Senile cataract. The case against light.
A photochemical theory of the etiology of senile cataract is developed on the assumption that observed prevalences are representable by cumulants of tolerances, the latter being distributed normally and depending in a quantitatively defined way on the amount of short-wavelength radiation absorbed during life. The theoretical risk-curves are consistent with the observed ones. The variation of the predicted and observed values has a slope not differing significantly from unity, but the intercept differs from zero. It is concluded tentatively that the photochemical hypothesis accounts for the observations better and better as age advances, and more so where the radiation is more intense.


[Spatial reorganization of horizontal connections of cat cortical area 17 induced by eye rotation].
In six cats with experimental unilateral or bilateral strabismus, surgically induced early in postnatal life, torsion eye rotation with a deviation angle of 10 to 20 degrees was also detected. Spatial distribution of retrogradely labeled neurons in area 17 was studied following microiontophoretic injection of horseradish peroxidase in area 17 or 18 cortical columns. Eye rotation was shown to cause the increase of the length of horizontal neuronal connections in area 17 along the projection of visual field vertical meridian. The reorganization of neuronal connections, detected in this work, may promote the functional changes, described in the literature, that compensate for the eye rotation.


Molecular characterization of a new immunoglobulin superfamily protein with potential roles in opioid binding and cell contact.
A purified opioid-binding protein has been characterized by cDNA cloning. The cDNA sequence predicts an extracellularly located glycoprotein of 345 amino acids. This protein does not possess a membrane-spanning domain but contains a C-terminal hydrophobic sequence characteristic of membrane attachment by a phosphatidylinositol linkage. It displays homology to the immunoglobulin protein superfamily, featuring three domains that resemble disulfide-bonded constant regions. More specifically, the protein is most homologous to a subfamily of proteins which includes the neural cell adhesion molecule (NCAM) and myelin-associated glycoprotein (MAG) and one subgroup of the tyrosine kinase growth factor receptors comprising the platelet-derived growth factor receptor (PDGF R), the colony-stimulating factor 1 receptor (CSF-1 R) and the c-kit protooncogene. These sequence homologies suggest that the protein could be involved in either cell recognition and adhesion, peptidergic ligand binding or both.


[Design and synthesis of novel PPARgamma agonists].
To design and synthesize novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. A series of novel PPARgamma agonists were designed based on the binding character of PPARgamma agonists and the distribution of pharmacophore. The target compounds were synthesized using p-hydroxybenzaldehyde, 1, 2-dibromoethane, phenol, hydantoin and 2-thiohydantoin as materials. Twelve compounds were synthesized by etherification and Knoevenagle condensation. The target compounds were efficiently synthesized under mild condition and the structures of the target compounds were confirmed by 1HNMR and MS.


Genetic determinants of Nef-mediated CD4 and HLA class I down-regulation differences between HIV-1 subtypes B and C.
HIV-1 subtype C Nef sequences have a significantly lower ability overall to down-regulate CD4 and HLA-I than subtype B Nef sequences. Here we investigated whether Nef amino acids differing in frequency between HIV-1 subtypes B and C explain lower CD4 and HLA-I down-regulation ability of subtype C. Subtype-specific mutations were introduced into representative subtype B and C Nef sequences and the CD4 and HLA-I down-regulation ability of these mutants was measured by flow cytometry in a CD4+ T cell line. Subtype C consensus 20I and subtype B consensus 20M reduced and increased HLA-I down-regulation respectively, and the S88G immune escape mutation (which is significantly more frequent in subtype C than subtype B) reduced CD4 and HLA-I down-regulation. Our data suggest that these subtype-specific differences may partly contribute to inter-subtype functional differences, and identification of an immune escape mutation - S88G - that impairs Nef function is of relevance to vaccine design.


Vaginal Birth at Term - Part 1. Guideline of the DGGG, OEGGG and SGGG (S3-Level, AWMF Registry No. 015/083, December 2020).
Purpose This guideline aims to summarize the current state of knowledge about vaginal birth at term. The guideline focuses on definitions of the physiological stages of labor as well as differentiating between various pathological developments and conditions. It also assesses the need for intervention and the options to avoid interventions. This first part presents recommendations and statements about patient information and counselling, general patient care, monitoring of patients, pain management and quality control measures for vaginal birth. Methods The German recommendations largely reproduce the recommendations of the National Institute for Health and Care Excellence (NICE) CG 190 guideline "Intrapartum care for healthy women and babies". Other international guidelines were also consulted in specific cases when compiling this guideline. In addition, a systematic search and analysis of the literature was carried out using PICO questions, if this was considered necessary, and other systematic reviews and individual studies were taken into account. For easier comprehension, the assessment tools of the Scottish Intercollegiate Guidelines Network (SIGN) were used to evaluate the quality of the additionally consulted studies. Otherwise, the GRADE system was used for the NICE guideline and the evidence reports of the IQWiG were used to evaluate the quality of the evidence. Recommendations Recommendations and statements were formulated based on identified evidence and/or a structured consensus.


Short-term temporal variation in sporulation dynamics of arbuscular mycorrhizal (AM) fungi and physico-chemical edaphic properties of wheat rhizosphere.
In this study, we investigated the pattern of short-term temporal variation in the arbuscular mycorrhizal (AM) fungi and physico-chemical edaphic properties of some wheat growing areas of the Bundelkhand region, Central India. Rhizospheric soil samples were collected every month from December 2007 to May 2008 from four wheat growing sites around Jhansi (Bundelkhand region). AM fungal root colonization, sporulation and physico-chemical edaphic properties during this period were determined and compared to evaluate the dynamics of response of wheat towards the AMF along crop maturation. Maximum AMF root colonization recorded was 54.3% indicating that AMF, particularly in low phosphorus (P) soils, can be important even in case of less responsive crop like wheat. In the two out of four sites studied, the AMF spore density increased with the increase in soil temperature. Absence of this type of pattern in remaining two sites indicated that site-specific environmental and agricultural conditions may affect the degree of wheat response to AMF. It also suggested that AMF communities inhabiting agroecosystems may exhibit considerable temporal sporulation patterns. The maximum AMF colonization was observed during February-March 2008, whereas maximum AMF sporulation was noticed during March-April 2008. Statistically significant negative correlation of AMF spore density with pH, organic carbon (OC) and available P was observed in the one of the sites studied. Overall assessment of the data indicated that season and location significantly affected the interaction of AM fungi with winter wheat necessitating the further need to understand the ecology of AMF populations with reference to specific host species under different micro-climatic conditions of Bundelkhand region.


Go/no-go training affects frontal midline theta and mu oscillations to passively observed food stimuli.
The mere perception of high-calorie food items can trigger strong action tendencies towards these foods. Go/no-go training has successfully been applied to reduce such action tendencies. This study investigated the electrophysiological mechanisms that may underlie the beneficial effects of go/no-go training on food consumption. EEG was measured while 19 participants passively observed pictures of food and non-food items, both before and after the go/no-go training. During training, 50% of the food and non-food items were consistently paired with a go/no-go response. After training, food items that had been associated with a response induced larger mu desynchronization at electrodes over sensorimotor regions, whereas food items that had been associated with withholding from responding induced larger increases in theta power at frontal midline electrodes. These findings suggest that the exerted cognitive control during go/no-go training with attractive food stimuli may become associated with these stimuli and signal the required level of control during subsequent encounters.


Efficacy of percutaneous electrical nerve stimulation and therapeutic exercise for older adults with chronic low back pain: a randomized controlled trial.
Chronic low back pain (CLBP) in older adults may be disabling and therapeutically challenging, largely because of the inefficacy and/or morbidity associated with traditional pain treatment. We conducted a randomized controlled trial in 200 men and women > or = age 65 with CLBP to evaluate the efficacy of percutaneous electrical nerve stimulation (PENS) with and without general conditioning and aerobic exercise (GCAE), for reducing pain and improving physical function. Participants were randomized to receive (1) PENS, (2) control-PENS (brief electrical stimulation to control for treatment expectancy), (3) PENS+GCAE, or (4) control-PENS+GCAE, twice a week for 6 weeks. All four groups experienced significantly reduced pain (range -2.3 to -4.1 on the McGill Pain Questionnaire short form), improved self-reported disability (range -2.1 to -3.0 on Roland scale) and improved gait velocity (0.04-0.07 m/s), sustained at 6 months. The GCAE groups experienced significantly fewer fear avoidance beliefs immediately post-intervention and at 6 months than non-GCAE groups. There were no significant side effects. Since brief electrical stimulation (i.e., control-PENS) facilitated comparably reduced pain and improved function at 6 months as compared with PENS, the exact dose of electrical stimulation required for analgesia cannot be determined. GCAE was more effective than PENS alone in reducing fear avoidance beliefs, but not in reducing pain or in improving physical function.


Immunohistochemical analysis of P53 protein in odontogenic cysts.
The p53 is a well-known tumor suppressor gene, the mutations of which are closely related to the decreased differentiation of cells. Findings of studies on immunohistochemical P53 expression in odontogenic cysts are controversial. The present study was carried-out to investigate the immunohistochemical expression of P53 protein in odontogenic cysts. Thirty paraffin blocks of diagnosed odontogenic cysts were processed to determine the immunohistochemical expression of P53 protein. Nine of the 11 odontogenic keratocysts (81.8%) expressed P53, one of three dentigerous cyst cases expressed P53, while none of the 16 radicular cysts expressed P53 protein. The findings of the present work supported the reclassification of OKC as keratocystic odontogenic tumor.


Thyroidectomy Hemostasis.
Total thyroidectomy has significantly changed over the years from a morbid procedure to one that is performed routinely on an outpatient basis. This article reviews the history of thyroid surgery with regard to hemostasis, discusses surgical vascular anatomy, and describes the methods of hemostasis. It compares traditional hemostatic surgical techniques with newer techniques such as the Harmonic Scalpel and LigaSure hand pieces. The use of adjunctive hemostatic agents and indications for a drain in thyroid are discussed.


