Downregulation of miR-152 contributes to the progression of liver fibrosis via targeting Gli3 in vivo and in vitro.
The Gli family is known to be required for the activation of hedgehog signalling, which participates in the pathogenesis of liver fibrosis. The aim of the present study was to identify the association between microRNA (miR)-152 and GLI family zinc finger 3 (Gli3) and their roles in liver fibrosis. In a carbon tetrachloride (CCl4)-treated rat model, fibrogenesis-associated indexes, including hydroxyproline content, collagen deposition, and α-smooth muscle actin (α-SMA) and albumin expression, were examined in in vivo and in vitro models. The expression of miR-152 and Gli3 in cells and tissues was determined by reverse transcription quantitative polymerase chain reaction and western blot analysis. The interaction of Gli3 and miR-152 was evaluated by bioinformatical analysis and a dual-luciferase reporter assay. The results demonstrated that miR-152 was significantly downregulated in serum samples from clinical patients, liver tissues from CCl4-treated rats and activated LX2 cells. Furthermore, at the cellular level, the mRNA and protein expression levels of α-SMA and albumin were increased and decreased, respectively, in LX2 cells. Nevertheless, following transfection with an miR-152 mimic, the expression levels of α-SMA and albumin were reversed, and Gli3 expression was notably decreased in LX2 cells. Additionally, the target interaction between miR-152 and Gli3 was demonstrated. Finally, an miR-152 mimic was introduced into the rat model and additionally demonstrated that the changes in α-SMA, albumin and Gli3 expression levels were similar to the expression pattern in LX2 cells following miR-152 mimic transfection. These data provided insight into the potential function of miR-152 as an anti-fibrotic therapy through the modulation of Gli3.


Pharmacological characterization of the autonomous innervation of the guinea pig tracheobronchial smooth muscle.
From the trachea, main bronchi and hilus bronchi of guinea pigs, preparations were isolated for registration of mechanical tension on electrical field stimulation and drugs. The trachea contracted on short trains of electrical stimulation. Usually these contractions were followed by a relaxant response. The contractions were abolished while the relaxations were potentiated by atropine. In the main bronchi field stimulation induced a contractile response which was abolished by atropine. In the latter preparation relaxant responses were never observed, even not after atropine. In the trachea and main bronchi neither the alpha 1 blocker prazosin nor the alpha2 blocker yohimbine affected the contractile or relaxant responses when used in alpha-blocking concentrations. The relaxant response in trachea was neither affected by the "P1 blocker" theophylline nor by the "P2 blocker" quinidine but it was partially inhibited by guanethidine or beta-blocking agents. The hilus bronchi contracted on field stimulation as well as histamine. The contractile response on electrical stimulation was only slightly inhibited by atropine or guanethidine. In all three preparations responses on field stimulation were abolished by tetrodotoxin. It is suggested that in both trachea and main bronchi excitatory cholinergic innervation is present. Further, the trachea but not the main bronchi is innervated by both adrenergic and nonadrenergic inhibitory nerves. The hilus bronchi contains a non-adrenergic non-cholinergic excitatory nervous system.


Asbestosis hospitalizations in Poland (2006-2016): results from the National Hospital Discharge Registry.
Occupational asbestos exposure is one of the major public health issues. Although asbestos use in Poland has decreased, asbestosis continues to remain an important health concern in the area of occupational medicine. The aim of the study is to perform a descriptive analysis of hospitalization cases in patients suffering from asbestosis in Poland. The authors used hospital discharge records to conduct a retrospective, population-based study. To estimate the asbestosis hospitalization rate, data from the Nationwide General Hospital Morbidity Study conducted by the National Institute of Public Health were used. Events were defined as in-patient hospital discharges during 2006-2016. 1,101 hospitalization records of 764 patients were included in the study. In the study group of first-time hospitalized patients, the mean and median ages were 68.1 and 69 years, respectively; CI: 67.3-68.9; SD: 11.1, min-max:16-99 years. In this group, significant gender differences were observed (560 males vs. 204 female; P<0.001). No statistical differences were observed regarding the place of residence. During the observation period, 61 in-hospital deaths were reported (8% of all patients), 40 of whom (5.2 % of all patients) took place during the first-time hospitalizations. Asbestosis hospitalizations were mainly clustered in the south-western region, whereas the highest hospitalization rates were clustered in several areas of Poland. The authors believe this study to be the first evaluation of asbestosis in Poland made on the basis of the hospital morbidity database. The data presented may be helpful in comparative studies on the epidemiology of asbestosis across European countries.


Conditioned medium of bone marrow mesenchymal stem cells improves sperm parameters and reduces histological alteration in rat testicular ischaemia/reperfusion model.
Testis ischaemia-reperfusion (I/R) plays a vital role in male infertility. Recent studies have demonstrated that paracrine factors of mesenchymal stem cells exert the transplanted cells' reparative effects. The present experimental study aimed to investigate the effects of conditioned medium (CM) of bone marrow-derived mesenchymal stem cells (BMMSCs). In this study, 21 rats were separated into three groups of 7 animals: sham, I/R and I/R plus CM. Sperm parameters were measured at the end of this study. Moreover, histological parameters were examined. 2-Deoxyuridine 5-triphosphate nick-end labelling (TUNEL) assay was done to assess the apoptotic cells. The count of adhered neutrophils was measured in subtunical venules. Testicular I/R led to a significant reduction in the viability and concentration of sperm and resulted in a significant elevation in the rate of abnormal sperms in comparison with sham. The CM-treated group demonstrated a significant reduction in the rate of abnormal sperm and a significant elevation in the viability and concentration of sperm compared with the I/R group. Based on the morphometric analysis, in the I/R group, epithelial thickness and seminiferous tubule diameter significantly decreased in comparison with sham. A significant reduction was seen between the I/R and sham groups regarding the mean testicular biopsy score (MTBS) value. However, an improvement was observed in the I/R + CM group MTBS value in comparison with the I/R group. TUNEL assay showed that the apoptotic cells in the seminiferous tubules belonging to the I/R group were significantly higher compared with the control. Nevertheless, apoptotic cells were reduced in the I/R + CM group compared with the I/R group. Results of the present study showed that CM of BMMSCs exerts protective effects on the testicular I/R damages.


Effects of society and culture on parents' ratings of children's mental health problems in 45 societies.
To improve international needs assessment for child mental health services, it is necessary to employ standardized assessment methods that can be easily administered and scored, can be interpreted by practitioners and researchers with various kinds of training, and that perform similarly across many societies. To this end, we tested the effects of both society and culture on parents' ratings of children's problems. We used hierarchical linear modeling as well as analyses of variance to analyze parents' Child Behavior Checklist ratings of 72,493 6- to 16-year-olds from 45 societies. The 45 societies were nested within 10 culture clusters based on the Global Leadership and Organizational Behavior Effectiveness (GLOBE) taxonomy. Societal differences accounted for 3.8-10.7% of variance in various kinds of problems, while differences between culture clusters (e.g., Anglo vs. Confucian) accounted for 0.1-10.0%. By contrast, differences associated with parents' ratings of individual children accounted for 85.5-93.3% of variance. Averaged across 17 problem scales, society plus culture cluster accounted for about 10% of the variance in parents' ratings of children's problems, whereas individual differences and other possible variables accounted for about 90%. These findings indicate that parents' standardized ratings can be used to assess effects associated with individual differences in child and adolescent psychopathology, over and above differences associated with societies and culture clusters.


In vivo selection of high-metastatic subline of bladder cancer cell and its characterization.
The majority of deaths associated with solid tumors are caused by tumor metastasis. To prevent metastasis, it is vital to understand its detailed process. In hematogenous metastasis of bladder cancer, some cancer cells disseminating into blood circulation extravasate into the lung tissues to form metastases. To study the molecular basis of the lung metastasis of bladder cancer, we employed an in vivo selection system that mimics hematogenous metastasis of bladder cancer on a low-metastatic bladder cancer cell line (KK-47). We have successfully isolated a high-metastatic bladder cancer subline, KK-47HM4, from KK-47 cells. We characterized KK-47HM4 in in vitro experimental systems. No significant difference in growth rate and susceptibility to NK cell attack between KK-47 and KK-47HM4 cells was observed. However, KK-47HM4 exhibited the higher capacities of Matrigel Matrix invasion and transendothelial invasion than KK-47. These results suggest that the extravasation of KK-47HM4 cells was enhanced among the multiple steps of the lung metastasis of bladder cancer. Our cDNA microarray analysis identified 67 genes whose expression was up- or downregulated in KK-47HM4 cells compared with KK-47 cells. This analysis data implied that one possible cause for enhanced extravasation of KK-47HM4 is its higher adhesion to extracellular matrix proteins. KK-47HM4 is the first bladder cancer subline with enhanced extravasation potential using the in vivo selection system. The information provided by our cDNA microarray analysis using KK-47HM4 will be useful for further investigation into the molecular basis of extravasation of cancer cells.


Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells.
Anthraquinone compounds have been recognized to possess antiinflammatory, anti-fibrotic and anti-tumour properties and thus applied in human and veterinary therapeutics as active substances of medicinal products. Amongst the anthraquinones isolated from Rheum palmatum, also known as da-huang, rhein was detected as one of the highest metabolite contents in the bloodstream of mammals. The biological activities of rhein therefore deserve detailed investigation. In this study, we aimed to delineate the mechanism of inhibitory actions of rhein on fibrotic and tumorigenic processes by means of various biochemical assays, such as immunofluorescent staining, real-time polymerase chain reaction (PCR) and western blotting analyses in rat pancreatic stellate cells (LTC-14), human pancreatic ductal adenocarcinoma cells (PANC-1) and human colon carcinoma cells (SW480 and SW620). Our results demonstrated that the application of rhein notably suppressed the mRNA and protein levels of various fibrotic and tumorigenic mediators including alpha-smooth muscle actin, type I collagen, fibronectin, N-cadherin and matrix metalloproteinases in the testing mammalian cells. The mechanism of the suppressive actions of rhein was associated with the modulation of the sonic hedgehog and serine-threonine kinase signalling pathways. In conclusion, we suggest that rhein may serve as a therapeutic or an adjuvant agent in anti-fibrotic and anti-tumorigenic approaches.


