Attenuated sensitivity of ozone to precursors in Beijing-Tianjin-Hebei region with the continuous NOx reduction within 2014-2018.
Facing the elevated surface summer O3 over North China in recent years with the continuous NOx reduction, we conducted the ozone-precursor sensitivity study in summer (July) in Beijing-Tianjin-Hebei region (BTH) under the 2018 and 2014 emissions, based on WRF-Chem model. On 2018 emission condition, 30% precursor reduction simulations presented the positive contribution of VOCs and the negative contribution of NOx to daytime O3. The occurrence probabilities of VOCs-sensitive, NOx-titration, mixed sensitive, NOx-sensitive, and non-sensitive regimes respectively reached 3-49%, 2-82%, 0-7%, 0-6% and 14-82% in the urban grids, and 2-32%,1-19%, 1-6%, 0-5% and 54-86% in the rural grids. For several widely used photochemical indicators, their values in VOCs-sensitive regime were well separated from those in NOx-sensitive regime, but the NOx-sensitive values were very similar to the non-sensitive values, which implied the inefficiency of these indicators in indicating NOx-sensitive regime. Finally, VOCs-sensitive regime was discerned based on the indicator HCHO/NO2, occupying about a third of areas in morning and dusk but shrinking to about a tenth of areas in 11:00-16:00 in BTH. And these areas apparently decreased from 2014 emission to 2018 emission. However, the rest areas of this region were under non-sensitive regime but not NOx-sensitive regime, for the noticeable O3 drop never happened in NOx reduction scenario. Meanwhile, the modeled O3/PAN in the areas under non-sensitive regime exceeded 60, which also implied the minor impact of local photochemistry on O3 there. Additionally, the responses of daytime O3 to precursor emissions in the urban grids were calculated, declining by 20.8% for NOx and 6.9% for VOCs from 2014 to 2018. Therefore, to solve the ozone pollution problem of BTH, the cross-region strategy coupled with the VOCs and NOx co-control will be essential.


A pyruvate kinase variant in different mouse transplanted tumors.
Mouse transplanted tumors, in contrast to normal tissues, contain a pyruvate kinase (PK) variant sensitive to the inhibitory action of L-cysteine and less sensitive to saturated fatty acids than the normal enzyme. In selected normal and tumor materials two fractions of PK were separated. Fraction A (20-30% (NH4)2SO4 saturation) dominated in normal liver, and fraction B (50-60% (NH4)2SO4 saturation) in skeletal muscles and Ehrlich ascites tumor. Only this fraction B from tumor material was sensitive to L-cysteine, and seems to contain a tumor-specific PK variant which might be considered as a marker of neoplastic transformation in a broad spectrum of mouse experimental tumors.


Association of KRAS Variant Subtypes With Survival and Recurrence in Patients With Surgically Treated Intrahepatic Cholangiocarcinoma.
KRAS variants are associated with tumor progression; however, the prevalence of KRAS variant subtypes and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (ICC) after curative resection are largely unknown. To explore the prognostic association of KRAS variant subtypes with survival and recurrence in patients with ICC. In this cohort study, patients who underwent curative resection for ICC from January 2009 through December 2016 at a single hospital in China were recruited, and whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify KRAS variants. Kaplan-Meier and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Data were analyzed from April 2020 to January 2021. Hepatectomy in patients with ICC. The association of KRAS variant subtypes with OS and DFS. Of 1024 included patients with ICC, 621 (60.6%) were male, and the mean (SD) age was 59.2 (10.2) years. A total of 14 different subtypes of KRAS somatic variants affecting 127 patients (12.4%) were identified. G12D was the most frequent allele in this cohort, accounting for 55 of 127 identified KRAS variants (43.3%), followed by G12V (25 [19.7%]), G12C (9 [7.1%]), and G13D (8 [6.3%]). Compared with patients with wild-type KRAS, patients with variant KRAS were more likely to have high levels of carbohydrate antigen 19-9 (92 of 127 [72.4%] vs 546 of 897 [60.9%]; P = .01) and γ-glutamyltransferase (72 of 127 [56.7%] vs 420 of 897 [46.8%]; P = .04). Multivariable analysis revealed that G12 KRAS variants but not non-G12 KRAS variants were independently associated with worse OS (hazard ratio [HR], 1.69; 95% CI, 1.31-2.18; P < .001) and DFS (HR, 1.47; 95% CI, 1.16-1.88; P = .002). Among the patients with G12 KRAS variants, the G12V KRAS variant was the strongest prognostic determinant for the worst OS (HR, 3.05; 95% CI, 1.94-4.79; P < .001) and DFS (HR, 1.79; 95% CI, 1.13-2.85; P = .01). In this cohort study, the distribution of KRAS variant subtypes was characterized in a large cohort of patients with ICC from China. The presence of G12 KRAS variants but not non-G12 KRAS variants was associated with worse survival and increased risk of recurrence. Patients with the G12V variant exhibited the worst outcomes in the whole cohort.


Recombinant purine nucleoside phosphorylases from thermophiles: preparation, properties and activity towards purine and pyrimidine nucleosides.
Thermostable nucleoside phosphorylases are attractive biocatalysts for the synthesis of modified nucleosides. Hence we report on the recombinant expression of three 'high molecular mass' purine nucleoside phosphorylases (PNPs) derived from the thermophilic bacteria Deinococcus geothermalis, Geobacillus thermoglucosidasius and from the hyperthermophilic archaeon Aeropyrum pernix (5'-methythioadenosine phosphorylase; ApMTAP). Thermostability studies, kinetic analysis and substrate specificities are reported. The PNPs were stable at their optimal temperatures (DgPNP, 55 °C; GtPNP, 70 °C; ApMTAP, activity rising to 99 °C). Substrate properties were investigated for natural purine nucleosides [adenosine, inosine and their C2'-deoxy counterparts (activity within 50-500 U·mg(-1))], analogues with 2'-amino modified 2'-deoxy-adenosine and -inosine (within 0.1-3 U·mg(-1)) as well as 2'-deoxy-2'-fluoroadenosine (9) and its C2'-arabino diastereomer (10, within 0.01-0.03 U·mg(-1)). Our results reveal that the structure of the heterocyclic base (e.g. adenine or hypoxanthine) can play a critical role in the phosphorolysis reaction. The implications of this finding may be helpful for reaction mechanism studies or optimization of reaction conditions. Unexpectedly, the diastereomeric 2'-deoxyfluoro adenine ribo- and arabino-nucleosides displayed similar substrate properties. Moreover, cytidine and 2'-deoxycytidine were found to be moderate substrates of the prepared PNPs, with substrate activities in a range similar to those determined for 2'-deoxyfluoro adenine nucleosides 9 and 10. C2'-modified nucleosides are accepted as substrates by all recombinant enzymes studied, making these enzymes promising biocatalysts for the synthesis of modified nucleosides. Indeed, the prepared PNPs performed well in preliminary transglycosylation reactions resulting in the synthesis of 2'-deoxyfluoro adenine ribo- and arabino- nucleosides in moderate yield (24%).


Ratiometric fluorescent nanoprobe based on CdTe/SiO2/folic acid/silver nanoparticles core-shell-satellite assembly for determination of 6-mercaptopurine.
A sensitive and robust fluorescent assay of 6-MP is described which relies on the facile assembly of a fluorescence nanoprobe by design of silica nanosphere encapsulated CdTe quantum dots (CdTe QDs) as scaffold, coupling with chemically tethered folic acid (FA)-protected silver nanoparticles (AgNPs) that function as responsive element. In this way a stable ternary core-shell-satellite nanostructure with dual-emission signals can be established. On binding to the target molecules, 6-MP, FA molecules initially occupied by AgNPs are liberated to give dose-dependent fluorescence emission, which can further form a self-calibration ratiometric fluorescence assay using CdTe QDs as an internal reference. The nanoprobe color vividly changes from red to blue, enabling the direct visual detection. The linear concentration range is 0.15~50 μM with the detection limit of 67 nM. By virtue of the favorable selectivity and robust assays, the nanoprobe was applied to 6-MP detection in urine samples, with recoveries from 97.3 to 106% and relative standard deviations (RSD) less than 5%. Graphical abstract.


Semiconducting polymer thin films by surface-confined stepwise click polymerization.
Surface-confined stepwise click polymerization was used to prepare surface-attached thin films of semiconducting polymers. These highly uniform films showed extended UV/vis absorption characteristics and a remarkable degree of molecular organization with a unidirectional alignment of the polymer chains normal to the surface.


Water-immiscible room temperature ionic liquids (RTILs) as drug reservoirs for controlled release.
Water-immiscible room temperature ionic liquids (RTILs) have a largely unexplored potential as pharmaceutical solvents and reservoirs. This paper explores some relevant properties of the hexafluorophosphate (PF6(-)) salts of butyl, hexyl and octyl-3-methylimidazolium cations (BMIM, HMIM, OMIM, respectively). The dodecyl analogue is solid at room temperature, but its melting point can be lowered by addition of the lower homologues. Although water-immiscible, the liquids absorb water to an extent depending on their structure, the higher alkyl analogues having a lower affinity for absorbed water. The RTIL/water partition coefficients of sucrose, penicillin V potassium, dexametasone, progesterone and dehydro-epiandrosterone have been compared with octanol-water coefficients. The viscosities of the salts were measured in anhydrous, water-saturated and intermediate states. The PF6(-) ionic liquids display a low and decreasing aqueous solubility as the alkyl chain length is increased: 0.035 moll(-1) (BMIM), 0.032 moll(-1) (HMIM) and 0.09 moll(-1) (OMIM). The release of sucrose and dexametasone from RTIL reservoirs into water can be prolonged over 48 h. Saturated solutions of these RTILs show little toxicity towards Caco-2 cells, although the OMIM derivative, which is more surface-active, has a small effect on cell viability.


Simplified purification approach of urinary neutrophil gelatinase-associated lipocalin by tangential flow filtration and ion exchange chromatography.
This investigation reports a simplified approach for the purification of urinary siderocalin known as neutrophil gelatinase-associated lipocalin (NGAL). Urinary NGAL was purified by tangential flow filtration and ion exchange chromatography. Isolated NGAL was analyzed by SDS-PAGE, immunoblotting and mass spectrometry (MS). The relative molecular mass of NGAL is 23674Da. Peptide mass fingerprinting of the purified NGAL yielded peptides that partially matched with known sequence of P80188 (NGAL_HUMAN). The tryptic digestion profile of isolated NGAL infers that it may be unique and additive molecule in the dictionary of urinary proteins. This is the first report of purification and validation of urinary NGAL from large volume sample by using tangential flow filtration and peptide sequencing respectively. This cost-effective and simplified approach to purification of NGAL, together with the easy availability of urine sample makes the large-scale production of NGAL possible, allowing exploration of various bioclinical as well as biodiagnostic applications.