Successes and failures of chemokine-pathway targeting in rheumatoid arthritis.
Chemokines and chemokine receptors are involved in leukocyte recruitment and angiogenesis underlying the pathogenesis of rheumatoid arthritis (RA) and other inflammatory rheumatic diseases. Numerous chemokines, along with both conventional and atypical cell-surface chemokine receptors, are found in inflamed synovia. Preclinical studies carried out in animal models of arthritis involving agents targeting chemokines and chemokine receptors have yielded promising results. However, most human trials of treatment of RA with antibodies and synthetic compounds targeting chemokine signalling have failed to show clinical improvements. Chemokines can have overlapping actions, and their activities can be altered by chemical modification or proteolytic degradation. Effective targeting of chemokine pathways must take acount of these properties, and can also require high levels of receptor occupancy by therapeutic agents to prevent signalling. CCR1 is a promising target for chemokine-receptor blockade.


Pharmacological properties of musk.
The general pharmacological properties of musk were studied. After the application of musk, inhibition of acetic acid-induced writhing, hemolytic effect and excitation of spontaneous uterine motility of rats, inhibition of spontaneous motility in isolated ileum of rabbits, and anti-inflammatory effects and potentiation of beta-adrenergic action in isolated preparations of guinea pig trachea were observed. These effects were not observed after application of muscone or allantoin, constituents of musk.


Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury.
Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. STATEMENT OF SIGNIFICANCE: TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo.


Effects of extreme precipitation on hospitalization risk and disease burden of schizophrenia in urban and rural Lu'an, China, from 2010 to 2019.
With the increasing frequency of extreme events caused by global climate change, the association between extreme precipitation (EP) and disease has aroused concern currently. However, no study has examined the relationship between EP and schizophrenia. Our study aimed to explore the relationship between EP and schizophrenia, and to further examine the difference between urban and rural areas. This study used quasi-Poisson generalized linear regression model combined with distributed lag non-linear model (DLNM) to estimate the association between EP (≥ 95th percentile) and hospitalization for schizophrenia from 2010 to 2019 in the city of Lu'an, China. EP could significantly increase the risk of hospitalization for schizophrenia. The effect firstly appeared at lag1 [relative risk (RR): 1.056, 95% confidence interval (95%CI): 1.003-1.110] and continued until lag17 (RR: 1.039, 95%CI: 1.004-1.075). Our research showed that EP had a significant effect on the hospitalization for schizophrenia in both urban and rural areas, and no significant difference was found (p>0.05). EP exerted more acute effects on schizophrenia living in rural areas than those in urban areas in the cold season. Further studies on the burden of schizophrenia found that patients who are male, aged ≤ 39 years or less, and living in urban areas are a priority for future warnings. We should pay more attention to the impact of EP on burden of schizophrenia, especially during the cold season, targeting those vulnerable groups, thereby implementing more accurate and timely preventive measures.


Dietary phytate and mineral bioavailability.
The relation between the dietary phytate (InsP6), mineral status and InsP6 levels in the organism, using three controlled diets (AIN-76A, AIN-76A + 1% phytate, AIN-76A + 6% carob seed germ), are studied. AIN-76A is a purified diet in which InsP6 is practically absent. No important or significant differences in the mineral status (Zn, Cu, Fe) of blood, kidneys, liver, brain and bone, were observed, except iron in the brain. Thus, the amounts of iron found in the brain of rats fed AIN-76A + 1% InsP6 were significantly inferior to those found in rats fed AIN-76A diet. The amounts of InsP6 found in organs of rats fed AIN-76A diet became very low or even undetectable while the ones found in rats fed diets that contained 1% and 0.12% (AIN-76A + 6% carob seed germ) InsP6, were considerably higher and similar. Moreover the majority of rats fed AIN-76A diet exhibited calcifications at the corticomedullary junctions, whereas no calcifications were detected in rats fed the other two diets. From these results, it can be deduced that there was no important adverse effects on mineral status as a consequence of the presence of InsP6 in the studied diets. Besides, considering that a 0.12% InsP6 contained in the AIN-76A purified diet through the addition of a 6% of carob seed germ to this diet, produced the same beneficial effects as the direct addition of a 1% of InsP6 and no negative effects on mineral status was observed, it can be concluded that the value of the presence of InsP6 at adequate amounts in the diet is remarkable and must be favourably considered.


Epidemiology of tennis, squash, and racquetball injuries.
This article enumerates and examines the existing epidemiologic data on racquet sports injuries. A framework is provided for the evaluation and interpretation of future studies and research.


Comparison of transient severe motion in gadoxetate disodium and gadopentetate dimeglumine-enhanced MRI: effect of modified breath-holding method.
To compare the occurrence of transient severe motion (TSM) between gadoxetate disodium- and gadopentetate dimeglumine-enhanced MRI and between gadoxetate disodium-enhanced MRI scans obtained with and without the application of a modified breath-holding technique. We reviewed 80 patients who underwent two magnetic resonance examinations (gadoxetate disodium-enhanced MRI and gadopentetate dimeglumine-enhanced MRI) with the application of a modified breath-holding technique (dual group). This group was compared with 100 patients who underwent gadoxetate disodium-enhanced MRI without the application of the modified breath-holding technique (single group). Patient risk factors and motion scores (1 [none] to 5 [non-diagnostic]) for each dynamic-phase imaging were analysed. In the dual group, mean motion scores did not differ significantly between gadoxetate disodium- and gadopentetate dimeglumine-enhanced MRI (p=0.096-0.807) in any phase. However, in all phases except the late dynamic phase, mean motion scores of the dual group were significantly lower than those in the single group. TSM incidence did not differ significantly between gadoxetate disodium- and gadopentetate dimeglumine-enhanced MRI in the dual group (3.8% vs. 1.3%, p=0.620). With proper application of the modified breath-holding technique, TSM occurrence with gadoxetate disodium-enhanced MRI was comparable to that associated with gadopentetate dimeglumine-enhanced MRI. • The modified breath-holding method significantly reduced the incidence of TSM. • Gadoxetate disodium and gadopentetate dimeglumine showed comparable motion scores. • TSM incidence was comparable between gadoxetate disodium- and gadopentetate dimeglumine-enhanced MRI.


Effect of liposomal antigens on the priming and activation of the immune system by dendritic cells.
Dendritic cells (DCs) are recognized as the sole professional antigen-presenting cells capable of priming naive T cells of the helper and cytotoxic phenotypes. This property is presently exploited with success in vaccinal strategies against pathogens or tumor cells that otherwise escape immune recognition, but the repeated infusions of ex vivo expanded and sensitized DCs are usually required to achieve protection. In this paper, we demonstrate that liposomal antigens can efficiently relay and propagate the action of DCs, inducing a strong long-term response against their associated antigen. Their effect is mainly achieved by improving the ex vivo loading of DCs and by efficiently channeling the activation stimulus into the induction of effector function. This is demonstrated by the sustained immunoglobulin production as well as by the sustained lymphoproliferation and the increased cytokine secretion that can be achieved upon restimulation of DC-primed immune cells with limited amount of liposomal antigenic material. Being well-tolerated and easily prepared, liposomal antigens could therefore be expected to significantly contribute to the efficiency and to a more general utilization of the highly promising but rather cumbersome DC-based immunotherapies.


Liver Injury and the Activation of the Hepatic Myofibroblasts.
Liver fibrosis is a wound healing process, the end result of chronic liver injury elicited by different noxious stimuli. Activated hepatic stellate cells or myofibroblasts and portal myofibroblasts are considered as the main producers of the extracellular matrix in the liver. Upon liver injury the quiescent stellate cells transdifferentiate into myofibroblasts a process highlighted by the loss of vitamin A stores, upregulation of interstitial type collagens, smooth muscle α actin, matrix metalloproteinases, proteoglycans, and the induction of cell survival pathways. Activation of hepatic stellate cells is a result of a complex interplay between the parenchymal cells, immune cells, extracellular matrix mechanics and extrahepatic milieu such as the gut microbiome. In this review we will focus on the pathomechanism of stellate cell activation following chronic liver injury; with the aim of identifying possible treatment targets for anti-fibrogenic agents.


Optimal Sampling Duration for Continuous Glucose Monitoring for the Estimation of Glycemia Risk Index.
Objective: To evaluate optimal continuous glucose monitoring (CGM) sampling duration to estimate glycemia risk index (GRI). Methods: Up to 90 days of CGM data from 225 nonpregnant adults with type 1 diabetes (median age 40 years, 60% females, and 20 years of diabetes duration) and not using hybrid closed-loop system were collected. The association between GRI from various sampling periods and GRI using all 90 days of data was determined using the squared value of the Pearson correlation coefficient (R2). Results: With increasing duration of the CGM sampling period, there was higher correlation with the 90-day GRI: R2 of 0.79 for 7 days, R2 of 0.88 for 14 days, and R2 of 0.93 for 30 days. In a sensitivity analysis, correlation (r) or correlation coefficient (R2) for CGM sampling period for GRI estimation was not different among participants with time <70 mg/dL of <4% and participants with time <70 mg/dL of >4%. Conclusion: Though 14 days of CGM sampling duration is optimal for estimation of GRI, 7 days of CGM data may be enough to estimate GRI to monitor change in quality of glycemia with intervention.


