Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals.
Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators.


Study of CC chemokine receptor 5 in renal allograft rejection.
Allospecific recruitment of T cells is primary to the pathogenesis of renal transplant rejection. Chemokines and their receptors inducing a Th1 cytokine response play a central role in this recruitment. Renal allograft biopsies of 28 patients with acute cellular rejection and 10 protocol biopsies (controls) were examined in accordance with Banff grading 2007 schema. Immunohistochemistry for CD3 and CC chemokine receptor 5 (CCR5) in sequential sections was performed and quantitatively assessed in the glomeruli, tubules, and interstitium. Histopathologic and clinical correlations were carried out. CD3- and CCR5-positive cells were observed in significantly higher numbers in rejection cases than in controls (P = 0.010). A larger proportion of CCR5-positive cells were noted in the foci of tubulitis compared to the interstitial infiltrates and glomeruli in all cases, and it correlated with the grade of cellular rejection (P = 0.010). A greater number of CCR5-positive cells were seen in early rejection (<6 months posttransplant) compared to late rejection. No clinical correlation with serum creatinine levels was found. CCR5-positive cells represent the alloaggressive subset of T cells in ACR, and their numbers correlate with rejection severity. CCR5 may be used as a marker of early acute rejection and may be an important target for future antirejection therapies.


Multilevel interactions between ethylene and auxin in Arabidopsis roots.
Hormones play a central role in the coordination of internal developmental processes with environmental signals. Herein, a combination of physiological, genetic, cellular, and whole-genome expression profiling approaches has been employed to investigate the mechanisms of interaction between two key plant hormones: ethylene and auxin. Quantification of the morphological effects of ethylene and auxin in a variety of mutant backgrounds indicates that auxin biosynthesis, transport, signaling, and response are required for the ethylene-induced growth inhibition in roots but not in hypocotyls of dark-grown seedlings. Analysis of the activation of early auxin and ethylene responses at the cellular level, as well as of global changes in gene expression in the wild type versus auxin and ethylene mutants, suggests a simple mechanistic model for the interaction between these two hormones in roots, according to which ethylene and auxin can reciprocally regulate each other's biosyntheses, influence each other's response pathways, and/or act independently on the same target genes. This model not only implies existence of several levels of interaction but also provides a likely explanation for the strong ethylene response defects observed in auxin mutants.


Effects of presurgical orthopedic treatment in infants with complete bilateral cleft lip and palate.
To align the protruding premaxilla in infants with bilateral cleft lip and palate (BCLP), an intraoral appliance (i.e., Hotz plate) and an extraoral appliance consisting of a band covering the head and elastics are used as a presurgical orthopedic treatment in our clinic. The aim of this study was to analyze the configuration and position of the premaxilla and the vomer in infants with BCLP and to investigate the factors generating deviation and bending of the vomer and twisting of the premaxilla. Palatal casts were obtained serially from 10 infants with complete BCLP from 1 to 3 months of age. These casts were automatically measured using a highly accurate contact-type measuring apparatus. After three-dimensional wire frame models generated from the serial casts were automatically superimposed, the magnitude and direction of the shift were calculated. A discriminant analysis was used for investigation of predictor variables generating the twisting or bending vomer. The vomer was found to be bent in two infants and the premaxilla was twisted in three infants. In the infants whose vomers were bent, the magnitude of the posterior shift of the premaxilla was greater than that of the inferior shift. A discriminant analysis indicated that at 1 month of age, a greater inclination and a smaller deviation of the vomer and a longer distance between the cleft edges of the lateral segments had a tendency to be associated with bending of the vomer or twisting of the premaxilla.


Improving diabetic retinopathy screening ratios using telemedicine-based digital retinal imaging technology: the Vine Hill study.
To evaluate the impact of a telemedicine, digital retinal imaging strategy on diabetic retinopathy screening rates in an inner-city primary care clinic. This retrospective cohort study included all diabetic patients aged > or = 18 years (n = 495) seen at Vine Hill Community Clinic between 1 September 2003 and 31 August 2004. Patients were offered ophthalmology referral or digital screening. Patients choosing referral received the next available (within 3 months) appointment at the Vanderbilt Eye Clinic; patients choosing digital screening were screened during the visit. Retinal screening was documented for 293 (59.2%) patients, a significant improvement compared with the 23% baseline rate. Of 293 patients screened, 92 (31.4%) were screened in ophthalmology, and 201 (68.6%) were digitally screened. Among the 201 digitally screened patients, 104 (51.7%) screened negative and were advised to rescreen in 1 year, 75 (37.3%) screened positive and were nonurgently referred to ophthalmology, and 22 (11.0%) screened positive for sight-threatening eye disease and were urgently referred for ophthalmological follow-up. Digital imaging technical failure rate was 0.5%. Referral status was associated with race/ethnicity (chi2 = 7.9, P < 0.02) with whites more likely to screen negative than non-whites (62.4 vs. 47.8%, respectively). Sight-threatening disease among non-whites (14.7%) was more than double that observed for whites (5.9%). Digital imaging technology in the primary care visit can significantly improve screening rates over conventional methods, increase access to recommended diabetic eye care, and focus specialty care on medically indigent patients with greatest need.


Non-canonical Bases in the Genome: The Regulatory Information Layer in DNA.
Multicellular organisms developed the concept of specialized cells that perform specific functions. Examples are neurons and fibroblast to name just two out of more than 200. These cellular differences are established based on the same sequence information stored in the cell nucleus of all cells of an organism. The sequence information needs consequently different interpretations by the different cell types. During cellular development this interpretation of the genetic code has to be tightly regulated in space and time. Interpretation of the sequence information involves the controlled activation and silencing of specific genes so that certain proteins are made in one cell type but not in others. This involves an additional regulatory information layer beyond the pure base sequence. One aspect of this regulatory information layer relies on functional groups that are attached to the C(5) position of the canonical base dC. Currently four regulatory, non-canonical bases with a methyl (CH3 )-, a hydroxymethyl (CH2 OH)-, a formyl (CHO)- and a carboxyl (COOH)- group are known. While 5-methyl-cytidine is long recognised to be a regulatory base in the genome, the other three bases and the enzymes responsible for generating them, were just recently discovered.


[Genetic analysis of wild measles virus strains isolated in the european part of the Russian Federation].
Eleven wild measles virus isolated, in 1988 and in 1999-2001 in the European territory of the Russian Federation, were investigated. On the basis of an analysis of N-gene region sequences, encoding the COOH terminal end of nucleoprotein, the isolates were divided into 2 subgroups. According to the WHO classification, subgroup 1 was in line with genotype A and subgroup 2--with genotype D. Subgroup 2 was close to genotype D4 but differed from it according to its composition of nucleotides on the average by 2.8%, and according to its amino-acid composition--by 2.6%. with respect to the WHO criteria, the latter can be referred to preliminarily as an independent genotype. Finally, the measles viruses' strains of genetic groups A and D circulated in the Russian Federation in 1988, and in 1999-2001.


Proliferation and cell shape changes during ciliary body morphogenesis in the mouse.
Very little is known about the structure and development of the ciliary processes in the mouse eye. Our scanning electron microscope (SEM) studies reveal that, unlike other mammals, the ciliary processes form an irregular pattern, crossing over and interweaving rather than lying parallel to one another. Histological and SEM studies from embryonic day (E) 14.5 to postnatal day (P) 7 reveal that the first morphological sign of the ciliary zone is an annular bulge; this is then gradually molded to form discrete ciliary processes. The striking similarity between the developing capillary network and the adult ciliary folds suggests that the patterning template for the ciliary processes could be the underlying capillary network. Cell proliferation measurements and cell height assessments indicated that one of the first events occurring during the morphogenesis of ciliary processes is a proliferative surge around P0 in the outer ciliary epithelium. It is likely that this surge together with increasing cell heights leads to a bulging of this layer. After a slight delay, the inner ciliary epithelium responds by proliferating and extending inward toward the lens. Final shaping of the ciliary processes is achieved through cell height reductions in the inner ciliary epithelium. Thus, in the mouse, the temporal correlation between mitotic and cell height changes during ciliary body morphogenesis suggests that these processes play an integral role in the shaping of ciliary processes.


[Influence of psychosocial therapy on funcioning of adolescents with schizophrenia spectrum disorders (a pilot study)].
Authors studied the influence of psychosocial group therapy (PST) in adolescents with schizophrenia spectrum disorders on the dynamics of their social functioning based on the PedsQL questionnaire and the CGAS children general functioning assessment scale. There was a statistically significant improvement of basic indicators of adolescent social functioning in the main group after the PST cycle (3 months), while no proven between main and comparison groups difference was detected in the therapeutic dynamics, according to the PANSS scale, that confirmed the effectiveness of PST inclusion into psychosocial therapy and rehabilitation of adolescents with schizophrenia spectrum disorders. Three groups of adolescents were defined within the main group; trends towards changes in social functioning, depending on the type of disease course, were noted.


Understanding Government Decisions to De-fund Medical Services Analyzing the Impact of Problem Frames on Resource Allocation Policies.
Many medical services lack robust evidence of effectiveness and may therefore be considered "unnecessary" care. Proactively withdrawing resources from, or de-funding, such services and redirecting the savings to services that have proven effectiveness would enhance overall health system performance. Despite this, governments have been reluctant to discontinue funding of services once funding is in place. The focus of this study is to understand how the framing of an issue or problem influences government decision-making related to de-funding of medical services. To achieve this, a framework describing how problem frames, or explanatory naratives, influence government policy decisions was developed and applied to actual cases. The two cases selected were the Ontario government's decisions to de-fund the drug Oxycontin and blood glucose test strips used by patients with diabetes. A qualitative content analysis of public discourse (political debate and media coverage) surrounding these two resource withdrawal examples was conducted and described using the framework. In the framework, government decision-making is a partial reflection of the visibility of the policy issue and complexity of the causal story told within a problem frame. By applying this framework and considering these two key characteristics of problem frames, we can better understand, and possibly predict, the shape and timing of government policy decisions to withdraw resources from medical services.


