Complications of hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent painful nodules and abscesses involving intertriginous areas. Repeated episodes of profound inflammation in HS can lead to a number of complications, causing significant morbidity and decreasing quality of life. Complications of HS may affect the skin alone or may have systemic impact. Cutaneous complications of HS include sinus tracts, fistulae, scarring and contractures, squamous cell carcinoma, and lymphedema. Systemic complications of HS include chronic pain, systemic amyloidosis, and possibly anemia. Preventing disease complications by controlling primary disease is a key component of HS management. Clinicians should be prepared to recognize complications early, as prompt management is necessary to minimize negative impacts.


Recurrent plasmacytomas after allografting in a patient with multiple myeloma.
Extramedullary recurrence in multiple myeloma patients has been reported after both autologous and allogeneic hematopoietic cell transplantation and, more recently, after treatment with so-called new drugs with potent antimyeloma activity. Only a very few sizable reports focused on its clinical presentation and its incidence, which may be highly underestimated, and most observations are based on single patients reported from several institutions. Given the unusual sites of recurrence, diagnosis may be rather difficult and delayed treatment may play a relevant role in prognosis. Here we report a case of a myeloma patient, initially treated with an allograft, who enjoyed an eleven-year disease-free remission with very good quality of life. She eventually relapsed first with an extramedullary plasmacytoma in the breast and, two years later, with a right atrial cardiac mass.


Limnohabitans radicicola sp. nov., a slow-growing bacterium isolated from rhizosphere of rice plant and emended description of the genus Limnohabitans.
In the present study, in an attempt to explore the diversity of bacteria in the roots of rice plants, a Gram-stain-negative, motile, facultatively anaerobic, non-pigmented, catalase-positive, oxidase-negative and rod-shaped bacterium with polar flagella was isolated. Phylogenetic analysis based on 16S rRNA gene sequences revealed highest sequence similarity to Limnohabitans parvus KCTC 42859T (98.2%) followed by Limnohabitans curvus KCTC 42562T (98%), Limnohabitans planktonicicus II-D5T (97.9%) and Limnohabitans australis MWH-BRAZ-DAM2DT (97.4%). Growth of strain JUR4T occurred at 10-37 °C (optimum, 30 °C), at pH 5.5-8.0 (optimum, 6.5-7) and in the presence of 0-0.2% NaCl (optimum, 0%, w/v). The genome size of strain JUR4T was found to be 3.34 Mb containing 3139 predicted protein-coding genes with a DNA G+C content of 61.5 mol%. The digital DNA-DNA hybridization and average nucleotide identity values between the genome sequence of strain JUR4T and closely related reference strains were 21.0-24.8% and 74.7-81.4%, respectively. Strain JUR4T contained diphosphatidylglycerol, phoshatidylethanolamine, one unidentified phosphoglycolipid, one unidentified aminophosphoglycolipid, one unidentified phospholipid and seven unidentified glycolipids. The major fatty acids were C16:0 and summed feature 3 (comprising C16:1 ω7c and/or C16:1 ω6c), and ubiquinone Q-8 was the sole isoprenoid quinone. So far, all species belonging to the genus Limnohabitans have been described as non-motile and devoid of flagella. All species were isolated from freshwater and are therefore denoted as planktonic bacteria. This present study introduces a novel motile member of Limnohabitans isolated from the root of rice plant, and introduces the genes associated with motility and methyl-accepting chemotaxis proteins. Phylogenetic, phenotypic, chemotaxonomic and genotypic data clearly indicates that strain JUR4T represents a novel species of the genus Limnohabitans for which the name Limnohabitans radicicola sp. nov. is proposed. The type strain is JUR4T (=KACC 21745T=NBRC 114484T).


Rare case of Bing-Neel syndrome treated successfully with ibrutinib.
Waldenstrom's macroglobulinaemia (WM) is a lymphoproliferative disorder of the B cell origin. It is characterised by the presence of IgM paraprotein in the serum and lymphoplasmacytic lymphoma cells in the bone marrow with extranodal involvement relatively uncommon. Bing-Neel syndrome (BNS) is a neurological complication of WM that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. We present an interesting case of BNS that responded remarkably to ibrutinib monotherapy.


Variation in left posterior parietal-motor cortex interhemispheric facilitation following right parietal continuous theta-burst stimulation in healthy adults.
Spatial neglect is modeled on an imbalance of interhemispheric inhibition (IHI); however evidence is emerging that it may not explain neglect in all cases. The aim of this study was to investigate the IHI imbalance model of visual neglect in healthy adults, using paired pulse transcranial magnetic stimulation to probe excitability of projections from posterior parietal cortex (PPC) to contralateral primary motor cortex (M1) bilaterally. Motor-evoked potentials (MEPs) were recorded from the first dorsal interossei and facilitation was determined as ratio of conditioned to non-conditioned MEP amplitude. A laterality index reflecting the balance of excitability between the two hemispheres was calculated. A temporal order judgment task (TOJ) assessed visual attention. Continuous theta-burst stimulation was used to transiently suppress right parietal cortex activity and the effect on laterality and judgment task measured, along with associations between baseline and post stimulation measures. Stimulation had conflicting results on laterality, with most participants demonstrating an effect in the negative direction with no decrement in the TOJ task. Correlation analysis suggests a strong association between laterality direction and degree of facilitation of left PPC-to right M1 following stimulation (r=.902), with larger MEP facilitation at baseline demonstrating greater reduction (r=-.908). Findings indicate there was relative balance between the cortices at baseline but right PPC suppression did not evoke left PPC facilitation in most participants, contrary to the IHI imbalance model. Left M1 facilitation prior to stimulation may predict an individual's response to continuous theta-burst stimulation of right PPC.


Predictors of early mortality in patients with ischemic stroke.
Accurate predictors of early outcome in stroke patients have a number of important applications, such as introducing secondary prevention strategies, supporting treatment decisions or designing randomized clinical trials. Surprisingly, a generally accepted, reliable and well-validated mortality-prediction model is still unavailable. This review outlines the most important predictors of in-hospital mortality that could be assessed at admission to hospital emergency room within 24 h of ischemic stroke onset. A number of factors are discussed such as nonmodifiable factors (e.g., age, gender and genetic factors); type of stroke and its severity - measured by different clinical score scales; predictive models; laboratory markers; special neuroradiological and neurophysiological tests; and comorbid conditions at admission and quality of hospital care.


Acoustic-phonetics of coronal stops: a cross-language study of Canadian English and Canadian French.
The study was conducted to provide an acoustic description of coronal stops in Canadian English (CE) and Canadian French (CF). CE and CF stops differ in VOT and place of articulation. CE has a two-way voicing distinction (in syllable initial position) between simultaneous and aspirated release; coronal stops are articulated at alveolar place. CF, on the other hand, has a two-way voicing distinction between prevoiced and simultaneous release; coronal stops are articulated at dental place. Acoustic analyses of stop consonants produced by monolingual speakers of CE and of CF, for both VOT and alveolar/dental place of articulation, are reported. Results from the analysis of VOT replicate and confirm differences in phonetic implementation of VOT across the two languages. Analysis of coronal stops with respect to place differences indicates systematic differences across the two languages in relative burst intensity and measures of burst spectral shape, specifically mean frequency, standard deviation, and kurtosis. The majority of CE and CF talkers reliably and consistently produced tokens differing in the SD of burst frequency, a measure of the diffuseness of the burst. Results from the study are interpreted in the context of acoustic and articulatory data on coronal stops from several other languages.


Radiation exposure by radio-diagnostics in Switzerland: a pilot patient-oriented survey.
A patient-oriented survey was conducted in Switzerland with the aim to establishing the distribution of medical X-ray examinations among the population. A sample of 1235 people aged between 15 and 74 y (589 males and 637 females) was contacted. The participants were asked to give the number of medical X-ray examinations performed during the previous 12 months. Three-fourths of the sample did not undergo any medical X-ray examination during a 12 month-period, and 10% of the population underwent more than 1 medical X-ray examination in a year. These results were independent of the geographic region. The age distributions of the participants who did not undergo any medical X-ray examination and those who underwent one medical X-ray examination were similar. On the other hand, the age distribution of the participants who underwent more than one medical X-ray examination was characterised by a higher contribution from the elderly.


Prolyl 3-hydroxylase 1 null mice display abnormalities in fibrillar collagen-rich tissues such as tendons, skin, and bones.
Osteogenesis imperfecta (OI) is a skeletal disorder primarily caused by mutations in the type I collagen genes. However, recent investigations have revealed that mutations in the genes encoding for cartilage-associated protein (CRTAP) or prolyl 3-hydroxylase 1 (P3H1) can cause a severe, recessive form of OI. These reports show minimal 3-hydroxylation of key proline residues in type I collagen as a result of CRTAP or P3H1 deficiency and demonstrate the importance of P3H1 and CRTAP to bone structure and development. P3H1 and CRTAP have previously been shown to form a stable complex with cyclophilin B, and P3H1 was shown to catalyze the 3-hydroxylation of specific proline residues in procollagen I in vitro. Here we describe a mouse model in which the P3H1 gene has been inactivated. Our data demonstrate abnormalities in collagen fibril ultrastructure in tendons from P3H1 null mice by electron microscopy. Differences are also seen in skin architecture, as well as in developing limbs by histology. Additionally bone mass and strength were significantly lower in the P3H1 mice as compared with wild-type littermates. Altogether these investigations demonstrate disturbances of collagen fiber architecture in tissues rich in fibrillar collagen, including bone, tendon, and skin. This model system presents a good opportunity to study the underlying mechanisms of recessive OI and to better understand its effects in humans.