Deep learning architectures for Parkinson's disease detection by using multi-modal features.
The use of multi-modal features for improving the diagnosing accuracy of Parkinson's disease (PD) is still under consideration. Early diagnosis of PD is very crucial for better management and treatment planning of PD, as the delay in the diagnosis may even lead to death of the patient. Two frameworks, feature-level and modal-level, both of which are based on deep learning, are presented to classify the given subjects into PD and healthy by using neuroimaging (T1 weighted MRI scans and SPECT) and biological (CSF) features as the dataset. In the feature-level framework, all these features are integrated to form a heterogeneous dataset which is then supplied to two deep learning models to diagnose PD. In the modal-level framework, the number of features from T1 weighted MRI scans is reduced first, by using the filter feature selection method ReliefF. Those reduced number of features from the MRI scans are integrated with SPECT and CSF features to form another heterogeneous dataset, which is then fed to a deep learning model. Due to imbalanced nature of the dataset (consists of 73 PD and 59 healthy subjects), F1-score, geometric-mean, sensitivity, and specificity are measured, in addition to measuring the accuracy, to evaluate the performance of the developed models. A maximum accuracy of 93.33% and 92.38% is observed, for CNN, in the feature-level framework and modal-level framework, respectively. Though the complexity of the approach based on multi-modal features is high as compared to an approach that uses only one type of feature, i.e., either neuroimaging or biological; the results prove that the approach based on multi-modal features is useful for classifying the given subjects into PD and healthy and can help the clinicians in accurately diagnosing the PD.


Rare compound heterozygous missense SPATA7 variations and risk of schizophrenia; whole-exome sequencing in a consanguineous family with affected siblings, follow-up sequencing and a case-control study.
Whole-exome sequencing (WES) of multiplex families is a promising strategy for identifying causative variations for common diseases. To identify rare recessive risk variations for schizophrenia, we performed a WES study in a consanguineous family with affected siblings. We then performed follow-up sequencing of SPATA7 in schizophrenia-affected families. In addition, we performed a case-control study to investigate association between SPATA7 variations and schizophrenia. WES was performed on two affected siblings and their unaffected parents, who were second cousins, of a multiplex schizophrenia family. Subsequently, we sequenced the coding region of SPATA7, a potential risk gene identified by the WES analysis, in 142 affected offspring from 137 families for whom parental DNA samples were available. We further tested rare recessive SPATA7 variations, identified by WES and sequencing, for associations with schizophrenia in 2,756 patients and 2,646 controls. Our WES analysis identified rare compound heterozygous missense SPATA7 variations, p.Asp134Gly and p.Ile332Thr, in both affected siblings. Sequencing SPATA7 coding regions from 137 families identified no rare recessive variations in affected offspring. In the case-control study, we did not detect the rare compound heterozygous SPATA7 missense variations in patients or controls. Our data does not support the role of the rare compound heterozygous SPATA7 missense variations p.Asp134Gly and p.Ile332Thr in conferring a substantial risk of schizophrenia.


Characteristics of umami peptides identified from porcine bone soup and molecular docking to the taste receptor T1R1/T1R3.
To study the umami peptides derived from porcine bone soup, ultrafiltration fractions with molecular weight less than 1 kDa were screened by sensory analysis which showed higher umami intensity. Four potential umami peptides were identified from the screened fractions by Nano-LC-Q-TOF-MS/MS, among which FSGLDGAK, FAGDDAPR and FSGLDGSK were proved to have dominant umami taste by sensory evaluation and electronic tongue. The threshold of the three peptides ranged from 0.1 mM to 0.89 mM. In addition, FSGLDGSK had the highest umami intensity and exhibited a significant umami-enhancing effect in a 0.35% monosodium glutamate solution. The results of molecular docking simulation showed that the key binding sites of taste receptor type 1 member 1 (His71, Asp108 and Glu301) and taste receptor type 1 member 3 (Glu48, Ser104 and His145) were crucial to the interaction with the umami peptides. Besides, electrostatic interaction and hydrogen bond mainly contributed to the mechanism of umami taste.


"Presynaptic silence" may be golden.
Conversion of "silent" synapses into active ones is a likely mechanism for long-term potentiation (LTP), an experimental paradigm for studying information storage. A widely accepted mechanism that has been suggested for synaptic silence is that functional AMPA glutamate receptors (AMPARs) are absent on the subsynaptic membrane. Evidence is presented here that in many cases the cause of apparent "silence" is presynaptic and due to a low level of glutamate release. Increased transmitter release is crucial for early LTP maintenance. Delayed modifications in postsynaptic receptors matched with transmitter release changes underlie structural alterations associated with late LTP phases.


Layered Double Hydroxide Nanoplatelets with Excellent Tribological Properties under High Contact Pressure as Water-Based Lubricant Additives.
High efficient and sustainable utilization of water-based lubricant is essential for saving energy. In this paper, a kind of layered double hydroxide (LDH) nanoplatelets is synthesized and well dispersed in water due to the surface modification with oleylamine. The excellent tribological properties of the oleylamine-modified Ni-Al LDH (NiAl-LDH/OAm) nanoplatelets as water-based lubricant additives are evaluated by the tribological tests in an aqueous environment. The modified LDH nanoplatelets are found to not only reduce the friction but also enhance the wear resistance, compared with the water-based cutting fluid and lubricants containing other particle additives. By adding 0.5 wt% LDH nanoplatelets, under 1.5 GPa initial contact pressure, the friction coefficient, scar diameter, depth and width of the wear track dramatically decrease by 83.1%, 43.2%, 88.5% and 59.5%, respectively. It is considered that the sufficiently small size and the excellent dispersion of NiAl-LDH/OAm nanoplatelets in water are the key factors, so as to make them enter the contact area, form a lubricating film and prevent direct collision of asperity peaks. Our investigations demonstrate that the LDH nanoplatelet as a water-based lubricant additive has a great potential value in industrial application.


Assessing the severity of atopic dermatitis in clinical trials and practice.
There is a tremendous need for accurate and reproducible scoring systems for the grading of skin disease to further the development of research and standards of care. There are presently greater than 60 measures that have been used to assess the severity of atopic dermatitis. These assessments vary considerably with respect to content, scale, instructions, validity, and concordance. This contribution reviews the available scoring systems of atopic dermatitis signs based on their design and merit in specific settings. These scores assess lesional intensity and/or extent, symptoms, disease course, and epidermal function. Scoring atopic dermatitis, Investigator Global Assessment, and Eczema Area and Severity Index are the most commonly used assessments of atopic dermatitis signs. Eczema Area and Severity Index has emerged as the preferred outcome measure of atopic dermatitis signs for use in clinical trials. Unfortunately, Eczema Area and Severity Index can be cumbersome in clinical practice. Itch intensity (visual analog or numeric rating scales) and Patient-Oriented Eczema Measure have emerged as the preferred patient-reported outcome in clinical trials. Clinicians' gestalt global assessment of severity, Patient-Oriented Eczema Measure, and intensity of itch may be feasible for clinical practice.


Adverse effects of immunotherapeutics involving the immune system.
Immunotherapeutics are pharmaceutical products intended to modify immune functions either directly or indirectly by influencing physiological systems that affect immunological functions. They include conventional immunosuppressants, monoclonal antibodies, recombinant cytokines, gene therapy products or therapeutic vaccines. A variety of adverse effects involving the immune system have been described in laboratory animals as well as in the clinic. Some of these adverse effects can be predicted, at least to some extent, from the immunopharmacological profile of these drugs, but a number of unpredicted adverse effects have been described. Immunosuppression, allergy, autoimmunity, immunoactivation are the major adverse consequences to be expected as illustrated by this overview of the leading immunotherapeutics already used in the clinic. These untoward and potentially severe consequences support the need for a careful preclinical and clinical evaluation of the immunotoxicity of these products.


Increased prevalence of infectious endocarditis in patients with type II diabetes mellitus.
Patients with diabetes mellitus (DM) are at increased risk of infection. However, there are controversial reports about DM association with infectious endocarditis (IE). We evaluated the occurrence of IE in DM patients compared to a matched control. Treatment files of inpatients' admission that contained discharge diagnosis (ICD-9 codes) from Veterans Health Administration hospitals were used for this study. ICD-9 codes for DM (n=293,124) and a control group with ICD-9 codes for hypertension without DM (n=552,623) were utilized for comparison. The prevalence of IE was studied using ICD-9 codes for IE. Multivariate analysis was performed adjusting for chronic and acute renal failure and aortic and mitral valve disease. Continuous variables were analyzed by unpaired t tests. Binary variables were analyzed using the chi-square test and Fisher's Exact Tests. IE was present in 1340 (0.5%) DM patients versus 1412 (0.3%) patients from the control group (relative increase of 40%). Using multivariate analysis adjusting for renal failure and valvular abnormalities, DM remained independently associated with IE (odds ratio=1.9; 95% confidence interval=1.8-2.1; P<.0001). Patients with type II DM have significantly higher prevalence of IE independent of renal failure or valvular abnormalities consistent with increased vulnerability of DM patients for infections.


Neonatal mortality in small for gestational age infants based on reference local newborn curve at secondary and tertiary hospitals in Indonesia.
Small for gestational (SGA) infants during the neonatal period have risks of mortality and sequelae for survival. Two - third of neonatal mortality occurs in the first weeks of life. Prevalence of SGA depends on the newbon curve used. Objectives of the study were to know the conditions that posed the risk of early neonatal and neonatal mortality, to identify preterm/full-term and SGA/appropriate gestational age (AGA) infants with cumulative mortality incident (CMI), to compare 5- year-period of early and neonatal mortality, and to investigate CMI on neonatal mortality of four categories during 5-year-period. A retrospective cohort study on all live births, during 1998-2017, was conducted in Sleman and Sardjito hospitals, Yogyakarta, Indonesia. Based on the reference local curve, the eligible subjects were categorized into SGA and AGA infants. The analyses were based on preterm/full-term and SGA/AGA, thus resulting in 4 categories: preterm-SGA, preterm-AGA, full-term-SGA and full-term-AGA. Analysis was made with Unadjusted Hazard Ratio (HR) by Simple Cox Regression and Adjusted HR was calculated by Multiple Cox Regression, survival analysis to calculate CMI, and analysis mortality for 5-year period ( 1998-2002, 2003-2007, 2008-2012, 2013-2017). There were 35,649 live births eligible for the study. Respiratory distress was the highest risk with HR 9,46, followed by asphyxia with HR 5,08, mother's death with HR 227, extra-health facility with HR 1,97, symmetrical SGA with HR 1,97, preterm-AGA with HR 1,75, low birth weight (LBW) with HR 1,64, primary health facility with HR 1,33, and boys with HR 1,16 consecutively. Early neonatal mortality in 4 categories by survival analysis revealed the highest CMI in preterm SGA. Similar result was found in neonatal mortality. Analysis of 5-year period unveiled the highest CMI during 1998-2002. The highest CMI based on the four categories, however, was found in preterm-SGA. Respiratory distress posed the highest HR in early and neonatal mortality. Survival analysis showing the highest CMI on early and neonatal mortality was identified in preterm-SGA. The 5 - year - period of neonatal mortality showed the highest CMI during 1998-2002 period, whereas based on 4 SGA categories, preterm-SGA demonstrated the highest CMI.