SARS-CoV-2 and COVID-19: How much do we know?
The recent outbreak of coronavirus disease (COVID-19) globally threatens the public health. COVID-19 is a pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as the 2019 novel coronavirus (2019-nCoV). Typical symptoms of COVID-19 include fever, cough and fatigue. As a novel disease, there are still many unsolved questions regarding COVID-19. Nevertheless, genetic analysis has demonstrated that the virus is strongly associated with certain SARS-like coronavirus originated from bats. The COVID-19 outbreak started in a seafood wholesale market in Wuhan, China, but the exact origin of the virus is still highly debatable. Since there is currently no registered antiviral drug for the disease, symptomatic treatments have been applied routinely to manage COVID-19 cases. However, various drugs and vaccines have been currently under research. This review aims to consolidate and discuss the likely origins and genetic features of SARS-CoV-2 as well as the recent clinical findings and potential effective treatments of COVID-19. Keywords: COVID-19; SARS-CoV-2; 2019-nCoV; SARS; coronavirus.


Fully active QAE isoform confers thermal hysteresis activity on a defective SP isoform of type III antifreeze protein.
Type III antifreeze protein is naturally expressed as a mixture of sulfopropyl-Sephadex (SP) and quaternary aminoethyl-Sephadex (QAE)-binding isoforms, whose sequence identity is approximately 55%. We studied the ice-binding properties of a SP isoform (nfeAFP6) and the differences from those of a QAE isoform (nfeAFP8); both of these isoforms have been identified from the Japanese fish Zoarces elongatus Kner. The two isoforms possessed ice-shaping ability, such as the creation of an ice bipyramid, but nfeAFP6 was unable to halt crystal growth and exhibited no thermal hysteresis activity. For example, the ice growth rate for nfeAFP6 was 1000-fold higher than that for nfeAFP8 when measured for 0.1 mm protein solution at 0.25 degrees C below the melting point. Nevertheless, nfeAFP6 exhibited full thermal hysteresis activity in the presence of only 1% nfeAFP8 (i.e. [nfeAFP8]/[nfeAFP6] = 0.01), the effectiveness of which was indistinguishable from that of nfeAFP8 alone. We also observed a burst of ice crystal growth from the tip of the ice bipyramid for both isoforms on lowering the temperature. These results suggest that the ice growth inhibitory activity of an antifreeze protein isoform lacking the active component is restored by the addition of a minute amount of the active isoform.


[Automatic selection of optimal cardiac-phase in coronary CT angiography--its clinical usefulness for patients with atrial fibrillation].
The optimal cardiac phases for coronary CT angiography (CTA) are end-systole and mid-diastole, in which cardiac movement is slow. In conventional methods, these cardiac phases are determined by visual selection. We have compared the images in the optimal cardiac phases that were selected by the conventional method and cardiac-phase search software (Phase Navi), and examined the clinical usefulness of Phase Navi in patients with atrial fibrillation. The subjects were 38 patients (regular rhythm: 20, atrial fibrillation: 18). The continuity scores of patients with regular rhythm (Phase Navi, conventional methods) were 2.4+/-0.3-2.5+/-0.3 in end-systole and 2.4+/-0.5-2.4+/-0.4 in mid-diastole. The scores of patients with atrial fibrillation (Phase Navi, conventional methods) were 2.3+/-0.4-2.3+/-0.4 in end-systole, and 2.2+/-0.5-2.1+/-0.6 in mid-diastole. Because the continuity scores of the optimal images from Phase Navi were similar to those from the conventional method, Phase Navi had clinical usefulness in patients with atrial fibrillation.


Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism.
To investigate striatal and cortical pre- and postsynaptic dopaminergic function in parkin-linked parkinsonism, 13 unrelated patients homozygous or compound heterozygous for parkin mutations were studied with [(18)F]dopa and [(11)C]raclopride (RAC) PET. Data were compared with a young-onset Parkinson's disease (YOPD) cohort, matched for age, disease severity and duration, but negative for parkin mutations. Significant changes in [(18)F]dopa uptake and RAC binding potential (BP) were localized in striatum using regions of interest (ROIs) and throughout the entire brain volume with statistical parametric mapping (SPM). As expected, both YOPD and parkin patients showed significant decreases in striatal [(18)F]dopa uptake; however, in parkin patients, additional reductions in caudate and midbrain were localized with SPM. The RAC-BP was significantly decreased in striatal, thalamic and cortical areas (temporal, orbito-frontal and parietal cortex) in parkin compared with YOPD patients. Our [(18)F]dopa PET findings suggest that, compared with YOPD, parkin disease is associated with more severe and widespread presynaptic dopaminergic deficits. The global decreases in D2 binding found in parkin compared with YOPD patients could be a direct consequence of the parkin genetic defect itself or a greater susceptibility to receptor downregulation following long-term dopaminergic agent exposure. Cortical reductions in D2 binding may contribute to the behavioural problems reported in parkin patients.


Proximal inferior vena cava obstruction without portal hypertension.
A case of symptomatic proximal inferior vena cava obstruction was corrected successfully by surgery. Though the nature of the obstruction was not definitively verfied, it probably resulted from persistence of the inferior vena cava valve, or possibly from congenital proximal membrane obstruction. The case illustrates that promimal obstruction of the inferior vena cava may be a surgically correctable lesion but may be overlooked because signs of portal hypertension may be absent and because the usual tests to evaluate edema in the lower extremities may not detect such lesions.


Role of Rho kinase in sphingosine 1-phosphate-mediated endothelial and smooth muscle cell migration and differentiation.
The role of sphingosine 1-phosphate (S1P)-induced Rho kinase (ROCK) activation in the angiogenic responses of pulmonary artery-derived endothelial cells (PAEC) and smooth muscle cells (PASMC) was examined. S1P, a biologically active phospholipid that regulates angiogenesis, promoted PAEC chemotaxis and capillary morphogenesis; furthermore, this activity was unaltered by pretreatment with the pharmacological inhibitor of ROCK, H1152. In contrast, S1P (500 nM) significantly inhibited spontaneous PASMC chemotaxis and differentiation; however, this inhibition was eradicated upon H1152 pretreatment. Similarly, PASMCs transfected with ROCK II siRNA diminished S1P-induced inhibition of the development of multi-cellular structures. Analysis by RT-PCR identified the presence of S1P(1) and S1P(3) receptors on both PAECs and PASMCs, while S1P(2) receptor expression was confined to only PASMCs. Consistent with this observation, the S1P(1) and S1P(3) receptor antagonist, VPC23019, virtually abolished the S1P-initiated PAEC differentiation but did not impede the S1P-induced inhibition of PASMC differentiation. However, the S1P(2) receptor antagonist, JTE013, had no effect on S1P-mediated differentiation of PAECs but abolished the S1P-induced inhibition of PASMC function. Co-cultured endothelial and smooth muscle cells differentiated into "neovascular-like" networks, which were significantly inhibited by S1P. The inhibition of co-culture differentiation in both PAECs and PASMCs was negated by H1152 pretreatment. However, when smooth muscle cells were added to S1P-initiated endothelial cell networks, additional S1P treatment did not inhibit the cellular networks generated by these cells. In conclusion, S1P-induced PAEC angiogenic responses are regulated by S1P(1) and/or S1P(3) receptors independent of Rho kinase activation, whereas S1P(2) receptor-mediated curtailment of PASMC function by S1P.


Neoplastic angioendotheliomatosis in a dog: an angiotropic lymphoma.
Neoplastic angioendotheliomatosis was diagnosed in a nine-year-old, intact male German Shorthaired Pointer exhibiting progressive neurological signs over a six-month period. At necropsy, there was multifocal asymmetric, hemorrhagic necrosis within the cerebral hemispheres, centrum semiovale, caudate nucleus, and internal capsule. Histologically, there was extensive intravascular proliferation of pleomorphic mononuclear cells within the brain and multiple parenchymatous organs. Transmission electron microscopy demonstrated the absence of intercellular junctions between neoplastic cells. These cells were not attached to the vascular lining endothelium; Weibel-Palade bodies and a basement membrane were lacking. By indirect immunofluorescence, positive cytoplasmic staining of intravascular neoplastic cells for IgG was demonstrated. Peroxidase-antiperoxidase technique for Factor VIII related antigen was negative. As in man, this rare neoplastic disorder appears to be a lymphoma, apparently of the B cell line.


The potential role of Protein disulfide isomerases (PDIs) during parasitic infections: A focus on Leishmania spp.
Leishmaniasis is a group of vector-borne diseases caused by intracellular protozoan parasites belonging to the genus Leishmania. Leishmania parasites can employ different and numerous sophisticated strategies including modulating host proteins, cell signaling, and cell responses by parasite proteins to change the infected host conditions to favor the parasite persistence and induce pathogenesis. In this sense, Protein Disulfide Isomerases (PDIs) have been described as crucial proteins that can be modulated during leishmaniasis and affect the pathogenesis process. The effect of modulated PDIs can be investigated in both aspects, parasite-PDIs, and infected host cells-PDIs, during infection. The information concerning PDIs is not sufficient in parasitology; however, this study aimed to provide data regarding the biological functions of such crucial proteins in parasites with a focus on Leishmania spp. and their relevant effects on the pathogenesis process. Although there are no clinical trial vaccines and therapeutic approaches, highlighting this information might be fruitful for the development of novel strategies based on PDIs for the management of parasitic diseases, especially leishmaniasis.