Consistency in structural energetics of protein folding and peptide recognition.
We report a new free energy decomposition that includes structure-derived atomic contact energies for the desolvation component, and show that it applies equally well to the analysis of single-domain protein folding and to the binding of flexible peptides to proteins. Specifically, we selected the 17 single-domain proteins for which the three-dimensional structures and thermodynamic unfolding free energies are available. By calculating all terms except the backbone conformational entropy change and comparing the result to the experimentally measured free energy, we estimated that the mean entropy gain by the backbone chain upon unfolding (delta Sbb) is 5.3 cal/K per mole of residue, and that the average backbone entropy for glycine is 6.7 cal/K. Both numbers are in close agreement with recent estimates made by entirely different methods, suggesting a promising degree of consistency between data obtained from disparate sources. In addition, a quantitative analysis of the folding free energy indicates that the unfavorable backbone entropy for each of the proteins is balanced predominantly by favorable backbone interactions. Finally, because the binding of flexible peptides to receptors is physically similar to folding, the free energy function should, in principle, be equally applicable to flexible docking. By combining atomic contact energies, electrostatics, and sequence-dependent backbone entropy, we calculated a priori the free energy changes associated with the binding of four different peptides to HLA-A2, 1 MHC molecule and found agreement with experiment to within 10% without parameter adjustment.


Automated Operant Conditioning in the Mouse Home Cage.
Recent advances in neuroimaging and genetics have made mice an advantageous animal model for studying the neurophysiology of sensation, cognition, and locomotion. A key benefit of mice is that they provide a large population of test subjects for behavioral screening. Reflex-based assays of hearing in mice, such as the widely used acoustic startle response, are less accurate than operant conditioning in measuring auditory processing. To date, however, there are few cost-effective options for scalable operant conditioning systems. Here, we describe a new system for automated operant conditioning, the Psibox. It is assembled from low cost parts, designed to fit within typical commercial wire-top cages, and allows large numbers of mice to train independently in their home cages on positive reinforcement tasks. We found that groups of mice trained together learned to accurately detect sounds within 2 weeks of training. In addition, individual mice isolated from groups also showed good task performance. The Psibox facilitates high-throughput testing of sensory, motor, and cognitive skills in mice, and provides a readily available animal population for studies ranging from experience-dependent neural plasticity to rodent models of mental disorders.


The journey to professional excellence: a matter of priorities.
Today and for the foreseeable future, it appears that we will confront continual challenges and almost overwhelming change that could easily disillusion and distract us from our primary purpose of patient care. To avoid that possibility and to ensure our continuing journey to excellence, let us remember and teach: It is always a matter of priorities.


Surgical management of severe spontaneous hemorrhage of the abdominal wall complicating acenocoumarol treatment.
Acenocoumarol is a vitamin K antagonist that is used for the treatment of acquired and congenital, both arterial and venous, thrombotic diseases. Its use is complicated by the narrow therapeutic range. Bleeding following oral anticoagulation, despite rare, remains the major complication. Most cases of hemorrhagic episodes usually require short hospitalization and transfusion, while surgical drainage of the hematoma is not recommended. However, in cases that conservative treatment isn't successful, surgical intervention remains an option. We present a case of severe spontaneous bleeding of the rectus abdominis muscle which was successfully managed surgically.


Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in ulcerative colitis.
To examine the expression of metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the colonic mucosa of patients with ulcerative colitis (UC). Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to study the expression of MMP-1 and TIMP-1 at both mRNA and protein levels in patients with UC and controls. The relationship between MMP-1 mRNA, TIMP-1 mRNA, MMP-1 mRNA/TIMP-1 mRNA ratio and the severity of clinical symptoms of the patients with UC were also analyzed. The expression of MMP-1 mRNA and TIMP-1 mRNA in the ulcerated and inflamed colonic mucosa was significantly higher than that in the non-inflamed colonic mucosa (P < 0.001), but there was no statistically significant difference in the non-inflamed colonic mucosa of UC patients and normal controls (P > 0.05). The mRNA expression of MMP-1 and TIMP-1 in ulcerated colonic mucosa of UC patients was increased by 80-fold and 2.2-fold, respectively when compared with the normal controls. In the inflamed colonic mucosa, the increase was 30-fold and 1.6-fold, respectively. Immunohistochemical analysis showed that among the ulcerated, inflamed, and non-inflamed colonic mucosae of UC patients and the normal controls, the positive rate of MMP-1 expression was 87%, 87%, 40% and 35% respectively, and the positive rate of TIMP-1 expression was 89%, 89%, 80% and 75%, respectively. Furthermore, the expression of MMP-1 mRNA, TIMP-1 mRNA and the MMP-1 mRNA/ TIMP-1 mRNA ratio were correlated with the severity of clinical symptoms (P <0.05). Excessive expression of MMP-1 in the diseased colonic mucosa causes excessive hydrolysis of the extracellular matrix (ECM) and ulceration in UC patients. MMP-1 mRNA, TIMP-1 mRNA and MMP-1 mRNA/TIMP-1 mRNA ratio can be used as biomarkers to judge the severity of clinical symptoms in patients with UC. Exogenous TIMP-1 or MMP-1 inhibitor therapy is a novel treatment for patients with UC.


Anomalous magnetoresistance in a nonconjugated radical polymer glass.
Macromolecules bearing open-shell entities offer unique transport properties for both electronic and spintronic devices. This work demonstrates that, unlike their conjugated polymer counterparts, the charge carriers in radical polymers (i.e., macromolecules with nonconjugated backbones and with stable open-shell sites present at their pendant groups) are singlet cations, which opens significant avenues for manipulating macromolecular design for advanced solid-state transport in these highly transparent conductors. Despite this key point, magnetoresistive effects are present in radical polymer thin films under applied magnetic fields due to the presence of impurity sites in low (i.e., <1%) concentrations. Additionally, thermal annealing of poly(4-glycidyloxy-2,2,6,6- tetramethylpiperidine-1-oxyl) (PTEO), a nonconjugated polymer with stable open-shell pendant groups, facilitated better electron exchange and pairwise spin interactions resulting in an unexpected magnetoresistance signal at relatively low field strengths (i.e., <2 T). The addition of 4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxy (TEMPO-OH), a paramagnetic species, increased the magnitude of the MR effect when the small molecule was added to the radical polymer matrix. These macroscopic experimental observables are explained using computational approaches that detail the fundamental molecular principles. This intrinsic localized charge transport behavior differs from the current state of the art regarding closed-shell conjugated macromolecules, and it opens an avenue towards next-generation transport in organic electronic materials.


Coulomb explosion of dichloroethene geometric isomers at 1 PW cm(-2).
Strikingly different Coulomb explosion behavior under intense laser fields is shown between the cis and trans geometric isomers of dichloroethene using 40-fs pulses at 0.8 μm. Although the fragment-ion distributions in the mass spectra did not aid in the identification of the geometric and positional isomers of the dichloroethenes, we found that the angular distributions of atomic ions were strongly dependent on the geometric structures. The angular distributions of chlorine ions, carbon ions, and protons were similar between 1,1- and cis-1,2-dichloroethene, whereas trans-1,2-dichloroethene showed a very sharp distribution of chlorine ions and quite different distributions of carbon ions and protons. The origin of the anisotropic ion angular distributions is the geometric selection of molecules in the tunnel-ionization process followed by a Coulomb explosion, although molecules are randomly oriented in the gas phase. The highly charged molecular ions exploded into pieces, and the direction of atomic-ion ejection was strongly correlated with the relative configuration of atoms with respect to the electron-extraction axis, the repulsion with adjacent atomic ions within the molecule, and the degree of the persistence of a molecular frame. We propose herein that the most probable electron-extraction axis by tunneling, which is governed by the configuration of molecular orbitals, is different among three dichloroethene isomers. Because multiple ionization under intense laser fields occurs by sequential tunneling processes, the first ionization step at the leading edge of the laser pulse dominates the further ionization steps. Therefore, the shapes of the highest occupied molecular orbitals and probably the underlying orbitals determine the anisotropic emission of atomic ions that can be used to identify isomers.


Rural-to-urban migrations: acculturation experiences among university students in Botswana.
Many students in Botswana migrate from small rural villages and towns to the larger urban centres to attend university, and are subsequently required to adapt or acculturate to their new environments. However, the existing literature and research on acculturation experiences of students who migrate from rural-to-urban centres in Botswana is almost non-existent. The current study was therefore a qualitative exploratory investigation of the experiences of the students who migrate from rural-to-urban centres. Purposive sampling was used to recruit participants who contributed to a Talking Circle focus group. Researchers transcribed the interviews and used content analysis to uncover response themes. Findings indicated that the majority of students experienced some culture shock and a number of environmental and specific systemic stressors in their first two years of university life. Theoretical implications for understanding rural-to-urban acculturation and practical implications for university counselling approaches are also discussed.


Interchange of the quantum states of confined excitons caused by radiative corrections in CuCl films.
The energy states of a particle confined in a narrow space are discrete and lined up in the order of n=1,2,3,.... However, if the particle interacts with a radiation field, modification of the energy, referred to radiative correction, will occur and quantum states are expected to interchange. We investigated the center-of-mass confinement of excitons in CuCl films by a new method based on "nondegenerate two-photon excitation scattering." The energies of confined excitons in a 19.3 nm thick film are found to be lined up in the order of n=1,3,5, because the radiative correction is very weak. On the other hand, in a 35.3 nm thick film, in which the radiative correction becomes large, the energies of quantum states are ordered n=2,3,4,1,5,7. This interchange is confirmed by comparing the calculated scattering spectra, in which radiative correction is taken into account, with the measured ones.


