findings exclude the causative role of ATAD3B on this severe phenotype, expand the phenotypical spectrum of ATAD3A pathogenic variants and emphasize the vital role of ATAD3A in mitochondrial biogenesis.


Variant histone H2A.Z, but not the HMG proteins Nhp6a/b, is essential for the recruitment of Swi/Snf, Mediator, and SAGA to the yeast GAL1 UAS(G).
Chromatin architecture is very important for the regulation of transcriptional activation. Here, we investigated the role of two different chromatin components, the histone variant H2A.Z and HMG proteins Nhp6a/b, in regulating GAL1 gene expression. We have shown that recruitment of the Mediator complex is significantly affected in the absence of H2A.Z. Furthermore, H2A.Z is also required to fully recruit the SAGA and Swi/Snf complexes to the yeast GAL1-10 UAS(G). On the other hand, the HMG protein Nhp6a/b is not required to recruit the aforementioned components to the GAL1 promoter. The Nhp6 protein has been shown to interact with nucleosomes, and we show that its distribution is unaffected in the absence of H2A.Z. Our results suggest that the incorporation of the histone variant H2A.Z, but not the HMG proteins Nhp6a/b, in promoter regions creates a specialized chromatin domain that is required for pre-initiation complex assembly at the GAL1 locus.


A monolayer culture of gastric mucous cells from adult rabbits.
A new method for the primary monolayer cultures of adult rabbit gastric mucous cells has been developed. Rabbit gastric mucosal cells were isolated with etylenediaminetetraacetic acid and collagenase. Cells were cultured in Coon's modified Ham's F-12 medium supplemented with 10% fetal bovine serum, 15mM HEPES buffer, antibiotics, and antimycotic. The cells reached confluency on days 3-4. Histochemically 92% of the cells contained PAS positive gramules (mucous cells), 3% of cells showed a strong reaction for succinic dehydrogenase activity (parietal cells), 2% of the cells showed positive granules by Bowie staining (chief cells), and G6PDH staining was positive in 5% of the cells (surface mucous cells). Fibroblasts were rarely seen until day 7 (less than 1%). Thus rabbit cultured gastric cells were considered to be mainly comosed of mucous neck cells. These cells produced prostaglandin (PG) E2 and PGI2. Quantitatively cultured cells synthesized 1.475 +/- 0.039 ng/mg protein/hour of PGE2 and 0.244 +/- 0.042 pg/mg protein/hour of PGI2. This relatively simple and convenient technique provides a useful model for the study of cellular functions of gastric mucosa.


Repositioning buttress internal graft as a modification to distal osteotomy bunionectomies.
The author proposes a novel use of redundant bone resulting from the lateral transposition of the first metatarsal head upon the shaft during a distal osteotomy bunionectomy. The bone, which is usually discarded, may be transposed to the lateral side of the shaft, fixated in place, and used to buttress the metatarsal head, thereby increasing the amount of transpostional shift that can safely occur with stability. By doing this, one could extend the range of intermetatarsal angles suitable to a distal osteotomy.


Protective effect of Du-Zhong-Wan against osteoporotic fracture by targeting the osteoblastogenesis and angiogenesis couple factor SLIT3.
Du-Zhong-Wan (DZW) is a traditional Chinese medicine (TCM) composed of Eucommia ulmoides Oliv. and Dipsacus asper Wall. ex C.B. Clarke in the ratio 1:1. Based on the TCM theory, DZW nourishes the kidney to strengthen the bones. The literature research revealed that DZW possesses anti-fatigue, anti-depressant, and anti-osteoporotic properties. However, the action and mechanism of DZW on osteoporotic fracture remains slightly unclear. To evaluate the pharmacological effect of DZW on ovariectomized mice with an open femoral fracture and reveal the underlying mechanism. We conducted ovariectomy for 5 weeks, followed by unilateral open transverse femoral fracture for another 3 weeks in C57BL/6 mice; during this process, DZW was administrated. The femur bone and vertebra tissues were collected and analyzed by micro-computed tomography, histomorphometry, mechanical strength testing, immunohistochemistry staining, and qRT-PCR analyses. In addition, alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were performed to determine the extent of osteoblastogenesis from bone marrow mesenchymal stem cells (BMSCs). Western blotting was performed to examine the protein expression. DZW treatment significantly improved the bone histomorphometric parameters in mice undergoing ovariectomy when combined with the femoral fracture, including an increase in the bone volume, trabecular number, and bone formation rate and a decrease in the bone erosion area. Simultaneously, DZW treatment histologically promoted fractured callus formation. Mechanical strength testing revealed significantly higher stiffness and an ultimate load after treatment with DZW. The angiogenesis of H-type vessels was enhanced by DZW, as evidenced by increased levels of CD31 and endomucin (EMCN), the H-type vessel endothelium markers, at the fractured endosteum and metaphysis regions. Relative to the osteoporotic fracture mice, the DZW treatment group showed an increased proangiogenic factor SLIT3 level. The increased level of SLIT3 was also recorded during the process of DZW-stimulated osteoblastogenesis from BMSCs. For the first time, we demonstrated that DZW promoted osteoporotic fracture healing by enhancing osteoblastogenesis and angiogenesis of the H-type vessels. This enhanced combination of osteoblastogenesis and angiogenesis was possibly related to the production of proangiogenic factor SLIT3 induced by DZW.


The risk of developing depression when suffering from neurological diseases.
To investigate the comorbidity of Alzheimer's/dementia, epilepsy, multiple sclerosis and Parkinson's with depression. 42,914 patients who were newly diagnosed with the four comorbid diseases were included in the study. We analyzed how many of these patients developed depression within five years. Between 21% (males with epilepsy) and 39% (women with Parkinson's)/44% (Alzheimer's patients under 60 years) developed depression within five years. We recommend routine checks for depression in patients diagnosed with one of these diseases, especially in the most comorbid ones.


Unidirectional gas flow in soil porosity resulting from barometric pressure cycles.
During numerical simulation of air flow in the vadose zone, it was noticed that a small sinusoidal pressure would cause a gradual one-way migration of the pore gas. This was found to be a physical phenomenon, not a numerical artifact of the finite element simulation. The one-way migration occurs because the atmospheric pressure, and hence the air density, is slightly greater when air is flowing into the ground than when air is flowing out of the ground. A simple analytic theory of the phenomenon is presented, together with analytic calculations using actual barometric pressure data. In soil of one Darcy permeability, the one-way migration is of the order of a few tenths of a meter per year for either plane flow from ground surface or for radial flow from an open borehole. The migration is sufficiently small that it will have no practical consequences in most circumstances; however, investigators who conduct detailed numerical modeling should recognize that this phenomenon is not a numerical artifact in an apparently linear system.


Botulinum neurotoxin A2 reduces incidence of seizures in mouse models of temporal lobe epilepsy.
Temporal lobe epilepsy often shows pharmacoresistance, and well-known anti-convulsants sometimes are not effective for blocking chronic seizures. Botulinum neurotoxins are metalloproteases that act on presynaptic proteins and inhibit neurotransmitter release in both the peripheral and central nerve systems. That is why neurotoxins may elicit an effect for the restraint of the seizures. Meanwhile, it has been suggested that a property and the stability of neurotoxin activities differ among the types A-G, in which type A neurotoxin (ANTX) is, especially, the most stable and can continue having activity for a long term. The present study therefore investigated the effects of hippocampal injections of A2NTX on seizures derived in TLE model mice, received repeated kindling stimulations in the amygdala. The injections induced complete disappearance of grand mal seizures in half of the population of amygdala kindled mice for 4 days. The injections also induced reduction of the evoked seizure level significantly for at least 18 days after injections. Taken together, these results suggest that A2NTX prevents from epileptic seizures, proposing that A2NTX is available as a new antiepileptic reagent.