Task-switching inefficiencies in currently ill, but not remitted anorexia nervosa.
Models of anorexia nervosa (AN) posit that set-shifting deficits may contribute to behavioral inflexibility and extreme dietary restriction. Findings from neurocognitive studies of set-shifting in AN have been somewhat mixed, perhaps due to the use of tasks that cannot distinguish shifting from other processes (i.e., learning). To more precisely characterize cognitive flexibility and selectively assess this process independent of rule learning and feedback sensitivity, we examined task-switching ability in AN. Women ill with AN, subthreshold AN or atypical AN (IAN; n = 40), women remitted from AN (RAN; n = 24), and age-matched healthy control women (n = 42) completed a computerized cued color-shape task-switching paradigm. Groups were compared on mix costs (reflecting global cognitive control) and switch costs (reflecting transient cognitive control). Although mix costs were equivalent across groups, switch costs were more pronounced in the IAN group, as indicated by a group-by-trial type interaction for reaction times on stay and switch trials. Findings indicate that IAN, but not RAN, have difficulty flexibly switching between cognitive task sets, and suggest that prior findings of set-shifting deficits in AN may reflect difficulty with cognitive flexibility independent of learning deficits. As such, task-switching may represent a promising adjunctive treatment target.


All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer.
Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.


Amyloid detection and typing yield of skin biopsy in systemic amyloidosis and polyneuropathy.
Disease-modifying therapies are available for amyloidosis but are ineffective if end-organ damage is severe. As small fiber neuropathy is an early and common feature of amyloidosis, we assessed detection and typing yield of skin biopsy for amyloid in patients with confirmed systemic amyloidosis and neuropathic symptoms. In this case-control study, patients with transthyretin and light chain amyloidosis (ATTRv, ATTRwt, and AL) were consecutively recruited. They were sex and age-matched to three control groups (1) non-neuropathic controls (NNC), (2) monoclonal gammopathy of undetermined significance (MGUS), and (3) other neuropathic disease controls (ONC). Patients underwent a double 3 mm skin biopsy in proximal and distal leg. Amyloid index and burden, protein typing by immuno-electron microscopy, intraepidermal nerve fiber density, electroneuromyography, and clinical characteristics were analyzed. We studied 15 subjects with confirmed systemic amyloidosis, 20 NNC, 18 MGUS, and 20 ONC. Amyloid was detected in 100% of patients with amyloidosis (87% in ankle and 73% in thigh). It was not detected in any of the control groups. A small fiber neuropathy was encountered in 100% of amyloidosis patients, in 80% of MGUS, and in 78% of ONC. Amyloid burden was higher in ATTRv, followed by AL and ATTRwt. The ultrastructural examination allowed the identification of the precursor protein by immunotyping in most of the cases. Skin biopsy is a minimally invasive test with optimal sensitivity for amyloid. It allows amyloid typing by electron microscope to identify the precursor protein. The diagnostic work up of systemic amyloidosis should include a skin biopsy.


Further guidance for broadband antireflection coating design.
Recent investigations have added to and refined the understanding of the behavior of broadband antireflection coating designs and provided further guidance for achieving more nearly optimal designs. The ability to optimize designs wherein the overall optical thickness of the design is constrained to a specific value has allowed this investigation. A broader bandwidth than previously reported has been studied and statistically fit more precisely by a polynomial equation, and also two linear equations for routine approximations have been derived. It has also been found that the optimal number of layers in the design can be predicted as a function of the bandwidth.


When tumor suppressor TGFβ meets the HER2 (ERBB2) oncogene.
Despite its tumor suppressive role in normal mammary epithelial cells, TGFβ has been reported to promote the migration, invasion and survival in breast cancer cells overexpressing the HER2 (ERBB2; neu) oncogene, and to accelerate the metastasis of neu-induced mammary tumors in mice. A clearer understanding of the molecular mechanisms underlying the crosstalk between TGFβ and HER2 has started to emerge. In recent studies reviewed here, the synergistic effect of TGFβ and HER2 on tumor progression has been shown to likely be a combined result of two distinct features: (1) loss of TGFβ's tumor suppressive effect through functional alterations in the anti-mitogenic effect of Smad-mediated transcription, and (2) gain of pro-survival and pro-migratory function through HER2-dependent mechanisms. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. Thus, the transformed cellular context imparted by constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, aborts the tumor suppressive role of TGFβ and facilitated the oncogenic role of this pathway. In turn, TGFβ potentiates oncogenic HER2 signaling by inducing shedding of the ERBB ligands and clustering of HER2 with integrins. Here we discuss recent studies examining Smad-dependent and -independent mechanisms of crosstalk between TGFβ and HER2. Therefore, blockade of TGFβ:HER2 crosstalk may suppress breast cancer progression and metastasis, and enhance the efficiency of conventional therapies in patients with HER2-overexpressing breast cancer.


["Open field" rat behavior following exposure to a magnetic field].
The influence of the magnetic field on a complex physiological reaction in the "open field" test was studied in experiments on 160 rats. The behaviour in the "open field" was observed within three consecutive days simultaneously of control rats and those subjected directly before each test to a three to four hour general effect of a weakly pulsing magnetic field with a 0.3 T induction or a strictly constant magnetic field of 1.6 T. Individual behavioural reactions to the MF action were characterized by great variability and could be of different direction. According to mean data, the 0.3 T MF action depressed motor and investigating behaviour of the rats in the "open field". An increase of magnetic induction up to 1.6 T, far from enhancing the inhibitory effect, showed a tendency towards activation of behaviour in the "open field". Apparently, in conditions of the intensities used, pulsation is a biologically more significant characteristics of the magnetic field than the magnitude of induction.


Transient sick sinus syndrome with complete atrioventricular block associated with ergonovine intake: A case report.
More mature or older women are more likely to undergo in vitro fertilization and embryo implant. These women have a greater chance of receiving ergonovine therapy because of a suspected abortion. We present this case report to call attention to a latent lethal adverse effect in everyday obstetric practice using ergonovine. It requires more attention and close monitoring PATIENT CONCERNS:: We presented the case of a 38-year-old female patient with general weakness and mild chest tightness after ergonovine use. She was diagnosed as transient sick sinus syndrome and complete atrioventricular block with junctional escape rhythm after diagnostic work up. Conservative treatment with discontinuation of ergonovine and bed rest. Her sinus rhythm returned to normal the day after ergonovine was discontinued. The patient remained symptom-free since recovery of her sinus rhythm. Ergonovine may cause symptomatic and lethal bradyarrhythmia. Withdrawal of the causative medication and adequate supportive care can lead to a favorable outcome in these patients. More related cases should be reported. Further evaluation for treatment and prognosis are necessary.


Evaluation of a single plate microbiological growth inhibition assay as a screening test for the presence of antimicrobial agents in compound animal feedingstuffs at therapeutic and contaminating concentrations.
The Inhibitory Substance Test (IST), a microbiological growth inhibition test, is used for screening animal feedingstuffs for the presence of (contaminating) antimicrobial compounds. The effectiveness of the IST was established for 33 compounds that may be incorporated in feedingstuffs. Minimum detectable concentrations (MDCs) for standard solutions were established and compared with those obtained following solvent extraction of an antimicrobial-free compound feedingstuff spiked with each compound at 0-20 mg/kg. Of the 33 standard solutions examined, the test organism was not sensitive to 11 and the MDC for one was greater than its maximum inclusion rate in complete feedingstuffs. Following routine extraction (25% acetone-phosphate buffer) of feedingstuffs spiked with each of the 22 compounds to which the organism was sensitive, 10 were not detected, 15 were detectable at both minimum and maximum feed-inclusion rates and four were only detectable at their maximum feed-inclusion rates. Extraction with methanol (25%) had a deleterious effect with 12 compounds not detected, nine detectable at both minimum and maximum feed-inclusion rates and five detectable at their maximum feed-inclusion rates. Increasing acetone and methanol concentrations to 40 and 55% respectively resulted in larger inhibitory zones for antibiotic-free feedingstuff (25.3 + 2.43 mm vs 21.1 + 1.02 mm) compared with both 25% acetone (11.3 + 0.22 mm) and 25% methanol (11.2 + 0.22 mm), requiring the establishment of greater threshold zone diameters and negating any advantage in increasing the solvent concentration under these test conditions. It is concluded that the IST may be particularly useful for detection of a number of the zootechnical feed-additives recently banned in the EU, which, if used illegally, may be present at sufficiently high inclusion rates to facilitate detection. Further alteration of extraction conditions may improve the scope of the assay.


Genome-Wide Analysis of the Universal Stress Protein Gene Family in Blueberry and Their Transcriptional Responses to UV-B Irradiation and Abscisic Acid.
Universal stress proteins (USPs) play essential roles in plant development, hormonal regulation, and abiotic stress responses. However, the characteristics and functional divergence of USP family members have not been studied in blueberry (Vaccinium corymbosum). In this study, we identified 72 VcUSP genes from the Genome Database for Vaccinium. These VcUSPs could be divided into five groups based on their phylogenetic relationships. VcUSPs from groups Ⅰ, Ⅳ, and Ⅴ each possess one UspA domain; group Ⅰ proteins also contain an ATP-binding site that is not present in group Ⅳ and Ⅴ proteins. Groups Ⅱ and Ⅲ include more complex proteins possessing one to three UspA domains and UspE or UspF domains. Prediction of cis-regulatory elements in the upstream sequences of VcUSP genes indicated that their protein products are likely involved in phytohormone signaling pathways and abiotic stress responses. Analysis of RNA deep sequencing data showed that 21 and 7 VcUSP genes were differentially expressed in response to UV-B radiation and exogenous abscisic acid (ABA) treatments, respectively. VcUSP41 and VcUSP68 expressions responded to both treatments, and their encoded proteins may integrate the UV-B and ABA signaling pathways. Weighted gene co-expression network analysis revealed that VcUSP22, VcUSP26, VcUSP67, VcUSP68, and VcUSP41 were co-expressed with many transcription factor genes, most of which encode members of the MYB, WRKY, zinc finger, bHLH, and AP2 families, and may be involved in plant hormone signal transduction, circadian rhythms, the MAPK signaling pathway, and UV-B-induced flavonoid biosynthesis under UV-B and exogenous ABA treatments. Our study provides a useful reference for the further functional analysis of VcUSP genes and blueberry molecular breeding.