[Thiamine deficiency and brain atrophy in alcoholic patients].
CT brain scans of 65 alcohol-dependent inpatients were compared before and after 6 weeks of confirmed abstinence. Linear measurements revealed a significant reduction of the enlargement of the ventricular system in accordance with the re-expansion of the brain after alcohol abstinence (ANOVA, significant time effects). 22 patients showed a moderate or severe thiamine deficiency. CT findings on thiamine-deficient patients did not differ from those on patients without thiamine deficiency (ANOVA, no significant group effects). Correlations between thiamine deficiency and subcortical atrophy before treatment were not significant. The results are discussed in relation to the pathogenesis of reversible brain shrinkage in chronic alcoholics.


Low-energy collision-induced dissociation fragmentation analysis of cysteinyl-modified peptides.
The development of methods to chemically modify and isolate cysteinyl-residue-containing peptides (Cys-peptides) for LC-MS/MS analysis has generated considerable interest in the field of proteomics. Methods using isotope-coded affinity tags (ICAT) and (+)-biotinyl-iodoacetamidyl-3,6-dioxaoctanediamine (iodoacetyl-PEO-biotin) employ similar Cys-modifying reagents that contain a thiolate-specific biotin group to modify and isolate Cys-containing peptides in conjunction with immobilized avidin. For these strategies to be effective on a proteome-wide level, the presence of the ICAT or acetyl-PEO-biotin tag should not interfere with the efficiency of induced dissociation in MS/MS experiments or with the identification of the modified Cys-peptides by automated database searching algorithms. We have compared the collision-induced dissociation (CID) fragmentation patterns of peptides labeled with iodoacetyl-PEO-biotin and the ICAT reagent to those of the unmodified peptides. CID of Cys-peptides modified with either reagent resulted in the formation of ions attributed to the modified Cys-peptides as well as those unique to the labeling reagent. As demonstrated by analyzing acetyl-PEO-biotin labeled peptides from ribonuclease A and the ICAT-labeled proteome of Deinococcus radiodurans, the presence of these label-specific product ions provides a useful identifier to discern whether a peptide has been modified with the Cys-specific reagent, especially when a number of peptides analyzed using these methods do not contain a modified Cys residue, and to differentiate identical Cys-peptides labeled with either ICAT-d0 or ICAT-d8.


Microbial fuel cells: methodology and technology.
Microbial fuel cell (MFC) research is a rapidly evolving field that lacks established terminology and methods for the analysis of system performance. This makes it difficult for researchers to compare devices on an equivalent basis. The construction and analysis of MFCs requires knowledge of different scientific and engineering fields, ranging from microbiology and electrochemistry to materials and environmental engineering. Describing MFC systems therefore involves an understanding of these different scientific and engineering principles. In this paper, we provide a review of the different materials and methods used to construct MFCs, techniques used to analyze system performance, and recommendations on what information to include in MFC studies and the most useful ways to present results.


PDMS-coated hypercrosslinked porous organic polymers modified via double postsynthetic acidifications for ammonia capture.
A hypercrosslinked porous organic polymer was modified by post-oxidation and post-sulfonation to obtain a porous platform with a high density of acidic groups. Such an acidified material exhibits record high NH3 adsorption capacity per surface area, fast adsorption rate, and recyclability at low desorption temperature. Noticeably, the coating of the polymer with PDMS represents a facile and efficient route to enable both a significant improvement of low-pressure NH3 adsorption capacity (∼40-fold enhancement; from 0.04 to 1.41 mmol g-1) with respect to the non-modified polymer at 500 ppm and hydrophobicity associated with the selective sorption of NH3 over water vapor (hydrophilic for the non-coated material). This material is easy to prepare, cost-effective, and scalable to mass production.


Non-pharmacological modulation of cerebral white matter organization: A systematic review of non-psychiatric and psychiatric studies.
Neuroplasticity is a well-described phenomenon, but effects of non-pharmacological interventions on white matter (WM) are unclear. Here we review associations between active non-pharmacological interventions and WM organization in healthy subjects and in psychiatric patients. A systematic review of non-psychiatric and psychiatric studies in MEDLINE and EMBASE databases. We included longitudinal, controlled studies in human participants aged 18-60 years published in peer-reviewed journals between 2000 and 2017. Studies required active interventions lasting between one day and one year, targeting cognitive-, motor- or sensory domains. The primary outcome was intervention-related brain changes in diffusion-weighted imaging (DWI) derived measures. We included 25 studies. Twenty studies reported positive findings. Five studies investigated psychiatric patients. Nine randomized, controlled trials (RCTs) reported DWI changes following cognitive interventions. Interventions were too heterogeneous to perform a meta-analysis. Intervention duration of at least eight weeks appeared required to induce consistent WM changes. Non-pharmacological interventions can induce changes in WM. DWI is a relevant correlate of e.g. cognitive training in prospective, long-term RCTs of psychiatric patients.


Sex Differences and Caffeine Impact in Adenosine-Induced Hyperemia.
Caffeine consumption before adenosine stress myocardial perfusion imaging (MPI) is known to affect the hemodynamic response and, thus, reduce the stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) assessments. However, it is not clear if any sex-specific differences in the hemodynamic response after caffeine consumption exist. This study aimed to evaluate if such differences exist and, if so, their impact on MBF and MFR assessments. Methods: This study comprised 40 healthy volunteers (19 women). All volunteers underwent 4 serial rest/stress MPI sessions using 82Rb; 2 sessions were acquired without controlled caffeine consumption, and 2 sessions after oral ingestion of either 100 and 300 mg of caffeine or 200 and 400 mg of caffeine. For the caffeine imaging sessions, caffeine was ingested orally 1 h before the MPI scan. Results: Increase in plasma caffeine concentration (PCC) (mg/L) after consumption of caffeine was larger in women (MPI session without caffeine vs. MPI session with caffeine: women = 0.3 ± 0.2 vs. 5.4 ± 5.1, men = 0.1 ± 0.2 vs. 2.7 ± 2.6, both P < 0.001). Caffeine consumption led to reduced stress MBF and MFR assessments for men whereas no changes were reported for women (women [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 3.3 ± 0.6 vs. 3.0 ± 0.8 mL/g/min, P = 0.07; MFR = 3.7 ± 0.6 vs. 3.5 ± 1.0, P = 0.35; men [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 2.7 ± 0.7 vs. 2.1 ± 1.0 mL/g/min, P = 0.005; MFR = 3.8 ± 1.0 vs. 3.1 ± 1.4, P = 0.018). Significant differences in the stress MBF were observed for the 2 sexes (both P ≤ 0.001), whereas similar MFR was reported (both P ≥ 0.12). Conclusion: Associations between increases in PCC and reductions in stress MBF and MFR were observed for men, whereas women did not have the same hemodynamic response. Stress MBF was affected at lower PCCs in men than women.


Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse.
Most, if not all, nociceptor sensory neurons are dependent on nerve growth factor (NGF) during early embryonic development. A large subpopulation of these sensory neurons loses NGF dependency between embryonic day 16 and postnatal day 14 and become responsive to glial cell line-derived growth factor (GDNF), a member of the transforming growth factor beta (TGF-beta) family. To examine the survival and phenotypic effects of GDNF on sensory neurons in vivo, we generated transgenic mice that overexpress GDNF in the skin. GDNF-overexpresser mice had increased numbers of small unmyelinated sensory neurons that express the tyrosine kinase receptor Ret and bind the plant isolectin B4 (IB4). Surprisingly, in wild-type and transgenic mice, few ( approximately 2%) IB4-positive neurons expressed the vanilloid receptor VR1, a heat-sensitive receptor expressed by many IB4-positive neurons of the rat. Thus, in mouse, GDNF-dependent IB4-positive neurons must use a non-VR1 heat receptor. In addition, the behavior of GDNF-overexpresser animals to noxious heat or mechanical stimuli was indistinguishable from wild-type animals, indicating that, on a behavioral level, peripherally applied GDNF does not alter the sensitivity of the somatosensory system.


Interaction of human spermatozoa with the zona pellucida of oocyte: development of the acrosome reaction.
Mammalian spermatozoa are not able to fertilize an oocyte upon ejaculation. To gain fertilizing ability, spermatozoa must, either in vivo or in vitro, undergo a process termed capacitation. Since a reliable marker for capacitation does not exist, it is considered that this process is completed when the spermatozoa are able to undergo acrosomal x intestinal mucosa which might require tandem signaling events for this process is the presence of a vascular countercurrent arrangement in the subepithelial compartment. As happens for absorbed solutes, this countercurrent phenomenon may distort transepithelial solute gradient. For example, perfusion of mammalian intestinal loops in vivo with solutions containing fMLP was previously found to induce neutrophil attachment to endothelial cells and structurally defined endothelial activation, but failed to elicit directed migration across the lamina propria (Madara, unpublished observations), suggesting that directed migration may require a more stable gradient than that afforded by the usual soluble signals. For example, once present in inflamed tissue, IL-8 is likely to retain its biological activity for several hours, as shown by local intradermal administration in animals and humans. In contrast to Il-8, chemokines such as fMLP or LTB4 are degraded rapidly by oxidation or hydrolysis. Fertilization is a very complex phenomenon, involving sequential interactions between the fertilizing spermatozoon and cumulus oophorus, ZP, and oolemma. The AR may be playing a key role in penetration of spermatozoa through these egg vestments.