Optimization of contrast delivery for pulmonary CT angiography.
Pulmonary CT angiography is becoming an increasingly important tool for diagnosing Pulmonary Emboli. An important aspect in optimizing the quality of these studies is achieving maximum levels of enhancement of the pulmonary arteries. In this study we reviewed the current literature to see if there was any standardization of protocols to achieve this purpose, and found that there was no consensus. Using well described techniques for determining blood flow we were able to demonstrate the proper time delays to achieve the highest levels of enhancement. As contrast flows into the pulmonary arteries, the degree of enhancement rapidly reaches a plateau phase. This is then followed by a recirculation phase where enhancement starts to increase again. The proper time delays between scan time and start of contrast infusion should allow for enhancement to be within this recirculation phase. An experimental model was developed to demonstrate the principles.


Phylogenetic diversity of Flavobacteria isolated from the North Sea on solid media.
Flavobacteria are abundant in the North Sea, an epeiric sea on the continental shelf of Europe. However, this abundance has so far not been reflected by the number of strains in culture collections. In this study, Flavobacteria were isolated from pelagic and benthic samples, such as seawater, phytoplankton, sediment and its porewater, and from surfaces of animals and seaweeds on agar plates with a variety of carbon sources. Dilution cultivation with a new medium, incubation at low temperatures and with long incubation times, and colony screening by a Flavobacteria-Cytophagia-specific PCR detecting 16S rRNA gene sequences led to a collection of phylogenetically diverse strains. Two strains affiliated with Flammeovirgaceae and seven strains affiliated with Cyclobacteriaceae, whereas within the Flavobacteriaceae 20 isolated strains presumably represented seven novel candidate genera and 355 strains affiliated with 26 of 80 validly described marine Flavobacteriaceae genera, based on a genus boundary of 95.0% 16S rRNA gene sequence identity. The majority of strains (276) affiliated with 37 known species in 16 genera (based on a boundary of 98.7% 16S rRNA gene sequence identity), whereas 79 strains likely represented 42 novel species in 22 established Flavobacteriaceae genera. Pigmentation, iridescence, gliding motility, agar lysis, and flexirubin as a chemical marker supported the taxonomy at the species level. This study demonstrated the culturability on solid medium of phylogenetically diverse Flavobacteria originating from the North Sea.


Microscopic Imaging of Chiral Amino Acids in Agar Gel through Circularly Polarized Luminescence of EuIII Complex.
We recently found that [Eu(pda)2 ]- (pda: 1,10-phenanthroline-2,9-dicarboxylic acid), which has an achiral structure in crystals, exhibits circularly polarized luminescence (CPL) in aqueous solutions containing chiral amino acids such as arginine and histidine. CPL measurements were performed for agar gel, which includes an aqueous solution of [Eu(pda)2 ]- and chiral arginine or histidine. The spectral shape, concentration, and pH dependences on CPL intensity in the agar gels were very close to those in aqueous solutions, indicating that the CPL of the EuIII complex in the agar gels was induced by mechanism similar to that in aqueous solutions. We performed spatially resolved CPL measurements using a laboratory-built microscopic CPL spectroscopic system for agar-gel samples, where d- and l- amino acids were separately dispersed. We successfully recorded CPL imaging maps showing spatial dispersions of d- and l-amino acid in the agar gels.


Short-term outcomes following total colectomy for inflammatory bowel disease in Denmark after implementation of laparoscopy: a nationwide population-based study.
A laparoscopic approach to total colectomy (TC) for inflammatory bowel disease (IBD) is being increasingly used, but data on its comparative benefits over open TC are conflicting. The aim of this study was to examine 90-day outcomes following laparoscopic and open TC for IBD in a nationwide cohort after the introduction of laparoscopy. IBD patients undergoing TC in Denmark from 2005 to 2017 were identified from the Danish National Patient Registry. We used Kaplan-Meier methodology to estimate mortality and Cox regression analysis to estimate adjusted mortality rate ratios (aMRRs) and adjusted hazard ratios (aHRs) of reoperation, readmission and intensive care unit (ICU) transfer, comparing patients undergoing laparoscopic versus open TC. We identified 1095 patients undergoing laparoscopic TC and 1523 patients undergoing open TC. Following emergency TC, 90-day mortality was 2.8% (1.6%-4.9%) after laparoscopic TC and 9.1% (7.0%-11.8%) after open TC. Ninety-day mortality was 0.9% (0.3%-2.5%) after laparoscopic TC and 2.6% (1.5%-4.3%) after open elective TC. The aMRRs associated with laparoscopic TC were 0.45 (95% CI 0.25-0.80) in emergency cases and 0.29 (95% CI 0.10-0.86) in elective cases. Risks of readmission were comparable following laparoscopic versus open TC, both in emergency [aHR = 0.93 (95% CI 0.76-1.15)] and elective [aHR = 0.83 (95% CI 0.68-1.02)] cases, while risks of ICU transfer and reoperation were lower following laparoscopic TC, both in emergency cases [aHR = 0.53 (95% CI 0.35-0.82) and aHR = 0.26 (95% CI 0.15-0.47)] and elective [aHR = 0.58 (95% CI 0.35-0.95) and aHR = 0.37 (95% CI 0.21-0.66)] cases. The introduction of laparoscopic TC for IBD in Denmark was not associated with increased mortality or morbidity. In fact, laparoscopic TC for IBD may be associated with lower short-term mortality and morbidity compared with open TC.


Density functional study of bare gold clusters: the ten-vertex neutral system.
Four novel Au10 structures have been located by means of density functional methods and their geometry and electronic structure are discussed. Furthermore, the behavior of less extensive basis sets in conjunction with the B3PW91 functional is compared to a highly accurate and more extensive energy-consistent scalar-relativistic pseudopotential and basis set for neutral ten-vertex gold clusters. The values obtained for several structural parameters for known and novel optimized Au10 systems are discussed.


Identification of Sendai virus mRNA species.
Cell-free translation of separated Sendai virus mRNA species identified the message for polypeptide M and suggested the identity of the message for polypeptide NP.


Visceral theory of sleep and origins of mental disorders.
Visceral theory of sleep states that the same brain neurons, which process external information in wakefulness, during sleep switch to the processing of internal information coming from various visceral systems. Here we hypothesize that a failure in the commutation of exteroceptive and interoceptive information flows in the brain can manifest itself as a mental illness.


Uncovering the effect of polyethyleneimine on methane production in anaerobic digestion of sewage sludge.
The potential effect of polyethyleneimine as a flocculant on anaerobic digestion of sludge was investigated. Polyethyleneimine above 12 g/kg total suspended solids inhibited the entire anaerobic digestion process including solubilization, hydrolysis, acidification, and methanogenesis. The addition of 24 g/kg total suspended solids polyethyleneimine reduced methane production from 167 ± 5 L/kg volatile suspended solids in the control reactor (without polyethyleneimine) to 141 ± 5 L/kg volatile suspended solids. Polyethyleneimine bound to extracellular polymeric substances, thus enhancing sludge agglomeration and hindering the release of organics. Meanwhile, the reduction of cytochrome C impeded electron transport, consequently curbed direct interspecies electron transfer. The adsorption of carbon dioxide by amine groups also hampered methane conversion. This study elucidated the concept that polyethyleneimine reduces mass transfer in anaerobic digestion, providing new insights into the potential behavior of flocculants in sludge treatment.