[Structural Basis of the Multifunctional Hub Protein and Identification of a Small-molecule Compound for Drug Discovery].
Translesion DNA synthesis (TLS) is an emergency system activated to inhibit cell death caused by DNA damage-induced replication arrest. Thus, TLS enables cancer cells to acquire resistance to alkylate anticancer drugs. REV7 functions as the hub protein that interacts with both the inserter DNA polymerase REV1 and the extender DNA polymerase REV3 in TLS. REV7-mediated protein-protein interactions (PPIs) are essential for the activation of TLS, and are therefore attractive targets for anticancer drug development. To clarify the REV7-REV3 and REV7-REV1 PPIs, we determined the structures of REV7-REV3 and REV7-REV3-REV1 complexes. In the structures of REV7-REV3 and REV7-REV3-REV1 complexes, REV7 wraps around the REV3 fragment, and the REV1-binding interface is distinct from the REV3-binding site of REV7. We also identified a novel REV7 binding protein, transcription factor II-I (TFII-I), which is required for TLS. Of note, TFII-I binds the REV7-REV3-REV1 complex, suggesting that REV7-TFII-I PPIs are independent of other REV7-mediated PPIs. Furthermore, we found a small-molecule compound that inhibits TLS by targeting the REV7-REV3 PPIs. Lastly, we determined the structure of REV7 in complex with chromosome alignment maintaining phosphoprotein (CAMP), a known kinetochore-microtubule attachment protein. The overall structure of the REV7-CAMP complex is similar to that of the REV7-REV3 complex, but the REV7-CAMP PPIs are markedly different from the REV7-REV3 PPIs. These findings improve our understanding of multifunctional hub proteins, and are helpful for designing small-molecule compounds for novel anticancer drug development.


Antigen-Conjugated Silica Solid Sphere as Nanovaccine for Cancer Immunotherapy.
Nanocarriers could deliver significantly higher amounts of antigen to antigen-presenting cells (APCs), which have great potential to stimulate humoral and cellular response in cancer immunotherapy. Thereafter, silica solid nanosphere (SiO2) was prepared, and a model antigen (ovalbumin, OVA) was covalently conjugated on the surface of SiO2 to form nanovaccine (OVA@SiO2). And the application of OVA@SiO2 for cancer immunotherapy was evaluated. SiO2 solid nanosphere was prepared by the Stöber method, then successively aminated by aminopropyltriethoxysilane and activated with glutaraldehyde. OVA was covalently conjugated on the surface of activated SiO2 to obtain nanovaccine (OVA@SiO2). Dynamic light scattering, scanning electron microscope, and transmission electron microscope were conducted to identify the size distribution, zeta potential and morphology of OVA@SiO2. The OVA loading capacity was investigated by varying glutaraldehyde concentration. The biocompatibility of OVA@SiO2 to DC2.4 and RAW246.7 cells was evaluated by a Cell Counting Kit-8 assay. The uptake of OVA@SiO2 by DC2.4 and its internalization pathway were evaluated in the absence or presence of different inhibitors. The activation and maturation of bone marrow-derived DC cells by OVA@SiO2 were also investigated. Finally, the in vivo transport of OVA@SiO2 and its toxicity to organs were appraised. All results indicated the successful covalent conjugation of OVA on the surface of SiO2. The as-prepared OVA@SiO2 possessed high antigen loading capacity, which had good biocompatibility to APCs and major organs. Besides, OVA@SiO2 facilitated antigen uptake by DC2.4 cells and its cytosolic release. Noteworthily, OVA@SiO2 significantly promoted the maturation of dendritic cells and up-regulation of cytokine secretion by co-administration of adjuvant CpG-ODN. The as-prepared SiO2 shows promising potential for use as an antigen delivery carrier.


Follicle Stimulating Hormone (FSH) as a Predictor of Decreased Oocyte Yield in Patients with Normal Anti-Müllerian Hormone (AMH) and Antral Follicle Count (AFC).
The purpose of the current study was to determine the utility of early follicular phase follicle-stimulating hormone (FSH) testing in patients undergoing in vitro fertilization (IVF). This was a retrospective review of patients from 2012 to 2015 at Mayo Clinic in Rochester, Minnesota, USA. Included subjects had a normal anti-Müllerian hormone (AMH) of 1 to 9 ng/ml and antral follicle count (AFC) of 10 to 29. Patients were stratified by FSH level when associated estradiol was less than 50 ng/ml. In total, 225 patients were categorized into three groups: high FSH (FSH ≥10 IU/L; n= 36), normal FSH (>5 IU/L and <10 IU/L; n=170), and low FSH (FSH ≤5 IU/L; n= 19). ANOVA and multiple logistic regression were used for statistical comparisons and for evaluation of the relationships between variables; significance level was set at <0.05. There were no significant differences in demographics, IVF cycle type, or peak estradiol level between the groups. Patients with a high basal FSH level had a similar clinical pregnancy rate and live birth rate compared to controls and patients with low FSH. High FSH level was associated with decreased follicular development (17 versus 22; p<0.01), oocyte yield (15 versus 18; p=0.02), and embryo yield (8 versus 10; p=0.04) despite higher total doses of gonadotropins. Patients with normal AMH and AFC levels could be further stratified into lower responders and starting doses of medications can be adjusted based on high basal FSH levels. Therefore, it is suggested to counsel patients on pregnancy outcomes which seem to be quite similar regardless of the FSH level.


Comparison of contrast-normalization and threshold models of the responses of simple cells in cat striate cortex.
In almost every study of the linearity of spatiotemporal summation in simple cells of the cat's visual cortex, there have been systematic mismatches between the experimental observations and the predictions of the linear theory. These mismatches have generally been explained by supposing that the initial spatiotemporal summation stage is strictly linear, but that the following output stage of the simple cell is subject to some contrast-dependent nonlinearity. Two main models of the output nonlinearity have been proposed: the threshold model (e.g. Tolhurst & Dean, 1987) and the contrast-normalization model (e.g. Heeger, 1992a,b). In this paper, the two models are fitted rigorously to a variety of previously published neurophysiological data, in order to determine whether one model is a better explanation of the data. We reexamine data on the interaction between two bar stimuli presented in different parts of the receptive field; on the relationship between the receptive-field map and the inverse Fourier transform of the spatial-frequency tuning curve; on the dependence of response amplitude and phase on the spatial phase of stationary gratings; on the relationships between the responses to moving and modulated gratings; and on the suppressive action of gratings moving in a neuron's nonpreferred direction. In many situations, the predictions of the two models are similar, but the contrast-normalization model usually fits the data slightly better than the threshold model, and it is easier to apply the equations of the normalization model. More importantly, the normalization model is naturally able to account very well for the details and subtlety of the results in experiments where the total contrast energy of the stimuli changes; some of these phenomena are completely beyond the scope of the threshold model. Rigorous application of the models' equations has revealed some situations where neither model fits quite well enough, and we must suppose, therefore, that there are some subtle nonlinearities still to be characterized.


Effect of service dogs on manual wheelchair users with spinal cord injury: a pilot study.
Service dogs help people with mobility impairments. They are trained to perform a variety of tasks, such as opening doors, retrieving the telephone, picking up objects, and pulling manual wheelchairs (MWCs). More specifically, using the traction provided by the service dog has physical benefits because MWC users can operate their MWCs with less effort. The objective of this study was to document the effect of a service dog on MWC mobility and user shoulder pain, social participation, and quality of life. Eleven MWC users with spinal cord injury were assessed before and after training with a service dog and 7 mo later. Based on a standardized protocol, all study participants learned how to use the service dog safely and how to move around efficiently in different environments and under different conditions. Results showed that using a service dog increased the distance covered by the MWC users and also significantly decreased shoulder pain and intensity of effort. Using the service dog also produced slight but significant improvements in MWC user skills and social participation and may indicate a trend for improvement in quality of life. More extensive research is needed to precisely identify the effect of service dogs on the long-term management of MWC use.


The Effect of Parathyroidectomy on Risk of Hip Fracture in Secondary Hyperparathyroidism.
Secondary hyperparathyroidism increases the risk for fractures. Despite improvement in medical therapy, surgical parathyroidectomy (PTX) often becomes necessary, but its effect on risk of fractures is not clear. Our aim was to study the effect of parathyroidectomy on the risk of hip fractures in patients on dialysis or with a functioning renal graft at time of parathyroidectomy. In a cohort of 20,056 patients on dialysis or with functioning renal allograft, we identified 590 patients who underwent parathyroidectomy between 1991 and 2009. Of these, 579 were matched with 1970 non-PTX patients on age, sex, cause of renal disease and functioning renal allograft or not at the time of PTX or at the corresponding time for non-PTX patients (t). We calculated the risk for hip fracture after PTX using crude and adjusted Cox proportional hazards regressions, adjusting for time in renal replacement therapy before t, time with functioning renal allograft before and after t, comorbidity at t and a hip fracture before t. The adjusted hazard ratio (95% confidence interval) for hip fracture was 0.40 (0.18-0.88) for PTX patients, compared to non-PTX patients. When analyses were performed separately for sex, only women had a lower risk of hip fracture after PTX compared to non-PTX patients. The risk of hip fracture after PTX was similar in patients with or without functioning renal allograft at time for PTX. Parathyroidectomy is associated with a lower risk of hip fracture in female patients with secondary hyperparathyroidism.