Human papillomavirus (HPV) is not the main cause of preinvasive and invasive cervical cancer among patients in Delta Region, Egypt.
Cervical cancer remains a significant problem worldwide particularly in underdeveloped countries. It is necessary to have a persistent infection of the cervix with a high-risk or oncogenic human Papillomavirus (HPV) virus to develop cervical cancer. To study the association between HPV and pre-invasive and invasive cancer cervix among patients referred to Early Cancer Detection Clinic of Obstetrics and Gynecology Department, Mansoura University Hospital, Delta region, Egypt. Cervical specimens of 100 histologically confirmed premalignant and malignant cervical lesions were subjected to HPV detection and genotyping by extraction of DNA from cervical biopsy using a commercial PCR kit. HPV DNA testing was done, 36 cases were positive (36%). Correlations of age, duration of marriage, and parity were non significant (P = 0.56, 0.72, and 0.35 respectively) while correlations of residence, oral contraceptive use, smoking, and immunosuppresion were sig- nificant (P = 0.006, 0.001, 0.001, and 0.01 respectively). The prevalence of HPV in premalignant and malignant cervical lesions in our study was 39.5% & 33.3% respec tively. The commonest HPV genotypes associated with premalignant cervical lesions were HPV16; 11/17(64.7%) and HPV18; 11/17 (64.7%) mostly in the form of mul- tiple infections with HPV16+18; 7/17 (41.17%). The commonest HPV genotypes associated with malignant cervical lesions in our cases were HPV16; 15/19 (78.9%) and HPV18; 13/19 (68.42%) also in the form of multiple infections with HPV16+18; 10/19 (52.63%). The prevalence of HPV in premalignant and malignant cervical lesions was 39.5% & 33.3% respectively, this means that HPV is not the main cause of premalignant and malignant cervical lesions in Delta region in Egypt. HPV infection mostly in the form of multiple infections with HPV16+18 genotypes. Further studies are needed to clarify actual association of HPV and premalignant and malignant cervical lesions to determine the usefulness of HPV vaccination in our locality.


Tunable Nonvolatile Memory Behaviors of PCBM-MoS2 2D Nanocomposites through Surface Deposition Ratio Control.
Efficient preparation of single-layer two-dimensional (2D) transition metal dichalcogenides, especially molybdenum disulfide (MoS2), offers readily available 2D surface in nanoscale to template various materials to form nanocomposites with van der Waals heterostructures (vdWHs), opening up a new dimension for the design of functional electronic and optoelectronic materials and devices. Here, we report the tunable memory properties of the facilely prepared [6,6]-phenyl-C61-butyric acid methyl ester (PCBM)-MoS2 nanocomposites in a conventional diode device structure, where the vdWHs dominate the electric characteristics of the devices for various memory behaviors depending on different surface deposition ratios of PCBM on MoS2 nanosheets. Both nonvolatile WORM and flash memory devices have been realized using the new developed PCBM-MoS2 2D composites. Specially, the flash characteristic devices show rewritable resistive switching with low switching voltages (∼2 V), high current on/off ratios (∼3 × 102), and superior electrical bistability (>104 s). This research, through successfully allocating massive vdWHs on the MoS2 surface for organic/inorganic 2D nanocomposites, illustrates the great potential of 2D vdWHs in rectifying the electronic properties for high-performance memory devices and paves a way for the design of promising 2D nanocomposites with electronically active vdWHs for advanced device applications.


The history of the United States Navy flight surgeon/naval aviator program.
Early in the history of aviation the need for a special kind of physician who could understand the physical and psychological problems encountered by flyers was well recognized. These physicians were called flight surgeons. In 1922, RADM W. A. Moffett, USN, the first Chief of the Bureau of Aeronautics and the "Father of Naval Aviation," called for a group of Navy medical officers to be trained as flight surgeons. He believed that all Navy flight surgeons should be trained as pilots "primarily in order that they may experience the emergencies and conditions that arise in flying." This article traces the history of the Navy flight surgeon/naval aviator. It chronicles the evolution of the Navy's flight surgeon/naval aviator program from the World War I doctor who flew seaplanes at a Naval Air Station in Italy to the present day flight surgeon/naval aviator who flys operational and test aircraft as a research pilot.


An exploratory and mechanistic study of the defluorination of an (aminofluorophenyl)oxazolidinone: S(N)1(Ar*) vs. S(R(+)N)1(Ar*) mechanism.
The morpholinofluorophenyloxazolidinone 1 (the antibacterial drug linezolid) is found to undergo reductive defluorination upon irradiation in water (Phi 0.33), in some of the products accompanied by the simultaneous oxidative degradation of the morpholine side chain. In the presence of chloride, iodide and pyrrole, the fluorine is substituted by these groups (with pyrrole, in position 2). The defluorination is less efficient in methanol and mainly leads to reduction (Phi 0.053). These data can be accommodated through two different mechanisms, viz. either C-F bond heterolysis to give a phenyl cation [S(N)1(Ar*)], or ionization to give a radical cation [S(R(+)N)1(Ar*)]. Steady-state and time resolved data have been gathered for clarifying this issue. It is found that, indeed, ionization of 1 is efficient and proceeds from the singlet, but leads to no irreversible change. On the contrary, triplet (3)1 (lifetime 0.5 micros in MeOH, <0.1 micros in water) fragments and gives the corresponding triplet phenyl cation. The last intermediate explains well the observed hydrogen abstraction both inter- (from the solvent, when this is reducing) and intramolecularly (from the morpholine group), as well as addition to a charged anion or to a neutral pi nucleophile such as pyrrole. The rationalization is supported by the study of some related molecules. Thus, the only photochemical reaction from the non fluorinated analogue of linezolid (that ionizes just as 1) is an inefficient degradation of the morpholine chain (Phi 0.001), while a simple model such as N-(2-fluorophenyl)morpholine undergoes photosolvolysis in water and is not trapped by pyrrole.


Intravitreal bevacizumab (Avastin) for occult choroidal neovascularization in age-related macular degeneration.
The purpose of the study is to report data on short-term safety of intravitreal bevacizumab treatment and its effect on visual function, central retinal thickness, and angiographical changes of occult choroidal neovascularization due to age-related macular degeneration. A consecutive interventional case series of 30 patients with active subfoveal occult choroidal neovascularization secondary to age-related macular degeneration was followed after one intravitreal injection of 1.25 mg bevacizumab at baseline and subsequent injections following standardized criteria. At baseline and follow-up visits patients had visual acuity assessment, intraocular pressure measurement, fluorescein angiography, and optical coherence tomography imaging. No serious ocular or systemic adverse events were identified. A significant increase of intraocular pressure or signs of retinal toxicity or endophthalmitis were not detected in any patient. Optical coherence tomography revealed significant decrease (p < 0.001) in central retinal thickness after 1 week, 4 weeks, and 12 weeks, respectively. Fluorescein leakage decreased within 1 week and improvement was maintained at week 12 in the majority of patients. Visual acuity improved or remained stable in 29 of 30 patients; improvement of 3 or more lines was seen in 14 of 30 patients; one patients showed improvement of 6 lines. No patient had severe vision loss of 6 lines or more; moderate vision loss of 3 lines was seen in one patient. Re-injections of bevacizumab according to standard criteria were performed one to two times during the follow-up period of 12 weeks with a re-injection interval of 4 to 18 weeks (median 8 weeks). Short-term results suggest that intravitreal injection of bevacizumab is well tolerated and for the majority of patients with occult choroidal neovascularization in AMD results in improvement of visual acuity, decrease in central retina thickness, and reduction of angiographic leakage of the lesion. Bevacizumab as intravitreal treatment may provide a novel therapeutic option for selected patients with exudative AMD. Randomized prospective multicenter trials seem justified to further evaluate long term effects and impact of intravitreal bevacizumab on different subtypes of AMD compared to established therapies.


Transfer of doxazosin into breast milk.
To the best of our knowledge, there have been no published studies of doxazosin transfer into human milk. In rats, milk concentrations twentyfold higher than in plasma have been reported. Based on these animal data, some references advise to avoid breastfeeding during doxazosin therapy. However, the physicochemical properties of doxazosin suggest low transfer into human milk. A 37-year-old breastfeeding woman who was administered doxazosin 4 mg daily for 2 doses was studied. Doxazosin concentrations in milk and plasma were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The milk/plasma area under the concentration-time curve (AUC0-18 hours) ratio was 0.1. This finding is consistent with what could be predicted based on the physicochemical properties of doxazosin. The average and maximum milk concentrations were 2.9 and 4.2 µg/L. These values correspond to estimated relative infant doses of 0.06% and 0.09%, respectively, assuming standard infant milk intake. These values are well below the generally accepted cutoff of 10% for predicting safety during breastfeeding. A low relative infant dose of < 0.1% suggests that maternal doxazosin therapy may be compatible with breastfeeding after careful individual risk-benefit analysis.


Immunodominant antigens that induce Th1 and Th17 responses protect mice against Helicobacter pylori infection.
Helicobacter pylori has infected more than half of the world's population, causing gastritis, gastric ulcers, gastric mucosa-associated lymphoid tissue lymphoma and gastric cancer. The oral recombinant Helicobacter pylori vaccine currently used has made great progress in addressing this problem, however, its efficacy and longevity still need to be improved. Th1 and Th17 cells play essential roles in local protection against Helicobacter pylori in the stomach mucosa. Additionally, protective immunodominant antigens are the preferred for a vaccine. In this work, Helicobacter pylori whole cell lysate was separated into 30 groups based on molecular weight by molecular sieve chromatography. The group best promoting CD4 T cells proliferation was selected and evaluated by immunization. The detail proteins were then analyzed by LC-MS/MS and expressed in Escherichia coli. Eleven proteins were selected and the dominant ones were demonstrated. As a result, three protective immunodominant antigens, inosine 5'-monophosphate dehydrogenase, type II citrate synthase, and urease subunit beta, were selected from Helicobacter pylori whole cell. Two of them (inosine 5'-monophosphate dehydrogenase and type II citrate synthase) were newly identified, and one (urease subunit beta) was confirmed as previously reported. The mixture of the three antigens showed satisfactory protective efficiency, with significant lower H. pylori colonization level (P < 0.001) and stronger Th1 (P < 0.001) and Th17 (P < 0.001) responses than PBS control group. Thus, inosine 5'-monophosphate dehydrogenase, type II citrate synthase, and urease subunit beta are three protective antigens inducing dominant Th1 and Th17 responses to defend against Helicobacter pylori infection.