Exercise blod flow and microvascualr distensibility in skeletal muscle normalize after heart transplantation.
This study investigated the effect of heart transplantation (HTX) on reduced exercise blood flow and microvascular stiffness in patients with congestive heart failure (CHF). Skeletal muscle blood flow (SMBF) during graded maximal supine bicycle exercise and microvascular distensibility (i.e., stiffness) were measured in musculus tibialis anterior by the isotope washout method. Measurements were performed in a cross-sectional study with 31 CHF patients and 28 patients, mean 9 months after HTX, and in a longitudinal study in 12 CHF patients before, 3 months, and 14 months after HTX, and in 31 healthy controls. Maximal SMBF: In the cross-sectional study, maximal SMBF was reduced in severe CHF patients (3.6 +/- 2.5 mL (100 g min)(-1)) and increased after HTX (7.7 +/- 4.8; p < 0.01 versus controls (11 +/- 4.1). Maximal SMBF was reduced in CHF patients (5.8 +/- 4.0) and reversed to normalization 3 months after HTX (10.3 +/- 4.4) in the longitudinal study. Microvascular distensibility: The distensibility was reduced (severe CHF, 12 +/- 8%; moderate CHF, 23 +/- 14%) in the cross-sectional study and increased after HTX towards normalization (38 +/-20%; controls: 44 +/- 17). In the longitudinal study, distensibility in CHF patients (14 +/- 6%) increased gradually to 32 +/- 12% (p < 0.005) at 3 months and normalized 14 months after HTX (46 +/- 17%). HTX gradually reversed the reduced SMBF and microvascular distensibility in CHF patients towards normalization.


[Clinical, metabolic, age-related, and biorhythmologic aspects of daily arterial pressure profiles in patients with arterial hypertension].
The work was designed to study daily arterial pressure (AP) profile in 103 patients aged 20-70 (48.6 +/- 12.) years with grade I-II arterial hypertension and its relation to selected metabolic parameters, heliogeophysical factors and age. The patients underwent 24-hr AP monitoring, calculation of body mass index, measurement of blood glucose and cholesterol levels. Non-dippers showed higher mean nocturnal AP values than dippers probably due to higher BMI, glucose and cholesterol levels. These patients were more sensitive to heliophysical factors. Patients above 60 years displayed higher AP values in morning hours compared with 21-40 year-old ones. These data can be used in the development of primary and secondary prophylaxis of arterial hypertension.


[Size of the patient list and quality of the general practice].
A list patient system will be introduced in Norway from 2001. In England and Holland, countries with long experience with this system, the average consultation is much shorter than in the present Norwegian system. Research reports indicate a significant association between longer consultations and patient satisfaction with service as well as quality. The challenge in these countries has been to find mechanisms that reduce list size in order to enhance the quality of care. On the basis of the author's own data and a summary of relevant literature, a model for estimating average list size in Norway is developed. The model shows the impact of various time-consuming factors in general practice on the workload associated with a patient list. The article describes some objective criteria for calculating a list size which corresponds to a full normal medical man-year, with due consideration for quality of care.


Synthesis of reassortant infectious bursal disease virus in chickens injected directly with infectious clones from different virus strains.
The infectious bursal disease virus (IBDV), a member of the Birnaviridae family, containing a bisegmented double-stranded RNA genome, encodes four structural viral proteins, VP1, VP2, VP3, and VP4, as well as a non-structural protein, VP5. In the present paper, the segment A from two IBDV strains, field isolate ZJ2000 and attenuated strain HZ2, were inserted into one NaeI site by site-directed silent mutagenesis and subcloned into the eukaryotic expression plasmid pCI under the control of the human cytomegalovirus (hCMV) immediate early enhancer and promoter to construct the recombinant plasmids pCI-AKZJ2000 and pCI-AKHZ2, respectively. Each of the two recombinants was combined with another recombinant pCI plasmid containing the marked segment B of strain HZ2 (pCI-mB), and injected intramuscularly into non-immunized chickens. Two chimeric IBDV strains were recovered from the chickens. Two out of eight chickens in each of two groups showed the bursal histopathological change. The reassortant virus derived from pCI-AKZJ2000/pCI-mB can infect chicken embryos and shows relatively low virulence. We have developed a novel virus reverse genetic approach for the study of IBDV. The results also form the basis for investigating the role of VP1 in viral replication and pathogenecity.


Formation of biopolymer-coated liposomes by electrostatic deposition of chitosan.
The purpose of this study was to prepare stable biopolymer-coated liposome suspensions using an electrostatic deposition method. Liposome suspensions were produced by homogenizing 1% soy lecithin in acetate buffer (0.1 M, pH 3). Cationic chitosan (Mw approximately 200 kDa) solutions were mixed with anionic liposome suspensions (d approximately 100 and 200 nm), and the effect of phospholipid concentration, chitosan concentration, and liposome size on the properties of the particles formed was determined. The particle size and charge (zeta-potential) were measured using dynamic light scattering and particle electrophoresis. The particle charge changed from -38 mV in the absence of chitosan to +60 mV in the presence of chitosan, indicating complex formation between the anionic liposomes and cationic chitosan molecules. Below a minimum critical chitosan concentration (c(min)), large aggregates were formed that phase separated within minutes, whose origin was attributed to formation of coacervates. On the other hand, above a maximum critical chitosan concentration (c(max)), large flocs were formed that sedimented within hours, whose formation was attributed to depletion flocculation. Minimum and maximum critical chitosan concentrations depended on liposomal concentration and size. At c(min) < c < c(max'), chitosan-coated liposomes were formed that did not aggregate and were stable to sedimentation. Coated liposomes had better stability to aggregation than uncoated liposomes when stored at ambient temperatures for 45 d. This study indicates that chitosan can be used to form biopolymer-coated liposomes with enhanced stability over uncoated liposomes.


The importance of transformational leadership style for the well-being of employees working with older people.
This paper is a report of a study to explore the relationships between transformational leadership, followers' perceived working conditions and employee well-being and job satisfaction. There is some evidence that transformational leadership style is linked to employee job satisfaction and well-being. However, it is not clear whether this is due to (i) a direct relationship between leadership and job satisfaction and well-being outcomes or (ii) whether followers' perceived working conditions mediate this relationship. A cross-sectional design was applied to data from a questionnaire study of 447 staff caring for older people in Denmark. Data were collected in 2005. A theory-driven model of the relationships between leadership, working conditions, job satisfaction and well-being was tested using structural equation modelling. The transformational leadership style was closely associated with followers' working conditions, namely involvement, influence and meaningfulness. Involvement was associated with job satisfaction and meaningfulness was associated with well-being. However, working conditions were closely correlated with each other, and thus the mediating mechanisms may operate through several different working conditions. A direct path between leadership behaviour and employee well-being was also found. Considering working conditions in the absence of studying leadership behaviour (or vice versa) may reveal an incomplete picture of the impact of work and work relationships on well-being. Work re-design interventions focused on influence may benefit from the consideration of training managers to exert transformational leadership behaviours.


Image-guided radiotherapy using a mobile kilovoltage x-ray device.
A mobile isocentric C-arm kilovoltage imager has been evaluated as a potential tool for image-guided radiotherapy. The C-arm is equipped with an amorphous silicon flat panel for high-quality image acquisition. Additionally, the device is capable of cone beam computed tomography (CT) and volumetric reconstruction. This is achieved through the application of a modified Feldkamp algorithm with acquisition over a 180 degrees scan arc. The number of projections can be varied from 100 to 1000, resulting in a reconstructed volume 20 cm in diameter by 15-cm long. While acquisition time depends upon number of projections, acceptable quality images can be obtained in less than 60 seconds. Image resolution and contrast of cone-beam phantom images have been compared with images from a conventional CT scanner. The system has a spatial resolution of > or = 10 lp/cm and resolution is approximately equal in all 3 dimensions. Conversely, subject contrast is poorer than conventional CT, compromised by the increased scatter and underlying noise inherent in cone beam reconstruction, as well as the absence of filtering prior to reconstruction. The mobility of the C-arm makes it necessary to determine the C-arm position relative to the linear accelerator isocenter. Two solutions have been investigated: (1) the use of fiducial markers, embedded in the linac couch, that can subsequently be registered in the image sets; and (2), a navigation approach for infrared tracking of the C-arm relative to the linac isocenter. Observed accuracy in phantom positioning ranged from 1.0 to 1.5 mm using the navigation approach and 1.5 to 2.5 mm using the fiducial-based approach. As part of this work, the impact of respiratory motion on cone-beam image quality was evaluated, and a scheme for retrospective gating was devised. Results demonstrated that kilovoltage cone beam CT provides spatial integrity and resolution comparable to conventional CT. Cone-beam CT studies of patients undergoing radiotherapy have demonstrated acceptable soft tissue contrast, allowing assessment of daily changes in target anatomy. Of the 2 approaches developed to register images to the linac isocenter, the navigation method demonstrated superior accuracy for daily patient positioning relative to the fiducial-based method. Finally, significant image degradation due to respiratory motion was observed. It was demonstrated that this could be improved by correlating the acquisition of individual 2D projections with respiration for retrospective reconstruction of phase-based volumetric datasets.