[Arthroscopically assisted reduction of acute acromioclavicular joint separations: comparison of clinical and radiological results of single versus double TightRope™ technique].
The aim of this study was to compare the results of the single (STR) versus double TightRope™ (DTR) technique for stabilisation of acute separations of the AC joint with the hypothesis that DTR achieves lower CC distance. A total of 29 consecutive patients treated operatively with the TR technique (mean age 38.1 years, n=26 male) were analysed in a cohort study with a mean follow-up of 13.3 months (12.0-21.7). Acute AC joint separations types III and V according to Rockwood (R) were included; R types I, II, IV and VI were excluded. The prospective scores determined pre-op and 3, 6 and 12 months post-op and X-rays were evaluated. Of the patients 12 suffered an R type III and 17 an R V separation; 14 were treated with STR and 15 with DTR. With STR, 8 R III and 6 R V injuries and with DTR 4 R III and 11 R V injuries were treated arthroscopically. STR achieved an increased CC distance >125% compared to the contralateral AC joint in five cases (36%). Two of them occurred as R V and three as R III injury. DTR achieved a CC distance >125% in two cases of an R V injury (13%). The DTR technique provides lower CC distance compared to the STR technique, without a significant difference of CC distance and scores.


Impact of delayed arterial cord blood sampling for lactate assay: a prospective observational study.
Umbilical cord sampling at delivery provides important data on the newborn's metabolism. To evaluate the impact of delayed sampling on arterial cord blood lactate values. Observational study of 168 consecutive deliveries at a tertiary teaching hospital. Arterial cord blood lactate was determined with a test strip method on paired samples obtained immediately and 5-30 min after birth. At least 90 paired measurements were necessary to show a difference in lactate levels of >or=0.5 mmol/l between the first and second samples. Lactate levels according to the time interval between birth and sampling. One hundred and two paired samples were available for analysis. The lactate value was always higher in the second sample than in the first. Lactate levels increased linearly with time, by 0.062 mmol/l per min. The degree of increase was independent of the initial lactate level and the route of delivery. Delayed sampling resulted in abnormal lactate levels in 16% of neonates born with normal lactate levels. Our results show that delayed sampling of arterial cord blood is unreliable for neonatal lactate assay. Cord blood sampling and lactate assay should therefore be performed immediately after delivery.


Genotoxicity potential of a new natural formicide.
Assessment of environmental impacts from pesticide utilization should include genotoxicity studies, where the possible effects of mutagenic/genotoxic substances on individuals are assessed. In this study, the genotoxicity profile of the new formicide Macex® was evaluated with two genotoxicity tests, namely, the micronucleus test with mouse bone marrow and Vicia faba, and a mutagenicity test using the Ames Salmonella assay. The bacterial reverse mutation test (Salmonella typhimurium strains TA97, TA98, TA100, TA102, and TA1535), the Vicia root tip and mouse micronucleus tests were conducted according to published protocols. In the range of the formicide Macex® concentrations tested from 0.06 to 1.0 g L⁻¹ (or mgkg⁻¹ in the mouse test), no genotoxicity was observed in the prokaryotic or eukaryotic test organisms. However, at Macex® concentrations of 0.5 g L⁻¹ and above a significant decrease in the mitotic index (P ≤ 0.05) in the V. faba was observed. Micronucleus formation was likewise increased in the test organism at concentrations starting at 2.0 g L⁻¹. These data allow us to classify this natural formicide preparation as a product with no geno-environmental-impact when applied at recommended concentrations.


Central nervous system myeloid cells as drug targets: current status and translational challenges.
Myeloid cells of the central nervous system (CNS), which include parenchymal microglia, macrophages at CNS interfaces and monocytes recruited from the circulation during disease, are increasingly being recognized as targets for therapeutic intervention in neurological and psychiatric diseases. The origin of these cells in the immune system distinguishes them from ectodermal neurons and other glia and endows them with potential drug targets distinct from classical CNS target groups. However, despite the identification of several promising therapeutic approaches and molecular targets, no agents directly targeting these cells are currently available. Here, we assess strategies for targeting CNS myeloid cells and address key issues associated with their translation into the clinic.


Dynamics of carbon monoxide binding to CooA.
CooA is a dimeric CO-sensing heme protein from Rhodospirillum rubrum. The heme iron in reduced CooA is six-coordinate; the axial ligands are His-77 and Pro-2. CO displaces Pro-2 and induces a conformation change that allows CooA to bind DNA and activate transcription of coo genes. Equilibrium CO binding is cooperative, with a Hill coefficient of n = 1.4, P(50) = 2.2 microm, and estimated Adair constants K(1) = 0.16 and K(2) = 1.3 microm(-1). The rates of CO binding and release are both strongly biphasic, with roughly equal amplitudes for the fast and slow phases. The association rates show a hyperbolic dependence on [CO], consistent with Pro-2 dissociation being rate-limiting. The kinetic characteristics of the transiently formed five-coordinate heme are probed via flash photolysis. These observations are integrated into a kinetic model, in which CO binding to one subunit decreases the rate of Pro-2 rebinding in the second, leading to a net increase in affinity for the second CO. The CO adduct exists in slowly interconverting "open" and "closed" forms. This interconversion probably involves the large-scale motions required to bring the DNA-binding domains into proper orientation. The combination of low CO affinity, slow CO binding, and slow conformational transitions ensures that activation of CooA only occurs at high (micromolar) and sustained (> or =1 min) levels of CO. When micromolar levels do occur, positive cooperativity allows efficient activation over a narrow range of CO concentrations.


In vitro expression of beta-thalassaemia gene (IVS1-1G>C) reveals complete inactivation of the normal 5' splice site and alternative aberrant RNA splicing.
We previously reported a case of heterozygous beta-thalassaemia with IVS1-1G > C substitution in the beta-globin gene and a non-detectable level of mutant mRNA in the patient's reticulocytes. The purpose of this study was to determine whether the transcription and RNA splicing and processing of the mutant gene occurred. We analysed the expression of the mRNA encoded by the cloned mutant gene in COS-1 cells by reverse transcription-polymerase chain reaction followed by agarose gel electrophoresis and nucleotide sequencing. The G > C mutation completely inactivated the normal 5' splice site and resulted in the activation of two cryptic 5' splice sites, located 16 and 38 nt upstream of the normal site. The usage of these two cryptic sites accords with the findings of reports on IVS1-1G > A or IVS1-1G > C substitution of exon 1 of the beta-globin gene. Additional experiments that involved transfection of equal amounts of both normal and mutant vectors into COS-1 cells indicated the presence of mutant mRNAs. In conclusion, the beta-thalassaemia gene (IVS1-1G > C) was expressed in transfected cells, but showed aberrant RNA splicing. Further studies will be required to clarify the molecular mechanism that results in severe reduction in the mutant mRNA level in vivo.


Microarray analysis of metallothioneins in human diseases--A review.
Metallothioneins (MTs), low molecular mass cysteine-rich proteins, which are able to bind up to 20 monovalent and up to 7 divalent heavy metal ions are widely studied due to their functions in detoxification of metals, scavenging free radicals and cells protection against the oxidative stress. It was found that the loss of the protective effects of MT leads to an escalation of pathogenic processes and carcinogenesis. The most extensive area is MTs expression for oncological applications, where the information about gene patterns is helpful for the identification biological function, resistance to drugs and creating the correct chemotherapy. In other medical applications the effect of oxidative stress to cell lines exposed to heavy metals and hydrogen peroxide is studied as well as influence of drugs and cytokines on MTs expression and MTs expression in the adipose tissue. The precise detection of low metallothionein concentrations and its isoforms is necessary to understand the connection between quantity and isoforms of MTs to size, localization and type of cancer. This information is necessary for well-timed therapy and increase the chance to survival. Microarray chips appear as good possibility for finding all information about expression of MTs genes and isoforms not only in cancer, but also in other diseases, especially diabetes, obesity, cardiovascular diseases, ageing, osteoporosis, psychiatric disorders and as the effects of toxic drugs and pollutants, which is discussed in this review.