The NHX family of Na+-H+ exchangers in Caenorhabditis elegans.
Na+-H+ exchangers prevent cellular acidification by catalyzing the electroneutral exchange of extracellular sodium for an intracellular proton. To date, seven Na+-H+ exchangers have been identified in mammals, and although several members of this family have been extensively studied and characterized, it is clear that there are major gaps in our understanding with respect to the remaining family members. To initiate the study of Na+-H+ exchangers in a genomically defined and genetically tractable model system, we have cloned the complete cDNAs and analyzed splice site variation for nine putative homologs from the nematode Caenorhabditis elegans, which we have called NHX-1 through -9. The expression patterns and cellular distributions of the NHX proteins were determined using transcriptional and translational promoter-transgene fusion constructs to green fluorescent protein. Four of the putative exchangers were expressed at the cell surface, whereas five of the exchangers were associated with the membranes of intracellular organelles. Individual isoforms were expressed exclusively in the intestine, seam cells, hypodermal cells of the main body syncytium, and the excretory cell, all of which are polarized epithelial cells, suggesting a role for these proteins in epithelial membrane transport processes in the nematode. Other isoforms were found to express either ubiquitously or in a pan-neural pattern, suggesting a more conserved role in cell pH regulation or neuronal function. Finally, we show that recombinant NHX-4, the ubiquitous nematode Na+-H+ exchanger, mediates Na+-dependent pH recovery after intracellular acidification. NHX-4 has a K(a) for Na+ of approximately 32 mm, is not Cl- -dependent, and is relatively insensitive to the amiloride analog EIPA.


Synthesis and function of ribonucleic acid polymerase and ribosomes in Escherichia coli B/r after a nutritional shift-up.
The syntheses of stable ribosomal ribonucleic acid (RNA) and transfer RNA in bacteria depend on the concentration and activity of RNA polymerase and on the fraction of active RNA polymerase synthesizing stable RNA. These parameters were measured in Escherichia coli B/r after a nutritional shift-up from succinate-minimal to glucose-amino acids medium and were found to change in complex patterns during a 1- to 2-h period after the shift-up before reaching a final steady-state level characteristic for the postshift growth medium. The combined effect of these changes was an immediate, one-step increase in the exponential rate of stable RNA synthesis and thus of ribosome synthesis. This suggests that the distribution of transcribing RNA polymerase over ribosomal and nonribosomal genes and the polymerase activity are continuously adjusted during postshift growth to some growth-limiting reaction whose rate increases exponentially. It is proposed that this reaction is the production of amino-acylated transfer RNA and that is exponentially increasing rate results in part from a gradually increasing concentration of aminoacyl transfer RNA synthetases after a shift-up. This idea was tested and is supported by a computer simulation of a nutritional shift-up.


Ankyrin repeat-rich membrane spanning protein (kidins220) is required for neurotrophin and ephrin receptor-dependent dendrite development.
Dendrites are the primary sites on neurons for receiving and integrating inputs from their presynaptic partners. Defects in dendrite development perturb the formation of neural circuitry and impair information processing in the brain. Extracellular cues are important for shaping the dendritic morphogenesis, but the underlying molecular mechanisms are not well understood. In this study, we examined the role of ARMS (ankyrin repeat-rich membrane spanning protein), also known as Kidins220 (kinase D-interacting substrate of 220 kDa), previously identified as a downstream target of neurotrophin and ephrin receptors, in dendrite development. We report here that knockdown of ARMS/Kidins220 by in utero electroporation impairs dendritic branching in mouse cerebral cortex, and silencing of ARMS/Kidins220 in primary rat hippocampal neurons results in a significant decrease in the length, number, and complexity of the dendritic arbors. Overexpression of cell surface receptor tyrosine kinases, including TrkB and EphB2, in ARMS/Kidins220-deficient neurons can partially rescue the defective dendritic phenotype. More importantly, we show that PI3K (phosphoinositide-3-kinase)- and Akt-mediated signaling pathway is crucial for ARMS/Kidins220-dependent dendrite development. Furthermore, loss of ARMS/Kidins220 significantly reduced the clustering of EphB2 receptor signaling complex in neurons. Our results collectively suggest that ARMS/Kidins220 is a key player in organizing the signaling complex to transduce the extracellular stimuli to cellular responses during dendrite development.


Failure of hearing screening in high-risk neonates does not increase parental anxiety.
The aim of this study was to determine whether a failure of neonatal hearing screening affected the anxiety level of parents of high-risk infants. Two hundred and eighty-eight parents of infants included in the neonatal hearing screening protocol of our Institution were tested with the Spielberger State-Trait Anxiety Inventory and with an open-question questionnaire investigating parents' attitude to hearing problems in their child, done at the time of audiological follow-up. 105 were parents of high-risk infants who had been discharged from neonatal intensive care unit (NICU) and 183 of low-risk infants discharged from well-baby nursery. No differences in anxiety levels were seen between parents of high-risk infants passing and failing neonatal hearing screening using homogeneous case-control pairs. Additionally, no differences in the level of anxiety were found between parents of high- and low-risk infants failing neonatal auditory screening. Failure of neonatal auditory screening does not affect the anxiety levels of parents of high-risk infants at post discharge from NICU. This finding is a key factor to be considered when evaluating the costs and benefits of tests for universal neonatal hearing screening.


Elective ascending aortic aneurysm repair outcomes in a nationwide US cohort.
To quantify contemporary outcomes following elective ascending aortic aneurysm repair, to determine risk factors for adverse events and to evaluate difference by institutional surgical volume. We included all elective hospitalisations of adult patients with an ascending aortic aneurysm who underwent aneurysm repair in the Nationwide Readmissions Database between 2016 and 2019. The primary outcome was a composite of in-hospital mortality, stroke (ischaemic and non-ischaemic) and myocardial infarction (MI). We identified independent predictor of adverse events and investigated outcomes by institutional volume. Among 12 043 patients (mean 62.8 years of age, 28.0% female), MI, stroke or in-hospital death occurred in 598 (4.9%) patients during the index admission (acute stroke: 2.7%, MI: 0.7%, in-hospital death: 2.0%). The strongest predictors of in-hospital death, stroke or MI were chronic weight loss, pulmonary circulation disorder and concomitant descending aortic surgery. Higher procedural volume was associated with a lower incidence of in-hospital death, stroke or MI (OR comparing the highest with the lowest tertile 0.71, 95% CI 0.57 to 0.87; p=0.001) and in-hospital death (OR 0.51, 95% CI 0.37 to 0.72; p<0.001), but no difference in 30-day readmissions. The overall rate of in-hospital death, stroke and MI is nearly 5% in patients undergoing elective ascending aortic aneurysm repair. Among several predictors, chronic weight loss is associated with the largest increase in the risk of poor outcomes. Higher hospital volume is associated with a lower in-hospital mortality, highlighting the importance to refer patients to high-volume centres while discussing the risks and benefits of proceeding with repair.


Incidental findings, genetic screening and the challenge of personalisation.
Genetic tests frequently produce more information than is initially expected. Several documents have addressed this issue and offer suggestions regarding how this information should be managed and, in particular, concerning the expedience of revealing (or not revealing) it to the persons concerned. While the approaches to the management of these incidental findings (IFs) vary, it is usually recommended that the information be disclosed if there is confirmed clinical utility and the possibility of treatment or prevention. However, this leaves unsolved some fundamental issues such as the different ways of interpreting "clinical utility", countless sources of uncertainty and varying ways of defining the notion of "incidental". Guidelines and other reference documents can offer indications to those responsible for managing IFs but should not be allowed to relieve researchers and healthcare professionals of their responsibilities.


Motoric Cognitive Risk Syndrome: Association with Incident Dementia and Disability.
It is important to examine the etiology of motoric cognitive risk syndrome (MCR) and its association with dementia and disability to obtain biological insights and to develop preventive strategies. This study aimed to examine the association of MCR with incidence of dementia and disability in a Japanese community-dwelling sample of older adults. Participants were 4,235 older adults (50% women, mean age: 72.0 years). MCR was diagnosed at baseline using established criteria in non-demented seniors with self-reported cognitive complaints and slow gait. Incident cases of dementia were identified from insurance data monthly. Disability was regarded as certification by long-term care insurance. At baseline, 265 participants (6.3%) met criteria for MCR. During follow-up (mean duration: 29 months), there were 138 incident cases of dementia (3.3%) and 207 incident cases of disability (4.9%). Cox-proportional hazards models, adjusted for demographical data, lifestyle, and medical conditions, showed that presence of MCR at baseline was a major risk factor for developing dementia (HR 2.49, 95% CI 1.52-4.10, p < 0.001). MCR also predicted risk for disability (HR 1.69, 95% CI 1.08-2.02, p < 0.001). MCR is helpful in the short-term prediction of risk for dementia and disability in the elderly Japanese population. Identification of seniors with MCR is recommended for early detection and instituting preventive measures for reducing the risk of dementia and disability.


The use of biologic response modifiers in human clinical trials.
To optimize regeneration of the periodontium, new cementum, periodontal ligament, and bone must be formed. Conventional periodontal surgery decreases the likelihood of continued progressive periodontal disease however, it does not lead to significant periodontal regeneration. In vitro studies have identified a class of biologic response modifiers loosely referred to as growth factors, which stimulate the cellular events of tissue regeneration. The most promising are mitogenic and differentiation factors. Based on promising results from animal studies, the application of growth factors to predictably stimulate periodontal regeneration is entering human clinical trials. This manuscript deals with several important considerations in testing biologic response modifiers in humans. Suggestions are made regarding the following parameters: 1) selection of the unit of measurement; 2) patient and lesion selection; 3) identification of controls; 4) selection of outcome parameters; 5) statistical approach; and 6) considerations in treatment regimens.