A single amino acid difference between archaeal and human type 2 methionine aminopeptidases differentiates their affinity towards ovalicin.
In almost all living cells, methionine aminopeptidase (MetAP) co-translationally cleaves the initiator methionine in at least 70% of the newly synthesized polypeptides. MetAPs are typically classified into Type 1 and Type 2. While prokaryotes and archaea contain only either Type 1 or Type 2 MetAPs respectively, eukaryotes contain both types of enzymes. Almost all MetAPs published till date cleave only methionine from the amino terminus of the substrate peptides. Earlier experiments on crude Type 2a MetAP isolated from Pyrococcus furiosus (PfuMetAP2a) cosmid protein library was shown to cleave leucine in addition to methionine. Authors in that study have ruled out the PfuMetAP2a activity against leucine substrates and assumed it to be a background reaction contributed by other contaminating proteases. In the current paper, using the pure recombinant enzyme, we report that indeed activity against leucine is directly carried out by the PfuMetAP2a. In addition, the natural product ovalicin which is a specific covalent inhibitor of Type 2 MetAPs does not show efficient inhibition against the PfuMetAP2a. Bioinformatic analysis suggested that a glycine in eukaryotic MetAP2s (G222 in human MetAP2b) and asparagine (N53 in PfuMetAP2a) in archaeal MetAP2s positioned at the analogous position. N53 side chain forms a hydrogen bond with a conserved histidine (H62) at the entrance of the active site and alters its orientation to accommodate the ovalicin. This slight orientational difference of the H62, reduces affinity of the ovalicin by 300,000-fold when compared with the HsMetAP2b inhibition. This difference in the activity is partly reduced in the case of N53G mutation of the PfuMetAP2a.


Radical trachelectomy via a trans-sacral approach: a case report.
Endometrial cancer may arise in patients previously treated for rectal cancer. Surgical management can be challenging, and the gynecologic oncologist may need to employ alternative surgical approaches. A 71-year-old female with a history of Dukes class B rectal cancer previously treated by abdominoperineal resection and pelvic radiation therapy subsequently developed an endometrial cancer. Initial surgical management was difficult, and the entire cervix could not be removed. The patient recurred locally the following year and was managed by radical trachelectomy via a trans-sacral approach. Locally recurrent endometrial cancer can pose difficult management decisions. Radical resection may be the only alternative. Unusual situations may require adaptation of different surgical approaches of which the gynecologic oncologist must be aware.


Cardio-renal syndrome: new perspective in diagnostics.
Chronic heart failure and chronic renal failure are at epidemic proportions. These patients have significantly altered cardiac, renal, and all-cause outcomes. Much of the current research has focused on treating these individual organs in isolation. Although there are positive data on outcomes with neurohormonal modulation, they, however, remain underused. At present, data lacks for novel treatment options, while evidence continues to point at significantly worsened prognosis. Current diagnostic tools that detect acute changes in renal function or renal injury appear retrospective, which often hinder meaningful diagnostic and therapeutic decisions. This review is aimed at exploring the importance of accurate assessment of renal function for the heart failure patient by providing a synopsis on cardio-renal physiology and establishing the possibility of novel approaches in bridging the divide.


[Acute hematogenous osteomyelitis of the neck of the femur in children: 28 cases].
Osteomyelitis of the neck of the femur is uncommon, often with a misleading clinical presentation. We report a series of 28 cases of osteomyelitis of the femoral neck to illustrate the particular clinical and imaging findings related to this localization. This was a series of 28 children treated in our unit from 1990 through 2004: 17 boys and 11 girls, mean age eight years (range one month to 14 years). We analyzed the data in this series using a standard checklist, which noted the diagnostic and therapeutic measures. Results were analyzed by studying the complications, anatomic and functional outcome at mean follow-up of 3.5 years. Time from symptom onset to consultation was five days on average with a delay of 4.5 days from consultation to hospitalization. Intense pain was noted for eight patients (28%) and total functional incapacity of the limb was noted for 15 (53%). Hip stiffness was observed in 11 patients (39%). The diagnosis of osteomyelitis of the femoral neck was established on the basis of imaging (MRI or scintigraphy) in three patients with bacteriological proof in two, of operative findings which confirmed the neck localization in 19, and on changes in the X-ray image of the neck in six. A positive bacteriology was noted in 71%. The germ was isolated from blood cultures and local samples obtained by arthrotomy in five patients (same germ), only in blood cultures for four, and only in local samples in 11. Met-S Staphylococcus aureus was isolated in 18 patients, Met-R S. aureus in one and a Streptococcus in one. All patients were given medical treatment and 25 underwent surgery. There were five thromboembolic complications and five patients who developed femoral pandiaphysitis. Results were analyzed at mean 3.5 years (range four months to 14 years). Complete hip motion was recovered in 78%. There were four cases of hip stiffness and two cases of ankylosis. Partial cephalic necrosis was noted in two hips and total necrosis of the head and neck in two. Little data is available in the literature on isolated osteomyelitis of the femoral neck. Based on the pathogenic mechanisms known for osteomyelitis, an isolated localization in the neck of the femur, with no other site in the hip joint, is quite possible in an early stage of infection. We discuss the specific clinical and imaging features of this localization. Analysis of our findings show that the prognosis of femoral neck osteomyelitis is directly related to time to management. Outcome is poorer when treatment is started late. Prognosis is poor if pandiaphysitis develops.


The melody of crying.
As the speech of a normal hearing and a deaf person are different, author expects differences between the crying sound of normal hearing and hard-of-hearing infants as well. In this study the author determined by computerized algorithms the melody of 2762 crying sounds from 316 infants, and compared the results between infants with hearing disorders and normal hearing. The analysis of the crying sounds is aimed to work out a new, cheaper hearing screening method, which would give a new potential to the early detection of hearing disorders. All the applied steps were developed by automatic, computer-executed methods providing reproducible, objective results in contradistinction to some previous studies, which had applied manual methods and reached subjective results. Several possible ways for digital signal processing of the infant cry are discussed. A novel melody shape classification system was created to obtain a more precise distribution of the melodies by their shapes. The system determined 77 different categories, where the first 20 categories covered the 95% of the melodies. The applied methods were created and tested in a huge number of melodies.


Residents provide feedback to their clinical teachers: reflection through dialogue.
Physicians play a crucial role in teaching residents in clinical practice. Feedback on their teaching performance to support this role needs to be provided in a carefully designed and constructive way. We investigated an evaluation system for evaluating supervisors and providing formative feedback. In a design based research approach, the 'Evaluation and Feedback For Effective Clinical Teaching System' (EFFECT-S) was examined by conducting semi-structured interviews with residents and supervisors of five departments in five different hospitals about feedback conditions, acceptance and its effects. Interviews were analysed by three researchers, using qualitative research software (ATLAS-Ti). Principles and characteristics of the design are supported by evaluating EFFECT-S. All steps of EFFECT-S appear necessary. A new step, team evaluation, was added. Supervisors perceived the feedback as instructive; residents felt capable of providing feedback. Creating safety and honesty require different actions for residents and supervisors. Outcomes include awareness of clinical teaching, residents learning feedback skills, reduced hierarchy and an improved learning climate. EFFECT-S appeared useful for evaluating supervisors. Key mechanism was creating a safe environment for residents to provide honest and constructive feedback. Residents learned providing feedback, being part of the CanMEDS and ACGME competencies of medical education programmes.


Effects of insulin on vasoconstrictive responses to norepinephrine and angiotensin II in rabbit femoral artery and vein.
To determine whether insulin has a vasodilator action on the artery and vein, the effects of insulin at varying concentrations (120 microU/ml, 1.2 mU/ml, 12 mU/ml, and 120 mU/ml) on vasoconstriction by norepinephrine (NE) and angiotensin II (ANG II) were studied in the isolated rabbit femoral artery and vein. Helical strips were suspended in an organ bath filled with modified Krebs solution (pH 7.4), were gassed with 95% O2/5% CO2 at 36 degrees C, and isotonic contractions were measured. Insulin significantly and dose dependently inhibited the vasoconstriction induced by NE (10(-8) M for the artery and 10(-7) M for the vein) at greater than or equal to 1.2 mU/ml for both the artery and vein and the vasoconstriction induced by ANG II (3 x 10(-10) M for the artery and 3 x 10(-9) M for the vein) at greater than or equal to 1.2 mU/ml for the artery and greater than or equal to 12 mU/ml for the vein. The results indicate that insulin has an inhibitory effect on NE- and ANG II-induced contraction in both the artery and vein, and this appeared to be a contributory factor in the hypotensive effect observed in diabetic patients treated with insulin.


[No ordinary anal fistula...].
We present the case of a 63 year-old male Swiss patient with chronic diarrhea, mucous anal discharge, anal fistula, chronic anal ulceration and history of tuberculosis 56 years ago. Imaging and endoscopy was highly suspicious for Crohn's Disease, but histology and culture for M. tuberculosis proved tuberculous proctitis with perianal involvement and fistulation. The consideration of extrapulmonal tuberculosis with its various manifestations is crucial for the investigation of chronic abdominal complaints in order to avoid serious consequences of tuberculosis treated with immunosuppressive therapy.


Synchronous and collaborative online concept mapping of membrane transport.
The rush to remote learning during the COVD-19 pandemic has caused instructors to rapidly adapt mechanisms of learning. Here, I describe an online concept mapping activity for membrane transport mechanisms that can be accomplished by students working together remotely and either synchronously or asynchronously.