ATF3 promotes migration and M1/M2 polarization of macrophages by activating tenascin‑C via Wnt/β‑catenin pathway.
There are different polarization states of macrophages, including the classically activated M1 phenotype and the alternatively activated M2 phenotype. These have different functions in the inflammation process. Activating transcription factor 3 (ATF3) is a key transcriptional regulator that inhibits the inflammatory response. However, the effects of ATF3 on migration and anti‑inflammatory control mechanisms of macrophages have not been thoroughly investigated. The present study investigated the effect of ATF3 on macrophage migration and M1/M2 polarization. Results revealed that overexpression of ATF3 promoted macrophage migration and the expression of the M2 phenotype markers [cluster of differentiation (CD) 163, mannose receptor C type 1, arginase 1 and peroxisome proliferator‑activated receptor γ] and inhibited expression of the M1 phenotype markers (monocyte chemoattractant protein‑1, inducible nitric oxide synthase, CD16 and tumor necrosis factor‑α), whereas knockdown of ATF3 resulted in a contrary effect. In addition, the wingless‑type MMTV integration site family member (Wnt)/β‑catenin signaling pathway was activated and the expression level of tenascin (TNC) was significantly upregulated by overexpression of ATF3. Additionally, inhibition of Wnt/β‑catenin signaling significantly attenuated the upregulatory effect of ATF3 on TNC. Finally, the effect of ATF3 on macrophage migration and markers of the M1 or M2 state was investigated using TNC‑specific siRNA. In conclusion, the results of the present study suggested that ATF3 promotes macrophage migration and reverses M1‑polarized macrophages to the M2 phenotype by upregulation of TNC via the Wnt/β‑catenin signaling pathway.


Relationship between umbilical cord blood insulin-like growth factors and anthropometry in term newborns.
Birth size is associated with long-term morbidity. Insulin-like growth factor (IGF) system is the most important endocrine factor influencing fetal growth. During rapid somatic growth, free-to-total IGF-I ratio is increased, resulting in higher IGF-I bioavailability. The purpose of this study was to investigate the association of free-to-total IGF-I ratios, IGF-II, and IGF-binding protein (IGFBP)-3 umbilical cord levels with anthropometric data of term neonates. Umbilical venous plasma samples were obtained from 95 term neonates and analyzed by enzyme-linked immunosorbent assay. The large-for-gestational age (LGA) neonates had higher free IGF-I, total IGF-I, and IGFBP-3 levels than small-for-gestational age (SGA) neonates (P < 0.01, 0.001, 0.01, respectively) and higher total IGF-I and IGFBP-3 levels than appropriate-for-gestational age (AGA) neonates (P < 0.05, 0.01, respectively). The free-to-total IGF-I ratios and IGF-II levels were not different among SGA, AGA, and LGA neonates. Free IGF-I, total IGF-I, and IGFBP-3 levels were positively correlated with birth weight (r = 0.34, P < 0.001; r = 0.41, P < 0.001; r = 0.25, P < 0.05, respectively). Multiple linear regression analyses revealed that only total IGF-I levels was the independent predictive variable for birth weight. Our data suggest total IGF-I is the most important factor in the IGF system for determining fetal growth, at least near term gestation. Free-to-total IGF-I ratios may mostly be determined by total IGF-I. If birth size is associated with adult chronic metabolic diseases, total IGF-I may be involved in the pathogenesis.


Canadian guideline on genetic screening for hereditary renal cell cancers.
Hereditary renal cell cancer (RCC) is an ideal model for germline genetic testing. We propose a guideline of hereditary RCC specific criteria to suggest referral for genetic assessment. A review of the literature and stakeholder resources for existing guidelines or consensus statements was performed. Referral criteria were developed by expert consensus. The criteria included characteristics for patients with RCC (age ≤45 years, bilateral or multifocal tumours, associated medical conditions and non-clear cell histologies with unusual features) and for patients with or without RCC, but a family history of specific clinical or genetic diagnoses. This guideline represents a practical RCC-specific reference to allow healthcare providers to identify patients who may have a hereditary RCC syndrome, without extensive knowledge of each syndrome. RCC survivors and their families can also use the document to guide their discussions with healthcare providers about their need for referral. The criteria refer to the most common hereditary renal tumour syndromes and do not represent a comprehensive or exclusive list. Prospective validation of the criteria is warranted.


Potentiation by lithium and protection by rubidium of digitalis intoxication.
Investigating the effects of Li and Rb on the toxicity of digoxin and ouabain revealed Li to be a potentiator while Rb to be a protector. The effects of Rb in this respect are, more or less, qualitatively comparable to those of K; the intensity of Rb effects is more than that of K. In case of digoxin the effect produced from the combined use of both Rb and K is more than each individual effect. With ouabain, however, whereas Rb offered protection K failed to do so. Electrolyte changes in cardiac tissue showed that Li increased the tissue content of Ca while Rb produced the opposite effect. In comparing Rb with K, both increased the K level in the cardiac muscle. However, in the case of ouabain the infusion of K failed to decrease the Ca level and this might explain its failure to protect against ouabain toxicity. This points to the importance of Ca, rather than K, in controlling the excitability of the cardiac muscle and in effecting the toxicity of cardiac glycosides. Evidences presented indicate the superiority of Rb over K and propose its trial in clinical practice.


Lost and found: The identification process of human bodies recovered from the North Sea.
Files of the Dutch bureau of missing persons at the North Sea (BVPN) were investigated to analyse the process that led to identification of human bodies recovered from the North Sea between 1980 and 2013. Of the 94 cases that were analysed 41.5% was identified by the family, 23.4% by the use of DNA and 17% by the use of the dental status. The linking pin for the identification was the place where the body was found (14.9%), the general appearance (12.8%), jewellery (11.6%) and media attention (9.6%). In only a few cases the DNA or fingerprint database was used for identification. When a person is not reported missing the identification is problematic because of the lack of antemortem data. National and international databases of people who have gone missing, can help solve this problem.


Structure, stability and relaxivity of trinuclear triangular complexes.
The self-assembly of a carbonylpyridine-based heptadentate ligand with Ln(III) results in the formation of triangular trinuclear europium complexes, which exhibit interesting luminescent properties in the solid state and in solution. With a view to developing multimodal responsive systems, we report here the preparation and characterisation of analogous complexes with Gd(III). The X-ray crystal structure of Gd(3)L2(3) indeed reveals the isostructurality with the Eu(III) complexes. A combination of (1)H NMRD and variable temperature studies yields the parameters elucidating the exchange of coordinated water and relaxivity properties. Conveniently, the competitive spectrophotometric titrations with EDTA and NTA are used to determine the thermodynamic stability constants of the europium complexes in aqueous media. In addition, the exchange reaction with EDTA is monitored with NMR and fluorimetry. The interactions of the Eu(III) trinuclear complex with some potentially interfering ligands are qualitatively investigated by means of luminescence titrations.


Improving Preventive Care for Children With Sickle Cell Anemia: A Quality Improvement Initiative.
Sickle cell disease is a complex chronic disorder associated with increased morbidity and early mortality. The Pediatric Quality Measures Program has developed new sickle cell-specific quality measures focused on hydroxyurea (HU) counseling and annual transcranial Doppler (TCD) screening; however, these measures have not been used in a clinical setting to inform quality improvement (QI) efforts. From 2017 to 2018, 9 sickle cell subspecialty clinics from the Pacific Sickle Cell Regional Collaborative conducted a year-long QI collaborative focused on improving the percentage of patients with HU counseling and TCD screening based on the new quality measures. After an initial kick-off meeting, the 9 sites participated in monthly conference calls. We used run charts annotated with plan-do-study-act cycle activities to track each site's monthly progress and the overall mean percentage for the entire collaborative. There was an overall improvement in the aggregate HU counseling from 85% to 98% (P < 0.01). For TCD screening, referral frequency changed from 85% to 90% (P = 0.76). For both measures, the variation in frequencies decreased over the year. Over 1 year, we found that a regional QI collaborative increased HU counseling. Although referral for TCD screening increased, there was no overall change in TCD completion. Overall, this QI report's findings can help clinicians adopt and implement these quality measures to improve outcomes in children.


Facial nerve function insufficiency after radiosurgery versus microsurgery.
Due to the synergic role of the facial nerve and the nervus intermedius in the mechanical protection of the eye and taste, vestibular schwannomas and/or their treatment may prove to be dangerous for the visual function and taste. Our goal was to evaluate and compare the impact of the tumor itself and the impact of microsurgery (MS) or Gamma Knife radiosurgery (GKS). A functional questionnaire evaluating, among other items, patient complaints related to the eye and taste has been given out to a series of 200 patients 3 years after the GKS of a unilateral vestibular schwannoma not previously resected. Their answers were compared with those of a group of 200 patients operated on microsurgically. A Schirmer test was additionally performed before radiosurgery (RS) and more than 2 years after RS in 66 patients. The risk of dry eye and burning eye is much higher in patients operated by MS compared to patients operated by GKS due to the high incidence of facial palsy (FP) in the former (57/99) and its absence in the later (0/80). In the population operated on microsurgically, the presence of a permanent FP (57 patients among 99 responding to the questionnaire) was, of course, associated with a high rate of complaint, with burning eye in 27 and crying eye in 39. In patients from the two arms with no FP, a dry eye was reported in 8/64 after GKS and 7/42 after MS (not significant) and a burning eye in 9/64 after GKS and 9/42 after MS (not significant). Thus, 14% of patients with no clinical signs of impairment of the VIIth motor nerve presented signs indicating the injury of the intermedius nerve, with the same probability whatever the kind of surgery. When no permanent FP was observed, a crocodile tear syndrome was more frequently observed after MS (4/42 versus 1/64; p = 0.07). This suggests an early lesion of the VIIth motor nerve and nervus intermedius and a subsequent abnormal regrowth. The only patient reporting a crocodile tear syndrome after GKS turned out to have a transiently presented mild deficit of the orbicular muscle signing a transient partial facial nerve injury. In the absence of FP, a 'crying eye' was reported more frequently after MS (16/42 vs. 9/64; p = 0.01) leading us to suspect a frequent subclinical injury of the VIIth nerve in those patients operated on using MS with no obvious FP. Patients tested with the Schirmer test before and more than 2 years later were improved in 27.3%, stable in 56.1% and worse in 16.7% of cases. The answers about taste showed that 8.1% of patients after GKS and 45.5% of patients after MS complained of taste. This study is the first demonstrating that RS can induce nervus intermedius injury in a small percentage of cases (14%). These patients have been treated 11 years ago with what we can consider as 'archeo-GKS technology' compared to today's radiosurgical instruments. Influence of modern GKS on the nervus intermedius is currently under evaluation in our group. However, symptoms related to the eye and taste either due to the injury of the nervus intermedius or the VIIth motor nerve or both are much more frequent after MS than after RS.