Employing transposon mutagenesis to investigate foot-and-mouth disease virus replication.
Probing the molecular interactions within the foot-and-mouth disease virus (FMDV) RNA replication complex has been restricted in part by the lack of suitable reagents. Random insertional mutagenesis has proven an excellent method to reveal domains of proteins essential for virus replication as well as locations that can tolerate small genetic insertions. Such insertion sites can subsequently be adapted by the incorporation of commonly used epitope tags, facilitating their detection with commercially available reagents. In this study, we used random transposon-mediated mutagenesis to produce a library of 15 nt insertions in the FMDV nonstructural polyprotein. Using a replicon-based assay, we isolated multiple replication-competent as well as replication-defective insertions. We adapted the replication-competent insertion sites for the successful incorporation of epitope tags within FMDV non-structural proteins for use in a variety of downstream assays. Additionally, we showed that replication of some of the replication-defective insertion mutants could be rescued by co-transfection of a 'helper' replicon, demonstrating a novel use of random mutagenesis to identify intergenomic trans-complementation. Both the epitope tags and replication-defective insertions identified here will be valuable tools for probing interactions within picornavirus replication complexes.


Synthesis of evidence for reimbursement decisions: a Bayesian reanalysis.
The aim of this study was to compare Bayesian methods with the standard methods that are used for evidence-based policy making. We performed a Bayesian reanalysis of the data underlying a reimbursement advice by the Dutch National Health Insurance Board (CVZ) regarding the anti-diabetic drug exenatide (an alternative to insulin). We synthesized evidence from various sources that was available when the CVZ advice was drafted: expert opinion (as elicited from internists), experimental data (from direct comparison studies), and observational data. Subsequently, the original frequentist results and the results from the Bayesian reanalysis were compared in terms of outcomes and interpretations. These results were presented in a meeting with staff from CVZ, whose opinions about the usefulness of a Bayesian approach were assessed using a questionnaire. The Bayesian approach yields outcomes that summarize different pieces of evidence, which would have been difficult to obtain otherwise. Moreover, there are conceptual differences, and the Bayesian approach allows for determining probabilities of clinically relevant differences. The staff at CVZ were fairly positive with respect to the use of Bayesian methods, although practical barriers were also seen as important. The Bayesian outcomes are different and could be more suited to the informational needs of policy makers. The response from staff at CVZ provides some support for this statement, but more research at the interface of science and policy is needed.


Imaging of fiber-like structures in digital breast tomosynthesis.
Fiber-like features are an important aspect of breast imaging. Vessels and ducts are present in all breast images, and spiculations radiating from a mass can indicate malignancy. Accordingly, fiber objects are one of the three types of signals used in the American College of Radiology digital mammography (ACR-DM) accreditation phantom. Our work focuses on the image properties of fiber-like structures in digital breast tomosynthesis (DBT) and how image reconstruction can affect their appearance. The impact of DBT image reconstruction algorithm and regularization strength on the conspicuity of fiber-like signals of various orientations is investigated in simulation. A metric is developed to characterize this orientation dependence and allow for quantitative comparison of algorithms and associated parameters in the context of imaging fiber signals. The imaging properties of fibers, characterized in simulation, are then demonstrated in detail with physical DBT data of the ACR-DM phantom. The characterization of imaging of fiber signals is used to explain features of an actual clinical DBT case. For the algorithms investigated, at low regularization setting, the results show a striking variation in conspicuity as a function of orientation in the viewing plane. In particular, the conspicuity of fibers nearly aligned with the plane of the x-ray source trajectory is decreased relative to more obliquely oriented fibers. Increasing regularization strength mitigates this orientation dependence at the cost of increasing depth blur of these structures.


Effect of Self-Directed Home Therapy Adherence Combined with TheraBracelet on Poststroke Hand Recovery: A Pilot Study.
Hand impairment is a common consequence of stroke, resulting in long-term disability and reduced quality of life. Recovery may be augmented through self-directed therapy activities at home, complemented by the use of rehabilitation devices such as peripheral sensory stimulation. The objective of this study was to determine the effect of adherence to self-directed therapy and the use of TheraBracelet (subsensory random-frequency vibratory stimulation) on hand function for stroke survivors. In a double-blind, randomized controlled pilot trial, 12 chronic stroke survivors were assigned to a treatment or control group (n = 6/group). All participants were instructed to perform 200 repetitions of therapeutic hand tasks 5 days/week while wearing a wrist-worn device 8 hours/day for 4 weeks. The treatment group received TheraBracelet vibration from the device, while the control group received no vibration. Home task repetition adherence and device wear logs, as well as hand function assessment (Stroke Impact Scale Hand domain), were obtained weekly. Repetition adherence was comparable between groups but varied among participants. Participants wore the device to a greater extent than adhering to completing repetitions. A linear mixed model analysis showed a significant interaction between repetition and group (p = 0.01), with greater adherence resulting in greater hand function change for the treatment group (r = 0.94; R 2 = 0.88), but not for the control group. Secondary analysis revealed that repetition adherence was greater for those with lower motor capacity and greater self-efficacy at baseline. This pilot study suggests that adherence to self-directed therapy at home combined with subsensory stimulation may affect recovery outcomes in stroke survivors. This trial is registered with NCT04026399.


[Effects of histamine on proliferation, apoptosis and differentiation of human keratinocytes].
To investigate the effects of histamine on the proliferation, apoptosis and differentiation of human keratinocytes (HKC) and the mechanisms. The effect of histamine on the growth of HKC in vitro was examined by MTT assay and trypan blue exclusion assay. Cell cycle analysis and early apoptosis analysis by double staining with Annexin V-FITC and PI were carried out by flow cytometry. DNA ladder assay was performed for the detection of cell apoptosis. HKC free calcium concentration ([Ca(2+)](i)) was measured by laser scanning confocal microscopy in combination with calcium fluorescence probe Fluo-3/AM. HKC differentiation markers keratin 10 (K10) and involucrin was detected by streptavidinbiotin complex immunocytochemical assay. Histamine at high concentration inhibited the proliferation of HKC with cell viability ratio of 65.6% at 1 x 10(-4) mol/L, while histamine at low concentrations promoted proliferation of HKC with the cell viability ratio of 130.7% at 1 x 10(-8) mol/L. Histamine at 1 x 10(-4) mol/L altered cell cycle distribution of HKC with an increase in G0/G1-phase cell population to 30.97%, a decrease in S-phase population to 73.81% and inhibition of G1/S switching. Histamine at 1 x 10(-4) mol/L induced obvious apoptosis of HKC with early apoptosis ratio of 18.64% as compared with the control (5.60%, P<0.05). Histamine 1 x 10(-4) mol/L induced an increase of HKC [Ca(2+)](i) up to 58.9% and cimetidine (an H(2) receptor antagonist) decreased HKC [Ca(2+)](i) down to 25.4%. Histamine at this concentration down-regulated the expressions of K10 and involucrin of HKC but these changes were not significantly different from those of the control (P>0.05). Histamine at high concentrations inhibits cell cycle progress of HKC, mediates cell apoptosis and induces the increase of [Ca(2+)](i), which might be a partial explanation for growth arrest of HKC elicited by histamine. Histamine may regulate epidermal tissue turnover under physiological conditions, whereas under pathological circumstances of the skin as in trauma and inflammation, histamine at high concentrations may inhibit the regeneration of epidermis and the differentiation of HKC.


Effect of kainate on the membrane conductance of hilar glial precursor cells recorded in the perforated-patch configuration.
The effects of kainate on membrane current and membrane conductance were investigated in presumed hilar glial precursor cells of juvenile rats. The perforated-patch configuration was used also to reveal possible second-messenger effects. Kainate evoked an inward current that was accompanied by a biphasic change in membrane conductance in 69% of the cells. An initial conductance increase with a time course similar to that of the inward current was followed by a second delayed conductance increase. This second conductance was absent in whole-cell-clamp recordings, suggesting that it was mediated by a second messenger effect. Analysis of the reversal potentials of the membrane current during both phases of the kainate-induced conductance change revealed that the first conductance increase reflected the activation of AMPA receptors. Several lines of evidence suggest that the delayed second conductance increase was due to the indirect activation of Ca2+-dependent K+ channels via Ca2+-influx through AMPA receptors. (1) the delayed second conductance increase was blocked by Ba2+ and the reversal of its underlying current was significantly shifted towards EK+, suggesting that it is due to the activation of K+ channels. (2) The delayed second conductance increase disappeared in a Ca2+-free saline buffered with BAPTA, indicating that it depended on Ca2+-influx. (3) Co2+, Cd2+ and nimodipine failed to block the delayed second conductance increase excluding a major contribution of voltage-dependent Ca2+ channels. (4) The involvement of metabotropic glutamate receptors also appeared unlikely, because the kainate-induced delayed second conductance increase could not be blocked by a depletion of the intracellular Ca2+ stores with the Ca2+-ATPase inhibitor thapsigargin, and t-ACPD exerted no effect on membrane current and conductance. We conclude that kainate activates directly AMPA receptors in presumed hilar glial precursor cells. This results in a Ca2+ influx that could lead indirectly to the activation of Ca2+-dependent K+ channels.


Transition Structure Geometries for Transfers of Neutral and Anionic Nitrogen to Lithiated Carbanions.
The geometries of nucleophilic substitutions at neutral and anionic nitrogen by organolithium species have been investigated. The demonstration of an intramolecular conversion of 9 to 10 provides an endocyclic restriction test which supports a trigonal bipyramidal transition structure for nitrogen transfer. A lack of isotopic scrambling of 12a-18O during nitrogen transfer is taken to rule out reaction via an oriented ion pair. Attempted endocyclic restriction tests for transfers of formally anionic nitrogen with 32 and 33 were not successful. Reactions of n-butyl, s-butyl and tert-butyllithium reagents with 16, 23, 30, 31, and 36-38 generally afford higher yields with increasing substitution at the carbon of the organolithium reagent and with decreasing substitution adjacent to the nitrogen of the aminating reagent. These results are consistent with trigonal bipyramidal transition states for nucleophilic displacements of oxygen by carbon at neutral and anionic nitrogen.


Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study.
Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).