Synthesis and application of a dual-functional fluorescent probe for sequential recognition of Zn2+and glyphosate.
A novel fluorescent probe QL was designed and synthesized based on Schiff base by 2-hydrazinobenzothiazole to sequentially recognize Zn2+ and glyphosate. The probe QL was capable to detect Zn2+ in DMSO solution via fluorescence enhancement, and exhibited good selectivity and anti-interference ability. The combination mode was 1:2 between probe QL and Zn2+ according to the method of job's plot, and the detection limit of probe QL for Zn2+ was found to be 4.51 × 10-8 M, which exhibited excellent sensitivity. Furthermore, the system QL-Zn2+ could detect glyphosate by causing fluorescence quenching response and with a color change from yellow to colorless for naked-eye detection. The detection limit for glyphosate was found to be 4.93 × 10-8 M, which was far below the Standards for Drinking Water Quality (GB5749-2006) acceptable limits (0.7 μg/mL for glyphosate). Notably, the probe QL and its complex QL-Zn2+ have been successfully applied to detect Zn2+ and glyphosate in water, respectively.


Nano-Biomaterials for the Delivery of Therapeutic and Monitoring Cues for Aortic Diseases.
The aorta is the largest artery in the body, so any diseases or conditions which could cause damage to the aorta would put patients at considerable and life-threatening risk. In the management of aortic diseases, the major treatments include drug therapy, endovascular treatment, and surgical treatment, which are of great danger or with a poor prognosis. The delivery of nano-biomaterials provides a potential development trend and an emerging field where we could monitor patients' conditions and responses to the nanotherapeutics. One of the putative applications of nanotechnology is ultrasensitive monitoring of cardiovascular markers by detecting and identifying aneurysms. Moreover, the use of nanosystems for targeted drug delivery can minimize the systemic side effects and enhance drug positioning and efficacy compared to conventional drug therapies. This review shows some examples of utilizing nano-biomaterials in in vitro organ and cell culture experiments and explains some developing technologies in delivering and monitoring regenerative therapeutics.


Sudden sensorineural hearing loss after covid-19 vaccine; A possible adverse reaction?
Sudden Sensorineural Hearing Loss (SSNHL) is a relatively rare symptom after immunisation from commonly used vaccines such as rabies, hepatitis B, measles and H1N1 and it could be an occasional symptom of COVID-19, even in mild manifestations of the disease. We describe the case of a 57-year-old patient that reported SSNHL and tinnitus in his right ear 2 days after the inoculation of the Oxford-AstraZeneca (VAXZEVRIA) Covid-19 vaccine. The patient almost fully recovered after therapy and was referred to a long term follow-up program. The current report underlines the importance to consider SSNHL as a possible rare adverse effect of the Covid-19 vaccine and take in account this possibility to promptly proceed with diagnosis and treatment of suspect cases.


Adsorption of surfactant-rich stickies onto mineral surfaces.
"Stickies" are tacky species, present in recycled paper and coated broke, derived from coating formulations, adhesives etc. They impact negatively on paper quality and cause web runnability problems by deposit build-up. To sustain recycling, stickies are controlled by adsorbing them onto minerals added to the recycled stock. We report isotherms for a fatty acid ester defoamer and an acrylic acid ester copolymer adsorbing from colloidal suspension onto various talcs and modified calcium carbonates. We used commercial preparations of the fatty acid ester defoamer and acrylic acid ester copolymer to provide a simple analogue to the industrial process. The modified calcium carbonates are hydrophilic with anionic and cationic sites present. Adsorption isotherms for low surface area modified calcium carbonate conform to the Langmuir model, while those for high surface area modified calcium carbonate reflect a two stage process involving the formation of a monolayer over the mineral surface and subsequent partial aggregation. Talc platelets display hydrophilic edges and hydrophobic surfaces. Adsorption onto them appears to involve three stages; specifically, a hydrophilic interaction between hydrophilic groups on the molecules and the talc edges, followed by hydrophobic interactions between the molecules and the talc surfaces, and finally by formation of multilayers.


[Evaluation of a supervised physical exercise program in primary care].
To compare self-perception of health with physical parameters in a population group with chronic illnesses when conducting a group intervention of supervised physical exercise. Intervention study with test-retest evaluation. Serraparera Primary Care Centre (PCC) in the town of Cerdanyola del Vallès (24,735 inhabitants). Patients between 30 and 65 with a chronic illness and attended at the PCC (n = 87). A seven-month programme, based on regular supervised physical exercise, three times a week for an hour, supplemented by organised monthly walks on varying routes. Blood pressure, BMI, flexibility, sub-maximum and at-rest heart rates were measured, and the Nottingham Health Profile (NHP) self-perception test conducted. 87 patients began the programme and 51 reached the end. The following was observed in the 51: self-perception of overall improvement in health on the NHP of 9.51 points (CI 95%, 5.73-13.23); lowering of blood pressure, systolic 4.8 mmHg (CI 2.47-7.13) and diastolic 4.78 (CI 3.16-6.46); sub-maximum heart rate, with an average difference of 7.65 pulses per minute; and at-rest heart rate, with a difference of 4.61 ppm. Flexibility increased by 1.37 (CI 1.05-1.69). There was no significant reduction in BMI. Patients with chronic illnesses experienced a notable improvement in the control of their pathology and vital constants. There was also a significant difference detected in patients' perception of their own health.


Genomics approaches to drug discovery.
New approaches to drug discovery have come about in recent years as a result of important advances in genomics and bioinformatics. The availability of genome-scale sequence data, the development of new tools for high-throughput gene expression monitoring, and improvements in the ability to analyze large data sets have revolutionized the field. In this article, we discuss three applications of genomics data in the drug discovery process: target discovery, prodrug strategies, and vaccine development.


Aqueous Terminalia arjuna extract modulates expression of key atherosclerosis-related proteins in a hypercholesterolemic rabbit: A proteomic-based study.
The present study evaluates the effect of an aqueous extract of Terminalia arjuna (aqTAE) on protein expression in aortic plaques of hypercholesterolemic rabbits using a proteomic approach. Thirty male New Zealand rabbits (n = 6) were employed as Gp1 (stock diet); Gp2 (high-fat diet [HFD]); Gp3 (stock diet + aqTAE); Gp4 (HFD + aqTAE); and Gp5 (HFD + atorvastatin) and followed for 6 months. Protein lysates of aortic tissues were separated by 2DE and proteins were identified by MALDI-TOF/MS. Serum lipids were found to be significantly increased by an HFD and reduced by aqTAE both at 3 and 6 months (Gp4 vs. Gp2; p < 0.05). Total 79 spots were differentially expressed, among which 60 individual proteins were identified, 31 grouped as atherosclerosis-related proteins and 29 classified as others. aqTAE significantly attenuated the protein expression of tumor necrosis factor α, cyclooxygenase-2, MMP-9, HSP60, ICAM-5, Endothelin-3, Vimentin, Protein S100-A9 besides others. Many of the observed proteins are known to be consistently associated with endothelial dysfunction, inflammation, plaque rupture, and immune imbalance. Strong hypolipidemic effects of aqTAE and attenuation of these signature atherogenic biomarkers using proteomics highlights the fact that aqTAE may be useful in the prevention and management of atherosclerosis.


The VERB campaign: applying a branding strategy in public health.
A branding strategy was an integral component of the VERB Youth Media Campaign. Branding has a long history in commercial marketing, and recently it has also been applied to public health campaigns. This article describes the process that the CDC undertook to develop a physical activity brand that would resonate with children aged 9-13 years (tweens), to launch an unknown brand nationally, to build the brand's equity, and to protect and maintain the brand's integrity. Considerations for branding other public health campaigns are also discussed.


Predominance of activated, clonally expanded T helper type 17 cells within the CD4+ T cell population in psoriatic lesions.
Recent evidence points to the T helper type 17 (Th17) subset as key in the pathogenesis of psoriasis, but cells of this type in lesions remain to be fully characterized. Here we isolated, enumerated, functionally tested and clonotyped the CD4(+) Th cell population ex vivo from lesional biopsies and paired peripheral blood samples from psoriasis patients. Th17 cells were over-represented dramatically in lesions from all patients, representing 49-93% of CD4(+) Th cells compared with 3-18% in blood. Most lesional Th17 cells produced interleukin (IL)-17A ex vivo without further stimulation and expressed the CD45RO(+) phenotype characteristic of activated or memory cells. There was no increase in 'natural' [CD25(hi) forkhead box protein 3 (FoxP3(+))] regulatory T cells in lesions versus peripheral blood, but there was enrichment of 'induced' IL-10(+) regulatory T cell numbers in biopsies from some patients. The lesional Th17 cells exhibited a bias in T cell receptor Vβ chain usage, suggestive of specific expansion by antigen. The therapeutic challenge is to overcome the dominance of overwhelming numbers of such antigen-specific Th17 cells in psoriatic lesions.


Deciphering longitudinal optical-density measurements to guide clinical dosing regimen design: A model-based approach.
Model-based analysis of longitudinal optical density measurements from a bacterial suspension exposed to antibiotics has been proposed as a potentially efficient and effective method for extracting useful information to improve the individualized design of treatments for bacterial infections. To that end, the authors developed in previous work a mathematical modeling framework that can use such measurements for design of effective dosing regimens. Here we further explore ways to extract information from longitudinal optical density measurements to predict bactericidal efficacy of clinically relevant antibiotic exposures. Longitudinal optical density measurements were collected in an automated instrument where Acinetobacter baumannii, ATCC BAA747, was exposed to ceftazidime concentrations of 1, 4, 16, 64, and 256 mg/L and to ceftazidime/amikacin concentrations of 1/0.5, 4/2, 16/8, 64/32, and 256/128 (mg/L)/(mg/L) over 20 h. Calibrated conversion of measurements produced total (both live and dead) bacterial cell concentration data (CFU/mL equivalent) over time. Model-based data analysis predicted the bactericidal efficacy of ceftazidime and of ceftazidime/amikacin (at ratio 2:1) for periodic injection every 8 h and subsequent exponential decline with half-life of 2.5 h. Predictions were experimentally tested in an in vitro hollow-fiber infection model, using peak concentrations of 60 and 150 mg/L for injected ceftazidime and of 40/20 (mg/L)/(mg/L) for injected ceftazidime/amikacin. Model-based analysis predicted low (<62%) confidence in clinically relevant suppression of the bacterial population by periodic injections of ceftazidime alone, even at high peak concentrations. Conversely, analysis predicted high (>95%) confidence in bacterial suppression by periodic injections of ceftazidime/amikacin combinations at a wide range of peak concentrations ratioed at 2:1. Both predictions were experimentally confirmed in an in vitro hollow fiber infection model, where ceftazidime was periodically injected at peak concentrations 60 and 150 mg/L (with predicted suppression confidence 38% and 59%, respectively) and a combination of ceftazidime/amikacin was periodically injected at peak concentrations 40/20 (mg/L)/(mg/L) (with predicted suppression confidence 98%). The paper highlights the potential of clinicians using the proposed mathematical framework to determine the utility of different antibiotics to suppress a patient-specific isolate. Additional studies will be needed to consolidate and expand the utility of the proposed method.