Reparixin improves survival in critically ill and transplant patients: A meta-analysis.
Reparixin, an anti-inflammatory drug that inhibits interleukin 8 (IL-8) activity, might be life-saving for high-risk in-hospital patients without increasing the risk of infection according to a previous meta-analysis. With the increasing availability of randomised data the aim of the current study is to update previous findings by including any randomised control trials (RCTs) investigating the impact of reparixin on survival of critically ill or transplant patients. A search strategy was developed to identify all RCTs involving reparixin in critically ill or transplant patients, with the exclusion of oncological patients. Two trained and independent authors conducted a thorough search of relevant databases. In addition, backward snowballing was employed. Language restrictions were not imposed. Our analysis included a total of nine studies involving 733 patients: 437 received reparixin and 296 the comparator. The reparixin group had a significantly lower all-cause mortality rate compared to the control group [15/437 (3.4%) vs. 19/294 (6.4%), odds ratio = 0.47 (95% confidence interval 0.23-0.96), p-value for effect .04, I2 = 22%, number needed to treat = 33]. These findings had the same direction and magnitude of effect across COVID-19 patients (n = 325) and non-COVID-19 patients (n = 408). Furthermore, there were no significant differences in the rate of pneumonia, sepsis or non-serious infections between the two groups. The findings of this meta-analysis indicate that reparixin, an anti-inflammatory drug, improved survival in critically ill or transplant patients (including both COVID-19 and non-COVID-19 patients) without increasing the risk of infection.


SNP2Structure: A Public and Versatile Resource for Mapping and Three-Dimensional Modeling of Missense SNPs on Human Protein Structures.
One of the long-standing challenges in biology is to understand how non-synonymous single nucleotide polymorphisms (nsSNPs) change protein structure and further affect their function. While it is impractical to solve all the mutated protein structures experimentally, it is quite feasible to model the mutated structures in silico. Toward this goal, we built a publicly available structure database resource (SNP2Structure, https://apps.icbi.georgetown.edu/snp2structure) focusing on missense mutations, msSNP. Compared with web portals with similar aims, SNP2Structure has the following major advantages. First, our portal offers direct comparison of two related 3D structures. Second, the protein models include all interacting molecules in the original PDB structures, so users are able to determine regions of potential interaction changes when a protein mutation occurs. Third, the mutated structures are available to download locally for further structural and functional analysis. Fourth, we used Jsmol package to display the protein structure that has no system compatibility issue. SNP2Structure provides reliable, high quality mapping of nsSNPs to 3D protein structures enabling researchers to explore the likely functional impact of human disease-causing mutations.


The effect of dorsal column stimulation on the nociceptive response of dorsal horn cells and its relevance for pain suppression.
The effect of single and repetitive electrical stimulation of the dorsal columns on cells in laminae IV and V of the ipsilateral dorsal horn at S1 was examined in spinalized cats. About two-thirds of the cells responded to thermal nociceptive cutaneous stimulation and of these most responded also to low threshold mechanical stimulation. The other one-third of the cells were innervated by mechanoreceptors including type I or Haarscheiben. A single shock to the dorsal columns typically caused short latency activation of the cells, followed by inhibition lasting about 100 msec. Several minutes of repetitive dorsal column stimulation (DCS) at 3 Hz or 50 Hz had no prolonged effect on about two-thirds of the cells. The rest of the cells were less responsive for up to 30 min after the cessation of 50 Hz. Assuming that the studied interneurons have a pain-mediating function, the results indicate that some cumulative and poststimulatory DCS suppression of pain may be ascribed to spinal mechanisms. The more effective and longer lasting suppression produced by DCS in pain patients would, however, be dependent on other types of interneurons, on suprasegmental loops and/or on effects on pathophysiological mechanisms which may be operative in the chronic pain state. The lack of cumulative inhibition in most of the cells in this study is compatible with the previous observation of a retained perception of acute pain during DCS in man.


ALDH2 gene polymorphism is associated with fitness in the elderly Japanese population.
The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which is exclusive to the Asian population, is related to many diseases. A high reactive oxygen species production in mitochondria, and low muscle strength in athletes and non-athletes, has been observed, as our previous study demonstrated. The purpose of this research was to investigate the influence of ALDH2 rs671 on the loss of muscle strength with aging and replicate our previous study in non-athletes. Healthy Japanese individuals (n = 1804) aged 23-94 years were genotyped using DNA extracted from saliva. Muscle strength was assessed using grip strength and chair stand test (CST). The interaction between age and genotypes was analyzed by two-way analysis of covariance (ANCOVA) adjusted for sex, body mass index (BMI), and exercise habit. Individuals aged ≧55 with the AA genotype had a lower performance than those with the GG + GA genotype in the grip strength test (28.1 ± 9.1 kg vs. 29.1 ± 8.3 kg, p = 0.021). There was an interaction between age and genotype, where individuals with ≧55 years old AA genotype had a higher loss of strength compared to GG + GA genotypes in the CST (0.025). No interaction in other models and no sex differences were found. This study replicated previous results of the relationship between the AA genotype with lower muscle strength and as a novelty showed that this genotype is associated with a higher age-related loss of strength.


Pulmonary Hypertension Due to Left Heart Disease-A Practical Approach to Diagnosis and Management.
Pulmonary hypertension (PH) due to left heart disease (LHD) is a frequent complication of heart failure (HF) and is associated with exercise intolerance, poor quality of life, increased risk of hospitalisations, and reduced overall survival. Since the recent Sixth World Symposium on Pulmonary Hypertension in 2018, there have been significant changes in the hemodynamic definitions and clinical classification of PH-LHD. PH-LHD can be subdivided into (1) isolated postcapillary PH (IpcPH) and (2) combined precapillary and postcapillary PH (CpcPH). This categorisation of PH-LHD is important because CpcPH shares certain pathophysiologic, clinical, and hemodynamic characteristics with pulmonary arterial hypertension and is associated with worse outcomes compared with IpcPH. A systematic approach using clinical history and noninvasive investigations is required in the diagnosis of PH-LHD. Right heart catheterisation with and without provocative testing is performed in expert centres and is indicated in selected individuals. Although the definition of IpcPH and CpcPH is based on measurements made with right heart catheterisation, distinguishing between these two entities is not always necessary. Despite strong evidence for medical therapy in patients with pulmonary arterial hypertension, those options have limited benefit in PH-LHD. Expert PH centres in Canada have been established to provide ongoing care for the more complex patient subgroups.


Ikaros confers early temporal competence to mouse retinal progenitor cells.
In the developing mouse retina, multipotent retinal progenitor cells (RPCs) give rise to specific retinal cell types at different times, but the molecular mechanisms regulating how RPCs change over time remain unclear. In the Drosophila neuroblast lineage, the zinc finger transcription factor Hunchback (Hb) is both necessary and sufficient to specify early-born neuronal identity. We show here that Ikaros, a mouse ortholog of Hb, is expressed in all early embryonic RPCs, which then give rise to Ikaros-negative RPCs at later stages in the lineage. Remarkably, misexpression of Ikaros in late RPCs is sufficient to confer competence to generate early-born neurons. Conversely, Ikaros mutant mice have reduced numbers of early-born cell types, whereas late-born cell types are not affected. These results suggest a model in which Ikaros expression is both necessary and sufficient to confer early temporal competence to RPCs and raise the possibility that a similar strategy might be used to control the sequential order of cell birth in other parts of the nervous system.


Molecular characterization and antibiotic resistance profiling of Campylobacter isolated from cattle in Polish slaughterhouses.
A total of 812 samples from bovine hides and the corresponding carcasses collected at the slaughterhouse level in the eastern part of Poland were examined for the presence of Campylobacter jejuni and Campylobacter coli. Recovered isolates were confirmed using species-specific PCR, characterized by the presence of 11 putative virulence genes and antimicrobial susceptibility was determined using a microbroth dilution method. Furthermore, the genotypic relatedness of the isolates was determined by PFGE profiling and virulence pattern cluster analysis. The prevalence of Campylobacter was 25.6% and 2.7% in bovine hide and carcass samples, respectively. The presence of virulence markers varied between C. jejuni and C. coli species however, the majority of strains possessed the cadF, flhA, flaA genes, irrespective of the bacterial species and origin. The lower number of the strains was positive for the invasive associated markers -virB11 and wlaN. Antibiotic profiling showed that campylobacters were most frequently resistant to quinolones and fluoroquinolones (nalidixic acid and ciprofloxacin, 38.3% of each, respectively) followed by streptomycin (24.3%) and tetracycline (20.9%). Resistance to erythromycin and gentamicin was demonstrated in 4.3% and 2.6% of strains, respectively. Comparisons of the PFGE and virulence marker profiles of the isolates reflected the high genetic diversity of Campylobacter tested. Moreover, a poor correlation between the PFGE type, pathogenic gene marker and antimicrobial resistance patterns was observed.


Histopathologic amelioration of fibroproliferative change in rat irradiated lung using soluble transforming growth factor-beta (TGF-beta) receptor mediated by adenoviral vector.
To investigate whether an adenoviral-mediated soluble transforming growth factor-beta (TGF-beta) type II receptor could ameliorate fibroproliferative change in rat irradiated lung. We used an adenoviral vector expressing a soluble TGF-beta receptor (AdT beta-ExR), which adsorbs TGF-beta and inhibits the function of the wild-type receptor as a dominant-negative mutant. Rats were i.v. injected with either 0.5 mL of AdT beta-ExR (1.0 x 10(9) plaque-forming units/mL) or AdLacZ (1.0 x 10(9) plaque-forming units/mL), a control adenovirus expressing bacterial beta-galactosidase, or saline, then 3 days later they received 4-MV X-ray irradiation of 30 Gy in a single fraction to the right lung. Eight weeks after irradiation, the rats were killed, and their right lungs were examined histopathologically. The respiratory rates of all rats were observed with a charge-coupled device video system before the rats were irradiated and killed. A significant increase in breathing rates was observed in the saline- or AdLacZ-infected rats. The respiratory rate of the AdT beta-ExR-treated rats was significantly lower than that in the saline- or AdLacZ-infected rats. Fibroproliferative change in the irradiated lung was markedly reduced in the AdT beta-ExR-treated rats in comparison with the saline- or AdLacZ-infected rats. With respect to active TGF-beta 1 expression, myofibroblast proliferation, and macrophage/monocyte infiltration, the findings were identical to those for fibroproliferative change. Our results indicate that TGF-beta plays a critical role in radiation-induced fibroproliferation of the lung and suggest that the adenoviral-mediated soluble TGF-beta receptor may have potential for use in the amelioration of this intractable pulmonary damage.