[Development features of regional population aging in Finland].
"Population ageing has emerged as one of the crucial problems facing developed countries. In Finland, the old population (aged 65 and over) has doubled in numbers over the past 30 years. The phenomena underlying this ageing trend include a decline in fertility, increase of the average life expectancy, and the effects of migration. Considerable regional differences in population ageing can be observed between Finland's provinces, municipalities and between their different parts. The number of the elderly is projected to increase in all provinces, the highest relative increase taking place in the provinces of Lapland, Uusimaa and Oulu between 1990-2020." (SUMMARY IN ENG)


VO2max during horizontal and inclined treadmill running.
The VO2max response of 12 well-trained and highly motivated college males was measured using two treadmill protocols: horizontal (H) and inclined (I). The duration of each test averaged 10 min. In the H test the treadmill bed was horizontal with the running rate held constant for the first 6 min, after which time it was increased at 1-min intervals to near maximal subject running speed, according to the HR response, until exhaustion. The I method simulated the protocol of Costill and Fox, with the treadmill speed at about 80-90% of mean maximal running rate established from 12- and 15-min track runs. The treadmill bed was held horizontal during the first 4 min, after which time it was elevated to 4% and elevated 2% each 2 min thereafter until exhaustion. No significant differences were found in VO2max, 4.267 1/min (I), and 4.192 1/min (H), average max HR, 190.4/MIN (I), and 188.9/min (H); respiratory rate, 56.4/min (I), and 62.0/min (H); and VEBTPS, 145.2 1/min (I), and 143.3 1/min (H). It was concluded that the intensities of both treadmill methods, H and I, were sufficient to produce a nonsignificant difference in maximal VO2 values with the type subjects employed.


The singing-group: a new therapic rehabilitation for mood desorders.
Psychosocial rehabilitation, and choral singing in particular, allow the recovery of lost or compromised ability of patients with mental illness and they facilitate the reintegration of the user in his family and into his social context. The choral singing, used as an operational tool for psychosocial rehabilitation, allowed users of the Day Centre of the Unit of Mental Health Torre del Greco ASL NA 3 South to achieve concrete goals of rehabilitation: improvement of self-care and self-esteem, the management of emotions, the growing of their interests, the integration and socialization overcoming the isolation of their mental suffering. In particular patients with mood disorders have been significantly benefited from the rehabilitation activity. They improved their mood and all the related diseases and the quality of their life with the result of a positive therapeutic implication. The singing group and for some individuals, also psychotherapy and drug therapy, have allowed users to improve their lives and give them a concrete integration into the society. Working in a group with patients, caregivers, family members, volunteers, social workers allowed a consolidated rehabilitation with the passing of time.Using the chorus group "Sing that you go" as an operational tool for psychosocial rehabilitation and therapeutic element we promote the psychological well-being and the enhancement of mood.


The gRNA Vector Level Determines the Outcome of Systemic AAV CRISPR Therapy for Duchenne Muscular Dystrophy.
Adeno-associated virus (AAV)-mediated clustered regularly interspaced short palindromic repeats (CRISPR) editing holds promise to restore missing dystrophin in Duchenne muscular dystrophy (DMD). Intramuscular coinjection of CRISPR-associated protein 9 (Cas9) and guide RNA (gRNA) vectors resulted in robust dystrophin restoration in short-term studies in the mdx mouse model of DMD. Intriguingly, this strategy failed to yield efficient dystrophin rescue in muscle in a long-term (18-month) systemic injection study. In-depth analyses revealed a selective loss of the gRNA vector after long-term systemic, but not short-term local injection. To determine whether preferential gRNA vector depletion is due to the mode of delivery (local vs. systemic) or the duration of the study (short term vs. long term), we conducted a short-term systemic injection study. The gRNA (4e12 vg/mouse in the 1:1 group or 1.2e13 vg/mouse in the 3:1 group) and Cas9 (4e12 vg/mouse) vectors were coinjected intravenously into 4-week-old mdx mice. The ratio of the gRNA to Cas9 vector genome copy dropped from 1:1 and 3:1 at injection to 0.4:1 and 1:1 at harvest 3 months later, suggesting that the route of administration, rather than the experimental duration, determines preferential gRNA vector loss. Consistent with our long-term systemic injection study, the vector ratio did not influence Cas9 expression. However, the 3:1 group showed significantly higher dystrophin expression and genome editing, better myofiber size distribution, and a more pronounced improvement in muscle function and electrocardiography. Our data suggest that the gRNA vector dose determines the outcome of systemic AAV CRISPR therapy for DMD.


Stress and quality of life in patients with gastrointestinal cancer.
This study aimed to answer the question whether it is possible to predict the quality of life in individuals with gastrointestinal cancer based on the number of life events, perceived stress levels and coping strategies. The study included 60 individuals (44 male and 16 female) aged 48 to 87 years, with malignant gastrointestinal tract diseases (56 with colon or rectal cancer, 2 with stomach cancer and 2 with pancreatic cancer). The following instruments were used: Questionnaire on General Information and Lifestyle Habits (developed for the purpose of this study); Scale for Measuring Quality of Life; Coping Inventory for Stressful Situations; and Life Events Scale. Results showed that the number of life events, perceived stress levels, emotion-oriented coping and avoidance were not predictive for the quality of life. Education was the only predictor for factors contributing to the quality of life (predictive variables on the Scale for Measuring Quality of Life). Task-oriented coping and education were predictors for satisfaction with past life and task-oriented coping was predictive for criterion variables on the Scale for Measuring Quality of Life and for factor related to future expectations and comparison to other people, but the proportion of explained variance was modest. The results of this study suggest that it is important to consider other variables (e.g., personality traits and sociodemographic factors) in predicting the quality of life and psychotherapeutic work with gastrointestinal cancer patients. It is important to bear in mind that there is no universally good individual coping strategy that is acceptable in all situations, but that coping flexibility or the ability to adequately change coping strategies in response to situational demands is by far more important.


Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction.
Several findings suggest lower levels of serum uric acid in multiple sclerosis (MS) patients. The aim of this study is to investigate relationships of uric acid serum levels in relapse-remitting (RR) MS patients with clinical activity of disease and blood-brain barrier (BBB) condition. Sixty-three definite RRMS patients and 40 controls divided into two groups: 20 healthy donors and 20 patients with other inflammatory neurological diseases (OINDs) were analysed. By using a quantitative enzymatic assay according to the manufacture's protocol and a commercial uric acid standard solution, serum uric acid levels were measured and the results were standardized. To investigate BBB function, magnetic resonance imaging after administration of gadolinium was used. MS patients were found to have significantly lower serum uric acid levels (193.89 +/- 49.05 micromol/l; mean value +/-SD) in comparison with healthy donors (292.7 +/- 58.65 micromol/l; P=0.000) and OIND patients (242.7 +/- 46.66 micromol/l; P=0.001). We found that MS patients with relapse had significantly lower serum uric acid levels (161.49 +/- 23.61 micromol/l) than MS patients with remission (234.39 +/- 41.96 micromol/l; P=0.000) and more over, MS patients with BBB disruption had significantly lower serum uric acid levels (163.95 +/- 26.07 micromol/l) than those with normal BBB (252.48 +/- 25.94 micromol/l; P=0.000). Further, we also found that serum uric acid level independently correlated with disease activity, BBB disruption, and gender. These results indicate that lower uric acid levels in MS patients are associated with relapse and suggest that uric acid might be beneficial in the treatment of MS.


Amble Gait EEG Points at Complementary Cortical Networks Underlying Stereotypic Multi-Limb Co-ordination.
Walking is characterized by stable antiphase relations between upper and lower limb movements. Such bilateral rhythmic movement patterns are neuronally generated at levels of the spinal cord and brain stem, that are strongly interconnected with cortical circuitries, including the Supplementary Motor Area (SMA). To explore cerebral activity associated with multi-limb phase relations in human gait by manipulating mutual attunement of the upper and lower limb antiphase patterns. Cortical activity and gait were assessed by ambulant EEG, accelerometers and videorecordings in 35 healthy participants walking normally and 19 healthy participants walking in amble gait, where upper limbs moved in-phase with the lower limbs. Power changes across the EEG frequency spectrum were assessed by Event Related Spectral Perturbation analysis and gait analysis was performed. Amble gait was associated with enhanced Event Related Desynchronization (ERD) prior to and during especially the left swing phase and reduced Event Related Synchronization (ERS) at final swing phases. ERD enhancement was most pronounced over the putative right premotor, right primary motor and right parietal cortex, indicating involvement of higher-order organization and somatosensory guidance in the production of this more complex gait pattern, with an apparent right hemisphere dominance. The diminished within-step ERD/ERS pattern in amble gait, also over the SMA, suggests that this gait pattern is more stride driven instead of step driven. Increased four-limb phase complexity recruits distributed networks upstream of the primary motor cortex, primarily lateralized in the right hemisphere. Similar parietal-premotor involvement has been described to compensate impaired SMA function in Parkinson's disease bimanual antiphase movement, indicating a role as cortical support regions.


The Prefrontal-Hippocampal Comparator: Volition and Episodic Memory.
This review describes recent research that is relevant to the prefrontal-hippocampal comparator model with the following conclusions: 1. Hippocampal area CA1 serves, at least in part, as an associative match-mismatch comparator. 2. Voluntary movement strengthens episodic memories for goal-directed behavior. 3. Hippocampal theta power serves as a prediction error signal during hippocampal dependent tasks. 4. The self-referential component of episodic memory in humans is mediated by the corollary discharge (the efference copy of the action plan developed by prefrontal cortex and transmitted to hippocampus where it is stored as a working memory; CA1 uses this efference copy to compare the expected consequences of action to the actual consequences of action). 5. Impairments in the production or transmission of this corollary discharge may contribute to some of the symptoms of schizophrenia. Unresolved issues and suggestions for future research are discussed.