Understanding post-surgical decline in left ventricular function in primary mitral regurgitation using regression and machine learning models.
Class I echocardiographic guidelines in primary mitral regurgitation (PMR) risks left ventricular ejection fraction (LVEF) < 50% after mitral valve surgery even with pre-surgical LVEF > 60%. There are no models predicting LVEF < 50% after surgery in the complex interplay of increased preload and facilitated ejection in PMR using cardiac magnetic resonance (CMR). Use regression and machine learning models to identify a combination of CMR LV remodeling and function parameters that predict LVEF < 50% after mitral valve surgery. CMR with tissue tagging was performed in 51 pre-surgery PMR patients (median CMR LVEF 64%), 49 asymptomatic (median CMR LVEF 63%), and age-matched controls (median CMR LVEF 64%). To predict post-surgery LVEF < 50%, least absolute shrinkage and selection operator (LASSO), random forest (RF), extreme gradient boosting (XGBoost), and support vector machine (SVM) were developed and validated in pre-surgery PMR patients. Recursive feature elimination and LASSO reduced the number of features and model complexity. Data was split and tested 100 times and models were evaluated via stratified cross validation to avoid overfitting. The final RF model was tested in asymptomatic PMR patients to predict post-surgical LVEF < 50% if they had gone to mitral valve surgery. Thirteen pre-surgery PMR had LVEF < 50% after mitral valve surgery. In addition to LVEF (P = 0.005) and LVESD (P = 0.13), LV sphericity index (P = 0.047) and LV mid systolic circumferential strain rate (P = 0.024) were predictors of post-surgery LVEF < 50%. Using these four parameters, logistic regression achieved 77.92% classification accuracy while RF improved the accuracy to 86.17%. This final RF model was applied to asymptomatic PMR and predicted 14 (28.57%) out of 49 would have post-surgery LVEF < 50% if they had mitral valve surgery. These preliminary findings call for a longitudinal study to determine whether LV sphericity index and circumferential strain rate, or other combination of parameters, accurately predict post-surgical LVEF in PMR.


Ventricular repolarization time indexes following anthracycline treatment.
The anthracyclines, doxorubicin and daunorubicin, are antibiotics effective in the treatment of many malignancies. However, their usefulness is limited by the development of potentially fatal cardiotoxicity. Cardiac monitoring by a noninvasive test capable of identifying patients at high risk of cardiac damage, before the ejection fraction deteriorates would have clinical utility. Electrocardiograms and echocardiograms are routinely utilized for noninvasive assessment of myocardial function. However, of the ECG abnormalities described, none has been noted to be of consistent predictive value for cardiotoxicity. The aim of this study was to assess the effects of doxorubicin on ventricular repolarization time indexes, as they have been shown to be effective in the identification of electrical myocardial instability and, hence, in the identification of risk for either arrhythmia or heart failure. For this reason, electrocardiograms were compared in 35 cancer patients at the first presentation (drug-free state) and after 29.4 +/- 37.65 weeks of treatment with doxorubicin. The results of the present study showed that after only a short period of treatment with doxorubicin there was a significant increase in ventricular recovery time dispersion indexes (QTc, JT, and JTc dispersion, and their "adjusted" values). Thus, increased regional variation in ventricular repolarization could be, in the absence of a significant modification of the echocardiographic parameters, an early marker of an electropathy, due to the early cardiotoxic action of doxorubicin on myocardial cells, eventually leading to heart failure.


Current practice patterns and gaps in guideline-concordant breast cancer survivorship care.
Breast cancer-specific survivorship care guidelines for the more than 3.8 million survivors in the U.S. are available, but implementation in clinical practice remains challenging. We examined current practice patterns and factors associated with guideline-concordant survivorship care among oncologists. A national sample of medical oncologists, recruited using two databases, participated in a survey focused on practice patterns for breast cancer survivorship care. A "survivorship care composite score" was calculated for each respondent based on provision of services recommended in the survivorship guidelines. Descriptive statistics and multivariable linear regression analyses examined associations between physician and practice characteristics and composite scores. The survey was completed by 217 medical oncologists, with an overall response rate of 17.9% and eligibility rate of 56.9% for those who responded. Oncologists reported high engagement in evaluation of disease recurrence (78%). Performed less frequently were the provision of survivorship care plans (46%), assessment of psychosocial long-term and late effects (34%), and screening for subsequent cancers (34%). Lack of survivorship care training (p = 0.038) and not routinely informing patients about potential late effects (p = 0.003) were significantly associated with poorer survivorship care composite scores. Despite the availability of disease-specific survivorship care guidelines, adherence to their recommendations in clinical practice is suboptimal. Survey results identified key gaps in survivorship care for breast cancer survivors, particularly related to subsequent primary cancers and psychosocial long-term and late effects. Improving the delivery of comprehensive survivorship care for the growing population of breast cancer survivors is a high priority. Disease-specific clinical guidelines for cancer survivorship provide valuable recommendations, but innovative strategies are needed to integrate them into the care of long-term breast cancer survivors.


Engineered nanoparticles in plant growth: Phytotoxicity concerns and the strategies for their attenuation.
In the agricultural sector, the use of engineered nanoparticles (ENPs) has been acclaimed as the next big thing for sustaining and increasing crop productivity. A vast amount of literature is available regarding the growth-promoting attributes of different ENPs. In this context, it has been emphasized that the ENPs can bolster vegetative growth, leaf development, and seed setting and also help in mitigating the effects of abiotic and biotic stresses. At the same time, there have been a lot of speculations and concerns regarding the phytotoxicity of ENPs off-late. In this connection, many research articles have presented the negative effects of ENPs on plant systems. These studies have highlighted that almost all the ENPs impart a certain degree of phytotoxicity in terms of reduction in growth, biomass, impairment of photosynthesis, oxidative status of plant cells, etc. Mostly, the ENPs based on metal or metal oxides (Cd, Cr, Pb, Ag, Ce, etc.) and nonmetals (C) that are introduced into the environment are known to incite inhibitory effects. However, the phytotoxicity of ENPs are known to be determined mostly by the chemical nature of the element, size, surface charge, coating molecules, and abiotic factors like pH and light. This review article, therefore, elucidates the phytotoxic properties of different ENPs and the plant responses induced at the molecular level subjected to nanoparticle exposure. Moreover, the article highlights the probable strategies that may be adopted for the suppression of the phytotoxicity of ENPs to ensure the safe and sustainable application of ENPs in crop fields.


Assessment of the effects of urbanization on trace elements of toe bones.
Amphibians, particularly frogs and toads, are increasingly used as bioindicators of contaminant accumulation in pollution studies. We developed an analytical technique to analyse their elemental contents based on a small amount of toe bone samples. This method is environment-friendly as, unlike traditional methods, it is not necessary to kill animals during sampling. Using this technique, we explored the effects of urbanization on the elemental contents of toe bones. Bufo bufo specimens were collected from an urban and two rural ponds. The ratios of Ca and P at the ponds were: 20.5% Ca and 14.6% P at the urban pond and 30.4% and 29.6% Ca, 22.4% and 21.7% P at the rural ponds, respectively. For the other elements, the following percentage ratios were found: 0.7% B, 0.3% Mg and 0.06% Zn at the urban pond and 1.1% and 0.4% B, 0.4% Mg and 0.05% Zn at the rural ponds, respectively. Canonical discriminant analysis indicated the separation of the urban and the rural ponds based on the elemental concentrations of toe bones. Significant differences were found between the concentrations of Ca, P, Mg, B and Zn at the urban and the rural ponds (p < 0.05). Anthropogenic activity was found to have effects on the elemental contents of toe bones in the urbanized area. Our study also demonstrated that the developed method was appropriate for the elemental analysis of small samples to assess the effects of urbanization.


[Penile cancer--aftercare with results. How much is necessary?].
Penile cancer is a rare tumor entity but penile carcinoma is characterized by a high recurrence rate regarding local, lymphatic, and hematogenous recurrence. The critical period for tumor recurrence is in the first 5 years. Therapeutic options for tumor recurrence can be differentiated by the type of recurrence and the preceding therapy. The prognosis of local or small lymphatic recurrence-if detected early and diligently diagnosed-can be improved significantly by radical surgery. On the other hand, systemic therapy of advanced lymphatic recurrences and hematogenous metastases will influence disease progression only marginally. Based on these considerations, the follow-up of penile cancer should be risk adapted but close as suggested by our algorithm. With a reduced, but close follow-up we can offer our patients aftercare with the consequence of improved prognosis.