Obesity and symptomatic cholelithiasis in childhood: epidemiologic and case-control evidence for a strong relation.
The aims of this study were to correlate the temporal trends in obesity prevalence with hospitalization rates for symptomatic cholelithiasis and to estimate the strength of the association between obesity and symptomatic cholelithiasis in patients hospitalized at an urban children's hospital in New York serving a multiethnic population. Using obesity prevalence data from the National Health and Nutrition Examination Survey and the rates of hospitalization for cholelithiasis derived from the Kids' Inpatient Database for 1997-2007, we estimated a correlation and a linear regression. We conducted a retrospective, case-control study in which each case ages 4 to 20 years with symptomatic cholelithiasis was individually matched to a control admitted with appendicitis based on age, sex, ethnicity, and race. The prevalence of obesity and the cholelithiasis hospitalization rate increased over time (R=0.87, P=0.0025). For every 1% increase in the obesity rate among children, the rate of hospitalization for gallstones increased by 0.65/100,000 children (R²=0.75, P=0.0025, 95% confidence interval [CI] 0.32-0.99). The odds ratio for obesity in cases versus controls was 5.78 (n=518, P<0.0001, 95% CI 3.50-9.53). We found a significant dose-response effect, which showed that for every 1 z score increase in body mass index, the risk of cholelithiasis was increased by 79% (P<0.0001, 95% CI 1.5-2.13). The national trend in the prevalence of obesity from 1997 to 2009 was significantly correlated with increasing rates of hospitalization for pediatric cholelithiasis. Our case-control study suggests that obesity is a significant risk factor for hospital admission because of cholelithiasis.


Arthroscopic anterior cruciate ligament reconstruction.
Our understanding of the structure and function of the anterior cruciate ligament has progressed rapidly over the past decade. Arthroscope-assisted anterior cruciate ligament replacement is a new procedure that allows isometric placement of the anterior cruciate ligament graft. Postoperative rehabilitation is enhanced by preservation of the extensor mechanism.


Three new species of Atalophlebiinae (Ephemeroptera: Leptophlebiidae) of India, with a new record of the genus Megaglena Peters and Edmunds, 1970.
Three new species of Leptophlebiidae viz., Choroterpes (Choroterpes) andamanensis Vasanth, Subramanian Selvakumar n. sp., Edmundsula meghamalaiensis Vasanth, Subramanian Selvakumar n. sp. and Megaglena agasthiya Vasanth, Subramanian Selvakumar n. sp. are described based on our recent exploration of mayflies from the streams of Andaman Island, Tamil Nadu and Kerala part of the southern Western Ghats. The genus Megaglena Peters Edmunds, 1970 has extended the distribution in southern peninsular India as represented by the occurrence of M. agasthiya n. sp. Larval key is provided to the known and new species of subgenus Choroterpes of India along with the distribution map of new species.


Sequential Organ Failure Assessment score as a predictor of mortality in ventilated patients with multidrug-resistant bacteremia.
The occurrence of multidrug-resistant (MDR) bacteremia in ventilated patients may be associated with a high mortality rate. We evaluated whether Sequential Organ Failure Assessment (SOFA) score on the day of bacteremia could predict 90-day mortality in these patients. Data were obtained retrospectively from 202 patients (male, 60.4%; median age, 64 years) hospitalized at a single university-affiliated tertiary care hospital. All adult patients who had were ventilated and had one of the following six MDR bacteremias between March 2011 and February 2018 were enrolled: methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase-producing Gram-negative bacteria (Escherichia coli and Klebsiella pneumonia), carbapenem-resistant Gram-negative rods (Acinetobacter baumannii and Pseudomonas aeruginosa), or vancomycin-resistant Enterococcus faecium. The overall 90-day mortality rate after the day of bacteremia was 59.9%. The areas under the receiver operating characteristic curves for the SOFA and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were 0.732 (95% confidence interval [CI], 0.666 to 0.792; P<0.001) and 0.662 (95% CI, 0.593 to 0.727; P<0.001), respectively, with no difference between the two (P=0.059). Also, the cutoff value of the SOFA score was 9 (based on Youden's index). Multivariate Cox regression analysis showed that this cut-off value was significantly associated with higher mortality rate (hazard ratio, 2.886; 95% CI, 1.946 to 4.221; P<0.001). SOFA score measured on the day of bacteremia may be a useful prognostic indicator of 90-day mortality in ventilated patients with MDR bacteremia.


S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects.
Methionine restriction (MetR) can extend lifespan and delay the onset of aging-associated pathologies in most model organisms. Previously, we showed that supplementation with the metabolite S-adenosyl-L-homocysteine (SAH) extends lifespan and activates the energy sensor AMP-activated protein kinase (AMPK) in the budding yeast Saccharomyces cerevisiae. However, the mechanism involved and whether SAH can extend metazoan lifespan have remained unknown. Here, we show that SAH supplementation reduces Met levels and recapitulates many physiological and molecular effects of MetR. In yeast, SAH supplementation leads to inhibition of the target of rapamycin complex 1 (TORC1) and activation of autophagy. Furthermore, in Caenorhabditis elegans SAH treatment extends lifespan by activating AMPK and providing benefits of MetR. Therefore, we propose that SAH can be used as an intervention to lower intracellular Met and confer benefits of MetR.


Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation.
Human pluripotent stem cells (hPSCs) and three-dimensional organoids have ushered in a new era for disease modeling and drug discovery. Over the past decade, significant progress has been in deriving functional organoids from hPSCs, which have been applied to recapitulate disease phenotypes. In addition, these advancements have extended the application of hPSCs and organoids for drug screening and clinical-trial safety evaluations. This review provides an overview of the achievements and challenges in using hPSC-derived organoids to conduct relevant high-throughput, high-contentscreens and drug evaluation. These studies have greatly enhanced our knowledge and toolbox for precision medicine.


Spatiotemporal changes of apolipoprotein E immunoreactivity and apolipoprotein E mRNA expression after transient middle cerebral artery occlusion in rat brain.
Apolipoprotein E (ApoE) is a constituent of lipoprotein and plays an important role in the maintenance of neural networks. However, spatiotemporal differences in ApoE expression and its long-term role in neural process after brain ischemia have not been studied. We investigated changes of ApoE immunoreactivity and ApoE mRNA expression both in the core and in the periischemic area at 1, 7, 21, or 56 days after 90 min of transient middle cerebral artery occlusion. Double stainings for ApoE plus NeuN or plus ED1 were performed in order to identify cell type of ApoE-positive stainings. The maximal increase of ApoE expression was observed at 7 days in the core and at 7 and 21 days in the periischemic area. In the core, ApoE plus NeuN double-positive cells increased at 1 and 7 days, without ApoE mRNA expression, whereas they increased in the periischemic area, with a peak at 21 days, with ApoE mRNA expression in glial cells but not in neurons. On the other hand, ApoE plus ED1 double-positive cells increased only in the core, with a peak in number at 7 and 21 days and marked ApoE mRNA expression in macrophages. The present study suggests that ApoE plays various important roles in different type of cells, reflecting spatiotemporal dissociation between degenerative and regenerative processes after brain ischemia, and that ApoE is profoundly involved in pathological conditions, such as brain ischemia.


The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV.
Circumcision now to prevent heterosexual HIV transmission in 2030 makes sense.


Template-directed interference footprinting for RNA based on inosine-specific cleavage.
We report here the development of a Template-directed Interference (TDI) footprinting assay for RNA. The TDI nucleotide analogue inosine (I) lacks the exocyclic amine of G and is a suitable probe for the role of this group in RNA structure and function. Using an I-specific cleavage protocol we identified three functionally significant G residues in the Tetrahymena ribozyme. These residues are proximal to the active site of the folded intron and likely contribute to the positioning of substrates at the catalytic core.


Cognitive development and cortisol patterns in mid-life: findings from a British birth cohort.
Life-course associations among cortisol, cognitive development and educational attainment in the general population are not well understood. Using the 1958 British birth cohort, our aim was to establish whether cortisol patterns at age 45y are associated with childhood cognition and qualification level by adulthood. We measured salivary cortisol in 6527 individuals, 45min after waking (t(1)) and 3h later (t(2)). To identify lack of morning cortisol peak and diurnal rhythm, we defined groups with: (a) t(1) cortisol in the bottom 5% of the distribution, or (b) 'flat't(1)-t(2) cortisol. Data on cognitive tests at ages 7, 11 and 16y and educational level were used. All childhood cognitive tests (maths, reading, verbal and non-verbal ability) were inversely associated, although not always significantly, with low t(1) and flat t(1)-t(2) cortisol. For example, at age 11 for males, a standard deviation (SD) increase in maths score was associated with a 28% decreased odds for lowest t(1) cortisol, and with a 13% decreased odds of flat t(1)-t(2) cortisol. Associations for lowest t(1) and flat t(1)-t(2) cortisol were attenuated after adjustment for qualification level at 33y among males, although adjustment for childhood socio-economic position had little effect. Weaker associations for lowest t(1) cortisol among females were either unchanged or strengthened after adjustment for qualification level. Our results for males, but less so for females, are compatible with a causal relationship in either direction, namely from cortisol to cognitive ability or vice versa.