Identification and characterization of receptors for oxytocin in the myometrium of the pregnant ewe.
Receptors for oxytocin were identified in a particulate fraction from the myometrium of the pregnant ewe. Specific binding of [3H]-oxytocin was rapid, reversible, and saturable. It showed an absolute requirement for Mg2+ and the selectivity among oxytocin analogues expected for the receptor. On fractionation of the myometrium by differential and discontinuous gradient centrifugation, [3H]-oxytocin binding showed a fractionation pattern which was similar to that for plasma membrane markers, but different from those for endoplasmic reticulum or mitochondrial markers. It is concluded that oxytocin receptors are located in the plasma membrane of the ewe myometrium. This subcellular fraction is a useful preparation for the study of receptor mechanisms and the regulation of myometrial contractility.


The Nano-Bio Interactions of Nanomedicines: Understanding the Biochemical Driving Forces and Redox Reactions.
Engineered nanomaterials (ENMs) have been developed for imaging, drug delivery, diagnosis, and clinical therapeutic purposes because of their outstanding physicochemical characteristics. However, the function and ultimate efficiency of nanomedicines remain unsatisfactory for clinical application, mainly because of our insufficient understanding of nanomaterial/nanomedicine-biology (nano-bio) interactions. The nonequilibrated, complex, and heterogeneous nature of the biological milieu inevitably influences the dynamic bioidentity of nanoformulations at each site (i.e., the interfaces at different biological fluids (biofluids), environments, or biological structures) of nano-bio interactions. The continuous interplay between a nanomedicine and the biological molecules and structures in the biological environments can, for example, affect cellular uptake or completely alter the designed function of the nanomedicine. Accordingly, the weak and strong driving forces at the nano-bio interface may elicit structural reconformation, decrease bioactivity, and induce dysfunction of the nanomaterial and/or redox reactions with biological molecules, all of which may elicit unintended and unexpected biological outcomes. In contrast, these driving forces also can be manipulated to mitigate the toxicity of ENMs or improve the targeting abilities of ENMs. Therefore, a comprehensive understanding of the underlying mechanisms of nano-bio interactions is paramount for the intelligent design of safe and effective nanomedicines. In this Account, we summarize our recent progress in probing the nano-bio interaction of nanomedicines, focusing on the driving force and redox reaction at the nano-bio interface, which have been recognized as the main factors that regulate the functions and toxicities of nanomedicines. First, we provide insight into the driving force that shapes the boundary of different nano-bio interfaces (including proteins, cell membranes, and biofluids), for instance, hydrophobic, electrostatic, hydrogen bond, molecular recognition, metal-coordinate, and stereoselective interactions that influence the different nano-bio interactions at each contact site in the biological environment. The physicochemical properties of both the nanoparticle and the biomolecule are varied, causing structure recombination, dysfunction, and bioactivity loss of proteins; correspondingly, the surface properties, biological functions, intracellular uptake pathways, and fate of ENMs are also influenced. Second, with the help of these driving forces, four kinds of redox interactions with reactive oxygen species (ROS), antioxidant, sorbate, and the prosthetic group of oxidoreductases are utilized to regulate the intracellular redox equilibrium and construct synergetic nanomedicines for combating bacteria and cancers. Three kinds of electron-transfer mechanisms are involved in designing nanomedicines, including direct electron injection, sorbate-mediated, and irradiation-induced processes. Finally, we discuss the factors that influence the nano-bio interactions and propose corresponding strategies to manipulate the nano-bio interactions for advancing nanomedicine design. We expect our efforts in understanding the nano-bio interaction and the future development of this field will bring nanomedicine to human use more quickly.


Comparative study of the invasiveness of Salmonella serotypes Typhimurium, Choleraesuis and Dublin for Caco-2 cells, HEp-2 cells and rabbit ileal epithelia.
Patterns of invasiveness of Salmonella serotypes Typhimurium, Choleraesuis and Dublin in Caco-2 cells (without centrifugation) were compared with previously published studies of the rabbit ileal invasion assay (RIIA) and (where relevant) a HEp-2 cell invasion assay. Optimal conditions for the use of Caco-2 cell monolayers in bacterial invasion assays were defined. Centrifuge-assisted attachment of bacteria to cells was not used routinely as this increased the invasiveness of known hypo-invasive strains and detachment of Caco-2 cells. Inocula with too high bacterial numbers resulted in rapid acidification of media and detachment of the monolayers. The invasiveness of Typhimurium strains TML, WAKE, WII8, LT7, SL1027 and M206 in Caco-2 cells reflected that seen in the RIIA. The invasiveness of Choleraesuis strain A50 was similar to that in the RIIA except that bacteria grown at 37 degrees C and used without storage at 4 degrees C were slightly more invasive than those grown at 37 degrees C and stored at 4 degrees C before use. Dublin strain 3246 showed no apparent temperature-regulated invasiveness in Caco-2 cells, in contrast to the results observed in the RIIA. Dublin strain 3246 did not cleave tight junctions in the Caco-2 cell monolayer as it did in rabbit ileal epithelia both in vitro and in vivo. Three TnphoA insertion LPS mutants of Typhimurium TML were uniformly hypo-invasive in both Caco-2 cells and the RIIA; in contrast, they were differentially invasive in HEp-2 cells. Three smooth TnphoA insertion mutants of Typhimurium TML (invH, invG and pagC) were hypo-invasive in both the Caco-2 and HEp-2 cell invasion assays but not in the RIIA.


Murine models of graft versus host disease (GVHD): Focus on ocular GVHD.
Graft versus host disease (GVHD) remains a major and serious complication of allogeneic hematopoietic stem cell transplantation. Based on the time of onset, clinical phenotypes, progression kinetics, and pathophysiology, GVHD is stratified into acute, chronic, and overlapping types. The eyes are among the most commonly affected organs in GVHD. Mouse models have played an important role in understanding the several key elements of GVHD pathobiology. The current review discusses the immunology, pathology, and key phenotypic features of mouse models of systemic GVHD. Furthermore, a critical appraisal of mouse models of ocular GVHD (oGVHD) is provided. The disease mechanisms underlying the ocular surface, meibomian gland, and lacrimal gland injury in these models are reviewed, and the relevance of oGVHD murine models to clinical oGVHD is also included.


Strength of word-specific neural memory traces assessed electrophysiologically.
Memory traces for words are frequently conceptualized neurobiologically as networks of neurons interconnected via reciprocal links developed through associative learning in the process of language acquisition. Neurophysiological reflection of activation of such memory traces has been reported using the mismatch negativity brain potential (MMN), which demonstrates an enhanced response to meaningful words over meaningless items. This enhancement is believed to be generated by the activation of strongly intraconnected long-term memory circuits for words that can be automatically triggered by spoken linguistic input and that are absent for unfamiliar phonological stimuli. This conceptual framework critically predicts different amounts of activation depending on the strength of the word's lexical representation in the brain. The frequent use of words should lead to more strongly connected representations, whereas less frequent items would be associated with more weakly linked circuits. A word with higher frequency of occurrence in the subject's language should therefore lead to a more pronounced lexical MMN response than its low-frequency counterpart. We tested this prediction by comparing the event-related potentials elicited by low- and high-frequency words in a passive oddball paradigm; physical stimulus contrasts were kept identical. We found that, consistent with our prediction, presenting the high-frequency stimulus led to a significantly more pronounced MMN response relative to the low-frequency one, a finding that is highly similar to previously reported MMN enhancement to words over meaningless pseudowords. Furthermore, activation elicited by the higher-frequency word peaked earlier relative to low-frequency one, suggesting more rapid access to frequently used lexical entries. These results lend further support to the above view on word memory traces as strongly connected assemblies of neurons. The speed and magnitude of their activation appears to be linked to the strength of internal connections in a memory circuit, which is in turn determined by the everyday use of language elements.


Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.


Interpopulation differences in acoustic characteristics of phonation.
The purpose of this study was to investigate possible differences in acoustic characteristics of phonation between populations of European and African origin. The subjects were 33 adult males divided in two groups. Group One consisted of 17 men of African origin, and Group Two included 16 men of European origin. All subjects were without vocal pathology at the time of the investigation, smokers and non-smokers. Sustained phonation of the vowel /a/ was acoustically analyzed by the Real-time Frequency Analyzer (Bruel and Kjaer, type 2123). Variables included f0, intensity of f0, intensity of harmonics 1-7, jitter and noise level intensity. One-way variance analysis showed statistically significant difference between the two groups in intensity of the second harmonic only. The same analysis has been repeated with non-smokers and showed statistically significant differences in intensities of the second and the third harmonic leading to assumption that there may be fine differences in vocal fold vibration between Group One and Group Two. Factor congruence analysis showed differences between samples in factor structures. It could be possible that these differences reflect psychoacoustic level.


Impact of Single Constant Optimization on the Precision of IOL Power Calculation.
The primary objective of this research is to examine how precision in intraocular lens calculation formulas can be impacted by zeroing the mean error through adjustments in the effective lens position value. Additionally, the study aims to evaluate how this modification influences outcomes differently based on the source of the prediction error. In order to analyze the impact of individual variables on the standard deviation, the study maintained all variables constant except for one at a time. Subsequently, variations were introduced to specific parameters, such as corneal curvature radius, keratometric refractive index, axial length, and predicted implant position. According to our findings, when zeroing the mean error is applied to correct for inaccuracies in corneal power estimation, it results in a significant and exponential rise in standard deviation, thus adversely affecting the formula's precision. However, when zeroing is employed to compensate for prediction errors stemming from axial length measurements or predicted implant position, the effect on precision is minimal or potentially beneficial. The study highlights the potential risks associated with the indiscriminate but necessary zeroing of prediction errors in implant power calculation formulas. The impact on formula precision greatly depends on the source of the error, underscoring the importance of error source when analyzing variations in the standard deviation of the prediction error after zeroing. Our study contributes to the ongoing effort to enhance the accuracy and reliability of these formulas, thereby improving the surgical outcomes for cataract patients.