Comprehension of before and after in frontotemporal degeneration.
Frontotemporal lobar degeneration (FTLD) is a dementia syndrome with behavioural problems and deterioration of language functions. The other cognitive domains are relatively preserved for at least the first two years of the disease. We studied the ability of patients with FTLD to understand before and after constructions expressed in Finnish. Ten patients and eight controls were presented eight sentences with different relations and asked questions to test their comprehension. The results showed that the patients generally found after constructions more difficult. The difficulty was not, however, related to normal ageing, as was shown by the performance of the control group.


Longstanding and Refractory Anti-Muscle Specific Tyrosine Kinase Antibody-Associated Myasthenia Gravis (Anti-MuSK-MG) in a Child Successfully Treated with Rituximab.
Anti-muscle specific tyrosine kinase antibody-associated myasthenia gravis (MuSK-MG) is a rare subtype of MG characterized by more frequent relapses and a clinical course that is refractory to standard treatments. Rituximab, a monoclonal antibody targeting CD20+ B cells, has been used effectively in the adult population to achieve stable remission. We describe a pediatric patient with MuSK-MG who demonstrated an excellent response to rituximab after failing standard therapy.


Spontaneous multiquantal release at synapses in guinea-pig hypogastric ganglia: evidence that release can occur in bursts.
1. A study was made of some properties of the spontaneous synaptic potentials recorded in cells of the hypogastric ganglia of guinea-pigs. 2. The distribution of the amplitudes of the spontaneous synaptic potentials arising from a single preganglionic fibre was found to be multimodal, with peaks at roughly integral multiples of a unit peak. 3. It was found that the amplitudes of the larger spontaneous potentials were consistent with them being the result of synchronous or near-synchronous release of two or more unit-sized quanta (multiquantal release). 4. The proportion of multiquantal potentials observed was found to be dependent on the extracellular calcium ion concentration. 5. When the stochastic properties of the spontaneous potentials were examined, it was found that the spontaneous release process was not random and independent but appeared to be clustered. Indeed, the probability of occurrence of a unit spontaneous synaptic potential was greatly enhanced during the 40--60 msec immediately following any given spontaneous synaptic potential. 6. When unit spontaneous potentials were excluded from the analysis, the multiquantal potentials were still found to be clustered although the clustering was less marked than that seen in the over-all process. 7. These results suggested that the multiquantal spontaneous potentials arose from the release of unit quanta in short high frequency bursts and it was found that a mathematical model incorporating such a mechanism could describe the spontaneous quantal release process.


Fine structure of IMR-90 cells in culture as examined by scanning and transmission electron microscopy.
Cells from the new strain IMR-90 were examined by scanning (SEM) and transmission (TEM) electron microscopy at early, middle, and late population doubling levels. The cells are characteristically flattened and elongated and arranged in clusters from 1 to several cells thick. Long thin processes extend from the poles and sides of the cells. The number of blebs and microvilli on the cell surface varies. In later population doubling level (PDL) cultures, a larger number of cells have greater quantities of microvilli on their surface. It is suggested that the increased number of microvilli might represent an increased level of differentiation. By TEM the cells typically have elongated to oval shaped nuclei which are sometimes deeply invaginated. The cytoplasm contains a well developed Golgi region, elongated mitochondria, microtubules, filaments, a variety of vesicles, vacuoles and dense bodies and large amounts of RNA in the form of granular endoplasmic reticulum and ribosomes. Cytoplasmic appearance, particularly the number of dense bodies, varies widely at all PDL. With increasing PDL, cells tend to have nuclei with more condensed chromatin, and a cytoplasm containing less mitochondria and granular endoplasmic reticulum and more dense bodies. Also at later PDL there is a higher frequency of cells containing long, thin dense mitochondria as well as bizarre shaped mitochondria. In older populations there are many cells in a state of filamentous degeneration. Cells with large numbbers of surface projections (microvilli) tend to be correlated with an osmiophilic cytoplasm containing many filaments and numerous dense bodies.


Field evidences of fluorescent dissolved organic matter (FDOM) as potential fingerprints for agricultural and urban sources in river environment.
Field evidences of the fluorescence differences between agricultural and urban river reaches are still lack. In this study, the middle reaches of Danhe River (DH) and Mihe River (MH) in Shouguang, China, were designed as agricultural and urban river reaches, respectively, to compare the the fluorescence differences in disparate river reaches using excitation-emission matrix coupled with parallel factor analysis (EEM-PARAFAC). Three fluorescence components were identified. C1 (Ex/Em=230,255,295 nm/420 nm) was categorized as humic-like fluorophores, C2 (Ex/Em=230,275 nm/330 nm) was recognized as tryptophan-like substances, and C3 (Ex/Em=215 nm/290 nm) was noted as tyrosine-like and phenylalanine-like compounds. The results showed that the FDOM posed significant differences between agricultural and urban river reaches (P < 0.001). The monitoring sites in DH were rich in C2 (1.90 ± 0.62 Raman Unit (RU), mean ± standard deviation), and the monitoring sites in MH were rich in C3 (1.32 ± 0.51 RU). Redundancy analysis revealed that C2 could be regarded as a fluorescence indicator of agricultural sewage in river environment, while C3 was recognized as a fluorescence indicator of domestic sewage in river environment. In conclusion, this study provided field evidences of FDOM as potential fingerprints for agricultural and urban sources in river environment.


Off-target pharmacological activity at various kinases: Potential functional and pathological side effects.
In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of development to provide a mechanistic understanding of unexpected safety findings. Here, we present a compendium of the most likely functional and pathological outcomes associated with interaction(s) to a panel of 95 kinases based on an extensive curation of the scientific literature. This panel of kinases was designed by AbbVie based on safety-related data extracted from the literature, as well as from over 20 years of institutional knowledge generated from discovery efforts. For each kinase, the scientific literature was reviewed using online databases and the most often reported functional and pathological effects were summarized. This work should serve as a practical guide for small molecule drug discovery scientists and clinical investigators to predict and/or interpret adverse effects related to pharmacological interactions with these kinases.


Temporary joint-spanning external fixation before internal fixation of open intra-articular distal humeral fractures: a staged protocol.
This study determined outcomes after temporary joint-spanning external fixation before internal fixation of open intra-articular distal humeral fractures. A retrospective case analysis was done of all patients who were treated between 2000 and 2008 in 3 level I trauma centers with temporary joint-spanning external fixation before internal fixation of an open intra-articular distal humeral fracture. Healing rates, complications, Disabilities of Arm, Shoulder and Hand (DASH), and Smith and Cooney outcome scores were documented. The study included 16 patients. Mean follow-up was 35.2 months. Fractures united after an average of 5.2 months. No complications specifically related to the external fixation occurred. The DASH outcome score averaged 15.1. Although complications occurred in 12 patients (9 patients requiring surgery), 10 of 16 had an excellent/good outcome score. Temporary joint-spanning external fixation before internal fixation of open intra-articular distal humeral fractures is a safe adjunct.


Detection of Mycoplasma conjunctivae in sheep affected with conjunctivitis and infectious keratoconjunctivitis.
To determine the aetiology of a recurring and severe form of infectious keratoconjunctivitis (IKC) in sheep. Five sheep flocks that had experienced a severe form of IKC were examined. Clinical history, conjunctival swabs and blood samples were collected from affected animals. Culture for bacteria, and also specifically for Mycoplasma and Chlamydophila spp, and detection of Mycoplasma conjunctivae DNA by polymerase chain reaction (PCR) were attempted. Serum samples were tested for antibodies to M. agalactiae, M. capricolum, M. conjunctivae and Chlamydophila spp. Mycoplasma conjunctivae DNA was detected using PCR in 3/5 flocks, and in all flocks antibodies to M. conjunctivae were detected in sera. A pure growth of Branhamella ovis was cultured from conjunctival swabs from a small proportion of sheep in two flocks. No other pathogens were detected. This investigation demonstrated that M. conjunctivae was a primary pathogen causing severe IKC in sheep, and is the first report of detection of this organism in sheep in New Zealand. Introduction of clinically normal carrier sheep appeared to have caused the outbreaks. Infectious keratoconjunctivitis, Mycoplasma conjunctivae, Chlamydophila pecorum, Branhamella ovis, polymerase chain reaction, ELISA, complement fixation test.