A comparison of ultrasound and magnetic resonance imaging findings of a Morel-Lavallée lesion of the knee.
A Morel-Lavallée lesion (MLL) is a posttraumatic soft-tissue injury characterized by an accumulation of blood, lymph, and other physiologic breakdown products between subcutaneous tissue and underlying fascia. It was first described as occurring over the proximal lateral thigh, but it has since been documented at various anatomic locations. Diagnosis is typically made by careful physical examination and a radiographic analysis, most commonly with magnetic resonance imaging (MRI). Recently, musculoskeletal ultrasound (US) has been recognized as a useful adjunct to and potential replacement for MRI in the diagnosis and monitoring of an MLL. We present a case report of a patient with an MLL of the knee. We obtained magenetic resonance (MRI) and US images at the time of diagnosis, and follow-up US images during convalescence. By doing so, we were able to identify several key sonographic findings of an MLL at this location and compare them with MRI. Although there have been several published reports to date that describe the use of musculoskeletal US in the diagnosis of MLL, this is the first of which we are aware that does so at the knee.


The Differential Effects of Anti-Diabetic Thiazolidinedione on Prostate Cancer Progression Are Linked to the TR4 Nuclear Receptor Expression Status.
The insulin sensitizers, thiazolidinediones (TZDs), have been used as anti-diabetic drugs since the discovery of their ability to alter insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs). However, their side effects in hepatitis, cardiovascular diseases, and bladder cancer resulted in some selling restrictions in the USA and Europe. Here, we found that the potential impact of TZDs on the prostate cancer (PCa) progression might be linked to the TR4 nuclear receptor expression. Clinical surveys found that 9% of PCa patients had one allele TR4 deletion in their tumors. TZD increased cell growth and invasion in PCa cells when TR4 was knocked down. In contrast, TZD decreased PCa progression in PCa cells with wild type TR4. Mechanism dissection found that the Harvey Rat Sarcoma (HRAS) oncogene increased on TZD treatment of the TR4 knocked-down CWR22Rv1 and C4-2 cells, and interruption with HRAS inhibitor resulted in reversal of TZD-induced PCa progression. Together, these results suggest that TZD treatment may promote PCa progression depending on the TR4 expression status that may be clinically relevant since extra caution may be needed for those diabetic PCa patients receiving TZD treatment who have one allele TR4 deletion.


Noise exposure--sample size and confidence limit calculation.
In a previous paper a method for assessing noise exposure levels of workers from the same trade was presented. There was also discussed how to apply the NIOSH sample size method to noise exposed populations. In this paper both subjects are further discussed by including the calculation of confidence limits for the mean noise exposure as well as for the percentage of workers with noise exposure levels beyond a certain level. The calculation of the sample size of a population where standard deviation is known is also discussed.


Evaluation of candidate reference genes in Q-PCR studies of Atlantic cod (Gadus morhua) ontogeny, with emphasis on the gastrointestinal tract.
To obtain reliable relative qPCR data in developing fish larvae, stable reference genes have to be found. This study is focused on finding good candidates for normalization of qPCR data for ontogenetic studies of Atlantic cod. Ten commonly used reference genes; Acidic ribosomal protein, Actin-related protein 2, beta-actin, Elongation factor 1 A, Glyceraldehyde-3-phosphate dehydrogenase, Ribosomal protein 37, Ribosomal protein 4, Ribosomal protein S9, beta 2-Tubulin and Ubiquitin were analyzed in developing larvae from 3 to 97 day post hatch (DPH). Two different tools were used to evaluate the stabilities of these genes; the geNorm software ranks the most stable genes based on a pair-wise analysis whereas NormFinder uses a model-based approach. The same genes were also analyzed in GI tract homogenates and compared to whole larvae homogenates. During Atlantic cod larval development there are several strong candidates with Ubiquitin as the most stable. The ribosomal proteins RPL4 and RPS9 are also strong candidates. RPL37 may be used but only when normalizing qRT-PCR results from one type of tissue. We also suggest the use of multiple genes for normalization of qRT-PCR. Our study suggests that whole-larvae samples can be used to study relative expression of genes that are expressed only in certain tissues.


[News for adrenal insufficiency].
The congress of the Endocrine Society 2008 approached the diagnostic, etiologic, prognostic and therapeutic novelties of adrenal insufficiency (AI). Diagnosis of AI often requires serum cortisol measurement during dynamic tests. Salivary cortisol measurement was reported to have an equivalent diagnostic performance to serum cortisol and that is even better when CBG levels are altered. Iatrogenic AI is much more frequent than Addison's disease. Two studies have shown that patients with inhaled corticosteroid and opioid treatments should be tested for AI. A Norwegian study reported an increased mortality in the subgroup of young men that presented Addison's disease before the age of 40. Plasma cortisol concentration in patients with current glucocorticoid replacement therapy differs notably from those observed in physiological condition. This imperfect replacement may be responsible for adverse physical condition and impaired quality of life. Two formulations of delayed hydrocortisone tablets with different pharmacokinetics from usual hydrocortisone (DuoCort and Chronocort) are in development. The first study is promising and shows that these formulations better mimick the body's natural cortisol release. Its use in the treatment of AI in patients with congenital adrenal hyperplasia has also been tested.


Bivalent influenza vaccine in children with cancer.
Although it had been recommended that children with malignant diseases be immunized against influenza, few data were available to indicate the immune response or reactions that might be expected from this group. Forty-six children with malignant diseases received various dosages of killed split or whole bivalent (A/New Jersey/76-A/Victoria/75) influenza vaccine or a placebo by the intramuscular route. Two doses were administered four weeks apart. The children were receiving various regiments of cancer chemotherapy. The response to A/New Jersey/76 antigen in the children with malignant diseases was similar to that found in normal children who were immunized with bivalent or monovalent (A/New Jersey/76) vaccine in the National Influenza Immunization Trials. Fourteen of 26 children had antibodies to A/Victoria/75 before immunization; nine of the 12 children without these antibodies developed them after the first dose of vaccine. Adverse reactions after vaccination were minimal.


Synthesis and anti-cancer potential of potent peripheral MAOA inhibitors designed to limit blood:brain penetration.
Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.


Role of type specific herpes simplex virus serology in the diagnosis and management of genital herpes.
To investigate the indications for the use of a type specific antibody test for herpes simplex virus in a department of genitourinary medicine in the United Kingdom. Retrospective analysis of case records of 127 patients who accepted the test during a 20 month period. The test contributed to patient management in 79% of patients with recurrent genital ulceration of unknown cause. It was also useful for counselling a number of patients with initial episodes of disease and the asymptomatic partners of some patients when the partners were shown to possess antibodies specific to herpes simplex virus type 2. When evaluating sexual partners, the test was difficult to interpret if an isolate from the index case had not been typed. Access to viral typing may therefore be a greater priority than serological testing. As adverse psychological sequelae may follow the identification of an asymptomatic chronic infection, guidelines for the use of a type specific serological test are proposed.


Epidemiological investigation of morbidity and mortality of improved breeds of chickens in small holder poultry farms in selected districts of Sidama Region, Ethiopia.
A longitudinal study was conducted in six intensive and three semi-intensive poultry farms in Shebedino and Dale districts of Sidama Region, Ethiopia from November 2018 to May 2019. The objectives of the study were to estimate incidence rates of mortality and morbidity, identify the risk factors associated with morbidity and mortality and establish differential diagnosis of major diseases affecting poultry in the area. Chickens belonging to two breeds namely Sasso, and Bovans Brown reared in purposively selected small-scale farms was included from two districts. The chickens on the selected farms were monitored for morbidity and mortality every week. Diagnosis of different diseases was made based on the flock history, age of birds, clinical signs, characteristic gross and microscopic lesions, and fecal flotation technique for coccidiosis. Semi-structured questionnaires were also administered to gather information on the risk factors and farming practices. The incidence rate of morbidity and mortality in the studied farms was 16.14 and 12.69 per 1000 chicken-week at risk, respectively. The minimum and maximum incidence rates of morbidity were 2.02 and 58.43 cases per 1000 chicken-week at risk, respectively. The minimum and maximum incidence rates of mortality were 0.21 and 58.18 deaths per 1000 chicken-week at risk, respectively. Among the risk factors studied feed type, age of chickens, and number of sick chickens on farms were significantly associated (p < 0.05) with the incidence of disease. Age of chickens and number of sick chickens found on the farms were significantly associated (p < 0.05) with the incidence of death using multivariable logistic regression. Newcastle Disease (ND), Infectious Bursal Disease (IBD), Fowl typhoid, and Coccidiosis were the important diseases identified during the follow up period in the study area. Of the overall mortality and morbidity, 90.48% and 42% were respectively attributed to ND. Infectious bursal disease and Coccidia co-infection occurred in 31.55% of chicken in the infected farms. The present study documented the incidence rate of morbidity and mortality in smallholder poultry farms in selected districts of Sidama Region. The study findings indicated that infectious diseases appear to be a major constraint to improve chicken production in the study areas. Therefore, the veterinary and livestock authorities should take this into account when planning poultry development activities and setting up systems of livestock production and health monitoring.


Pseudomonas cytochrome c peroxidase. Initial delay of the peroxidatic reaction. Electron transfer properties.
A delay of some seconds is observed in the reaction of Pseudomonas cytochrome c peroxidase if the reaction is initiated by adding the enzyme to the reaction mixture containing reduced electron donor and hydrogen peroxide. This lag phase is avoided if the enzyme is incubated with the reduced electron donor and the reaction is started by adding hydrogen peroxide. The nature of the initial delay has been studied and it is shown that the peroxidase is reduced before a steady-state rate in the peroxidatic reaction is reached. The ability of the peroxidase to accept electrons from various electron donors emphasizes its cytochrome-like properties.


The complete amino acid sequence of staphylococcal enterotoxin C1.
This report presents the complete amino acid sequence of staphylococcal enterotoxin C1. It has a total of 239 amino acids and a calculated Mr = 27,500. Reaction of the native toxin with trypsin produced five peptides, designated A through E. Their structures were determined after further fragmentation with cyanogen bromide, trypsin, and chymotrypsin. Overlap peptides were prepared by cleavage at the two half-cystine residues, and by the reaction of enterotoxin C1 with hydroxylamine. The latter procedure was employed when it was found that one of the three asparaginyl-glycine loci in the toxin is refractory to direct sequencing. The sequence is compared to staphylococcal enterotoxin B. Extensive homology is found, particularly in the carboxyl-terminal region. However, the segment spanned by the disulfide bond in enterotoxin C1 is three residues shorter than the corresponding segment in the B variant.