[Disintegration of human spermatozoa in flow cytometry of semen].
In some cases, the pretreatment of human spermatozoa produced desintegration of various degrees, while in others a reduced staining was observed. For the evaluation of these phenomena the following techniques were applied: papain/DTE solution at pH 5.5 and 6.4, pepsin solution and a staining procedure without any preceeding decondensation of the spermatozoa nuclei. Pathological spermatozoa from patients with severe disorders of spermatogenesis showed an extended resistance to the pretreatment procedures, the spermatozoa being stained after papain/DTE pretreatment at pH 5.5 only. Contrary to this finding, normal spermatozoa and spermatozoa with slight morphological aberrations desintegrated when papain/DTE solutions were used. In this group the abortion rate was high.


Live-Attenuated Influenza Vaccine Induces Tonsillar Follicular T Helper Cell Responses That Correlate With Antibody Induction.
Influenza remains a major threat to public health. Live-attenuated influenza vaccines (LAIV) have been shown to be effective, particularly in children. Follicular T helper (TFH) cells provide B-cell help and are crucial for generating long-term humoral immunity. However the role of TFH cells in LAIV-induced immune responses is unknown. We collected tonsils, plasma, and saliva samples from children and adults receiving LAIV prior to tonsillectomy. We measured influenza-specific TFH-cell responses after LAIV by flow cytometry and immunohistochemistry. Systemic and local antibody responses were analysed by hemagglutination inhibition assay and enzyme-linked immunosorbent assay. We report that LAIV induced early (3-7 days post-vaccination) activation of tonsillar follicles and influenza-specific TFH-cell (CXCR5+CD57+CD4+ T cell) responses in children, and to a lesser extent in adults. Serological analyses showed that LAIV elicited rapid (day 14) and long-term (up to 1 year post-vaccination) antibody responses (hemagglutination inhibition, influenza-specific IgG) in children, but not adults. There was an inverse correlation between pre-existing influenza-specific salivary IgA concentrations and tonsillar TFH-cell responses, and a positive correlation between tonsillar TFH-cell and systemic IgG induction after LAIV. Our data, taken together, demonstrate an important role of tonsillar TFH cells in LAIV-induced immunity in humans.


Use of high-field intraoperative magnetic resonance imaging during endoscopic transsphenoidal surgery for functioning pituitary microadenomas and small adenomas located in the intrasellar region.
The usefulness of 1.5-T high-field intraoperative magnetic resonance (iMR) imaging during transsphenoidal surgery for functioning pituitary adenomas was retrospectively evaluated based on long-term endocrine remission from the records of 14 patients who underwent transsphenoidal surgery with iMR imaging for functioning pituitary microadenomas and small adenomas located in the intrasellar region. The maximum tumor diameter was 9.3 ± 2.6 mm. Patients were diagnosed with acromegaly (n = 7), prolactinoma (n = 4), and Cushing's disease (n = 3). If iMR imaging detected tumor remnants after resection, the resection cavity was reexamined and further resection was performed. Postoperative endocrine follow-up period was mean 33.7 ± 13.3 months. Tumor remnants were detected after the first resection in seven patients. Further resection was performed in five of these patients, and three achieved long-term endocrine remission. As a result, the overall long-term endocrine remission rate was 78.5% (11/14), instead of the 57.1% (8/14) that would be expected if iMR imaging had not been performed. Long-term endocrine remission had a tendency to be associated with the absence of tumor remnants on the final iMR images, but this was not significant (p = 0.09). Long-term endocrine remission was associated with presence of tumor remnants in the cavernous sinus on the final iMR images (p = 0.03). High-field iMR imaging is useful for depicting tumor remnants after resection, and increased the long-term endocrine remission rate for patients with functioning pituitary microadenomas and small adenomas.


Intracanalicular vestibular schwannomas: facial and hearing outcomes according to the location of the tumor in relation to the nerves of the internal auditory canal.
The objective was to evaluate whether the position of the nerves within the internal auditory canal (IAC) has any effect on preoperative and postoperative cochlear and facial nerve function in patients with intracanalicular vestibular schwannoma (VS) resected through the retrosigmoid transmeatal approach. Forty-four patients with sporadic intracanalicular VS, from a series of 710 patients with VS who underwent operations from January 1993 to April 2022, were retrospectively reviewed. The pattern of displacement of the cranial nerves and tumor within the IAC was recorded. Tumors were divided into 2 types: type T1A lesions had only anteriorly displaced nerves, and type T1B had posteriorly displaced vestibular nerves and anteriorly displaced facial and cochlear nerves. Differences in surgical outcomes between groups in terms of facial nerve function and hearing preservation were evaluated. Thirty-five cases (79.5%) were T1A tumors and 9 were T1B (20.5%). Gross-total resection and anatomical preservation of the facial and cochlear nerves were achieved in all patients. Postoperatively, all patients with T1A VS maintained normal facial nerve function; however, among T1B VS patients, 6 (67%) retained House-Brackmann grade I, 2 worsened to grade II, and 1 worsened to grade III at 6 months (p = 0.006). The 27 T1A VS patients with serviceable hearing maintained this status, and an additional patient with nonserviceable hearing improved to serviceable hearing; among T1B VS patients, only 2 of the 5 patients with serviceable hearing remained as such, 2 evolved to nonserviceable hearing, and 1 lost hearing after surgery (p = 0.0022). T1B VS patients had a 24-fold risk of facial nerve deterioration (relative risk [RR] 25.2, 95% CI 1.42-448.57, p = 0.028) and a 32-fold risk of hearing deterioration (RR 32.7, 95% CI 1.93-553, p = 0.016) after surgery. In intracanalicular VS, postoperative cochlear and facial nerve function are directly related to the location of the tumor in relation to the nerves, with worse outcomes in cases where the tumor is located between the vestibular and facial-cochlear nerves.


Attenuation of the macrophage inflammatory activity by TiO₂ nanotubes via inhibition of MAPK and NF-κB pathways.
Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity.


Isocyanate emission from PUR adhesives: influence of temperature, monomer content, and curing mechanism.
The isocyanate emission potential of polyurethane (PUR) adhesives was evaluated by measuring the area-specific emission rate (SERa;microg m(-2) h(-1)) in a laboratory emission test chamber. The chamber was constructed for the analysis of reactive substances allowing quantitative trapping of all isocyanate monomers emitted from the substrate. Isocyanates were analyzed as their 1-(2-pyridyl)piperazine derivatives by HPLC with fluorescence and UV detection. The influence of temperature, the content of the diisocyanate in the resin, and the system pressure were investigated. These parameter studies gave evidence thatthe diisocyanate emission from the resins is a gas-phase-limited mass transfer. The overall mass-transfer coefficient (beta = Ddelta(-1)) was calculated for HDI and MDI. From the temperature dependence of emission rates, the enthalpies of evaporation for 2,4'-MDI, 4,4'-MDI, and HDI from their resins were determined. The influence of monomer content on SERa followed Henry's and Raoult's laws in the cases of HDI and MDI, respectively, allowing the prediction of emission rates proportional to diisocyanate content. Therefore, from simple parameters such as application temperature and monomer content, isocyanate emission rates can be predicted. Additionally, MDI emission from curing PUR adhesives was studied. These results elucidate the influence of monomer reactivity and curing mechanism on the decrease of MDI emission with time.


Potential influence of the microbiome on infertility and assisted reproductive technology.
Although an altered vaginal microbiota has been demonstrated to affect parturition, its role in assisted reproductive technologies is uncertain. Nevertheless, the effect of known pathogens such as Mycoplasma tuberculosis, Chlamydia trachomatis, and Neisseria gonorrhoeae is clear, causing subclinical changes thought to be risk factors in subfertility. The Human Microbiome Project (HMP) has allowed for metagenomic studies to aid in characterizing normal vaginal flora. Recent findings from the HMP demonstrate that many different species of Lactobacillus are present in the vaginal tract, with a few that predominate. Studies that characterize the vaginal microbiome in assisted reproductive technology support the hypothesis that colonizing the transfer-catheter tip with Lactobacillus crispatus at the time of embryo transfer may increase the rates of implantation and live birth rate while decreasing the rate of infection. In addition, there is some evidence that a progesterone-resistant endometrium might increase the risk of an abnormal vaginal microbiome.


Up-regulation of miR-663a inhibits the cancer stem cell-like properties of glioma via repressing the KDM2A-mediated TGF-β/SMAD signaling pathway.
Emerging reports have shown that microRNAs (miRNAs) function as vital regulators in tumor development via modulating gene expression at the posttranscriptional level. Here, we explored the role and underlying mechanism of miR-663a in the proliferation, migration, invasion, and cancer stem cell-like (CSC) properties of glioma cells. Quantitative reverse transcription PCR (qRT-PCR) was implemented to detect miR-663a expression in glioblastoma tissues and the adjacent normal tissues. Additionally, gain- and loss-of-function assays of miR-633a were performed on U-251 MG cells or human primary glioblastoma cancer cells (pGBMC1). Cell proliferation, migration, invasion, CSC properties, and profiles of stem cell markers (including CD133, CD44) were examined by the MTT assay, Transwell assay, tumorsphere experiment, and Western blotting, respectively. The dual-luciferase reporter gene assay was performed to testify the targeted relationship between miR-663a and lysine demethylase 2A (KDM2A). The results showed that miR-663a was down-regulated in glioblastoma tissues and cells. Overexpressing miR-663a repressed the proliferation, migration, invasion, CSC properties of U-251 MG cells and pGBMC1, while miR-663a knockdown had the opposite effects. The in-vivo experiment confirmed that miR-663a repressed the growth of U-251 MG cells in nude mice. When cocultured with THP1 cells, U-251 MG cells gained enhanced proliferation, migration, invasion, and CSC properties. MiR-633a overexpression reversed THP1-mediated effects on U-251 MG cells, and reduced the "M2" polarization of THP1 cells. What's more, Mechanistically, KDM2A was targeted by miR-663a. KDM2A knockdown suppressed the progression and CSC properties of U-251 MG cells in vitro, and dampened TGF-β. Overall, those data revealed that up-regulating miR-663a reduced glioma progression by inhibiting the KDM2A-mediated TGF-β/Smad pathway.