Dynamic obstruction to left ventricular outflow: the case for its existence in hypertrophic cardiomyopathy.
The debate and controversy over the hemodynamics of obstruction and left ventricular ejection in HCM is an interesting and complex one in which periodic disagreement has appeared during the last 20 years. We believe that the available data unequivocally support the concept that in those patients with HCM who have left ventricular outflow gradients measured at catheterization (and who have associated marked SAM) a mechanical impediment to forward flow, and thus true obstruction to left ventricular outflow, does exist. Most importantly, the gradient has critical clinical implications by virtue of the markedly elevated intraventricular systolic pressures associated with it. These chronically elevated pressures are potentially detrimental to the left ventricle (a view held even by investigators opposed to the term "obstruction"), by virtue of increasing systolic myocardial wall stress and myocardial oxygen demand. Therefore, surgical abolition of the obstruction and normalization of these pressures remains an important and rational therapeutic objective in those severely symptomatic patients who have obstruction to left ventricular outflow and who have failed to benefit from drug therapy.


The tegmental-accumbal dopaminergic system mediates the anxiolytic effect of acupuncture during ethanol withdrawal.
This study investigated the involvement of the mesolimbic dopamine (DA) system in the anxiolytic effects of acupuncture during ethanol withdrawal (EW). Rats were intraperitoneally treated with 3g/kg/day of ethanol for 28 days and experienced 3 days of withdrawal. During EW, the rats were bilaterally treated with acupuncture at acupoints HT7 (Shenmen) or PC6 (Neiguan) or at a non-acupoint (tail) once daily for 1min over 3 days. High-performance liquid chromatographic (HPLC) analysis showed that EW significantly decreased both DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens shell (NaccSh); however, these processes were inhibited by acupuncture at HT7 but not at PC6. Real-time polymerase chain reaction and western blot assays also revealed that acupuncture at HT7 prevented the EW-induced reductions in tyrosine hydroxylase mRNA expression in the ventral tegmental area (VTA) and tyrosine hydroxylase protein expression in the NaccSh. A prior intra-NaccSh infusion of a cocktail of the selective DA1 receptor antagonist SCH23390 and the selective DA2 receptor antagonist eticlopride blocked the anxiolytic effect of acupuncture at HT7 in elevated plus maze tests. In addition, acupuncture at HT7 suppressed EW-induced increased BDNF levels in the VTA. These findings suggest that acupuncture at HT7 improves the VTA-Nacc DAergic function via inhibition of BDNF expression in the VTA, thereby exerting anxiolytic effects during EW.


Ospemifene, vulvovaginal atrophy, and breast cancer.
The incidence and severity of vulvovaginal atrophy (VVA) in postmenopausal breast cancer patients has a significant impact on quality of life. While the etiology of VVA is primarily related to low estrogen levels seen in menopause, women with breast cancer have an added risk of VVA induced by a combination of chemotherapy, hormonal therapy, and menopause. Ospemifene is a new, non-hormonal selective estrogen receptor modulator (SERM) triphenylethylene derivative that is effective in treating VVA in postmenopausal women. Although other SERMs have antagonistic effects on the vagina, ospemifene exerts an estrogen-like effect on the vaginal epithelium. This review will focus on data demonstrating the antiestrogenic activity of ospemifene in several unique breast cancer animal models, and the implications for utilizing ospemifene in patients with breast cancer suffering from VVA. Additional research addressing the expanded use of ospemifene in breast cancer patients is also warranted.


Five to 10-year followup of open partial nephrectomy in a solitary kidney.
Followup is limited in patients with a solitary kidney who undergo partial nephrectomy. We evaluated overall, cancer specific and recurrence-free survival, and renal function in patients 5 years or greater after open partial nephrectomy. We retrospectively reviewed the Cleveland Clinic kidney cancer database, including only patients with a solitary kidney treated with open partial nephrectomy 5 or more years ago (from 1980 to June 2006) who had 6 months or more of followup. Survival and recurrence analyses were calculated using a Cox proportional hazards model. Results are shown as Kaplan-Meier survival curves. Linear regression analysis was done to assess postoperative renal function. A total of 282 patients fit our study inclusion criteria (mean followup 175 months), of whom 233 underwent open partial nephrectomy 10 or more years ago. Actual overall survival was 78.5% and 59.5% at 5 and 10 years, respectively. The average estimated glomerular filtration rate at 5 years or greater and 10 years or greater since open partial nephrectomy was 35.1 and 34.5 ml/minute/1.73 m(2) in 89.7% and 89.6%, respectively, of patients with stage 3 or greater chronic kidney disease. Eight survivors were on intermittent hemodialysis 5 years or more postoperatively, including 5 at 10 years or more. There were 76 recurrences for a calculated 5 and 10-year recurrence-free survival rate of 72% (95% CI 66-879) and 63% (95% CI 57-71), respectively. Open partial nephrectomy in the solitary kidney provides reliable long-term oncological control at 5 and 10 years. Predicted and actual outcomes correspond well. Although most patients have chronic kidney disease postoperatively, it appears stable with minimal progression to dialysis.


Brain alterations associated with overweight evaluated by body mass index or body fat index in an elderly population: the PROOF study.
Obesity is a complex health issue in which the brain plays a role yet to be determined, especially in the elderly. Indeed, in the ageing population, the balance between fat and lean mass is different; thus, the co-influence between the brain and obesity may differ between the elderly and younger subjects. Our main goal is thus to explore the relationship between the brain and obesity using two different approaches to measure obesity: body mass index (BMI) and an index centred on fat mass, the body fat index (BFI). Among the 1,011 subjects of the PROOF population, 273 subjects aged 75 years underwent 3D magnetic resonance imaging as well as dual-energy X-ray absorptiometry to assess fat mass. Voxel-based morphometry was used to explore the local differences in brain volume with obesity. Higher BMI and BFI were associated with higher grey matter (GM) volume in the left cerebellum. Higher BMI and BFI were mainly associated with higher white matter volume in the left and right cerebellum and near the right medial orbital gyrus. Higher BMI was also associated with higher GM volume in the brainstem, whereas higher BFI was associated with higher GM volume in the left middle temporal gyrus. No decrease in white matter was associated with BMI or BFI. In the elderly, the relationship between the brain and obesity does not depend on the marker of obesity. Supra-tentorial brain structures seem to be slightly associated with obesity, whereas the cerebellum seems to be one of the key structures related to obesity.


A cross-cultural comparison of British and Pakistani medical students' understanding of schizophrenia.
This study aimed to compare British, British Pakistani and Native Pakistani (from Pakistan) medical students' beliefs about the manifestation, causes and cures of schizophrenia, prior to any psychiatric training. A total of 305 participants completed a questionnaire on general beliefs about people with schizophrenia, causal explanations concerning the aetiology of schizophrenia and the role of hospitals and society in treating people with schizophrenia. It was predicted that compared with the British and British Pakistanis, the Pakistanis would have more negative beliefs and attitudes, considering people with schizophrenia to be more dangerous and unpredictable; they were also expected to use more superstitious beliefs to explain the cause of schizophrenia and its symptoms; as well as believe more in seeking help from God and faith healers. There was strong evidence to suggest that Pakistanis possessed more negative beliefs and attitudes about people with schizophrenia, but there was no evidence to indicate that Pakistanis believed more in superstitious causal explanations. Pakistanis were more likely to consider seeking help from faith healers, but not God, compared with British Pakistanis and the British. Results confirm previous European-Asian difference in the understanding of the cause, manifestation and cure of schizophrenia. The impact of traditional and Western cultural influences on British Pakistanis is considered.