Joint hypermobility is a risk factor for musculoskeletal pain during adolescence: findings of a prospective cohort study.
To determine whether joint hypermobility (JH) in childhood is a risk factor for the subsequent development of musculoskeletal pain. JH was determined according to the Beighton score at age 13.8 years in children from the Avon Longitudinal Study of Parents and Children (ALSPAC), using a cutoff of ≥6 for the presence of hypermobility. Musculoskeletal pain was evaluated by questionnaire at age 17.8 years. Logistic regression analysis was performed in 2,901 participants (1,267 boys and 1,634 girls) who had complete data. A total of 4.6% of participants had JH at age 13.8 years. Moderately troublesome musculoskeletal pain at age 17.8 years was reported most commonly in the lower back (16.1%), shoulder (9.5%), upper back (8.9%), knee (8.8%), neck (8.6%), and ankle/foot (6.8%). JH was associated with an increased risk of at least moderately troublesome musculoskeletal pain at the shoulder (odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.04, 2.72]), knee (OR 1.83 [95% CI 1.10, 3.02]), and ankle/foot (OR 1.82 [95% CI 1.05, 3.16]) (adjusted for sex, maternal education, and body mass index). An equivalent relationship was not observed at other sites, including the spine, elbows, hands, and hips. In analyses examining interactions with obesity, associations between JH and knee pain showed higher ORs in obese participants (OR 11.01) as compared with nonobese participants (OR 1.57) (P=0.037 for the interaction of hypermobility and obesity). JH represents a risk factor for musculoskeletal pain during adolescence, comprising a specific distribution, namely, the shoulder, knee, and ankle/foot. These relationships were strongest in the presence of obesity, which is consistent with a causal pathway whereby JH leads to pain at sites exposed to the greatest mechanical forces.


Responsiveness of the Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire in women undergoing treatment for pelvic floor disorders.
This study evaluated the responsiveness and minimal important differences (MID) of the Chinese Pelvic Floor Distress Inventory (PFDI) and Pelvic Floor Impact Questionnaire (PFIQ) in women undergoing urodynamic stress incontinence (USI) and/or pelvic organ prolapse (POP) treatment. One hundred and fifty-six women were assessed using the PFDI and PFIQ before and after they received continence surgery and or pelvic floor repair (PFR) surgery, or vaginal pessary. Symptom severity was recorded using a visual analog scale (VAS) before and after treatment as was rating of their satisfaction with the treatment they received. Responsiveness of the PFDI and PFIQ were evaluated by effect sizes, standardized response mean, paired samples t test or Wilcoxon Signed Rank Test. MID in the PFDI and PFIQ for different treatments were determined by satisfaction rating, change in VAS scoring, and distribution-based methods. There were significant improvements in the respective subscales of PFDI and PFIQ, demonstrating moderate to great responsiveness after different treatments. The estimation of MID for the Urinary Distress Inventory (UDI) was -30 to -14 and the Urinary Impact Questionnaire (UIQ) was -28 to -14 for women who underwent continence surgery. The MID for the Pelvic Organ Prolapse Distress Inventory (POPDI) was -44 to -21, the Pelvic Organ Prolapse Impact Questionnaire (POPIQ) -40 to -27, the UDI -22 to -16, the UIQ -37 to -31, the Colo-Rectal-Anal Distress Inventory (CRADI) -37 to -14, and the Colo-Rectal-Anal Impact Questionnaire (CRAIQ) -34 to -6 for women who underwent PFR surgery; and estimation of MID for the POPDI was -16, the POPIQ -29, the UDI -28, the UIQ -17, the CRADI -25, and the CRAIQ -31 for women who received a vaginal pessary. The MID of the respective subscales were supported by the distribution-based methods. The Chinese PFDI and PFIQ instruments are responsive to change in women undergoing continence surgery, PFR surgery or vaginal pessary for USI or POP.


[Pain conditioned changes in animal behavior].
Other than in human beings, only nonverbal methods including motor reflexes, autonomic reflexes, neuroendocrine responses, and changes in overall behavior are available for pain evaluation in various animal species. Pain-like changes in most of these variables can be induced by approaching and handling conscious animals rendering increases in heart rate, blood pressure, and plasma catecholamine levels, etc. to nonspecific indicators for pain. In recent years, changes in overall behavior have been used for assessment of animal pain. Multiple Pain Discomfort Scales (MPDS) have been established for objective evaluation of behavioral changes in response to both noxious stimulation and analgesic drug therapy. These Multiple Pain Discomfort Scales include species specific behavioral patterns, making this approach a potentially more specific indicator of animal pain. This, however, needs to be confirmed by further extended studies in the near future.


[Antibacterial activity of ceftriaxone against various clinical strains isolated in 2004].
The susceptibility of clinical strains isolated from patients with infection to ceftriaxone (CTRX) and injectable beta-lactam antibiotics was determined in Japanese medical institutions in 2004. The in vitro antibacterial activity of the above antibiotics against clinical strains isolated in 2004 was compared with that against part of the clinical strains isolated about ten years ago (1994 - 1996). The antibacterial activity of CTRX against Streptococcus including penicillin-intermediate and penicillin-resistant Streptocuccus pneumoniae was potent and there were no large differences between clinical strains isolated in 1994 - 1996 and those in 2004 in the antibacterial activity of CTRX. CTRX inhibited the growth of all the strains of Haemophilus influenzae including beta-lactamase-negative, ampicillin-resistant (BLNAR) strains at 0.5 microg/mL or less and showed the potent antibacterial activity against these strains. In addition, since there are no large differences between strains isolated in the past and those isolated in 2004 in the antibacterial activity, CTRX is considered to be a useful antibiotic in the treatment of BLNAR infections which are increased by the causative organism of infections especially in the field of pediatrics in recent years. CTRX showed the excellent antibacterial activity against Escherichia coli and Klebsiella pneumoniae but one of the 50 strains of E. coli tested was highly resistant. The antibacterial activity of CTRX against Neisseria gonorrhoeae was the most potent in all the antibiotics tested. These results indicate that CTRX shows excellent antimicrobial activity against fresh strains isolated from patients with infections. CTRX is thus useful as a therapeutic antimicrobial for the treating a variety of infections.


Solution conformation of virginiamycins (staphylomycins).
The 1H (at 300 MHz) and 13C nuclear magnetic resonance spectra of virginiamycins S and S4 and vernamycin Balpha have been unravelled and analyzed. Together with model building and theoretical considerations, this allows the detailed description of their solution conformations. The depside bond can rotate and gives to the backbone some conformational mobility. The orientation of the depsicarbonyl bond depends on the surrounding. Apparent discrepancies between the different methods that are applicable for the disclosure of the nature of peptide H-bonding, have found a rational explanation.


Critical instability and friction scaling of fluid flows through pipes with rough inner surfaces.
It has been shown experimentally over nearly 80 years that surface fine roughness of circular pipes has a crucial effect on the natural transition to turbulence. In this Letter, a theoretical explanation is suggested for the roughness-induced instability. Once the nonlinear effect of roughness is introduced (through a pipe with fine corrugation surface), the mean velocity profile becomes unstable to three-dimensional, asymmetric, and helical traveling waves at moderate Reynolds numbers. The threshold of the aspect ratio or shape factor of the roughness element required to cause instability scales as Re-2. Inspired by the current model, a scaling form is proposed and the scaled friction factor measurements in rough pipes collapse onto a universal curve.


Associations Between Prenatal Exposure to Serotonergic Medications and Biobehavioral Stress Regulation: Protocol for a Systematic Review and Meta-analysis.
Up to 20% of mothers experience antenatal depression and approximately 30% of these women are treated with serotonergic psychotropic pharmacological therapy during pregnancy. Serotonergic antidepressants readily cross the placenta and the fetal blood-brain barrier, altering central synaptic serotonin signaling and potentially altering serotonin levels in the developing fetal brain. The aim of this study is to assess the impact of prenatal exposure to serotonergic antidepressants, accounting for maternal mood disturbances, on markers of stress regulation during childhood. We will follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and will search MEDLINE, Embase, CINAHL, PsycINFO, and ClinicalTrials.gov for full-length studies that assessed physiological (eg, cortisol level, heart rate variability, salivary amylase, pupillary size, C-reactive protein) indices of stress regulation in children of pregnant people who were treated with a serotonergic antidepressant at any point during pregnancy. We will assess the quality of observational studies using the Newcastle-Ottawa Scale and the quality of experimental studies using the Cochrane risk-of-bias tool. When possible, we will conduct a random-effects meta-analysis. If meta-analysis is not possible, we will conduct a narrative review. If a sufficient number of studies are found, we will perform subgroup analysis and assess outcomes measured by drug class, dose, trimester of exposure, and child's age and gender. We registered our review protocol with PROSPERO (International Prospective Register of Systematic Reviews; CRD42021275750), completed the literature search, and initiated title and abstract review in August 2021. We expect to finalize this review by April 2022. Findings should identify the impact of prenatal antidepressant effects on stress regulation and distinguish it from the impact of prenatal exposure to maternal mood disturbances. This review should inform decisions about serotonergic antidepressant use during pregnancy. PROSPERO CRD42021275750; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=275750. PRR1-10.2196/33363.


Conjugate eye deviation in acute stroke: incidence, hemispheric asymmetry, and lesion pattern.
The authors studied clinical features and lesion patterns associated with conjugate eye deviation (CED) in acute stroke. Consecutive patients with supratentorial stroke (<6 hours after symptom onset) were prospectively recruited. CED was classified according to the National Institute of Health Stroke Scale (NIHSS) item "gaze palsy" as being forced, partial, or absent. Lesion patterns on diffusion-weighted images (DWI) were analyzed in 46 patients using a normalization procedure for direct comparisons between patients. Perfusion data were analyzed for a subset of patients. Partial CED was found in 7 (6%) and forced CED in 31 (26.7%) of 116 patients. Forced and partial CED were associated with higher initial NIHSS scores compared with patients without CED (16 and 10 versus 5; P<0.05). DWI lesion volume was larger in patients with CED (103.24+/-102.4 mL, mean+/-SD) as compared with patients without CED (17+/-34.98 mL, P<0.001). CED was more frequent in right hemispheric stroke (44.6% versus 23%, P<0.02). DWI pattern analysis in patients with CED with right hemispheric stroke revealed a network of affected regions, including basal ganglia and temporoparietal cortex. In left hemispheric CED, lesions were larger than in patients without CED, but no consistent pattern could be established. In a subset of selected patients with CED, a small temporoparietal perfusion deficit was sufficient to elicit CED. Selective dysfunction of cortical areas involved in spatial attention and control of eye movements is sufficient to cause CED in patients with acute stroke. However, in the majority of cases, CED is an indicator of large infarcts involving more than one area, including both cortical and subcortical structures.