Carcinogenicity of 1,3-butadiene.
1,3-Butadiene, a high-production volume chemical used largely in the manufacture of synthetic rubber, is a multiple organ carcinogen in rats and mice. In inhalation studies conducted in mice by the National Toxicology Program, high rates of early lethal lymphomas occurring at exposure levels of 625 ppm or higher reduced the development and expression of later developing tumors at other sites. Use of survival-adjusted tumor rates to account for competing risk factors provided a clearer indication of the dose responses for 1,3-butadiene-induced neoplasms. An increase in lung tumors in female mice was observed at exposure concentrations as low as 6.25 ppm, the lowest concentration ever used in a long-term carcinogenicity study of this gas. Human exposures to 1,3-butadiene by workers employed at facilities that produce this chemical and at facilities that produce styrene-butadiene rubber have been measured at levels higher than those that cause cancer in animals. Furthermore, epidemiology studies have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers. In response to the carcinogenicity findings for 1,3-butadiene in animals and in humans, the Occupational Safety and Health Administration has proposed lowering the occupational exposure standard for this chemical from 1000 ppm to 2 ppm. Future work is needed to understand the mechanisms of tumor induction by 1,3-butadiene; however, the pursuit of this research should not delay the reduction of human exposure to this chemical.


Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration.
Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age-associated diseases. The ubiquitin-proteasome and autophagy-lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age-related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy-lysosome and ubiquitin-proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age-related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age-related neurodegeneration.


Dumbbell-Shaped Epidural Cavernous Hemangioma in the Thoracic Spine Mimicking Schwannoma.
Dumbbell-shaped epidural cavernous hemangiomas (CHs) are extremely rare, and they are easily misdiagnosed as spinal schwannomas. Herein, the authors report 1 rare case of dumbbell-shaped epidural CH in the thoracic spine. To the best of our knowledge, only a few cases of dumbbell-shaped epidural CHs in thoracic spine have been reported. Furthermore, the clinical characteristics and treatments for spinal epidural CHs were investigated and reviewed.


The influence of doxazosin, an alpha1-adrenergic receptor antagonist on the urinary bladder contractility in pigs.
In the present study influence of doxazosin on the porcine urinary bladder contractility has been examined. Immature pigs were treated for 30 days with: a) doxazosin (n = 5) per os at a dose of 0.1 mg/kg b.w. or b) placebo (n = 5; control group). Thereafter, animals were sacrificed and urinary bladder strips from the trigone were suspended in organ baths. The tension of the smooth musce was measured before and after exposition to acetylocholine (ACh; 10(-5) - 10(-3) M), norepinephrine (NE; 10(-9) - 10(-7) M) and 5-hydroxytryptamine (5-HT; 10(-7) - 10(-5) M). Both the ACh and 5-HT at the highest doses significantly increased the contractility in each group, but this response was weaker in doxazosin-treated animals. NE caused relaxation in both groups, but the effect was weaker in doxazosine-treated group. The results of our study have shown that long-term administration of doxazosin caused a desensitization of the detrusor smooth muscle for in vitro applied mediators of the autonomic nervous systems.


Strong Enhancement of the Spin Hall Effect by Spin Fluctuations near the Curie Point of Fe_{x}Pt_{1-x} Alloys.
Robust spin Hall effects (SHE) have recently been observed in nonmagnetic heavy metal systems with strong spin-orbit interactions. These SHE are either attributed to an intrinsic band-structure effect or to extrinsic spin-dependent scattering from impurities, namely, side jump or skew scattering. Here we report on an extraordinarily strong spin Hall effect, attributable to spin fluctuations, in ferromagnetic Fe_{x}Pt_{1-x} alloys near their Curie point, tunable with x. This results in a dampinglike spin-orbit torque being exerted on an adjacent ferromagnetic layer that is strongly temperature dependent in this transition region, with a peak value that indicates a lower bound 0.34±0.02 for the peak spin Hall ratio within the FePt. We also observe a pronounced peak in the effective spin-mixing conductance of the FM/FePt interface, and determine the spin diffusion length in these Fe_{x}Pt_{1-x} alloys. These results establish new opportunities for fundamental studies of spin dynamics and transport in ferromagnetic systems with strong spin fluctuations, and a new pathway for efficiently generating strong spin currents for applications.


Cytochrome P450 interactions are common and consequential in Massachusetts hospital discharges.
Despite the recognition that drug-drug interactions contribute substantially to preventable health-care costs, the prevalence of such interactions related to the cytochrome P450 system in clinical practice remains poorly characterized. This study drew retrospective hospital discharge cohorts from a large health claims data set and a large health system data set. For every hospital discharge, frequency of co-occurrence of substrates and inducers or inhibitors at cytochrome P450 2D6, 2C19, 3A4 and 1A2 were determined. A total of 124 520 individuals in the state of Massachusetts (health claims cohort) and 77 026 individuals in two large academic medical centers (electronic health record (EHR) cohort) were examined. In the claims cohort, 35 157 (28.2%) exhibited at least one CYP450 drug-drug interaction at hospital discharge, whereas in the EHR cohort, 36 750 (47.7%) had at least one interaction. The most commonly affected CYP450 systems were 2C19 and 2D6, with putative interactions observed in at least 10% of individuals at discharge in each cohort. Odds of hospital readmission within 90 days among those discharged with at least one interaction were 10-16% greater, with mean health-care cost $574/month greater over the subsequent year, after adjusting for age, sex, insurance type, total number of medications prescribed, Charlson comorbidity score and presence or absence of a psychiatric diagnosis. These two distinct clinical data types show that CYP450 drug-drug interactions are prevalent and associated with greater probability of early hospital readmission and greater health-care cost, despite the widespread availability and application of drug-drug interaction checking software.


Orientation of polymer functionalized nanorods in thin films.
A directed self assembly of anisotropic nanostructures offers a possibility to provide unique functional materials, which are e.g., important in optoelectronic devices. We use the liquid crystalline behavior of polymer functionalized TiO2 and ZnO nanorods to apply methods well known for low molecular liquid crystals to achieve oriented thin films. Convective forces in the meniscus on a structured substrate obtain thin layers of oriented nanoparticles with a ordering parameter of S = 0.7. As another method we present the orientation of polystyrene covered ZnO nanorods under an applied electric field. The method offers a perpendicular alignment of the rods to the surface.


[Cellular immune reaction in acute and chronic viral hepatitis (author's transl)].
The course of viral hepatitis is markedly influenced by the immunologic response to the infective agent. The immune defense of viral diseases is specially connected to an intact function of T lymphocytes. Investigation of T cell function during acute and chronic viral hepatitis showed an altered immune response, recognizable from the relative number of T lymphocytes, the affinity and ability of lymphocytes to be stimulated by phytohemagglutinin and the demonstration of in vivo activated lymphocytes. Although the interpretation of some of these findings is still difficult, the study of the various cellular immune reactions permits a better understanding of the pathogenesis and course of viral hepatitis.


Physiological responses of beet and cabbage plants exposed to copper and their potential insertion in human food chain.
Copper (Cu) can be toxic to vegetables when it is absorbed and accumulated at large concentrations, a fact that increases the risk of excessive addition of this metal to the human food chain. The aims of the current study are (1) to determine the Cu concentrations that have critical toxic effects on beet and cabbage plants, and the potential of these plants to enter the human food chain, as well as (2) to assess the physiological and biochemical responses of representatives of these vegetables grown in nutrient solution presenting increasing Cu concentrations. Beet and cabbage plants were grown for 75 days in pots filled with sand added with nutrient solution presenting six Cu concentrations: 0.00, 0.52, 1.02, 1.52, 2.02 and 2.52 mg Cu L-1. Dry matter yield and Cu accumulation in different plant organs were evaluated. Photosynthetic pigment contents, lipid peroxidation levels (TBARs), superoxide dismutase (SOD) and peroxidase (POD) activity and hydrogen peroxide (H2O2) concentrations in leaves were evaluated. Critical Cu concentrations that led to toxicity in plant organs such as beetroot and cabbage head, which are often found in human diets, corresponded to 1.43 mg Cu L-1 and 1.59 mg Cu L-1, respectively. High Cu concentrations in the nutrient solution have increased Cu concentrations and accumulation in plant tissues. This outcome justified the increased POD and SOD enzyme activity in the leaves of beet and cabbage plants, respectively, and was the cause of reduced plant growth in both crops. Cabbage plants presented higher tolerance to increased Cu levels in the growing environment than beet plants. However, it is necessary being careful at the time to consume both vegetables, when they are grown in Cu-enriched environments.