Preoperative smoking cessation counseling activities of anesthesiologists: a cross-sectional study.
Smokers undergoing surgery are at a higher risk of complications than non-smokers. Preoperative evaluation by an anesthesiologist could provide an excellent opportunity to promote smoking cessation. Previous surveys of anesthesiologists have found that self-reported smoking cessation counseling rates have room for improvement, but no study has surveyed patients to obtain more accurate estimates. A single-center study was conducted from January 2010 to June 2010 in a tertiary teaching hospital. A telephone survey was conducted, which included all adult cigarette smokers who visited the preoperative anesthesia clinic. The survey recorded anesthesiologist-delivered interventions to help patients quit smoking before surgery. At the end of the study period, the self-reported smoking cessation counseling of the anesthesiologist was evaluated by questionnaire. One thousand one hundred and sixty-five patients were evaluated, of which 217 were current smokers with a median pack-year of 15 (interquartile range 5.25-30.00) and 34% were scheduled to undergo major surgery. With regard to preoperative interventions, most anesthesiologists (85%) asked about smoking status, although only 31% advised patients about the health risks of smoking and 23% advised patients to quit before surgery. Provision of assistance to help patients quit was provided in 3% of cases. By contrast, 75% of anesthesiologists stated that they frequently or almost always advised patients about the health risks of smoking. This study shows significant discrepancies between direct patient surveys of preoperative smoking cessation counseling activities by anesthesiologists and the self-reported perceptions of the anesthesiologists. Future studies are urgently needed to evaluate the provision of educational materials and other interventions to improve smoking cessation counseling rates among anesthesiologists and to narrow these discrepancies.


Community-acquired Pseudomonas aeruginosa pneumonia manifested by bloody pleural effusion in a previously healthy infant: A case report.
Community-acquired Pseudomonas aeruginosa pneumonia in immunocompetent children is a rare occurrence. A retrospective analysis of the clinical manifestations, imaging characteristics, laboratory examinations, and treatment of a child with community-acquired Pseudomonas aeruginosa pneumonia presented with bloody pleural effusion. The 1-year-old previously healthy patient, who developed community-acquired pneumonia caused by Pseudomonas aeruginosa and influenza virus. The patient manifested bloody pleural effusion although his condition improved after anti-infective therapy and closed thoracic drainage. After 10 days of hospitalization, his symptoms worsened, accompanied by hemoptysis, and the pathogen developed resistance to carbapenems. The antibiotic strategy was adjusted to combined antipseudomonal regimen. He developed low-grade fever and was extubated, although these manifestations and imaging were eventually alleviated. Community-acquired Pseudomonas aeruginosa pneumonia in children may be non-septic, with bloody pleural effusion as presentation, and the disease may progress after 10 days of treatment due to drug resistance in Pseudomonas aeruginosa. Early extubation should be considered after adequate drainage.


Incorporating predicted functions of nonsynonymous variants into gene-based analysis of exome sequencing data: a comparative study.
Next-generation sequencing has opened up new avenues for the genetic study of complex traits. However, because of the small number of observations for any given rare allele and high sequencing error, it is a challenge to identify functional rare variants associated with the phenotype of interest. Recent research shows that grouping variants by gene and incorporating computationally predicted functions of variants may provide higher statistical power. On the other hand, many algorithms are available for predicting the damaging effects of nonsynonymous variants. Here, we use the simulated mini-exome data of Genetic Analysis Workshop 17 to study and compare the effects of incorporating the functional predictions of single-nucleotide polymorphisms using two popular algorithms, SIFT and PolyPhen-2, into a gene-based association test. We also propose a simple mixture model that can effectively combine test results based on different functional prediction algorithms.


Bers-ERK Schwann cells coordinate nerve regeneration.
In this issue of Neuron, Napoli et al. (2012) demonstrate that elevated ERK/MAPK signaling in Schwann cells is a crucial trigger for Schwann cell dedifferentiation in vivo. Moreover, the authors show that dedifferentiated Schwann cells have the potential to coordinate much of the peripheral nerve response to injury.


Patient and pathological predictors of management strategy for malignant polyps following polypectomy: a systematic review and meta-analysis.
Malignant polyps present a treatment dilemma for clinicians and patients. This meta-analysis sought to identify the factors that predicted the management strategy for patients diagnosed with a malignant polyp. A literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Collaboration prognostic studies guidelines. Reports from 1985 onwards were included, data on patient and pathological factors were extracted and random effects meta-analysis models were used. Fifteen studies were included. Seven studies evaluated lymphovascular invasion (LVI). The odds of surgery were significantly higher in malignant polyps with LVI (OR 2.20, 95% CI 1.36-3.55). Ten studies revealed the odds of surgery were significantly higher with positive polypectomy margins (OR 8.09, 95% CI 4.88-13.40). Tumour differentiation was compared in eight studies. There were significantly lower odds of surgery in malignant polyps with well/moderate differentiation compared with poor differentiation (OR 0.31, 95% CI 0.21-0.46). There were non-significant trends favouring surgical resection in younger patients, males and Haggitt 4/Kikuchi Sm3 lesions. There was considerable heterogeneity in the meta-analyses for the variables age, gender, polyp morphology and Haggitt/Kikuchi level (I2 > 75%). This meta-analysis has demonstrated that LVI, positive polypectomy resection margins, and poor tumour differentiation significantly predict malignant polypectomy patients who underwent subsequent surgery. Age and gender were important factors predicting management, but not consistently across studies, whilst polyp morphology and Haggitt/Kikuchi levels did not significantly predict the management strategy. Further research may assist in understanding the management preferences.


Quality of life in climacteric women assisted by primary health care.
This cross-sectional study evaluated the quality of life and associated factors of climacteric women in Brazil using a random and representative sample of women assisted by primary care professionals. We investigated the variables using the Menopause-Specific Quality of Life Questionnaire, MENQOL, whose mean scores were compared using Mann-Whitney and Kruskal-Wallis tests according to the sample characteristics. The variables associated with the outcomes in univariate analyses with a p≤0.2 were jointly evaluated using multiple linear regression. In this study, 849 women ranging in age from 40 to 65 years were evaluated. The predictors of poor quality of life in the vasomotor domain were women with severe climacteric symptoms (p<0.001), increased Body Mass Index (BMI) (p = 0.006), sleep (p = 0.022), and postmenopausal (p<0.001) alterations. For the psychosocial domain, the associated variables were severe climacteric symptoms (p<0.001) and sleep alterations (p<0.001); for the physical domain, the associated variables were severe climacteric symptoms (p<0.001), increased BMI (p<0.001), sleep (p<0.001), and postmenopausal (p<0.001) alterations. Severe climacteric symptoms, low sleep quality, increased BMI, and postmenopausal status were factors that were more associated with impairments in quality of life. With the increase in life expectancy, we suggest that greater attention should be paid to women's quality of life associated with climacteric symptoms.


Natural and anthropogenic sources of lead, zinc, and nickel in sediments of Lake Izabal, Guatemala.
Sediments in Lake Izabal, Guatemala, contain substantial lead (Pb), zinc (Zn), and nickel (Ni). The lack of historical data for heavy metal concentrations in the sediments makes it difficult to determine the sources or evaluate whether inputs of metals to the lake have changed through time. We measured the relative abundances and concentrations of Pb, Zn, and Ni by X-Ray Fluorescence core scanning and by Inductively Coupled Plasma Optical Emission Spectrometry in three sediment cores to explore stratigraphic distributions of metals in the lake deposits. High amounts of Pb and Zn in the core taken near the Polochic Delta suggest that galena and sphalerite mining increased Pb and Zn delivery to Lake Izabal between ~1945 and 1965 CE. An up-core Ni increase in the core taken near a different mine on the north shore of Lake Izabal suggests that recent nickel mining operations led to an increase in Ni concentrations in the local sediments, but amounts in the other cores indicate that Ni is not widely distributed throughout the lake. Sediment cores from Lake Izabal are reliable recorders of heavy metal input to the lake, and were measured to establish background metal levels, which would otherwise be unavailable. Concentrations of Pb, Zn, and Ni in older, pre-20th-century Lake Izabal sediments reflect input from natural erosion of bedrock. Our results provide previously unavailable estimates of background metal concentrations in Lake Izabal before the onset of mining. These results are necessary for future monitoring related to mining contamination of the lake ecosystem.