Shear-Induced Structural Changes and Origin of Ultralow Friction of Hydrogenated Diamond-like Carbon (DLC) in Dry Environment.
The origins of run-in and ultralow friction states of a sliding contact of hydrogenated diamond-like carbon (H-DLC) and sapphire were studied with an in situ Raman tribometer as well as ex situ analyses of transmission electron microscopy (TEM), Raman spectroscopy, and nanoindentation. Prior to ultralow friction behavior, H-DLC exhibits a run-in period. During the run-in period in dry nitrogen atmosphere, the transfer film was formed and its uniformity and thickness as well as structure were varied. The duration and friction behaviors during the run-in depended on the initial surface state of the H-DLC coatings. A comparative study of pristine and thermally oxidized H-DLC revealed the role of surface oxide layer on run-in friction and transfer film formation. Attainment of the ultralow friction state appeared to correlate with the uniformity and structure of the transfer film evolved during the run-in, rather than its final thickness. TEM cross-section imaging of the wear track and the counter surfaces showed a trace of nanocrystalline graphite and a thin modified surface layer on both rubbing bodies. The comparison of hardness and reduced modulus of the wear tracks and the unworn surfaces as well as the ex situ Raman spectra suggested the densification of the wear track surfaces. Combining the in situ and ex situ analysis results, a comprehensive model was proposed for the formation and structure of the ultralow friction sliding contact of H-DLC.


Post-crotonylation oxidation by a monooxygenase promotes acetyl-CoA synthetase degradation in Streptomyces roseosporus.
Protein post-translational modifications (PTMs) with various acyl groups play central roles in Streptomyces. But whether these acyl groups can be further modified, and the influences of these potential modifications on bacterial physiology have not been addressed. Here in Streptomyces roseosporus with rich crotonylation, a luciferase monooxygenase LimB is identified to elaborately regulate the crotonylation level, morphological development and antibiotic production by oxidation on the crotonyl groups of an acetyl-CoA synthetase Acs. This chemical modification on crotonylation leads to Acs degradation via the protease ClpP1/2 pathway and lowered intracellular crotonyl-CoA pool. Thus, we show that acyl groups after PTMs can be further modified, herein named post-PTM modification (PPM), and LimB is a PTM modifier to control the substrate protein turnover for cell development of Streptomyces. These findings expand our understanding of the complexity of chemical modifications on proteins for physiological regulation, and also suggest that PPM would be widespread.


DashBot: Insight-Driven Dashboard Generation Based on Deep Reinforcement Learning.
Analytical dashboards are popular in business intelligence to facilitate insight discovery with multiple charts. However, creating an effective dashboard is highly demanding, which requires users to have adequate data analysis background and be familiar with professional tools, such as Power BI. To create a dashboard, users have to configure charts by selecting data columns and exploring different chart combinations to optimize the communication of insights, which is trial-and-error. Recent research has started to use deep learning methods for dashboard generation to lower the burden of visualization creation. However, such efforts are greatly hindered by the lack of large-scale and high-quality datasets of dashboards. In this work, we propose using deep reinforcement learning to generate analytical dashboards that can use well-established visualization knowledge and the estimation capacity of reinforcement learning. Specifically, we use visualization knowledge to construct a training environment and rewards for agents to explore and imitate human exploration behavior with a well-designed agent network. The usefulness of the deep reinforcement learning model is demonstrated through ablation studies and user studies. In conclusion, our work opens up new opportunities to develop effective ML-based visualization recommenders without beforehand training datasets.


MCMV-mediated inhibition of the pro-apoptotic Bak protein is required for optimal in vivo replication.
Successful replication and transmission of large DNA viruses such as the cytomegaloviruses (CMV) family of viruses depends on the ability to interfere with multiple aspects of the host immune response. Apoptosis functions as a host innate defence mechanism against viral infection, and the capacity to interfere with this process is essential for the replication of many viruses. The Bcl-2 family of proteins are the principle regulators of apoptosis, with two pro-apoptotic members, Bax and Bak, essential for apoptosis to proceed. The m38.5 protein encoded by murine CMV (MCMV) has been identified as Bax-specific inhibitor of apoptosis. Recently, m41.1, a protein product encoded by the m41 open reading frame (ORF) of MCMV, has been shown to inhibit Bak activity in vitro. Here we show that m41.1 is critical for optimal MCMV replication in vivo. Growth of a m41.1 mutant was attenuated in multiple organs, a defect that was not apparent in Bak(-/-) mice. Thus, m41.1 promotes MCMV replication by inhibiting Bak-dependent apoptosis during in vivo infection. The results show that Bax and Bak mediate non-redundant functions during MCMV infection and that the virus produces distinct inhibitors for each protein to counter the activity of these proteins.


Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment.
Major depressive disorder is a chronic disabling disease, often triggered and exacerbated by stressors of a social nature. Hippocampal volume reductions have been reported in depressed patients. In support of the neurogenesis theory of depression, in several stress-based animal models of depression, adult hippocampal neurogenesis was reduced and subsequently rescued by parallel antidepressant treatment. Here, we investigated whether repeated social defeat and subsequent individual housing for 3 months induces long-lasting changes in adult hippocampal neurogenesis in rats, and whether these can be normalized by late antidepressant treatment, as would match human depression. Neurogenesis was analysed by stereological quantification of the number of immature doublecortin (DCX)-immunopositive cells, in particular young (class I) and more mature (class II) DCX(+) cells, to distinguish differential effects of stress or drug treatment on these subpopulations. Using this social defeat paradigm, the total DCX(+) cell number was significantly reduced. This was most profound for older (class II) DCX(+) cells with long apical dendrites, whereas younger, class I cells remained unaffected. Treatment with the broad-acting tricyclic antidepressant imipramine, only during the last 3 weeks of the 3-month period after social defeat, completely restored the reduction in neurogenesis by increasing both class I and II DCX(+) cell populations. We conclude that despite the lack of elevated corticosterone plasma levels, neurogenesis is affected in a lasting manner by a decline in a distinct neuronal population of more mature newborn cells. Thus, the neurogenic deficit induced by this social defeat paradigm is long-lasting, but can still be normalized by late imipramine treatment.


Are body fluctuating asymmetry and the ratio of 2nd to 4th digit length reliable predictors of semen quality?
Recent attention has been paid to patterns of fluctuating asymmetry (FA) in paired bilateral traits and the extent to which they reflect phenotypic and genetic quality. The FA-fertility hypothesis proposes that FA may be a reliable indicator of ejaculate quality in humans and other animals. The common control by the Hox genes of the differentiation of both the urogenital system and the appendicular skeleton in vertebrates has been proposed as an explanation for the recent finding that FA, and the second to fourth digit ratios (2D:4D) are both associated with semen quality in men. A group of 50 men was evaluated for FA, calculated by the sum of three different body FAs, 2D:4D ratios, and seminal parameters of masturbatory semen samples. Composite FA had a significant effect on semen parameters; the 2D:4D ratios did not predict semen quality. Comparison of our data with previous studies suggests that the putative relationship between semen quality and 2D:4D may have been driven by the inclusion of severely oligozoospermic men within the original subject group. Our sample included men with equally high 2D:4D ratios but who had normal semen. Thus, the 2D:4D ratio may not reliably indicate poor semen quality although FA might.


Peripheral dystonia.
We studied four patients with distal, action-induced involuntary postures of the hand that could be considered focal dystonia. All four patients had electrophysiologic findings consistent with peripheral nervous system lesions (pronator teres syndrome, radial nerve palsy, lower brachial plexus lesion, or median nerve lesion). With varying success, patients were treated with carbamazepine, trihexyphenidyl, methocarbamol, and wrist splinting. We wish to emphasize that peripheral entrapment and brachial plexopathy should be added to the causes of secondary dystonias.


Internet-based tools to assess diet and provide feedback in chronic kidney disease stage IV: a pilot study.
Successfully changing patients' dietary behavior is a challenging problem in the management of chronic kidney disease (CKD). We conducted a pilot study to test the feasibility and acceptability of an Internet-based, self-administered, dietary assessment tool equipped with instructional feedback, aimed at facilitating dietary adherence to disease-specific nutritional guidelines among CKD stage IV patients while reducing resource burdens on providers. Focus groups were used to develop a user-friendly dietary reporting format. The report was then calibrated to the dietary guidelines outlined by Kidney Disease Outcomes Quality Initiative (K/DOQI) and incorporated into the assessment tool. Elements of the report were developed based on the "transtheoretical model of behavior change" theory, aimed at facilitating patients to enter the action stage of change. The tool was later deployed in a nephrology care site at an academic medical center, where 12 patients diagnosed with stage IV CKD (late-stage, predialysis) completed a dietary assessment before their provider encounter as well as questionnaires gauging their computer literacy, nutritional education history, nutritional knowledge and awareness, and acceptability of the tool. The report was made available to the provider during the clinical encounter, and both patient and physician perception of the report's utility was assessed after the encounter. Approximately 25% to 30% of the patients were severely noncompliant to the K/DOQI guidelines for each nutrient. Awareness about the role of diet in CKD management was widely variable, ranging from 0% to 58% of the patients over different nutrients. All of the patients successfully completed the Web-based dietary assessment. Eighty-four percent of the patients positively rated the tool on its ability to record the patients' dietary data, 58% noted the tool was always able to satisfactorily estimate portion sizes, and 50% thought the navigation was easy or very easy. Eleven of the 12 patients were satisfied with the time taken (range: 10 to 40 minutes, median time: 20 minutes) to complete the dietary assessment. Patients and physicians differed considerably in their perception of the use of the report during the clinical encounter. Dietary knowledge and adherence to K/DOQI guidelines among CKD patients is suboptimal. However, interest and motivation is high. Web-based tools are well accepted among CKD patients as an aid to assessing dietary adherence to K/DOQI guidelines and may pose a cost-effective approach to bridging the adherence gap.