Photochemotherapy inhibits angiogenesis and induces apoptosis of endothelial cells in vitro.
Photochemotherapy has long been used in the treatment of psoriasis; however, its mechanism has not been completely elucidated. Psoriasis is now regarded as an angiogenesis-related disease. Recent studies indicated that the inhibition of angiogenesis by photochemotherapy could be an underlying mechanism. It was found that photochemotherapy can downregulate the expression of angiogenic factors in keratinocytes. However, the direct effect of photochemotherapy on endothelial cells has not been studied. In this study, we determined the effect of photochemotherapy on the proliferation of human microvascular endothelial cells through MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and cell cycle analysis. The migration assay and in vitro tube formation assay were used to investigate the migration properties and tube formation ability of human microvascular endothelial cells after psoralen plus UVA (PUVA) treatment. The apoptosis of endothelial cells elicited by photochemotherapy was also analyzed with fluorescence-activated cell sorting analysis (FACS). UVA (0.8-5.0 J/cm(2)) irradiation with the presence of 8-methoxypsoralen (8-MOP) (300 ng/ml) resulted in a dose-dependent reduction in the cell viabilities of endothelial cells. FACS data showed an accumulation of cells in G0/G1 phase of cell cycle and apoptotic features of cell death after UVA irradiation with psoralen. The migration properties and tube formation ability of endothelial cells were dramatically inhibited by photochemotherapy. Our results showed that photochemotherapy inhibits angiogenesis and induces apoptosis of human microvascular endothelial cells in vitro, which may be a possible mechanism of photochemotherapy in the treatment of psoriasis.


Social and other environmental influences on the cognitive and personality development of low birthweight infants.
Research on the cognitive development of low-birthweight infants was reviewed, followed by suggestions for promising future research strategies. On-going studies at the Rose F. Kennedy Center were described to illustrate the proposed model. Central features of the expanded approach are as follows: The study of high-risk populations should include, beyond biologic and broadly conceived social measures and beyond cognitive outcome, measures of development in the psychosocial domain. Further, detailed assessment of the children's daily life and behavior patterns can provide clues for causal linkages to account for the association between social economic status and cognitive development.


Metamemory in a familiar place: The effects of environmental context on feeling of knowing.
Feeling-of-knowing (FOK) judgments are judgments of future recognizability of currently inaccessible information. They are known to depend both on the access to partial information about a target of retrieval and on the familiarity of the cue that is used as a memory probe. In the present study we assessed whether FOK judgments could also be shaped by incidental environmental context in which these judgments are made. To this end, we investigated 2 phenomena previously documented in studies on recognition memory-a context familiarity effect and a context reinstatement effect-in the procedure used to investigate FOK judgments. In 2 experiments, we found that FOK judgments increase in the presence of a familiar environmental context. The results of both experiments further revealed still higher FOK judgments when made in the presence of environmental context matching the encoding context of both cue and its associated target. The effect of context familiarity on FOK judgment was paralleled by an effect on the latencies of an unsuccessful memory search, but the effect of context reinstatement was not. Importantly, the elevated feeling of knowing in reinstated and familiar contexts was not accompanied by an increase in the accuracy of those judgments. Together, these results demonstrate that metacognitive processes are shaped by the overall volume of memory information accessed at retrieval, independently of whether this memory information is related to a cue, a target, or a context in which remembering takes place. (PsycINFO Database Record


Sarcopenia and liver transplant: The relevance of too little muscle mass.
Loss of muscle mass and function is a common occurrence in both patients with decompensated cirrhosis and those undergoing liver transplantation. Sarcopenia is associated with morbidity and mortality before and after liver transplantation. The ability of skeletal muscle mass to recover after transplant is questionable, and long term adverse events associated with persistent sarcopenia have not been well studied. Limited data is available examining mechanisms by which decreased muscle mass might develop. It is not clear which interventions might reduce the prevalence of sarcopenia and associated health burdens. However, measures to either decrease portal hypertension or improve nutrition appear to have benefit. Research on sarcopenia in the liver transplant setting is hampered by differing methodology to quantify muscle mass and varied thresholds determining the presence of sarcopenia. One area highlighted in this review is the heterogeneity used when defining sarcopenia. The health consequences, clinical course and potential pathophysiologic mechanisms of sarcopenia in the setting of cirrhosis and liver transplantation are further discussed.


The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation.
The origin of brown adipocytes arising in white adipose tissue (WAT) after cold acclimatization is unclear. Here, we demonstrate that several UCP1-immunoreactive brown adipocytes occurring in WAT after cold acclimatization have a mixed morphology (paucilocular adipocytes). These cells also had a mixed mitochondrioma with classic "brown" and "white" mitochondria, suggesting intermediate steps in the process of direct transformation of white into brown adipocytes (transdifferentiation). Quantitative electron microscopy disclosed that cold exposure (6 degrees C for 10 days) did not induce an increase in WAT preadipocytes. beta(3)-adrenoceptor-knockout mice had a blunted brown adipocyte occurrence upon cold acclimatization. Administration of the beta(3)-adrenoceptor agonist CL316,243 induced the occurrence of brown adipocytes, with the typical morphological features found after cold acclimatization. In contrast, administration of the beta(1)-adrenoceptor agonist xamoterol increased only the number of preadipocytes. These findings indicate that transdifferentiation depends on beta(3)-adrenoceptor activation, whereas preadipocyte recruitment is mediated by beta(1)-adrenoceptor. RT-qPCR experiments disclosed that cold exposure induced enhanced expression of the thermogenic genes and of genes expressed selectively in brown adipose tissue (iBAT) and in both interscapular BAT and WAT. beta(3)-adrenoceptor suppression blunted their expression only in WAT. Furthermore, cold acclimatization induced an increased WAT expression of the gene coding for C/EBPalpha (an antimitotic protein), whereas Ccna1 expression (related to cell proliferation) was unchanged. Overall, our data strongly suggest that the cold-induced emergence of brown adipocytes in WAT predominantly reflects beta(3)-adrenoceptor-mediated transdifferentiation.


Assessment of Tear Film and Bulbar Redness by Keratograph 5M in Pediatric Patients After Orthokeratology.
To assess the tear meniscus height (TMH), noninvasive tear breakup time (NITBUT), and bulbar redness in pediatric patients after orthokeratology (OK). Pediatric patients who underwent overnight OK between December 2014 and November 2017 were retrospectively investigated. According to the time of wearing, subjects were divided into three groups: 1-week, 1-month, and over 1-year. Age-matched subjects were recruited as a control group. Keratograph 5M was used to assess TMH, NITBUT-first, NITBUT-average, and bulbar redness score. A total of 106 subjects aged from 7 to 15 years were included. Compared with control group, NITBUT-first was significantly lower in 1-week group (P=0.036) and NITBUT-average was significantly lower in 1-month group (P=0.019). Compared with over 1-year group, NITBUT-first was significantly lower in 1-week and 1-month groups (P=0.014, P=0.035, respectively), and NITBUT-average was significantly lower in 1-month group (P=0.022). Bulbar redness score was significantly lower in 1-month group than 1-week group (P=0.004). No significant difference in TMH was found between all groups. Significant correlation was found between NITBUT-first and NITBUT-average in all subjects (R=0.812, P<0.001). No other significant correlations were found between variables included TMH, NITBUT, bulbar redness score, or target correction. As a noninvasive method, Keratograph 5M was easily to be applied on pediatric patients. The OK lens did not induce significant tear deficiency or bulbar redness, but might affect tear film stability in a short term after wearing.


Between goat-farm biological variability of the nematode Muellerius capillaris first-stage larvea. Influence of anthelmintic treatment.
Seven dairy-goat farms from the centerwest of france were investigated for morphology and ecology of first-stage larvae (L1) of Muellerius capillaris before and after treatment of goats with febantel, a probenzimidazole anthelmintic. The lengths, survivals at 20 and -20 degrees C, and infectivity of L1 to intermediate host Helix aspersa, were different between farms. The between farms differences in survivals were reduced after treatment of goats with febantel. The observed between farm differences in L1 did not seem to be related to farm characteristics (intensity of treatments, susceptibility to febantel, and intermediate host species).


Zinc deficiency and peripheral neuropathy in chicks.
Zinc-deficient chicks develop an arthritic-like neuromuscular disorder. They walk with a stilted gait and tend to remain in a squat position, bearing little weight on the legs. The purpose of this study was to determine the basis of the syndrome by making electrophysiologic measurements of nerve function. Chicks were fed low zinc (6 mg/kg) and zinc-adequate (50 mg/kg) diets, the latter ad libitum and pair-fed. At the end of 3 weeks, sciatic nerve function was determined in vivo by use of an electrodiagnostic system. Motor nerve conduction velocity was significantly lower in chicks fed the low zinc than in those fed the zinc-adequate diet. Zinc repletion of the 2-week depleted chicks was achieved by feeding the adequate diet for 2 weeks. Repletion for this period cured clinical signs and restored nerve conduction velocity to normal, but reversal did not occur within 1 week. It was concluded that the abnormal posture and locomotion of zinc deficiency are associated with peripheral neuropathy.


Persistent Proclivity to a Proinflammatory State in a Human Enteroid Model of Necrotizing Enterocolitis.
Background: Necrotizing enterocolitis (NEC) is a devastating disease of premature neonates with substantial morbidity and mortality. Necrotizing enterocolitis is associated with prematurity, a hyperinflammatory response, and dysregulation of intestinal barrier function. We hypothesize that patients with NEC will have an increased hyperinflammatory intestinal response compared with those without NEC. Patients and Methods: Enteroids were generated from intestinal tissue from neonates undergoing resection. They were treated with 100 mcg/mL lipopolysaccharide (LPS), subjected to 24 hours of hypoxia inducing experimental NEC, then compared with untreated controls. Expression of tumor necrosis factor (TNF-α) and interleukin 8 (IL-8) were evaluated via reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure inflammatory response. Analysis of variance (ANOVA) determined statistical significance (p < 0.05). Results: Treated NEC-derived enteroids expressed significantly higher levels of IL-8 (RT-qPCR, p = 0.003; ELISA, p = 0.0002) compared with untreated NEC-derived enteroids with an increase in inflammatory marker concentration in those with a greater degree of prematurity (ELISA, p = 0.0015). A higher level of IL-8 was seen in NEC-derived enteroids compared with control after treatment (RT-qPCR, p = 0.024). Tumor necrosis factor-α levels were elevated in treated NEC-derived enteroids compared with untreated NEC-derived enteroids (RT-qPCR, p = 0.006; ELISA, p = 0.002) and compared with treated non-NEC-derived enteroids (RT-qPCR, p = 0.025; ELISA, p < 0.0001). Conclusions: Enteroids generated from neonates with NEC have an elevated hyperinflammatory response in response to NEC-inducing stimuli compared with controls. Enteroids generated from neonates with NEC with a greater degree of prematurity have a larger increase in inflammatory markers. This tendency toward a hyperinflammatory state may be correlated with an infant's proclivity to develop NEC and further demonstrates the hyperinflammatory state of prematurity.