Development of Scintillators in Nuclear Medicine.
High-quality image is necessary for accurate diagnosis in nuclear medicine. There are many factors in creating a good image and detector is the most important one. In recent years, several detectors are studied to get a better picture. The aim of this paper is comparison of some type of these detectors such as thallium activated sodium iodide bismuth germinate cesium activated yttrium aluminum garnet (YAG: Ce) YAP: Ce "lutetium aluminum garnet activated by cerium" CRY018 "CRY019" lanthanum bromide and cadmium zinc telluride. We studied different properties of these crystals including density, energy resolution and decay times that are more important factors affecting the image quality.


A parametric study ot protease production in batch and fed-batch cultures of Bacillus firmus.
Proteolytic enzymes produced by Bacillus species find a wide variety of applications in brewing, detergent, food, and leather industries. Owing to significant differences normally observed in culture conditions promoting cell growth and those promoting production of metabolites such as enzymes, for increased efficacy of bioreactor operations it is essential to identify these sets of conditions (including medium formulation). This study is focused on formulation of a semidefined medium that substantially enhances synthesis and secretion of an alkaline protease in batch cultures of Bacillus firmus NRS 783, a known superior producer of this enzyme. The series of experiments conducted to identify culture conditions that lead to improved protease production also enables investigation of the regulatory effects of important culture parameters including pH, dissolved oxygen, and concentrations of nitrogen and phosphorous sources and yeast extract in the medium on cell growth, synthesis and secretion of protease, and production of two major nonbiomass products, viz., acetic acid and ethanol. Cell growth and formation of the three nonbiomass products are hampered significantly under nitrogen, phosphorous, or oxygen limitation, with the cells being unable to grow in an oxygen-free environment. Improvement in protease production is achieved with respect to each culture parameter, leading in the process to 80% enhancement in protease activity over that attained using media reported in the literature. Results of a few fed-batch experiments with constant feed rate, conducted to examine possible enhancement in protease production and to further investigate repression of protease synthesis by excess of the principal carbon and nitrogen sources, are also discussed. The detailed investigation of stimulatory and repressory effects of simple and complex nutrients on protease production and metabolism of Bacillus firmus conducted in this study will provide useful guidelines for design of bioreactors for production of protease and bulk chemicals by this bacterium.


A case report of gastroparesis secondary to acute renal failure.
A 45-year-old female with a background of poorly differentiated ovarian adenocarcinoma treated with bilateral salpingo-oophorectomy presented with one week history of nausea, vomiting and decreased urine output. On examination, she was mildly dehydrated but haemodynamically stable. Abdominal examination revealed tender swelling in upper abdomen. Biochemistry revealed that she had acute renal failure and interestingly the acute renal failure was out of proportion to the degree of dehydration. Abdominal ultrasound showed marked distension of the stomach without any evidence of renal tract obstruction. She was aggressively treated with volume replacement and careful monitoring of input and output. She responded very well to fluid replacement and her renal failure resolved within four days of treatment. This case illustrates a case of acute renal failure secondary to gastroparesis which resolved after treatment of renal failure. Patients with chronic renal failure are prone to develop gastroparesis but it is extremely rare to have gastric stasis following acute renal failure. This case also illustrates the importance of aggressive treatment of a reversible but potentially fatal medical condition which could have been easily overlooked in view of patient's poorly differentiated ovarian cancer.


[Effects of environmental factors at different altitudes on leaves and fruit quality of Fuji apple].
To inquire the different performances of the leaves and fruit quality of Fuji apple tress at various altitudes and their responses to the environmental factors, indices including leaf morphology, anatomy, δ13 C, and fruit quality of the Fuji apple trees at respective altitudes of 1375 m, 1575 m and 1715 m were investigated and their responses to environmental factors were determined following stepwise regression analysis. The results showed that 6 factors like the warmth index, Bailey's index, photosynthetically active radiation (PAR), coldness index, ultraviolet B and the annual precipitation dominantly affected the characteristic parameters of leaves and fruit. Elevation increase was matched by the decreasing warmth index, rising Bailey' s index, intenser PAR, higher coldness index, stronger ultraviolet B and heavier annual precipitation; meanwhile, the leaf structure and fruit quality parameters also displayed evident trends of change accordingly, namely, leaf parameters like leaf thickness, cuticle thickness, ratio of palisade and spongy, maximum conduit diameter, δ13C and nitrogen content per unit area increased gradually, and oppositely, leaf length-width ratio, specific leaf area, stoma length-width ratio and ratio of upper and lower epidermis to the leaf thickness decreased gradually; similarly, fruit parameters such as fruit shape index, fruit hardness, sugar-acid ratio, total color and the a/b-value ascended while the titratable acid and the hue angle descended. With increasing the altitude, the photosynthetic rate and water use efficiency of leaves were enhanced, and the fruit sugar-acid ratio climbed and the fruit flavor and color improved. Therefore, it could be safely concluded that within the altitude range between 1375 and 1715 m, environmental factors at a higher altitude favored Fuji apple growth.


Identification and characterization of the promoter for the cytotactin gene.
The extracellular glycoprotein cytotactin is expressed in a characteristic and complex spatiotemporal sequence during development of the chicken embryo. To identify the various control elements underlying its expression, the promoter region of the cytotactin gene has been isolated and characterized. Clones were isolated from genomic libraries by using a fragment near the 5' end of the cDNA sequence. The sequence of this cDNA fragment was found to be distributed over two exons separated by a large first intron. The site of transcription initiation was determined by S1 nuclease and primer-extension mapping. Sequencing of a 4.3-kilobase (kb) genomic DNA clone that contains 3986 base pairs (bp) upstream of the RNA start site, the first exon, and part of the first intron revealed a number of sequence motifs implicated in the regulation and expression of eukaryotic genes. These included CCAAT boxes, phorbol ester-responsive elements, enhancer elements, and a consensus TATA sequence located 24 bp upstream of the major RNA cap site. The flanking sequence also contained a number of regions of dyad symmetry and direct repeats unique to cytotactin, as well as an array of A + T-rich sequences that resemble engrailed elements. Constructs containing fragments of the upstream region of the cytotactin gene fused to a promoterless gene for chloramphenicol acetyltransferase were transiently transfected into chicken embryo fibroblasts to define functional promoter sequences. Although sequences from -721 to +121 exhibited minimal promoter activity, the entire region between -3986 to +374 was required to yield maximal expression in chicken embryo fibroblasts. Transfection of the -3986/+374 chloramphenicol acetyltransferase plasmid into the human U251MG astrocytoma cells but not HT1080 fibrosarcoma cells resulted in chloramphenicol acetyltransferase expression, consistent with the observed synthesis of cytotactin protein only by the U251MG cell line. These data indicate that the chicken cytotactin promoter can control expression in a cell type-specific fashion within cells of another species. These studies provide a basis for the dissection of cis elements and trans factors that govern the developmental expression of the cytotactin gene.


SC-52458, an orally active angiotensin II-receptor antagonist: inhibition of blood pressure response to angiotensin II challenges and pharmacokinetics in normal volunteers.
This study was designed to assess in normal volunteers the potency, efficacy, and tolerability of the new nonpeptidic, orally active, angiotensin (Ang) II subtype 1 (AT1)-receptor antagonist SC-52458. After a randomized, single-blind, placebo-controlled protocol, two groups of eight healthy men ingested placebo or increasing single oral doses (10, 25, and 50 mg or 100, 150, and 200 mg) of SC-52458. Finger blood pressure (BP) was continuously monitored (Finapres), and BP response to repeated intravenous challenges with Ang II was compared with baseline BP response to the same dose of Ang II. Up to 24 h after drug intake, effects on plasma renin activity (PRA), Ang II, and aldosterone and pharmacokinetics were estimated. One, 4, and 10 h after the 200-mg dose, diastolic BP response to Ang II challenges was decreased from 30.3 to 2.6 mm Hg (mean +/- SEM; n = 8; i.e., to 8.3 +/- 1.1% of baseline response), 10.1 mm Hg (35.4 +/- 1.8%), and 17.5 mm Hg (58.7 +/- 1.8%), respectively. SC-52458 produced dose-related increases in PRA and Ang II concentrations < or = 10 h after drug intake. Plasma aldosterone concentrations tended to be decreased for < or = 24 h after SC-52458 doses of > or = 100 mg. No drug-related side effects were observed. The pharmacokinetics were linear over the dose range of 10-150 mg (t1/2 = 1.14-2.39 h). Efficacy was dose dependent, with a peak effect after 1 h. In conclusion, the novel AT1-receptor antagonist SC-52458 is well tolerated and orally active. It produces a rapid-onset inhibition of the renin-angiotensin system and reduces BP response to Ang II for > or = 10 h. These characteristics promise strong antihypertensive properties for SC-52458.


Genioglossus fatigue in obstructive sleep apnea.
Obstructive sleep apnea (OSA) is a prevalent disorder that may cause cardiovascular disease and fatal traffic accidents but the pathophysiology remains incompletely understood. Increased fatigability of the genioglossus (the principal upper airway dilator muscle) might be important in OSA pathophysiology but the existing literature is uncertain. We hypothesized that the genioglossus in OSA subjects would fatigue more than in controls. In 9 OSA subjects and 9 controls during wakefulness we measured maximum voluntary tongue protrusion force (Tpmax). Using surface electromyography arrays we measured the rate of decline in muscle fiber conduction velocity (MFCV) during an isometric fatiguing contraction at 30% Tpmax. The rate of decline in MFCV provides an objective means of quantifying localized muscle fatigue. Linear regression analysis of individual subject data demonstrated a significantly greater decrease in MFCV in OSA subjects compared to control subjects (29.2 ± 20.8% [mean ± SD] versus 11.2 ± 20.8%; p=0.04). These data support increased fatigability of the genioglossus muscle in OSA subjects which may be important in the pathophysiology of OSA.