Salicylate attenuates gentamicin-induced ototoxicity and facilitates the recovery in the basilar papilla of the lizard Podarcis siculus.
It is known that ototoxicity is the main cause of toxicity induced by aminoglycoside antibiotics. Effects on cochlea and vestibule in vertebrates are variable, depending on the typology of the aminoglycoside and the animal model examined. Despite this, they are routinely used to prevent postoperative and urinary tract infections and in the treatment of tuberculosis and cystic fibrosis. Gentamicin causes hearing loss by damaging stereocilia and by causing degeneration of hair cells due to free radical formation and eventual activation of caspase-dependent pathways. Its toxicity increases with the frequency of administration, dose concentration, and duration of treatment. Turnover of new hair cells may occur spontaneously, throughout life, or may be triggered by an acoustic or ototoxic insult to replace dead cells. Turnover and repair of damage are common in fish and amphibians and in birds' vestibule. In contrast, in the papilla basilaris of birds, and in the vestibule of mammals, hair cell regeneration is activated only after damage. Sensory epithelium repair and hair cell regeneration also occur in the reptiles' vestibule, but no data is available on regeneration or repair in the basilar papilla, involved in sound perception. The purpose of this work is therefore to assess the damage induced by gentamicin on the papilla basilaris of a reptile model organism, the Lacertidae Podarcis siculus. Recovery was also evaluated 3, 8 and 18 days after the end of exposure, in absence of gentamicin and in presence of the otoprotective salicylate. Scanning electron microscopy (SEM) was carried out to check for morphological damage while the occurrence of cell proliferation events was evaluated by fluorescence microscopy, after administration of 5-Bromo-2'-deoxyuridine (BrdU). Results show that salicylate administration facilitates recovery and reduces damage to hair cells after gentamicin treatment. Following the incorporation of bromodeoxyuridine, we demonstrated that sensory epithelium repair and hair cell regeneration have occurred, and that the recovery is due to either proliferation of the supporting cells and/or self-repair of hair cell bundles in the weakly damaged sensory cells.


A semiconductor-electrocatalyst nano interface constructed for successive photoelectrochemical water oxidation.
Photoelectrochemical water splitting has long been considered an ideal approach to producing green hydrogen by utilizing solar energy. However, the limited photocurrents and large overpotentials of the anodes seriously impede large-scale application of this technology. Here, we use an interfacial engineering strategy to construct a nanostructural photoelectrochemical catalyst by incorporating a semiconductor CdS/CdSe-MoS2 and NiFe layered double hydroxide for the oxygen evolution reaction. Impressively, the as-prepared photoelectrode requires an low potential of 1.001 V vs. reversible hydrogen electrode for a photocurrent density of 10 mA cm-2, and this is 228 mV lower than the theoretical water splitting potential (1.229 vs. reversible hydrogen electrode). Additionally, the generated current density (15 mA cm-2) of the photoelectrode at a given overpotential of 0.2 V remains at 95% after long-term testing (100 h). Operando X-ray absorption spectroscopy revealed that the formation of highly oxidized Ni species under illumination provides large photocurrent gains. This finding opens an avenue for designing high-efficiency photoelectrochemical catalysts for successive water splitting.


Reduction of granulosa cell progesterone secretion in vitro by intraovarian implants of antiandrogen.
Intra-ovarian Silastic implants containing the antiandrogen, Flutamide, or its active metabolite, reduced the level of progesterone secretion in porcine granulosa cell cultures by approximately 50%. These results complement recent observations in vitro suggesting a role for androgen in granulosa cell steroidogenesis during follicular development.


Regulation of germ cell function by SUMOylation.
Oogenesis and spermatogenesis are tightly regulated complex processes that are critical for fertility. Germ cells undergo meiosis to generate haploid cells necessary for reproduction. Errors in meiosis, including the generation of chromosomal abnormalities, can result in reproductive defects and infertility. Meiotic proteins are regulated by post-translational modifications including SUMOylation, the covalent attachment of small ubiquitin-like modifier (SUMO) proteins. Here, we review the role of SUMO proteins in controlling germ cell development and maturation based on recent findings from mouse models. Several studies have characterized the localization of SUMO proteins in male and female germ cells. However, a deeper understanding of how SUMOylation regulates proteins with essential roles in oogenesis and spermatogenesis will provide useful insight into the underlying mechanisms of germ cell development and fertility.


Transglutaminase 2 and Transglutaminase 2 Autoantibodies in Celiac Disease: a Review.
Celiac disease is a common inflammatory disorder with a prevalence of 1-2 % in which a distinct dietary wheat, rye, and barley component, gluten, induces small-bowel mucosal villous atrophy, crypt hyperplasia, and inflammation. The small-bowel mucosal damage can be reversed by a strict lifelong gluten-free diet, which is currently the only effective treatment for the condition. A key player in the pathogenetic process leading to the enteropathy is played by a protein called transglutaminase 2 (TG2), which is able to enzymatically modify gluten-derived gliadin peptides. The TG2-catalyzed deamidation of the gliadin peptides results in their increased binding affinity to the disease-predisposing human leukocyte antigen (HLA) DQ2 and DQ8 molecules, thus enabling a strong immune response to be launched. Blocking the enzymatic activity of TG2 has thus been suggested as a suitable novel pharmacological approach to treat celiac disease. By virtue of its transamidation capacity, TG2 is also able to cross-link gliadin peptides to itself, this resulting in the generation of TG2-gliadin peptide complexes whose presence might provide an explanation for the generation of the TG2 autoantibodies characteristic of celiac disease. Due to their excellent specificity for the disorder, the TG2-targeted autoantibodies are widely used in the diagnostics as a first-line test to select patients for gastrointestinal endoscopy. More recently, it has come to be appreciated that these autoantibodies and also the TG2-specific B cells might play an active role in the disease pathogenesis. In this review, we assess the role of TG2, TG2-specific B cells, and autoantibodies in celiac disease.


Growth hormone and thyrotropin secretory profiles and provocative testing in aged rats.
The impact of aging on both basal and induced GH and TSH secretion in male and female rats was investigated. Analysis of the individual GH secretory profiles in young (3-4 month) and old (19-20 month) rats indicated that sex-dependent patterns of GH secretion was preserved in old animals. However, we observed a reduction of individual GH peak amplitudes of 66% in old males and 53% in old females when compared to their respective young animals. Further, the GH response to an intravenous bolus of GH-releasing factor (GRF), morphine and clonidine was dramatically blunted or absent in old male and female animals. In contrast to GH, basal TSH secretion was elevated, while the TSH response to thyrotropin-releasing hormone (TRH) was not significantly affected in old animals of either sex. The present data provide evidence that reduced pituitary sensitivity to GRF may be a possible cause for reduced GH secretion in old animals. Further, the elevation in plasma TSH observed in old animals is not the result of an increased pituitary sensitivity to TRH.


Discoveries and Dilemmas Concerning Cytokinin Metabolism.
Natural cytokinin compounds that function as plant hormones are adenine molecules connected to an N6 side chain. Metabolic pathways produce various structural modifications to the adenine moiety and/or the side chain that affect cytokinin function, activity, stability, and transport in plants. This review focuses on recent research that is elucidating the genes and biochemical pathways involved in cytokinin conjugation, deconjugation, and interconversion. One area of new discovery concerns the process of O-glucoside conjugate formation. Genes have been identified for O-glucosyltransferase enzymes in Phaseolus (ZOG1 and ZOX1) and maize (cisZOG1) and have been used to study enzyme activity, structure, and function in plant development. New information about the genetic basis of the adenine salvage pathway and its relationship to cytokinin interconversion and regulation has also become available. However, various dilemmas about cytokinin metabolism remain and need to be resolved using a combination of research approaches.


PROGRESSIVE PERIPAPILLARY CHOROID THINNING AND RETINAL NEURODEGENERATION IN PATIENTS WITH DIABETES: A 3-Year Cohort Study.
To investigate longitudinal changes in peripapillary choroidal thickness (pCT) and retinal nerve fiber thickness (pRNFLT) in patients with Type 2 diabetes mellitus. This was a prospective observational cohort study. Patients with Type 2 diabetes mellitus without diabetic retinopathy (DR) at baseline were recruited, followed up for three years, and further divided into an incident DR group and a non-DR group according to the outcome. The pCT and pRNFLT were measured through swept-source optical coherence tomography at 1-year interval, and the mean rates of pCT and pRNFLT thinning were compared between the DR groups. A total of 682 patients (682 eyes) were included in the final analysis. After 3-years follow-up, 122 (17.89%) developed DR. Both pCT and pRNFLT progressively thinned (-2.37 [-2.80 to -1.95] µm/year; -0.40 [-0.55 to -0.25] µm/year, respectively, P < 0.05) and accelerated thinning was observed in the incident DR group. The rates of pCT thinning (-3.92 [-4.96 to -2.88] µm/year, -2.03 [-2.49 to -1.57] µm/year, respectively) and pRNFLT loss (-1.03 [-1.31 to -0.76] µm/year, -0.26 [-0.43 to -0.09] µm/year, respectively) in the incident DR group were 1.93 and 3.96 times faster than those in the non-DR group, respectively. In addition, pCT and pRNFLT thinning were negatively related in Type 2 diabetes mellitus population, and faster pCT thinning indicated slower pRNFLT loss. Patients with Type 2 diabetes mellitus were at a higher risk of developing DR when accelerated pCT and pRNFLT thinning were present, indicating that heavier choroidal damage and retinal neurodegeneration precede clinical DR. The pCT and pRNFLT have the potential to serve as novel sensitive biomarkers of preclinical and early DR.