Perfect study, poor evidence: interpretation of biases preceding study design.
In the interpretation of research evidence, data that have been accumulated in a specific isolated study are typically examined. However, important biases may precede the study design. A study may be misleading, useless, or even harmful, even though it seems to be perfectly designed, conducted, analyzed, and reported. Some biases pertain to setting the wider research agenda and include poor scientific relevance, minimal clinical utility, or failure to consider prior evidence (non-consideration of prior evidence, biased consideration of prior evidence, or consideration of biased prior evidence). Other biases reflect issues in setting the specific research questions: examples include straw man effects, avoidance of head-to-head comparisons, head-to-head comparisons bypassing demonstration of effectiveness, overpowered studies, unilateral aims (focusing on benefits and neglecting harms), and the approach of the industry towards research as bulk advertisement (including ghost management of the literature). The concerted presence of such biases may have a multiplicative, detrimental impact on the scientific literature. These issues should be considered carefully when interpreting research results.


Extensive exon reshuffling over evolutionary time coupled to trans-splicing in Drosophila.
The relative position of exons in genes can be altered only after large structural mutations. These mutations are frequently deleterious, impairing transcription, splicing, RNA stability, or protein function, as well as imposing strong inflexibility to protein evolution. Alternative cis- or trans-splicing may overcome the need for genomic structural stability, allowing genes to encode new proteins without the need to maintain a specific exon order. Trans-splicing in the Drosophila melanogaster modifier of mdg4 (mod[mdg4]) gene is the best documented example in which this process plays a major role in the maturation of mRNAs. Comparison of the genomic organization of this locus among several insect species suggests that the divergence between the lineages of the mosquito Anopheles gambiae and D. melanogaster involved an extensive exon rearrangement, requiring >11 breakpoints within the mod(mdg4) gene. The massive reorganization of the locus also included the deletion or addition of a new function as well as exon duplications. Whereas both DNA strands are sense strands in the Drosophila gene, the coding region in mosquito lays in a single strand, suggesting that trans-splicing may have originated in the Drosophila lineage and might have been the triggering factor for such a dramatic reorganization.


Access Osteotomy in the Maxillofacial Skeleton.
Surgical accesses for the facial skeleton are based on the concept of modular osteotomies. Various techniques and combination of osteotomies facilitate access to the most inaccessible tumors of craniomaxillofacial region. Most appropriate surgical access is determined by considering size, location, extension of the tumor, and experience of the surgical team. These are primarily used for tumors in the nasopharynx or the skull base. The aim of this paper is to review surgical accesses that aid in removal of inaccessible tumors of craniomaxillofacial region with series of cases operated in the Department of Oral and Maxillofacial Surgery, Armed Forces Medical College, Pune, India, between July 2008 and June 2010. The surgical approaches constituted of transfacial, transoral, lip-split mandibulotomy and modified osteotomy of the orbital rim in cases of juvenile nasoangiofibroma, squamous cell carcinoma of the base of the tongue, orbital floor tumour respectively. Only 3 cases (33.33%) reported with postoperative paresthesia of the infraorbital region and mandibular symphysis region which resolved in 6 months. None of the patients presented with occlusal discrepancy, neuromotor deficit or sign of recurrence in the follow up period of one year.


Surgical care of the HIV-infected patient: a moral imperative.
An increasing number of HIV-infected patients require surgical care. Many surgeons, regardless of their venue of practice, would prefer not to treat HIV-infected patients. The reasons for this attitude differ from individual to individual but include the fear of contracting an incurable fatal illness, a desire to avoid interaction with homosexuals and intravenous drug users, and fears that occupationally acquired HIV infection would result in restriction of clinical privileges and loss of income. At the same time, many individuals, institutions, and professional organizations have affirmed the obligation of all healthcare workers, including surgeons, to care for patients without regard to their HIV status. This article explores the nature of this obligation from the perspective of a clinical surgeon working in an inner city hospital.


The Criminal Justice Experience of African American Cocaine Users in Arkansas.
African Americans are incarcerated at rates much higher than other racial and ethnic groups in the United States. We sought to qualitatively explore the relationships between ongoing involvement in the criminal justice system and continued drug use in a population of urban and rural African American cocaine users in a southern state. Semi-structured qualitative interviews were conducted among African American cocaine users in Arkansas between 2010 and 2012. Participants resided in both rural (two counties located in the eastern Arkansas Mississippi delta region) and urban (the county including the capital city of Little Rock) areas. Numerous important themes emerged from participants' narratives, including chronic involvement with the criminal justice system (being a "career criminal"), continued access to drugs while incarcerated, relapse, and reincarceration and lack of access to effective drug treatment. Conclusion/Importance: The themes which emerged from our data speak to the collective experience that many substance using populations in the United States face in dealing with the criminal justice system. Our findings highlight the need to better, more holistic ways of engaging African American substance users in community based substance use treatment and supportive services.


Aminoglycosides modified by resistance enzymes display diminished binding to the bacterial ribosomal aminoacyl-tRNA site.
Understanding the basic principles that govern RNA binding by aminoglycosides is important for the design of new generations of antibiotics that do not suffer from the known mechanisms of drug resistance. With this goal in mind, we examined the binding of kanamycin A and four derivatives (the products of enzymic turnovers of kanamycin A by aminoglycoside-modifying enzymes) to a 27 nucleotide RNA representing the bacterial ribosomal A site. Modification of kanamycin A functional groups that have been directly implicated in the maintenance of specific interactions with RNA led to a decrease in affinity for the target RNA. Overall, the products of reactions catalyzed by aminoglycoside resistance enzymes exhibit diminished binding to the A site of bacterial 16S rRNA, which correlates well with a loss of antibacterial ability in resistant organisms that harbor these enzymes.


Prediction of volumetric change in the "triple ring" caused by glioma I-125 brachytherapy.
The aim of this study was to reveal the volumetric changes in tumor necrosis, reactive zone, and edema referred to as the "triple ring" appearing after low-dose-rate iodine-125 (I-125) interstitial irradiation of 20 inoperable low-grade gliomas. To enable prediction of these volumetric changes, we provide mathematical expressions that describe the dynamics of the triple ring. Volumes of the three regions on image-fused control CT/MR images were measured for a 24-month period. The delivered dose on the tumor surface was 50-60 Gy. Dose planning and image fusion were performed with Brain-Lab Target 1.19 software; mathematical and statistical computations were carried out with Matlab numeric computation and visualization software. To determine the volumes, control images with the triple rings were fused with the planning images. Relative volumes normalized with respect to the volume of reference dose were calculated and plotted in the time domain. First, the mean values of volumes were determined from the patients' measured data; then, polynomials were fitted to the mean values using the polynomial curve-fitting method. The accuracy of our results was verified by correlating the predicted data with the measured ones. The polynomial prediction approach proposed here reveals the dynamics of the triple ring. These polynomials will assist with (1) designing the best treatment, (2) following the patient's condition, and (3) planning reirradiation if necessary.


Design, Synthesis, and Fungicidal Activity against Rice Sheath Blight of Novel N-Acyl-1,2,3,4-tetrahydroquinoline Derivatives.
To discover fungicides with novel targets, a series of N-acyl-1,2,3,4-tetrahydroquinoline (NATHQ) derivatives were designed and synthesized by linking the active substructure NATHQ moiety in aspernigerin with the O-benzyl oxime-ether scaffold in commercial agrochemicals. Target compound structures were identified using proton and carbon-13 nuclear magnetic resonance spectroscopies and high-resolution mass spectrometry. Preliminary bioassays indicated that at 40 mg/L, some target compounds exhibited moderate to considerable in vitro fungicidal activities against Rhizoctonia solani and Botrytis cinerea. In particular, compound 3j exhibited higher fungicidal activities both in vitro (EC50 = 0.733 mg/L) and in vivo (EC50 = 15.2 mg/L) against R. solani than the commercial fungicide prochloraz; therefore, it should be a promising fungicide candidate against rice sheath blight. Additionally, compound 3j exhibited good laccase inhibitory activity (73.2% at 200 mg/L). Molecular docking revealed that the bis-cyano-oxime-ether moiety of compound 3j exhibited an excellent binding mode with the laccase target protein and could be used as a lead compound for developing laccase inhibitors. The structural features of these NATHQ derivatives will provide inspiration for developing laccase inhibitors and discovering more effective fungicides to control agricultural diseases.


Extended pancreatic resections and lymphadenectomy: An appraisal of the current evidence.
Surgery remains the mainstay of treatment for pancreatic ductal adenocarcinoma and complete removal of the cancer confers a definite survival advantage, especially in early disease. However, the majority of patients do not present with early disease, thus precluding the chance of a cure by standard pancreatoduodenectomy (PD), distal pancreatectomy or total pancreatectomy. For this reason, pancreatic surgeons have attempted to push the limits of resection over the last three decades. The aim of these resections has been to determine whether obtaining a complete resection by extending the limits of conventional resection in patients with advanced disease will yield the results seen with PD alone in early disease. This article revisits the data from such studies in an attempt to determine if the available literature supports the performance of extended resections for pancreatic cancer in terms of improvement of survival.