Limonoids and quinoline alkaloids from Dictamnus dasycarpus.
Phytochemical investigation on Dictamnus dasycarpus (Rutaceae) has led to the isolation of four new secondary metabolites (2, 6, 9, and 10) along with twelve known phytochemicals (1, 3- 5, 7, 8, 11-16). Compound 4 was isolated as a natural product for the first time. The structures of compounds 1-16 were elucidated by extensive spectroscopic analyses and comparison with previously reported spectroscopic data. The structures of 8 and 13 were further confirmed based on X-ray data analyses. The absolute configuration of compounds 8-12 were studied based on the CD spectra analyses.


Insulin binding and degradation in isolated hepatocytes from streptozotocin injected rats.
Isolated hepatocytes from streptozotocin injected rats bound the same amount of [125I]monoiodoinsulin as hepatocytes from control rats. Scatchard analysis confirmed that insulin receptor number and affinity were the same for both groups. Relatively more cell-associated radioactivity was located intracellularly in hepatocytes from streptozotocin injected rats. Pretreatment with chloroquine resulted in a smaller increase in intracellular [125I]monoiodoinsulin in cells isolated from streptozotocin injected rats than for control cells. These results suggest that intracellular insulin processing occurs more slowly in hepatocytes isolated from streptozotocin injected rats than from control rats.


Endocrine cells in the female genital tract.
Endocrine cells are normal inhabitants of the para-urethral, Bartholin's and endocervical glands and of mesonephric rests. All these cells were characterized as serotonin-storing cells. In the para-urethral and Bartholin's glands, serotonin-containing cells were most often found in the transitional epithelium of excretory ducts. Endocrine cells participated in some pathological conditions. Abundant argentaffin cells were observed among the terminal ductules in chronic bartholinitis and serotonin-storing cells were identified in a peculiar ectocervical epithelium. Numerous serotonin-storing cells were detected in a well-differentiated adenocarcinoma of cervix occurring in a patient with the Peutz-Jeghers syndrome. Argyrophilic cells were present in cases of endometrial carcinomas; a striking feature was the demonstration of gut peptide hormones in an unusual type of endometrial adenocarcinoma. Finally, serotonin-storing cells were a constituent of Brenner tumours. It is suggested that a similar endocrine pattern may be shared by tissues originating from both Müllerian ducts and the urogenital sinus.


Laboratory diagnosis of congenital human cytomegalovirus infection using polymerase chain reaction and shell vial culture.
Congenital HCMV infection was diagnosed at the 22th week of gestation. The infection was suspected because HCMV IgM was detected in a serum sample obtained from the woman's husband. HCMV infection was detected in the amniotic fluid by polymerase chain reaction, shell vial culture (immunoperoxidase assay) and conventional virus isolation. Serologic testing in paired sera of the woman and in umbilical cord blood for specific IgM and IgA remained negative. As serological data (preconceptional HCMV serostatus) were incomplete, a clear differentiation between primary and secondary infection could not be achieved; consequently, risk quantification could not be determined. Viruria was detected in the offspring during the 1st week post partum. No clinical signs of cytomegalic inclusion disease were diagnosed up to six weeks post partum. Our case report indicates that for pregnancy surveillance, serologic testing for HCMV antibody should also be performed in the spouse.


Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis.
Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer. Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models. This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active β-catenin and Snail proteins by decreasing GSK3β activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer. Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression.


High-LET radiation combined with oxaliplatin induce autophagy in U-87 glioblastoma cells.
Modern protocols of concomitant chemo/radiotherapy provide a very effective strategy to treat certain types of tumors. High-linear energy transfer (LET) radiations, on the other hand, have an increased efficacy against cancer with low radiosensibility and critical localization. We previously reported that oxaliplatin, a third generation platinum drug, was able to reinforce the cytotoxicity of an irradiation by fast neutrons towards human glioblastoma U-87 cells in culture. We show here that such a combination has the capacity to enhance the number of double strand breaks in DNA and to induce autophagy in these cells. Xenografts experiments were further performed in nude mice subcutaneously transplanted with U-87 cells. When injected shortly before a single irradiation by fast neutrons, oxaliplatin causes a marked reduction of tumor growth compared with the irradiation alone. Overall, our data indicate the unique cytotoxic mechanism of a combined high-LET irradiation and oxaliplatin treatment modality and suggest its potential application in anticancer therapy.


Multiple infected cerebral hydatid cysts.
We report an unusual patient with multiple infected cerebral hydatid cysts. A 20-year-old man presented with a 2-month history of headache and progressive left-sided hempiparesis. A cerebral CT scan showed a large and heterogeneous parieto-occipital lesion. During surgery an infected hydatid cyst was discovered with multiple daughter vesicles. Post-operatively the patient was treated with albendazol, cefotaxime and metronidazole. The clinical course was good with total recovery of the hemiparesis. A follow-up CT scan showed persistence of some small deep-seated cysts. Multiple infected cerebral hydatid cyst is uncommon and can be confused with other cystic brain lesions. The aim of surgery is to remove the cyst unruptured and this should be followed by antihelminthic and antibiotic treatment in order to avoid recurrences.


Enhancing bioflavor production by solid-state fermentation using Kluyveromyces marxianus and l-phenylalanine.
This study includes the utilization of sweet lemon peel (SLP) and sugarcane bagasse (SB) in solid-state fermentation using Kluyveromyces marxianus for bioflavor compounds production adopting response surface methodology. The major flavor compounds, 2-phenylethanol (2-PE) and 2-phenylethyl acetate (2-PEA) were quantified using gas chromatography-mass spectrometry with and without adding any supplements. Quantification of flavor compounds indicated that without adding any accessory in the substrate, the concentration of 2-PE using SLP and SB was 0.15 ± 0.003 mg/g and 0.14 ± 0.002 mg/g, respectively. Whereas 2-PEA concentration using SLP and SB was observed as 0.01 ± 0.008 mg/g and 0.02 ± 0.001 mg/g, respectively. The addition of l-phenylalanine (l-phe) in the substrates showed 30%-75% enhancement in the production of 2-PE and 2-PEA. The present study indicates that the K. marxianus is a potential microbial cell factory for the production of 2-PE and 2-PEA with the addition of synthetic l-phe having a plethora of applications in food and pharmaceutical industries.


Image-guided or needle-localized open biopsy of mammographic malignant-appearing microcalcifications?
The evaluation and initial management of abnormalities detected on screening mammography have evolved substantially over the last decade. This study was designed to evaluate the most appropriate initial diagnostic biopsy technique for patients presenting with malignant-appearing microcalcifications on screening or diagnostic mammography. An institutional review of a prospective database was performed to compare initial image-guided breast biopsy (IGBB) and needle-localized open biopsy (NLOB) in patients presenting with malignant-appearing microcalcifications. Patients with atypical hyperplasia (AH) or carcinoma in situ (CIS) were identified and reviewed separately. Measures of outcomes included the total number of procedures, time from initial biopsy to definitive treatment, charges, and percentages of patients who required both procedures. A total of 17,121 patients underwent mammography from July 1994 to December 1996 at Gundersen Lutheran Medical Center. Indeterminate microcalcifications were found in 167 patients and were the reason for IGBB in 112 and NLOB in 55 patients. Histologic results included 81 patients (48%) with benign lesions, 25 (15%) with invasive cancers, and 61 (37%) having a proliferative finding including AH or CIS. Ductal CIS was present in 42 (72%) of the 61 proliferative lesions. Comparisons were made between the groups of patients with CIS or AH who underwent initial NLOB (n = 25) versus those having initial IGBB that was followed by a secondary NLOB (n = 25). The median elapsed time to definitive therapy was 20 days (range 0 to 336 days) for initial IGBB followed by NLOB and 7 days (range 0 to 79 days) for an initial NLOB performed for suspicious microcalcifications (p = 0.0367). The total number of procedures performed on each patient and total costs were also less for patients having an initial NLOB. The time to definitive local therapy, the number of procedures, and overall charges were less for patients with AH or CIS having initial NLOB as opposed to initial IGBB. Careful initial evaluation of microcalcifications may identify some patients for whom an initial NLOB remains the most appropriate procedure. Such patients desiring breast-conserving therapy may benefit in terms of time to definitive treatment, total number of procedures performed, and cost if a careful NLOB is the initial procedure performed as a formal lumpectomy.


Existence of a connecting system in the flagellar apparatus and the accessory structures of Trypanosoma evansi.
The three-dimensional architecture of a quartet of microtubules (QM) of Trypanosoma evansi and its related structures was examined with a transmission electron microscope (TEM). The initiation of the QM as a successive bundle of microtubules was confirmed at the juxtaposition of the second barren body (SBB). After connecting with the distal part of the basal body (BB), the QM ascended to the level of the terminal plate (TP) and gained access most closely to the inner membrane of the flagellar pocket (FP) and formed the special structure together with macula adherens (MA) and the electron dense linear substance (EDLS); then it follows its way around the FP from the posterior to the anterior and fills the subpellicular space at the underneath of the flagellum. This special structure disappeared when the associated-flagellum became the extracellular flagellum (EF), where the QM intervened into the row of the subpellicular microtubules (SM). This EDLS is suggested to represent a demarcating line (DL). In the deep cytoplasm of the flagellar root, connections via several microtubules between the BB and the SBB and via electron zonal substance (EDZS) between the BB and the mitochondrion (M) were observed. As a result, a connecting system among the flagellar apparatus and its accessory structures seems probable.