Association of type 2 diabetes with depression, brain atrophy, and reduced fine motor speed in a 60- to 64-year-old community sample.
To examine the relationship of diabetes mellitus to depression, cognition, and structural brain anatomical variables in a 60-64-year-old community-dwelling sample. The authors hypothesized that subjects with Type 2 diabetes are more likely to be depressed, have more brain atrophy, and poorer cognitive function compared with nondiabetic comparison subjects. A random sample of 478 subjects aged 60-64 years from a larger community sample were interviewed and underwent physical examinations, assessment of depression, standard cognitive assessments, brain magnetic resonance imaging (MRI) scans, and fasting blood tests. Subjects were considered diabetic if they were on treatment for diabetes or recorded a fasting blood glucose level of greater than 10 mmol/L. The MRI scans were analyzed for brain atrophy, gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), hippocampal, and white matter hyperintensity (WMH) volumes. MRI data were available for 39 subjects with diabetes and 428 subjects without diabetes. Descriptive analyses showed that subjects with diabetes were more likely to have poor physical health, a higher body mass index, and higher scores of depression and anxiety compared with comparison subjects without diabetes. In multiple regression analyses, diabetes was associated with greater total brain atrophy and larger CSF volume, but did not differ in the WM, GM, and WMH volumes. Diabetes patients performed less well on a task of fine motor dexterity. Diabetes is related to increased brain atrophy and poor motor function in 60-64 year olds, independent of depression, vascular risk factors, and small vessel disease of the brain.


Nucleolar size and shape is sexually dimorphic in neurons of the lateral magnocellular nucleus of the anterior neostriatum (LMAN) in birds.
The lateral magnocellular nucleus of the anterior neostriatum (LMAN) in birds plays an important role in songlearning processes. Recently, it has been shown that structural changes at the cellular level in males are causally related to vocal learning. Whereas males sing, females do not. This sexual difference in behavior is also reflected in sexual differences in the neuronal structure in adult birds, with males having larger neuronal somata than do females. In the present report, the size and shape of the nucleoli were investigated to determine if sexual differences were also present at the nucleolar level. The data demonstrated a strong sexual difference in nucleolar size in both juvenile and adult birds, the cross-sectional area of the nucleoli being significantly larger in males than in females (30% and 50% larger in juvenile and adult birds, respectively). This difference between males and female finches was also reflected by the cross-sectional area of a specific type of nucleolus exhibiting a central light area. In both sexes, nucleoli exhibiting a central light area were significantly larger in juvenile and adult birds than nucleoli that lacked a central light area. The percentage of neurons exhibiting a central light area was higher in adult males than in adult females, but not in juvenile birds. The time course of development of nucleoli exhibiting a central light area in males was very similar to the development of neuronal somata size in LMAN neurons. The larger size of the nucleoli in LMAN neurons in males and the developmental changes in the incidence of nucleoli exhibiting a central light area may be indicative of a high level of ribosome production necessary for song-learning processes to occur.


Medial Patellofemoral Ligament Reconstruction in Skeletally Immature Patients.
Patellofemoral instability is a common problem affecting children and adolescents, with recurrent instability often requiring surgical intervention. Medial patellofemoral ligament (MPFL) reconstruction has become a mainstay for the treatment of patellofemoral instability because of the biomechanical importance of the MPFL against lateral dislocation as well as the high frequency of MPFL injury following traumatic patellar dislocation. The concern in managing skeletally immature patients is the potential for injury to the distal femoral physis. Here, we highlight 2 techniques for MPFL reconstruction. The first technique utilizes a hamstring autograft. The steps include: Step 1: Harvest the semitendinosus graft from a 2-cm posteromedial incision with use of an open tendon harvester proximally and a closed tendon harvester distally. Step 2: Prepare the graft for double-bundle reconstruction, allowing for approximately 50 to 60 mm for the reconstructed MPFL and 15 to 20 mm for graft placement within the patella and femoral sockets. Step 3: Use a guidewire and reamer to create 2 patellar sockets approximately 15 mm long each. Step 4: Use a guidewire under fluoroscopy to position and create a femoral socket distal to the distal femoral physis approximately 15 mm long. Step 5: Fix the graft on the femur with use of a tenodesis screw, pass the graft through the soft-tissue space between the fascia and synovium to the superior half of the patella, then dock the free ends of the graft onto the 2 patellar sockets with "PEEK (polyetheretherketone) SwiveLocks (Arthrex)" while the knee is in 30° of flexion. We also review a second technique of docking the hamstring graft onto the adductor tubercle and suturing it proximally to the deep distal medial aspect of the quadriceps tendon. Although only a limited number of studies have reported the outcomes of MPFL reconstruction in skeletally immature patients, such studies have demonstrated a high return to preoperative level of sports activity and a reduced prevalence of recurrent patellar instability.


Plaque and systemic disease: a reappraisal of the focal infection concept.
The review presented here covers metastatic local and systemic disease secondary to the accumulation of plaque or the formation of other pathogenic microbial depots in the mouth. At least 3 pathways may link oral infection to secondary disease, to wit metastatic infection due to transient bacteremia, metastatic immunological injury, and metastatic toxic injury. The available evidence is presented and examples are provided. They concern among others such divergent diseases as acute bacterial myocarditis, infective endocarditis, brain abscess, uveitis and iridocyclitis, trigeminal and atypical facial neuralgia, unilateral facial paralysis, fever of "unknown' origin, and neutrophil dysfunction.


Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors.
CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14alpha-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC(50) values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC(50) of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 microM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius(2) receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining.


[Indirect costs in health technology assessment].
In the health technology assessment it is crucial to define the perspective of the analysis. When the societal perspective is chosen it is necessary to include all the costs incurred by the society, also the costs of lost productivity resulting from absence of sick employees from work or their reduced efficiency at work. The aim of this article is to present the notion of indirect costs, their importance in health technology assessment and the methods of calculation. The economic literature has been reviewed for the state of knowledge on indirect costs. Three methods of calculation are described: human capital method, friction cost method or health state valuation. Indirect costs in Western European countries can amount to more than half of total costs attributed to the illness and its treatment. In the literature there is no consensus regarding the proper method of indirect costs calculation. It is necessary to conduct further theoretical and empirical research in the area of indirect costs and enhance discussion among Polish pharmacoeconomists.


Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types.
In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs. SMPs occur throughout the alignment, with many in the important A-loop region, and others spread between the N and C lobes of the kinase domain. Since mutations are pooled across the superfamily, these positions may be important to many protein kinases. We select eleven mutations from these positions for functional validation. All eleven mutations cause a reduction or loss of function in the affected kinase. The tested mutations are from four genes, including two tumor suppressors (TGFBR1 and CHEK2) and two oncogenes (KDR and ERBB2). They also represent multiple cancer types, and include both recurrent and non-recurrent events. Many of these mutations warrant further investigation as potential cancer drivers.


Experimental infection of rat (Rattus norvigus, strain Wistar) mammary gland by Mollicutes from the bovine udders.
Seven isolates of Mollicutes, Mycoplasma F-38; M. mycoides var. capri; mixed isolates of M. bovigenitalium and M. bovirhinis; M. bovigenitalium, Mycoplasma F-38 and M. bovirhinis; M. bovis, M. bovigenitalium, Mycoplasma F-38 and A. laidlawii; A. axanthum; A. laidlawii from bovine udders and a M. bovis type strain (NCTC-10131) produced significant histopathological changes characterized by infiltration of neutrophils in lumen of acini, interlobular and intralobular ducts along with the hyperplasia of lining cells of acini, interlobular and intralobular ducts and infiltration of mononuclear cells and fibroblasts in interstitium in the mammary gland of rat suggestive of mastitis. A. laidlawii and A. axanthum produced only mild changes suggestive of their negligible role in the bovine mastitis. Rat mammary gland is recommended as a suitable in vivo experimental laboratory model to screen the mastitogenic potential of Mollicutes.


Experience of Health Care Professionals Using Digital Tools in the Hospital: Qualitative Systematic Review.
The digitalization of health care has many potential benefits, but it may also negatively impact health care professionals' well-being. Burnout can, in part, result from inefficient work processes related to the suboptimal implementation and use of health information technologies. Although strategies to reduce stress and mitigate clinician burnout typically involve individual-based interventions, emerging evidence suggests that improving the experience of using health information technologies can have a notable impact. The aim of this systematic review was to collect evidence of the benefits and challenges associated with the use of digital tools in hospital settings with a particular focus on the experiences of health care professionals using these tools. We conducted a systematic literature review following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to explore the experience of health care professionals with digital tools in hospital settings. Using a rigorous selection process to ensure the methodological quality and validity of the study results, we included qualitative studies with distinct data that described the experiences of physicians and nurses. A panel of 3 independent researchers performed iterative data analysis and identified thematic constructs. Of the 1175 unique primary studies, we identified 17 (1.45%) publications that focused on health care professionals' experiences with various digital tools in their day-to-day practice. Of the 17 studies, 10 (59%) focused on clinical decision support tools, followed by 6 (35%) studies focusing on electronic health records and 1 (6%) on a remote patient-monitoring tool. We propose a theoretical framework for understanding the complex interplay between the use of digital tools, experience, and outcomes. We identified 6 constructs that encompass the positive and negative experiences of health care professionals when using digital tools, along with moderators and outcomes. Positive experiences included feeling confident, responsible, and satisfied, whereas negative experiences included frustration, feeling overwhelmed, and feeling frightened. Positive moderators that may reinforce the use of digital tools included sufficient training and adequate workflow integration, whereas negative moderators comprised unfavorable social structures and the lack of training. Positive outcomes included improved patient care and increased workflow efficiency, whereas negative outcomes included increased workload, increased safety risks, and issues with information quality. Although positive and negative outcomes and moderators that may affect the use of digital tools were commonly reported, the experiences of health care professionals, such as their thoughts and emotions, were less frequently discussed. On the basis of this finding, this study highlights the need for further research specifically targeting experiences as an important mediator of clinician well-being. It also emphasizes the importance of considering differences in the nature of specific tools as well as the profession and role of individual users. PROSPERO CRD42023393883; https://tinyurl.com/2htpzzxj.