Application of deep learning techniques for detection of COVID-19 cases using chest X-ray images: A comprehensive study.
The emergence of Coronavirus Disease 2019 (COVID-19) in early December 2019 has caused immense damage to health and global well-being. Currently, there are approximately five million confirmed cases and the novel virus is still spreading rapidly all over the world. Many hospitals across the globe are not yet equipped with an adequate amount of testing kits and the manual Reverse Transcription-Polymerase Chain Reaction (RT-PCR) test is time-consuming and troublesome. It is hence very important to design an automated and early diagnosis system which can provide fast decision and greatly reduce the diagnosis error. The chest X-ray images along with emerging Artificial Intelligence (AI) methodologies, in particular Deep Learning (DL) algorithms have recently become a worthy choice for early COVID-19 screening. This paper proposes a DL assisted automated method using X-ray images for early diagnosis of COVID-19 infection. We evaluate the effectiveness of eight pre-trained Convolutional Neural Network (CNN) models such as AlexNet, VGG-16, GoogleNet, MobileNet-V2, SqueezeNet, ResNet-34, ResNet-50 and Inception-V3 for classification of COVID-19 from normal cases. Also, comparative analyses have been made among these models by considering several important factors such as batch size, learning rate, number of epochs, and type of optimizers with an aim to find the best suited model. The models have been validated on publicly available chest X-ray images and the best performance is obtained by ResNet-34 with an accuracy of 98.33%. This study will be useful for researchers to think for the design of more effective CNN based models for early COVID-19 detection.


BVD seroprevalence in the Irish cattle population as the national BVD programme progresses toward eradication.
Bovine Viral Diarrhoea Virus (BVDV) infection remains endemic in many countries worldwide. Ireland, in common with several other European counties, commenced an BVDV eradication programme in the last decade, Managing eradication programmes requires careful monitoring of diseases prevalence and understanding factors associated with disease exposure to ensure eradication programmes remain evidence based and tailored to the evolving epidemiological situation. In this study, we explore the seroprevalence of BVDV exposure over a four-year period (2017 to 2020) in Ireland from a cohort of animals (n = 6,449) under 30 months of age sampled at slaughter, who were born subsequent to the commencement of a compulsory national eradication programme. Temporal trends and risk factor analysis were undertaken using multilevel logit regression models. There was a declining temporal trend in seroprevalence over the sample years of the study, and risk varied at both county- and herd-levels. The unadjusted marginal animal-level seroprevalence reduced from 9.1% in 2017 (95%; CI: 7.2-10.9) to 3.9% in 2020 (95%; CI: 3.2-4.6). The final model suggested that seropositivity in study cattle was strongly related with the presence of a PI animal in the herd during the year of the animal's birth, and to a lesser extent the status of the herd from which the animal was slaughtered. The risk of seroconversion increased significantly with increasing size of the herd of slaughter, in females relative to males, and in dairy relative to suckler herds. This study has shown that the BVDV serostatus of cattle at slaughter is correlated to the BVD infection history of the herd into which the animal was born and the herd from which it was slaughtered. Herd location, increased herd size and dairy production were associated with increased probability of serconversion. These findings will be used to inform the targeting of surveillance strategies once BVDV freedom has been achieved.


Fabrication and characterization of PHEMA-gelatin scaffold enriched with graphene oxide for bone tissue engineering.
Growing investigations demonstrate that graphene oxide (GO) has an undeniable impact on repairing damaged bone tissue. Moreover, it has been stated in the literatures that poly(2-hydroxyethyl methacrylate) (PHEMA) and gelatin could provide a biocompatible structure. In this research, we fabricated a scaffold using freeze-drying method comprised of PHEMA and gelatin, combined with GO. The validation of the successful fabrication of the scaffolds was performed utilizing Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction assay (XRD). The microstructure of the scaffolds was observed using scanning electron microscopy (SEM). The structural properties of the scaffolds including mechanical strength, hydrophilicity, electrical conductivity, and degradation rate were also evaluated. Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were used to evaluate the cytotoxicity of the prepared scaffolds. The osteogenic potential of the GO-containing scaffolds was studied by measuring the alkaline phosphatase (ALP) activity after 7, 14, and 21 days cell culturing. SEM assay showed a porous interconnected scaffold with approximate pore size of 50-300 μm, appropriate for bone regeneration. The increase in GO concentration from 0.25 to 0.75% w/v exhibited a significant improvement in scaffolds compressive modulus from 9.03 ± 0.36 to 42.82 ± 1.63 MPa. Conventional four-probe analysis confirmed the electrical conductivity of the scaffolds in the semiconductor range. The degradation rate of the samples appeared to be in compliance with bone healing process. The scaffolds exhibited no cytotoxicity using MTT assay against hBM-MSCs. ALP analysis indicated that the PHEMA-Gel-GO scaffolds could efficiently cause the differentiation of hBM-MSCs into osteoblasts after 21 days, even without the addition of the osteogenic differentiation medium. Based on the results of this research, it can be stated that the PHEMA-Gel-GO composition is a promising platform for bone tissue engineering.


The expression of different intermediate-sized filaments in human salivary glands and their tumours.
The intermediate-sized filaments can be divided into several groups which are characteristic of different types of tissues (e.g.: epithelial, mesenchymal, muscle, astrocytic and neural origin). Antibodies specific for some of these filament types have been used to analyse a group of salivary gland tumours. Prekeratin-positive cells were seen in the normal gland, cystadenolymphomas, mucoepidermoid tumours, and squamous cell carcinomas which are all tumours of epithelial origin. The pleomorphic adenomas showed the presence of some cells which appeared to contain both prekeratin and vimentin. The results are discussed with respect to their histogenetic implications.


Effect of vasoconstriction on pain after mandibular third molar surgery: A single-blind, randomized controlled trial.
Previous research has demonstrated the efficacy of using local compression to reduce postoperative pain after third molar surgery. It has been theorized that compression reduces pain intensity through vasoconstriction. The current research tests the veracity of this vasoconstriction hypothesis by testing the impact of local epinephrine (a local vasoconstrictor) versus a control on patients' pain ratings over 7 days following surgery. Fifty patients scheduled for mandibular third molar surgery were randomly assigned to receive one cartridge of Ultracaine DS Forte (the treatment group) or one cartridge of Ultracaine DS (the control group) after surgical removal of the third molar. Participants used the visual analog scale (VAS) to provide daily ratings of pain intensity for 7 days following surgery. In addition, on day 7, the perceived effectiveness of the pain treatment was measured with the global perceived effect (GPE) scale. A quality- of-life questionnaire was also completed. A repeated-measures ANOVA indicated that the treatment group perceived significantly less pain than the control group on days 2 to 7 following surgery. In addition, 77.8% of the treatment group perceived their pain treatment to be successful, while only 69.6% of the control group reported that their pain was reduced successfully by day 7. The results of this study provide an initial proof of concept that epinephrine may have an analgesic effect on the period following third molar surgery. Further research with larger sample sizes is needed to strengthen evidence for the clinical utility of offering localized epinephrine to patients following third molar surgery.


Chromosome Spread Analyses of Meiotic Sex Chromosome Inactivation.
A distinct form of X chromosome inactivation takes place during male meiosis, when the male sex chromosomes undergo a phenomenon known as meiotic sex chromosome inactivation (MSCI). MSCI is directed by DNA damage response signaling independent of Xist RNA to silence the transcriptional activity of the sex chromosomes, an essential event in male germ cell development. Here, we present protocols for the preparation and analyses of chromosome spread slides of mouse meiotic spermatocytes, thereby enabling a quick, inexpensive, and powerful cytological method to complement gene expression studies.


Mechanism of complement activation and its role in the inflammatory response after thoracoabdominal aortic aneurysm repair.
Complement activation contributes to ischemia-reperfusion injury. Patients undergoing thoracoabdominal aortic aneurysm (TAAA) repair suffer extensive ischemia-reperfusion and considerable systemic inflammation. The degree and mechanism of complement activation and its role in inflammation were investigated in 19 patients undergoing TAAA repair. Patients undergoing open infrarenal aortic surgery (n=5) or endovascular descending aortic aneurysm repair (n=6) served as control subjects. Substantial complement activation was seen in TAAA patients but not in controls. C1rs-C1-inhibitor complexes increased moderately, whereas C4bc, C3bBbP, C3bc, and the terminal SC5b-9 complex (TCC) increased markedly after reperfusion, reaching a maximum 8 hours after reperfusion. Interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and IL-8 increased significantly in TAAA patients but not in controls, peaking at 24 hours postoperatively and correlating closely with the degree of complement activation. IL-6 and IL-10 increased to a maximum 8 hours after reperfusion in the TAAA patients, were not correlated with complement activation, and increased moderately in the control subjects. Myeloperoxidase and lactoferrin increased markedly before reperfusion in all groups, whereas sICAM-1, sP-selectin, and sE-selectin were unchanged. No increase was observed in complement activation products, IL-1beta, TNF-alpha, or IL-8 in a mannose-binding lectin (MBL)-deficient TAAA patient, whereas IL-6, IL-10, myeloperoxidase, and lactoferrin increased as in the controls. Two other MBL-deficient TAAA patients receiving plasma attained significant MBL levels and showed complement and cytokine patterns identical to the MBL-sufficient TAAA patients. The data suggest that complement activation during TAAA repair is MBL mediated, amplified through the alternative pathway, and responsible in part for the inflammatory response.


Clinical genome sequencing: Three years' experience at a tertiary children's hospital.
Genome sequencing (GS) may shorten the diagnostic odyssey for patients, but clinical experience with this assay in nonresearch settings remains limited. Texas Children's Hospital began offering GS as a clinical test to admitted patients in 2020, providing an opportunity to study GS utilization, possibilities for test optimization, and testing outcomes. We retrospectively reviewed GS orders for admitted patients for a nearly 3-year period from March 2020 through December 2022. We gathered anonymized clinical data from the electronic health record to answer the study questions. The diagnostic yield over 97 admitted patients was 35%. The majority of GS clinical indications were neurologic or metabolic (61%) and most patients were in intensive care (58%). Tests were often characterized as candidates for intervention/improvement (56%), frequently because of redundancy with prior testing. Patients receiving GS without prior exome sequencing (ES) had higher diagnostic rates (45%) than the cohort as a whole. In 2 cases, GS revealed a molecular diagnosis that is unlikely to be detected by ES. The performance of GS in clinical settings likely justifies its use as a first-line diagnostic test, but the incremental benefit for patients with prior ES may be limited.


Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII.
Insulin regulates blood glucose by promoting uptake by fat and muscle, and inhibiting production by liver. Insulin-stimulated glucose uptake is mediated by GLUT4, which translocates from an intracellular compartment to the plasma membrane. GLUT4 traffic and insulin secretion both rely on calcium-dependent, regulated exocytosis. Deletion of the voltage-gated potassium channel Kv1.3 results in constitutive expression of GLUT4 at the plasma membrane. Inhibition of channel activity stimulated GLUT4 translocation through a calcium dependent mechanism. The synaptotagmins (Syt) are calcium sensors for vesicular traffic, and Syt VII mediates lysosomal and secretory granule exocytosis. We asked if Syt VII regulates insulin secretion by pancreatic beta cells, and GLUT4 translocation in insulin-sensitive tissues mouse model. Syt VII deletion (Syt VII -/-) results in glucose intolerance and a marked decrease in glucose-stimulated insulin secretion in vivo. Pancreatic islet cells isolated from Syt VII -/- cells secreted significantly less insulin than islets of littermate controls. Syt VII deletion disrupted GLUT4 traffic as evidenced by constitutive expression of GLUT4 present at the plasma membrane of fat and skeletal muscle cells and unresponsiveness to insulin. These data document a key role for Syt VII in peripheral glucose homeostasis through its action on both insulin secretion and GLUT4 traffic.


Randomized, blinded comparison of transgastric, transcolonic, and laparoscopic peritoneoscopy for the detection of peritoneal metastases in a human cadaver model.
Natural orifice transluminal endoscopic surgery peritoneoscopy may be able to replace laparoscopic peritoneoscopy (LAP) for staging of GI malignancies if it is proven to be equally accurate and safe. To compare transgastric peritoneoscopy (TGP) and transcolonic peritoneoscopy (TCP) to LAP, pairwise, in a randomized, blinded (to location and number of beads) human cadaver model with simulated peritoneal metastases. Metastases were simulated by 2.5-mm, color-coded beads, which were placed into the peritoneal cavity via an open approach. In previous porcine experiments, LAP resulted in a yield of 95%. By using a noninferiority design with a margin of equivalence of 15%, we needed a sample size of 34 beads for 80% power. Randomization was performed for number and location of beads. Eighteen experiments were performed on 6 fresh-frozen human cadavers. Experimental surgical laboratory. LAP, TGP, and TCP were performed in randomized order by one of two surgeons/endoscopists blinded for location and number of beads. Number of beads detected and touched. LAP found and touched 33 beads (yield 97%), TGP 26 beads (76%; difference in yield vs LAP was -20.5 [95% CI, -26.3 to -9.27]), and TCP 29 beads (85%; difference in yield vs LAP was -11.8 [95% CI, -14.6 to 4.98]). Beads that were missed were mostly located at the inferior liver surface: TGP missed 6 of 9 of these beads (67%), TCP 4 of 9 (44%). Cadaver model. In this prospective, blinded, comparative trial in a human cadaver model, TCP was comparable to LAP in detecting simulated metastases. TGP was inferior to LAP. Future development should focus on improved visualization of the inferior surface of the liver.


A Systematic Review and Meta-Analysis of the Relationship Between the Severity of Dental Fluorosis and Fluoride Biomarkers in Endemic Areas.
The intake of high concentrations of fluoride, mainly through drinking water, diet and fluoridated dentifrices, produces fluorosis, which in its early stages is manifested as dental fluorosis (DF). To recognize exposure to fluoride in endemic areas and to evaluate the risk of developing health impairment, the WHO has established several biomarkers that are used to determine systemic fluorine (F-) exposure. Thus, the aim of this study was to conduct a systematic review and meta-analysis of the relationship between the severity of DF and fluoride biomarkers in endemic areas. The protocol of this study was previously registered as CRD42021244974. A digital search was carried out in PubMed/Medline, SpringerLink, Scopus, Cochrane and Google Scholar by employing the keywords "urine", "nails", "hair", "plasma", "saliva" and "dental fluorosis" for the original studies with content associated with F- for the biomarkers and DF. The mean difference was established as the effect measure for the meta-analysis. Seven studies fulfilled the eligibility criteria, among which five assessed urine and two employed nails as fluoride biomarkers. A positive significant difference was found between the biomarkers and the severity of DF (0.27, p < 0.001) and individually for each biomarker (urine: 0.14, p = 0.001; nails: 0.88, p < 0.05). The F- concentration in urine and nails is correlated with the severity of DF, with the most evident differences between healthy individuals and those with mild severity. Both biomarkers are adequate to assess this relationship in endemic areas of fluoride and DF.


Effect of music intervention on burn patients' pain and anxiety during dressing changes.
For burn patients, the daily dressing process causes pain and anxiety. Although drugs can relieve them, the degree of pain during dressing changes is often moderate to severe. Therefore, relevant supporting interventions, like music as an ideal intervention, could alleviate the patient's pain. This study investigated the impact of music intervention at dressing change time on burn patients' pain and anxiety. This was a prospective, randomized clinical trial; patients were randomly assigned into control (standard intervention) and experimental groups (crystal music intervention) for five consecutive days (35 patients in each group). Patients' pain and anxiety measurements were collected before, during, and after dressing changes and morphine usage was recorded. The study period was October 2014 to September 2015. There was no difference in morphine dosage for both groups. By the fourth day of music intervention, burn patients' pain before, during, and after dressing changes had significantly decreased; anxiety on the fourth day during and after dressing changes had also significantly decreased. Nurses may use ordered prescription analgesics, but if non-pharmacological interventions are increased, such as providing timely music intervention and creating a friendly, comfortable hospital environment, patients' pain and anxiety will reduce.


Abnormal protein metabolism in skin fibroblasts in vitro from patients with Duchenne muscular dystrophy.
Rates of protein turnover have been measured on a statistical basis in Duchenne muscular dystrophy and normal skin fibroblasts populations in vitro. At comparable numbers of cumulative population doublings, protein synthesis was significantly reduced by about 24% in DMD fibroblasts as compared to normal fibroblasts (p less than 0.01, N = 12). Degradation of short lived proteins was significantly enhanced by about 60% (p less than 0.05, N = 18), and the degradation of long lived proteins was significantly increased by about 28% (p less than 0.05, N = 18) in DMD fibroblast populations in vitro. The enhanced degradation of long lived proteins in DMD fibroblasts can be reduced to basal levels of degradation by the use of the protease inhibitors leupeptin and Ep475 (p less than 0.05, N = 9).


Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.
Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.


Improved energy recovery from food waste through hydrothermal carbonization and anaerobic digestion.
Here we studied energy valorization of food waste by hydrothermal carbonization coupled with anaerobic digestion. Hydrothermal treatment was carried out at 200 °C and 230 °C for 1 h, obtaining hydrochar with properties suitable for solid biofuel according to ISO/TS 17225-8. The increase in temperature improved the fuel properties of hydrochar (higher heating value 20.3 and 23.7 MJ kg-1, fuel ratio 0.33 and 0.37, energy density 1.07 and 1.25). The anaerobic digestion of process water achieved methane yields around 150 mL CH4 STP g-1 CODadded and made it possible to remove some specific recalcitrant compounds, such as 2-methylpyridine and 2-ethyl-3-methylpyrazine. Energy recovery from hydrochar and process water seems to be an interesting alternative way to sustain the process energetically and economically, despite the significant energy inputs required for hydrothermal carbonization.


T2-based temperature monitoring in abdominal fat during MR-guided focused ultrasound treatment of patients with uterine fibroids.
Near-field heating is a potential problem in focused ultrasound treatments, as it can result in thermal injury to skin, subcutaneous fat, and other tissues. Our goals were to determine if T2-based temperature mapping could be used reliably to measure near-field heating in adipose tissue and whether it is practical to perform such mapping during focused ultrasound treatments. We investigated the dependence of T2 on temperature in ex vivo adipose tissue at 3T using a double-echo fast spin echo (FSE) sequence. We implemented and evaluated the T2-based temperature mapping technique in the adipose tissue of two healthy volunteers. Finally, we applied the technique during magnetic resonance-guided focused ultrasound (MRgFUS) treatments to measure near-field heating in eight patients with uterine fibroids. Calibration experiments in porcine adipose tissue determined a temperature coefficient of 6.16 ms/°C during heating and 5.37 ms/°C during cooling. The volunteer experiments demonstrated a strong correlation between the skin temperature and T2-based temperature measurements in the fat layer. During the treatments of patients with uterine fibroids, we observed a measurable change in the T2 of fat tissue within the path of the ultrasound beam and a temperature increase of up to 15 °C with sustained heating of more than 10 °C. Our results demonstrate the feasibility and importance of monitoring near-field heating in fatty tissues. The implementation of near-field monitoring between sonications can shorten treatments by reducing the cooling time. It can help improve safety by avoiding excessive heating in the near field.


Mycobacterium leprae induces NF-kappaB-dependent transcription repression in human Schwann cells.
Mycobacterium leprae, the causative agent of leprosy, invades peripheral nerve Schwann cells, resulting in deformities associated with this disease. NF-kappaB is an important transcription factor involved in the regulation of host immune antimicrobial responses. We aimed in this work to investigate NF-kappaB signaling pathways in the human ST88-14 Schwannoma cell line infected with M. leprae. Gel shift and supershift assays indicate that two NF-kappaB dimers, p65/p50 and p50/p50, translocate to the nucleus in Schwann cells treated with lethally irradiated M. leprae. Consistent with p65/p50 and p50/p50 activation, we observed IkappaB-alpha degradation and reduction of p105 levels. The nuclear translocation of p50/p50 complex due to M. leprae treatment correlated with repression of NF-kappaB-driven transcription induced by TNF-alpha. Moreover, thalidomide inhibited p50 homodimer nuclear translocation induced by M. leprae and consequently rescues Schwann cells from NF-kappaB-dependent transcriptional repression. Here, we report for the first time that M. leprae induces NF-kappaB activation in Schwann cells and thalidomide is able to modulate this activation.