Cyanide reactivity of cytochrome c derivatives.
The kinetic rates and equilibrium association constants for cyanide binding have been measured for a series of cytochrome c derivatives as a probe of heme accessibility. The series included horse and yeast cytochromes iodinated at Tyr 67 and 74, horse cytochrome formylated at Trp 59 in both a low and high redox potential form, the Met 80 sulfoxide derivative of horse cytochrome and the N-acylisourea heme propionate derivative of tuna cytochrome. Native cytochromes c are well known to bind cyanide slowly in a reaction simply first order both in cytochrome and cyanide up to at least 100 mM in cyanide. The derivative demonstrate markedly different kinetics which indicate the following conclusions. (1) In spite of chemical modification at different loci, all the derivatives have highly similar reactivity, suggesting common ligation structures and mechanisms for reaction. (2) Compared to native cytochromes, reaction rates are 10-20 fold greater. This is in accord with a more accessible heme crevice, but not a completely opened crevice. For the completely opened case, rate increases are expected to be between three and five orders of magnitude. (3) Reaction rates are either independent of cyanide concentration (zero order) or show only slight variation. A mechanism which accounts for the data over four orders of magnitude in concentration postulates a protein conformation step, opening of the heme crevice, as the rate determining step. This conformation change has a limiting rate of 6 . 10(-2) s-1.


Quantitative study on selective stacking of zwitterions in large-volume sample matrix by moving reaction boundary in capillary electrophoresis.
The paper advanced the theoretical procedures for quantitative design on selective stacking of zwitterions in full capillary sample matrix by a cathodic-direction moving reaction boundary (MRB) in capillary electrophoresis (CE) under control of electroosmotic flow (EOF). With the procedures, we conducted the theoretical computations on the selective stacking of two test analytes of L-histidine (His) and L-tryptophan (Trp) by the MRB created with 30 mM pH 3.0 formic acid-NaOH buffer and 2-80 mM sodium formate. The results revealed the following three predictions. At first, the MRB cannot stack His and Trp plugs if less than 12.5 mM sodium formate is used to form the MRB and prepare the sample matrix. Second, the MRB can stack His and/or Trp sample plugs completely if higher than 50 mM sodium formate is chosen to form the MRB. Third, the MRB can only focus His plug completely, but stack Trp plug partially if 20-50 mM sodium formate is used; this implied the complete MRB-induced selective stacking to His rather than Trp. All the three predictions were quantitatively proved by the experiments. With great dilution of sample matrix and control of EOF, controllable, simultaneous and MRB-induced selective stacking and separation of zwitterions were achieved. The theoretical results hold evident significances to the quantitative design of selective stacking conditions and the increase of detection sensitivity of zwitterions in CE. In addition, the control of EOF by cetyltrimethylammonium bromide (CTAB) can evidently improve the stacking efficiency to both His and Trp.


Tobacco use is not associated with increased risk of recurrent reflux 5 years after laparoscopic anti-reflux surgery.
Tobacco use worsens gastrointestinal reflux disease (GERD). Smoking cessation improves GERD symptoms, but its impact on the efficacy of laparoscopic anti-reflux surgery (LARS) is unclear. In this retrospective cohort study, we hypothesized that non-smokers would demonstrate greater long-term improvements in disease-specific quality of life than active smokers. Data were maintained in an IRB-approved prospective database, and patients were stratified according to tobacco use. Postoperative follow-up occurred in clinic and long-term follow-up via telephone interview. Outcomes measured were gastroesophageal health-related quality of life (GERD-HRQL) and GERD symptom scale (GERSS) scores, proton pump inhibitor (PPI) cessation, and satisfaction with surgery. Two hundred and thirty-five patients underwent primary LARS, and 31 (13%) were active smokers with 18 median pack-years [10-30]. Baseline PPI use (96% vs. 94%, p = 0.64), presence of a hiatal hernia (79% vs. 68%, p = 0.13), esophagitis (28% vs. 45%, p = 0.13), and DeMeester score (41.9 vs. 33.6, p = 0.47) were similar. Baseline GERD-HRQL and GERSS scores and their post-surgical decreases were also similar between groups. PPI cessation was achieved in 92% of non-smokers and 94% of smokers (p = 0.79), and GERD-HRQL scores decreased to 4 [1-7] and 5 [0-12], respectively (p = 0.53). After 59 [25-74] months, GERD-HRQL scores were 5 [2-11] and 2 [0-13] (p = 0.61) and PPI cessation was maintained in 69% and 79% of patients (p = 0.59). Satisfaction with surgery was similar between smokers and non-smokers (88% vs. 87%, p = 0.85). Female gender was significantly associated with increased improvements in GERD-HRQL (p < 0.01) and GERSS scores (p = 0.04) postoperatively but not at long-term follow-up. Patients without a hiatal hernia were less likely to achieve long-term PPI cessation compared to those with a hernia (OR 0.23, p < 0.01). After 5 years, smokers demonstrate similar symptom resolution, PPI cessation rates, and satisfaction with surgery as non-smokers. Active smoking does not appear to negatively impact long-term symptomatic outcomes of LARS.


Teaching Histology Using Self-Directed Learning Modules (SDLMs) in a Blended Approach.
New technologies like virtual microscopy have revolutionized histology education. However, first-year students often require additional assistance with virtual slides. Online self-directed learning modules (SDLMs) were developed to provide such support to learners by offering them short instructional videos that are uploaded to YouTube and the instructional website. The purpose of this study was to determine the effectiveness of SDLMs and to sample students' opinions about SDLMs. Over a 3-year time span, SDLMs were used to augment histology lessons, and their effectiveness (on learning outcomes) was measured by using traditional steeple-chase and/or virtual slide assessments. Average percentage scores for both methods of assessment were compared using paired or independent t-tests. Student opinions about SDLMs were collected using an anonymous survey. The survey results were analyzed by average scores and thematic analysis of the narrative responses. Using SDLMs in a blended approach showed significant improvement in students' academic performance - irrespective of the method of assessment. There was a strong positive correlation with the performance when students were assessed using the virtual slide method. However, a standalone approach using SDLMs did not positively impact learning outcomes. Survey results indicated that most students perceived the videos as helpful for understanding the subject better and as quick review opportunities. The results support the use of SDLMs in a blended instructional approach and as an adjunct resource to conventional microscopy. This use of SDLMs was positively received by learners and significantly improved the learning outcome. The online version contains supplementary material available at 10.1007/s40670-022-01669-9.


The effects of noise on histological measures of the cochlear vasculature and red blood cells: a review.
This paper compiles the results from seven experiments which have investigated noise exposure effects on histological measures of the cochlear vasculature and red blood cells. Two of these studies included at least two experimental conditions and all evaluated numerous histological parameters in several cochlear vessels. The combined results suggest that noise has a consistent general effect of reducing apparent cochlear blood flow as indicated by decreased RBC density, increased aggregation of RBCs, increased variability in RBC density, decreased number of RBC columns, increased vessel lumen irregularity and encroachment of perivascular cells upon the lumen wall. When considered at the level of the individual vessels, however, inconsistent results were observed. Fewer effects were noted in experiments which permitted animals to survive after the noise exposure than in those which sacrificed the animals immediately. Impulse noise resulted in more frequent vascular sequelae than did continuous noise. Further, impulse noise more frequently influenced vessels of the external wall than did continuous noise.