Analysing recurrent hospitalizations in heart failure: a review of statistical methodology, with application to CHARM-Preserved.
Heart failure is characterized by recurrent hospitalizations, but often only the first event is considered in clinical trial reports. In chronic diseases, such as heart failure, analysing all events gives a more complete picture of treatment benefit. We describe methods of analysing repeat hospitalizations, and illustrate their value in one major trial. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study compared candesartan with placebo in 3023 patients with heart failure and preserved systolic function. The heart failure hospitalization rates were 12.5 and 8.9 per 100 patient-years in the placebo and candesartan groups, respectively. The repeat hospitalizations were analysed using the Andersen-Gill, Poisson, and negative binomial methods. Death was incorporated into analyses by treating it as an additional event. The win ratio method and a method that jointly models hospitalizations and mortality were also considered. Using repeat events gave larger treatment benefits than time to first event analysis. The negative binomial method for the composite of recurrent heart failure hospitalizations and cardiovascular death gave a rate ratio of 0.75 [95% confidence interval (CI) 0.62-0.91, P = 0.003], whereas the hazard ratio for time to first heart failure hospitalization or cardiovascular death was 0.86 (95% CI 0.74-1.00, P = 0.050). In patients with preserved EF, candesartan reduces the rate of admissions for worsening heart failure, to a greater extent than apparent from analysing only first hospitalizations. Recurrent events should be routinely incorporated into the analysis of future clinical trials in heart failure.


New allergenic pollens of Delhi State, India, and their clinical significance.
Antigenic extracts of 26 new pollen types were assessed on 175 patients with respiratory allergy for their allergenicity, using the intradermal test. A total of 4,550 intradermal tests were performed in addition to 1,040 skin tests performed on 40 non-allergic healthy individuals as a control. Fisher's Extract Probability Test was used to determine the statistical significance of the allergenicity, expressed in percentages of markedly positive skin reactions (2+ and above). Only 13 of the 26 pollen types investigated proved to be statistically significant as possessing allergenicity. The relative sensitivity of different diagnostic tests was also assessed. Markedly positive reactions evaluated by Passive Transfer (P-K), conjunctival and bronchial challenge tests were found to be equally significant. The P-K and bronchial challenge tests gave significant correlation with markedly positive intradermal tests.


Sexually transmitted diseases and their relation to male infertility.
Controversy surrounds the role of sexually transmitted diseases in male infertility. Because our understanding of male infertility is limited, and because diagnostic tests such as semen analysis including culture and leukocyte count are variable, definitive conclusions on STDs and their effect on infertility cannot be substantiated. Prospective investigations of infertile couples using appropriate control groups, sophisticated semen collection protocols, proper microbiologic techniques, and standardization of seminal fluid analysis are required to understand the role of STDs in male infertility. Regardless of the ongoing research to delineate the role of STDs in male infertility, advocating primary prevention by increasing public awareness of the negative effects of STDs and the use of contraceptive methods to prevent the spread of STDs is mandatory for the health care professional.


Helicobacter pylori-negative peptic ulcer. What is its aetiopathogenesis and treatment?
Although the vast majority of peptic ulcers are widely considered as related to the germ Helicobacter pylori, ulcers exhibiting absence of this infection are increasingly seen in recent years. This fact has been partly related to a decreased prevalence of Helicobacter pylori among the population, a consequence of improved hygiene and housing conditions. Causes in relation to Helicobacter pylori-negative ulcers are: 1. Falsely negative infection diagnostic tests. They represent 25% of ulcers considered as Helicobacter pylori-negative in health-care practice (falsely negative diagnostic test 5%, previous or concomitant therapy with antibiotics, bismuth or proton pump inhibitors 20%). 2. Aspirin (ASA) or non-steroidal anti-inflammatory drug (NSAID) therapy. This is no doubt the most common cause, representing 50 to 60% of all infection-free ulcers. 3. Other causes (Zollinger-Ellison syndrome, Helicobacter heilmannii, generalised gut disease such as Crohn's disease, amyloidosis, eosinophilic gastroenteritis, etc.) may be responsible for less than 5% of all Helicobacter pylori-negative ulcers. 4. "Idiopathic" peptic ulcers. Thus are considered ulcers for which no potential cause may be found, representing 5-15% of all infection-free ulcers. Acid hyper-secretion is probably an important factor in them.


Is the clinicopathological pattern of colorectal carcinoma similar in the state and private healthcare systems of South Africa? Analysis of a Durban colorectal cancer database.
Previous state hospital-based local studies suggest varying population-based clinicopathological patterns of colorectal cancer (CRC). Patients diagnosed with CRC in the state and private sector hospitals in Durban, South Africa over a 12-month period (January-December 2009) form the basis of our study. Of 491 patients (172 state and 319 private sector patients), 258 were men. State patients were younger than private patients. Anatomical site distribution was similar in both groups with minor variations. Stage IV disease was more common in state patients. State patients were younger, presented with advanced disease and had a lower resection rate. Black patients were the youngest, presented with advanced disease and had the lowest resection rate.


Comparing eating disorder characteristics and treatment in self-identified competitive athletes and non-athletes from the National Eating Disorders Association online screening tool.
We compared eating disorder (ED) characteristics and treatment seeking behaviors between self-identified competitive athletes and non-athletes in a large, community-based sample. During the 2018 National Eating Disorders Awareness Week, 23,920 respondents, 14.7% of whom identified as competitive athletes, completed the National Eating Disorders Association online screen. Data were collected on demographics, disordered eating behaviors, probable ED diagnosis/risk, treatment history, and intent to seek treatment. The sample was predominantly White (81.8%), female (90.3%), and between 13 and 24 years (82.6%). Over 86% met criteria for an ED/subthreshold ED, and of those, only 2.5% were in treatment. Suicidal ideation was reported in over half of the sample. Athletes reported a significantly greater likelihood of engaging in and more frequent excessive exercise episodes than non-athletes. Athletes also reported a significantly lower likelihood of engaging in and less frequent binge-eating episodes compared with non-athletes. Athletes were more likely to screen positive for an ED/subthreshold ED than non-athletes, but percentages across all probable ED diagnoses were similar. No significant differences between athletes and non-athletes emerged on treatment history or intention to seek treatment post-screen (less than 30%). Although the distribution of probable ED diagnoses was similar in athletes and non-athletes, symptom profiles related to disordered eating behavior engagement and frequency may differ. Athletes may be less likely to seek treatment due to stigma, accessibility, and sport-specific barriers. Future work should directly connect survey respondents to tailored treatment tools and increase motivation to seek treatment.


Molecular and morphological identification of mealybug species (Hemiptera: Pseudococcidae) in Brazilian vineyards.
Mealybugs (Hemiptera: Pseudococcidae) are pests constraining the international trade of Brazilian table grapes. They damage grapes by transmitting viruses and toxins, causing defoliation, chlorosis, and vigor losses and favoring the development of sooty mold. Difficulties in mealybug identification remain an obstacle to the adequate management of these pests. In this study, our primary aim was to identify the principal mealybug species infesting the major table grape-producing regions in Brazil, by morphological and molecular characterization. Our secondary aim was to develop a rapid identification kit based on species-specific Polymerase Chain Reactions, to facilitate the routine identification of the most common pest species. We surveyed 40 sites infested with mealybugs and identified 17 species: Dysmicoccus brevipes (Cockerell), Dysmicoccus sylvarum Williams and Granara de Willink, Dysmicoccus texensis (Tinsley), Ferrisia cristinae Kaydan and Gullan, Ferrisia meridionalis Williams, Ferrisia terani Williams and Granara de Willink, Phenacoccus baccharidis Williams, Phenacoccus parvus Morrison, Phenacoccus solenopsis Tinsley, Planococcus citri (Risso), Pseudococcus viburni (Signoret), Pseudococcus cryptus Hempel, four taxa closely related each of to Pseudococcus viburni, Pseudococcus sociabilis Hambleton, Pseudococcus maritimus (Ehrhorn) and Pseudococcus meridionalis Prado, and one specimen from the genus Pseudococcus Westwood. The PCR method developed effectively identified five mealybug species of economic interest on grape in Brazil: D. brevipes, Pl. citri, Ps. viburni, Ph. solenopsis and Planococcus ficus (Signoret). Nevertheless, it is not possible to assure that this procedure is reliable for taxa that have not been sampled already and might be very closely related to the target species.


Dermal in vitro penetration of methiocarb, paclobutrazol, and pirimicarb.
The dominant route of occupational exposure to pesticides in horticulture is dermal. However, preventive measures are seldom used when handling plant cultures recently treated with pesticides, thus causing significant dermal exposure and potential absorption. Assessment of exposure often depends on biological monitoring of blood or urine samples. The skin often acts as a temporary reservoir for chemicals before absorption. Failure to consider the lag time between dermal exposure and appearance of pesticide or metabolites in the general circulation may lead to false conclusions about assessment of exposure. In an experimental model in which in vitro static diffusion cells were mounted with human skin, dermal penetration of three extensively used pesticides (methiocarb, paclobutrazol, pirimicarb) was evaluated. Pirimicarb and paclobutrazol had comparable rates of dermal penetration and lag times of around 18 hours. Methiocarb had a considerably shorter lag time. Dermal penetration continued for extended periods after exposure had ended. With lag times sometimes considerably longer than a normal working day, biological monitoring at the end of exposure may seriously underestimate the actual exposure. There may be implications for regulatory guidelines, which often require only 24 hour observation periods.