CircGSAP alleviates pulmonary microvascular endothelial cells dysfunction in pulmonary hypertension via regulating miR-27a-3p/BMPR2 axis.
Our previous study showed that circular RNA-gamma-secretase-activating protein (circGSAP) was down-regulated in pulmonary microvascular endothelial cells (PMECs) in response to hypoxia, and regulated the cell cycle of PMECs via miR-942-5p sponge in pulmonary hypertension (PH). However, the mechanism whether circGSAP affects the dysfunction of PEMCs through other microRNAs (miRNAs) remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of circGSAP regulating PMECs dysfunction by absorbing other miRNAs to regulate target genes in idiopathic pulmonary arterial hypertension (IPAH). Quantitative real-time polymerase chain reaction, immunofluorescence staining, Cell Counting Kit-8, Calcein-AM/PI staining, Transwell assay, dual-luciferase reporter assay, and ELISA were used to elucidate the roles of circGSAP. Here we showed that plasma circGSAP levels were significantly decreased in patients with IPAH and associated with poor outcomes. In vivo, circGSAP overexpression improved survival, and alleviated pulmonary vascular remodeling of monocrotaline-induced PH (MCT-PH) rats. In vitro, circGSAP overexpression inhibited hypoxia-induced PMECs proliferation, migration and increased mortality by absorbing miR-27a-3p. BMPR2 was identified as a miR-27a-3p target gene. BMPR2 silencing ameliorated the effect of the miR-27a-3p inhibitor on PMECs proliferation,migration and mortality. The levels of BMPR2 were upregulated in circGSAP-overexpressed PMECs and lung tissues of MCT-PH rats. Our findings demonstrated that circGSAP alleviated the dysfunction of PMECs via the increase of BMPR2 by competitively binding with miR-27a-3p, and mitigated pulmonary vascular remodeling of MCT-PH rats, providing potential therapeutic strategies for IPAH.


Sorafenib plus dacarbazine in solid tumors: a phase I study with dynamic contrast-enhanced ultrasonography and genomic analysis of sequential tumor biopsy samples.
Improved prognostic accuracy for treatment response and a wider understanding of drug effects in humans are crucial for enhancing the utility of sorafenib and other promising targeted therapies. We developed a strategy of global genomic investigation of sequential tumor biopsy samples at baseline and 21 days post treatment, and applied this approach in a phase I study of sorafenib plus dacarbazine in patients with solid tumors. The objective of this study was also to validate functional parameters of DCE-US as surrogate markers to predict earlier response. Patients received 21-day cycles of oral sorafenib, 400 mg twice daily and dacarbazine, 1,000 mg/m(2) in a 1-h intravenous infusion on day 1. Efficacy was assessed using response evaluation criteria in solid tumors. Sequential biopsy samples (baseline and day 21) were obtained from the same tumor. Changes from baseline in global gene expression (GE) measured by genomic microarrays and in tumor vascularity at baseline, D8, D21, D 42 and every 2 cycles using dynamic contrast-enhanced ultrasonography (DCE-US) were analyzed for patients with and without a clinical response to treatment at 3 months. Among 23 patients evaluable for treatment efficacy, 17 were eligible for gene expression and DCE-US analyses. One patient achieved a partial response; 14 exhibited stable disease. Ten patients were defined as exhibiting stable disease (SD) and 7, progressive disease (PD) at 3 months. Genomic analyses identified a 237-gene signature that distinguished SD from PD at 3 months. Of note, CDK4 overexpression and PDGFR downregulation were associated with PD. Functional parameters of DCE-US representing the blood volume at baseline, day 8, and day 21 were correlated with disease progression at 3 months. This novel approach of sequential investigations in a phase I trial was feasible, detecting early changes in gene expression and tumor vascularity evaluated using DCE-US that may be predictive of clinical outcome.


Clinical decision support models for oropharyngeal cancer treatment: design and evaluation of a multi-stage knowledge abstraction and formalization process.
Treatment decisions in oncology are demanding and affect survival, general health, and quality of life. Expert systems can handle the complexity of the oncological field. We propose the application of a hybrid modeling approach for decision support models consisting of expert-based implementation of a decision model structure and machine-learning (ML) based parameter generation. We demonstrate our approach for the treatment of oropharyngeal cancer. We created a clinical decision model based on Bayesian Networks and iteratively optimized its characteristics using structured knowledge engineering approaches. We combined manual adaptation of individual concepts with automatic learning of parameters and causalities. Using data from 94 patient records, we targeted the needed objectivity and clinical significance. In three iteration steps, we assessed the model with cross-validations. The initial aggregated accuracy of 0.529 could be increased to 0.883 in the final version. The predictive rates of the target nodes range from 0.557 to 0.960. Combining different methodological approaches requires balancing the complexity of the clinical subject matter with the amount of information available in the dataset for ML application. Our method showed promising results because flaws of one approach can be overcome by the other approach. However, technical integrability as well as clinical acceptance must always be ensured.


The decline effect in cardiovascular medicine: is the effect of cardiovascular medicine and stent on cardiovascular events decline over the years?
The term decline effect is referred to a diminution of scientifically discovered effects over time. Reasons for the decline effect are multifaceted and include publication bias, selective reporting, outcomes reporting bias, regression to the mean, scientific paradigm shift, overshadowing and habituation, among others. Such effects can be found in cardiovascular medicines through medications (e.g., aspirin, antithrombotics, proton pump inhibitor, beta-blockers, statins, estrogen/progestin, angiotensin converting enzyme inhibitor etc.), as well as with interventional devices (e.g., angioplasty, percutaneous coronary intervention, stents). The scientific community should understand the various dimensions of the decline effects, and effective steps should be undertaken to prevent or recognize such decline effects in cardiovascular medicines.


Longitudinal management and outcomes of acute coronary syndrome in persons living with HIV infection.
Persons living with HIV (PLWH) have increased cardiovascular mortality, which may in part be due to differences in the management of acute coronary syndromes (ACS). The purpose of this study was to compare the in-hospital and post-discharge management and outcomes of ACS among persons with and without HIV. This was a retrospective cohort study using data from Symphony Health, a data warehouse. All patients admitted between 1 January 2014 and 31 December 2016 with ACS were identified by International Classification of Diseases billing codes. Multivariate logistic regression models were used to examine in-hospital, 30-day and 12-month event rates between groups. A total of 1 125 126 individuals were included, 6612 (0.59%) with HIV. Persons living with HIV were younger (57.4 ± 10.5 vs. 67.4 ± 12.9 years, P< 0.0001) and had more medical comorbidities. Acute coronary syndrome type did not differ significantly with HIV status. Persons living with HIV were less likely to undergo coronary angiography (35.2% vs. 37.2%, adjusted OR 0.87, 95% CI 0.83-0.92, P < 0.0001), and those with both HIV and STEMI underwent fewer drug-eluting stents (60.1% vs. 68.5%, adjusted OR 0.81, 95% CI 0.68-0.96, P = 0.016). Persons living with HIV had higher adjusted rates of inpatient mortality (OR 1.29, 95% CI 1.15-1.44; P < 0.0001), 30-day readmission (OR 1.18, 95% CI 1.09-1.27; P < 0.0001) and 12-month mortality (OR 1.32, 95% CI 1.22-1.44; P < 0.0001). Twelve months following discharge, PLWH filled cardiac medications at lower rates. In a contemporary cohort of persons hospitalized for ACS, PLWH received less guideline-supported interventional and medical therapies and had worse clinical outcomes. Strategies to optimize care are warranted in this unique population.


Association of L-myc polymorphism with lung cancer susceptibility and prognosis in relation to age-selected controls and stratified cases.
The association of L-myc polymorphism with cancer susceptibility and prognosis has produced conflicting results. This may have been due to racial/ethnic differences and methodological variations in the studies, such as, control selection and case stratification. Therefore, we investigated the genotype distribution of the L-myc polymorphism in 169 lung cancer patients and 169 non-cancer controls, and analyzed the association of this polymorphism with cancer susceptibility and prognosis in relation to age-specific controls as well as stratified cases. The genotype frequencies in the Taiwanese non-cancer controls were 0.56 (L) and 0.44 (S). Chi-square (chi(2)) analysis indicated a significant difference in the Taiwanese genotype distribution of L-myc compared with that of African-Americans (P=0.001). Logistic regression analysis of cases/controls, adjusted for both age and sex, indicated that an increased frequency of the LL genotype was observed in early-staged patients compared with the non-cancer controls (OR=0.43, 95% CI, 0.20-0.94, P=0.03). In addition, the frequency of the LL genotype was significantly higher in stages I+II patients (47.4%) than in stages III+IV patients (28.4%) (P=0.05). Furthermore, the S allele frequency was significantly increased in stages III+IV patients (P=0.005). As both L-myc and p53 polymorphisms were analyzed for their prognostic value, the patients with an S allele of the L-myc gene and a Pro/Pro variant genotype of the p53 gene had significantly poorer prognoses compared with other patients (P=0.004, by the log rank test). These data suggest that the S allele of the L-myc polymorphism may be associated with lung cancer progression.


Intraoperative verification of conduction block in atrial fibrillation surgery.
Atrial tachycardia is a troublesome and medically refractory complication after surgery for atrial fibrillation. Incomplete surgical ablation during atrial fibrillation surgery can result in residual conduction over the lesions and postoperative atrial tachycardia. Intraoperative verification of conduction block would detect incomplete ablation lesions and direct repeat ablations to prevent postoperative atrial tachycardia. The incidence of postoperative atrial tachycardia was examined in 218 patients who underwent atrial fibrillation surgery between November of 1994 and October of 2007. No conduction block across any ablation lesions was confirmed intraoperatively in the first 128 patients (group C). Isolation of each pulmonary vein was verified by intraoperative pulmonary vein pacing in the following 72 patients (group PV). In the recent 18 consecutive patients, conduction block in the coronary sinus, in addition to pulmonary vein isolation, was confirmed by intraoperative coronary sinus pacing (group PV/CS). Postoperative atrial tachycardia was characterized by electroanatomic mapping. The incidence of postoperative atrial tachycardia in groups C and PV was 7% and 1%, respectively (P = .0985). No patients exhibited any postoperative atrial tachycardia in group PV/CS. The postoperative electroanatomic mapping revealed that the mechanisms of the atrial tachycardia were macro-reentry through incomplete coronary sinus and mitral valve ablation lesions (n = 9), and focal activation in the coronary sinus (n = 1). Intraoperative verification of conduction block directed the repeat ablation lesions to the pulmonary veins. The majority of postoperative atrial tachycardia was associated with an incomplete coronary sinus ablation. Intraoperative verification of conduction block may be helpful to prevent the occurrence of postoperative atrial tachycardia.


Lens fiber differentiation correlated with activation of two different DNAases in lens embryonic cells.
In order to identify the different DNAases present in the lens differentiating tissue, we have used an assay which reveals their activity directly on DNA-containing gels after SDS polyacrylamide gel electrophoresis. DNAase renaturation from nuclear embryonic lens extracts does not occur after separation in 0.1% SDS polyacrylamide gel electrophoresis in contrast to that observed with purified micrococcal nuclease. When the SDS concentration in the running buffer and separating gel is decreased to 0.075%, renaturation of lens DNAase and enzyme activities are observed. Isoelectrofocusing was carried out in a polyacrylamide gel which was overlaid with an agarose gel containing DNA, permitting the visualization of the pI of DNAase activity. The presence of several DNAase isoenzymes was demonstrated in 11-day embryonic lenses. In epithelial lens nuclei, high molecular weight (MW) isoenzymes with basic pI were predominant. In post-mitotic fiber lens nuclei, two lower MW isoenzymes with acidic pI were detected as well as high MW activity with a basic pI.