Effect of conditioned fear stress on serotonin metabolism in the rat brain.
The effects of electric foot-shock stress (EFS) and conditioned fear stress (CFS) on serotonin [5-hydroxytryptamine (5-HT)] metabolism in seven various brain regions of the rat were studied by measuring tryptophan, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA). EFS for 30 min increased tryptophan levels in almost all brain regions but did not change 5-HT levels in any regions. It increased 5-HIAA levels in the medial prefrontal cortex (mPFC), nucleus accumbens, and amygdala. CFS (exposure to an environment paired previously with foot-shock) increased defecation and induced freezing behavior. It failed to change tryptophan and 5-HT levels in any brain regions but increased 5-HIAA level only in the mPFC. In contrast to EFS, which increased 5-HT metabolism in several other brain regions, increased metabolism of 5-HT was especially marked in the mPFC after CFS, regarded as psychological stress.


The impact of boiling and in vitro human digestion of Solanum nigrum complex (Black nightshade) on phenolic compounds bioactivity and bioaccessibility.
Solanum nigrum complex (Black nightshade) is a wild leafy vegetable with phenolic antioxidant compounds related to the reduction of oxidative stress. Changes in phenolics and bioactivity due to cooking and gastrointestinal digestion of black nightshade were compared to spinach. Predominant compounds of black nightshade were myricetin, quercetin-3-O-robinoside, 3,4-dicaffeoylquinic acid, 3-caffeoylquinic acid, and rutin, which were improved after boiling but reduced after in vitro digestion. Phenolics were reduced after digestion of black nightshade and spinach; however, bioactivity was still retained, especially in preventing oxidative stress in Caco-2 cells. Hence, indicating their potential to reduce oxidative stress related diseases of the digestive tract.


The substrate attached material synthesized by clonal cell lines of nerve, glia, and muscle.
A large number of clonal cell lines were examined for the deposition of proteins (substrate attached material, SAM) on the substratum of culture dishes. Of the many cell types examined, only nerve, muscle, and glia synthesized SAM containing a predominant species of protein with a apparent molecular weight of 55,000. This 55,000 molecular weight protein is distinguishable from actin, tubulin, and collagen.


Detection of follicular transport of lidocaine and metabolism in adipose tissue in pig ear skin by DESI mass spectrometry imaging.
Desorption electrospray ionization (DESI) mass spectrometry imaging is demonstrated as a detection technique for penetration experiments of drugs in skin. Lidocaine ointment was used as the model compound in ex vivo experiments with whole pig ears as the skin model. Follicular transport of lidocaine into the deeper skin layers is demonstrated for the first time. Furthermore, metabolism of lidocaine to 3-OH-lidocaine was observed in subcutaneous tissue as well as in lobules of white adipose tissue surrounding the hair follicles. These results suggest that it is advantageous to use full thickness skin, including subcutaneous tissue, for skin metabolism studies.


Comparison of immunity and resistance to diseases in male and female poultry breeders in Lebanon.
The immune responses following vaccination and resistance to diseases were compared in male and female meat poultry breeders of the same flock. Female poultry breeders maintained antibody titres to Newcastle disease virus and infectious bronchitis virus up to the fifty-fifth day following vaccination, whereas those of the males declined significantly over the same period of time (P < 0.05). In the same flock, outbreaks of Gumboro disease (60 to 62 days of age), coccidiosis (68 to 74 days of age) and aortic rupture (99 to 112 days of age) produced significantly higher losses in males. Following vaccination against fowl pox by the wing web method, 96.7% of females had a vaccine reaction (vaccine take) compared to none of the males. Immune injuries, following vaccination, were observed in 85% of the males compared to none of the females. The immune injuries included appearance of facial papules, vesicles, and reddish brown to black scabs.


Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data.
Predicted loss of function (pLoF) variants are often highly deleterious and play an important role in disease biology, but many pLoF variants may not result in loss of function (LoF). Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines' PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 genes associated with autosomal-recessive disease from the Genome Aggregation Database (gnomAD v.2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in a low proportion expressed across transcripts (pext) scored region, or the presence of cryptic in-frame splice rescues. Variants predicted to evade LoF or to be potential artifacts were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of pLoF variants predicted as likely not LoF/not LoF, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.


Do costochondral grafts have any growth potential in temporomandibular joint surgery? A systematic review.
To assess the growth potential of costochondral graft in temporomandibular joint reconstruction in patients with temporomandibular ankylosis and hemifacial microsomia. Systematic review after inclusion of articles fulfilling the following criteria: (1) only human studies; (2) patients of temporomandibular joint ankylosis and hemifacial microsomia; and (3) studies with minimum of five cases and with a minimum follow-up for a period of 5 years. The primary outcome measure was the percentage of patients with optimum growth of costochondral graft. Secondary outcomes were any abnormal growth and restoration of function. Delphi's criteria were used for assessing the quality of the included studies. Only three studies satisfied all the inclusion criteria. A total of 96 costochondral grafts were placed in the included studies. Optimum growth was reported in 54 grafts, undergrowth in 1 graft, overgrowth in 7 grafts, lateral overgrowth in 1 graft and no growth in 1 graft. Graft resorption, reankylosis and sequestration were seen in 21, 8 and 3 cases, respectively. When the Delphi's criteria were applied to the case series for the assessment of quality, majority of the studies could be considered as satisfying at least 50% of the criteria. There are no randomised clinical trials and the only evidence is in the form of case series that is considered as the lowest level of evidence for any study. No inference can be interpreted regarding growth potential of costochondral graft. Thus, on the basis of available evidence, it can be concluded that use of costochondral graft for temporomandibular joint reconstruction lacks scientific evidence.


Distinct Mechanisms for Increased Cardiac Contraction Through Selective Alteration of Either Myosin or Troponin Activity.
Modulation of sarcomere contractility represents a new therapeutic opportunity for the treatment of heart failure by directly targeting the thick and thin filament proteins of the sarcomere to increase cardiac muscle contraction. This study compared the effect of 2 small molecules (M and T) that selectively alter myosin thick filament (M) or troponin thin filament (T) activity on overall cardiac muscle mechanics. This study revealed key differences related to the mechanism utilized by M and T to increase contractile force generation and suggests that targeting different proteins within the sarcomere may result in differentiating therapeutic profiles.


Rigid dinuclear ruthenium-arene complexes showing strong DNA interactions.
Six novel dinuclear Ru(II)-arene complexes [Ru2(η6-p-cymene)2(1,3-bib)2Cl2]×2·Solvent (X = Cl- (1), I- (2), NO3- (3), BF4- (4), PF6- (5), CF3SO3- (6); 1,3-bib = 1,3-di(1H-imidazol-1-yl) benzene) were synthesized and fully characterized by FT-IR, 1H NMR, ESI-MS, Elemental Analysis (EA) and Powder X-ray Diffraction (PXRD). Single crystal X-ray diffractions studies showed that 3 and 4 have rigid bowl-like structures, where one counter-anion (NO3- for 3 and BF4- for 4) was trapped inside the cavity to balance the charge, respectively. Even complexes 1-6 showed only moderate or little anti-proliferative activity toward cancer cells, strong interactions with DNA molecules through intercalation, however, were confirmed by UV-Vis, CD and fluorescence spectroscopy. Apoptosis and cell cycle arrest studies for complex 2 with cancer A549 cells indicated concentration-dependent late apoptosis and the G1/G0 phase arrest. Interactions with the tripeptide glutathione (γ-L-Glu-L-Cys-Gly, GSH) might explain the relatively low antiproliferative potency of these complexes. This class of rigid dinuclear cations hold potential as DNA-targeting anticancer agents if their uptake and delivery could be under controlled.