Effects of oolong tea on renal sympathetic nerve activity and spontaneous hypertension in rats.
In a previous study, evidence was presented that oolong tea (OT) reduced abdominal fat accumulation in diet-induced obese mice. In the study presented here, we examined the sympathetic and cardiovascular effects of intraduodenal injection of OT in urethane-anesthetized rats and found that it suppressed renal sympathetic nerve activity (RSNA) and blood pressure (BP). In addition, pretreatment with the histaminergic H3-receptor antagonist thioperamide or bilateral subdiaphragmatic vagotomy eliminated the effects of OT on RSNA and BP. Furthermore, OT drinking for 14 weeks reduced BP elevation in spontaneously hypertensive rats. These results thus suggest that OT may exert its hypotensive action through changes in autonomic neurotransmission via an afferent neural mechanism. Moreover, we found that intraduodenal injection of decaffeinated OT lowered RSNA and BP as well as OT, indicating that substances other than caffeine contained in OT may function as effective modulators of RSNA and BP.


Vitamin A metabolism in the retinal pigment epithelium: genes, mutations, and diseases.
Mutations in the genes necessary for the metabolism of vitamin A (all-trans retinol) and cycling of retinoids between the photoreceptors and retinal pigment epithelium (RPE) (the visual cycle) have recently emerged as an important class of genetic defects responsible for retinal dystrophies and dysfunctions. Research into the causes and treatment of diseases resulting from defects in retinal vitamin A metabolism is currently the subject of intense interest, since disorders affecting the RPE are, in principle, more accessible to therapeutic intervention than those affecting the proteins of photoreceptor cells. This chapter presents an overview of the visual cycle, as well as the function of the RPE genes involved in the conversion of vitamin A to 11-cis retinal, the chromophore of the visual pigments. The identification of disease-causing mutations in this group of genes is described as well as the associated phenotypes that range from stationary night blindness to childhood-onset severe visual handicap. Consideration is also given to alternative genetic paradigms potentially relevant to defects in vitamin A metabolism, including a discussion of the relationship of this pathway to age-related macular degeneration, a non-Mendelian disease of late onset. Finally, progress and prospects for targeted therapeutic intervention in vitamin A metabolism are presented, including retinoid and gene replacement therapy. On the basis of early successes in animal models, and plans underway for Phase I/II clinical trials, it is hoped that the near future will bring effective therapies for many retinal dystrophy patients with defects in vitamin A metabolism.


Acute coronary syndromes in women and men.
Evidence of sex-related disparities in the care and outcomes of patients with acute coronary syndrome (ACS) emerged >30 years ago, and yet the mechanisms behind these sex-specific differences remain unclear. In this Review, we discuss the current literature on differences between women and men in the clinical presentation, pathophysiology, evaluation, management, and outcomes of ACS. Although the symptoms of ACS and the benefits of therapy generally overlap between women and men, women continue to receive less-aggressive invasive and pharmacological therapy than men. In addition, young women in particular have worse short-term and long-term outcomes than men. To understand better the mechanisms behind these continued disparities, we have identified areas of future research that need to be urgently addressed in fields that range from clinical evaluation and management, to increasing representation of women in research.


DIVAS: a centralized genetic variant repository representing 150,000 individuals from multiple disease cohorts.
A plethora of sequenced and genotyped disease cohorts is available to the biomedical research community, spread across many portals and represented in various formats. We have gathered several large studies, including GERA and GRU, and computed population- and disease-specific genetic variant frequencies. In total, our portal provides fast access to genetic variants observed in 84,928 individuals from 39 disease populations. We also include 66,335 controls, such as the 1000 Genomes and Scripps Wellderly. Combining multiple studies helps validate disease-associated variants in each underlying data set, detect potential false positives using frequencies of control populations, and identify novel candidate disease-causing alterations in known or suspected genes. https://rvs.u.hpc.mssm.edu/divas email@example.com Supplementary data are available at Bioinformatics online.


Schiff base complex conjugates of bovine serum albumin as artificial metalloenzymes for eco-friendly enantioselective sulfoxidation.
Artificial metalloenzymes (BSA-ML) have been prepared by non-covalent insertion of transition metal Schiff-base complexes, ML (L = 2-hydroxynaphthalen-1-naphthaldehyde and 3,4-diaminobenzenesulfonic acid; M = Co, Mn, V, Fe, Cr), into bovine serum albumin (BSA) as the host protein and were characterized by UV-visible spectroscopy, ESI-TOF mass spectrometry and molecular docking studies. The catalytic activities of the BSA-ML in the selective oxidation of various prochiral sulfides in aqueous media, using H2O2 as oxidant, have been evaluated. During the optimization process, pH and the concentrations of catalyst and oxidant were found to have a remarkable influence on both yield and enantioselectivity. In certain cases, BSA-ML gave satisfactory results in the oxidation of organic sulfides to sulfoxides (up to 100% conversion, 100% chemoselectivity, 96% ee and 500 h-1 turnover frequency).


Towards a neural model of timing.
This paper describes a neural model of interval timing, which reproduces the duration discrimination experiments of Wearden, J.H., 1992, J. Exp. Psychol. 18, 134-144. The model comprises three layers of neural units. The units in the first layer represent clusters of neurons with probabilistic internal feedback that maintains self-sustained (short-term memory) activity for a random time. The unit in the second layer is a spiking neuron that fires as long as a sufficient number of input clusters are active. The unit in the third layer detects the offset of firing in the previous layer by producing a short burst of spikes. Analysis and simulation of the model shows spikes produced at random times with a distribution determined by the number of units in the first layer, their survival time constant, and the threshold of the unit in layer 2. Interval times can be learned with any of these parameters but lead to different Weber law relations. A variable threshold in layer 2 predicts S-shaped Weber curves, a variable number of units in layer 1 leads to a saturation of the Weber curve (decreasing Weber fraction) and a variable time constant in layer 1 causes a linear Weber curve.


Catechin hydrate inhibits proliferation and mediates apoptosis of SiHa human cervical cancer cells.
Catechin hydrate (CH), one of the chemical compounds in green tea, has been shown to inhibit tumor growth. Green tea possesses anticancer potential and is one of the most commonly used herbal medicines worldwide. In this study, we sought to characterize the DNA damage and downstream genes targeted by CH extracts using SiHa human cervical cancer cells. The efficacy of CH in killing cervical cancer cells in vitro was investigated in this study to determine whether CH possesses anticancer potential and could be developed as a therapeutic agent for cervical cancer upon further investigation. To scientifically validate the anticancer activities of CH on cervical cancer, CH was tested for its cytotoxic and growth-inhibition properties, specifically the induction of apoptosis in SiHa cervical cancer cells. CH showed a 50% inhibition of SiHa human cervical cancer cells at a concentration of 196.07 μg/mL at 24h. CH induced the several folds increase of caspase-3, -8, and -9 after 24h and 48 h; the increase of these genes may be involved in the induction of apoptosis. The analysis of apoptosis by DeadEnd terminal transferase-mediated dUTP-digoxigenin-end labeling (TUNEL) assay was used to further confirm that CH induced apoptosis. The results suggested that CH has the potential to benefit cervical cancer prevention. This is the first report that shows the possible mechanism of the anti-proliferative effects of CH in the prevention of cervical cancer in cell culture models. CH, either in its original form or in combination with other anticancer drugs, could potentially be an alternative medicine for cervical cancer. Further study may increase our understanding of the mechanism by which CH has an effect on cervical cancer therapy.


Histopathological and cytolosical abnormalities induced by fusarial toxins in mice (Mus musculus).
Three fusarial toxins vi z., zearal enone (ZEA), deoxynivalenol (DON) and T-2 were administered orally to mice (Mus musculus) under two different treatments. In the -first treatment, the toxins were -fed at the rate o-f 0.5 mg/kg body weight (ZEA), 3mg/kg body weight (DON), and 0.5mg/kg body weight (T-2) -for eight weeks (twice a week) . In another set o-f experiments the toxins were .given daily by mixing with the -feed at a concentration commonly -found in -food and -feed items as natural contaminants. The a-f-fected animals showed significant changes in body weight. T-2 toxins caused swelling o-f stomach in most o-f the treated animals. Portal and periportal fibrosis in liver was also very common. Enlargement o-f urinary bladder was observed in ZEA fed animals. Cytological studies in bonemarrow cells showed fragmentation, chromosome breaks, stickiness and clumping of chromosome.


Antigenemia for cytomegalovirus in renal transplantation: choosing a cutoff for the diagnosis criteria in cytomegalovirus disease.
Cytomegalovirus (CMV) infection is a frequent complication in transplant recipients, causing a high level of morbidity and mortality. We studied 203 consecutive renal transplant recipients performed between January 2000 and December 2001. Patients underwent weekly measurements of CMV pp65 antigen to assess CMV activity from the 4th to the 12th week posttransplantation. The results were reported as number of cells positive for the pp65 antigen among 10(5) granulocytes. In order to define a best cutoff to diagnose CMV disease with desirable sensitivity and specificity, we used a receiver operator characteristics (ROC) curve. The cutoff of four positive cells corresponded to a sensitivity of 93% and specificity of 60% (AUC = 0.87) for the diagnosis of CMV disease. The chosen cutoff for starting antiviral treatment was 10 cells, since this was associated with a sensitivity of 92% and specificity of 70% (AUC = 0.90). In conclusion, the highly sensitive cutoff points for the diagnosis of antigenemia was four cells and 10 cells for initiation of antiviral therapy.


Toward adaptive (computer-based) hospital care systems that can grow and improve as a function of user participation.
This paper describes a computer-based system that would allow doctors, patients, nurses, researchers and experts to participate in medical care in ways that will enhance the usefulness of the system, and will allow the system to grow, adapt and improve as a function of this participation.


Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial.
In this clinical trial, we investigated the blood glucose (BG)-lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline-adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long-term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase-4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the β-cell protective properties of DXM.