Effect of temperature gradients on single-strand conformation polymorphism analysis in a capillary electrophoresis system using Pluronic polymer matrix.
Capillary electrophoresis-single strand conformation polymorphism (CE-SSCP) analysis is a prominent bioseparation method based on the mobility diversity caused by sequence-induced conformational differences of single-stranded DNA. The use of Pluronic polymer matrix has opened up new opportunities for CE-SSCP, because it improved the resolution for various genetic analyses. However, there still exists a challenge in optimizing Pluronic-based CE-SSCP, because the physical properties of Pluronic solutions are sensitive to temperature, particularly near the gelation temperature, where the viscoelasticity of Pluronic F108 solutions sharply changes from that of a Newtonian fluid to a hydrogel upon heating. We have focused on a set of experiments to control the ambient temperature of the CE system with the aim of enhancing the reliability of the CE-SSCP analysis by using the Applied Biosystems ABI 3130xl genetic analyzer with Pluronic F108 solution matrix. The ambient temperature control allowed us to vary the inlet and outlet portion of the capillary column, while the temperature of the column was kept at 35°C. The resolution to separate 2 single-base-pair-differing DNA fragments was significantly enhanced by changing the temperature from 19 to 30°C. The viscoelastic properties of the F108 solution matrix upon heating were also investigated by ex situ rheological experiments with an effort to reveal how the development of gels in Pluronic solutions affects the resolution of CE-SSCP. We found that the column inlet and outlet temperatures of the capillary column have to be controlled to optimize the resolution in CE-SSCP by using the Pluronic matrix.


Putting some spine into alternative splicing.
Spinal muscular atrophy is a neurodegenerative disease caused by mutations of the SMN1 gene. The homologous SMN2 gene is unable to complement SMN1 because of a crucial mutation in an exonic splicing enhancer, leading to alternative splicing and exclusion of exon 7. Two recent papers show that the defect in splicing of exon 7 of SMN2 is specifically corrected by small synthetic effectors. These new and specific approaches have potential in the treatment of diseases caused by defective splicing.


Land surface phenology of Northeast China during 2000-2015: temporal changes and relationships with climate changes.
As an important crop growing area, Northeast China (NEC) plays a vital role in China's food security, which has been severely affected by climate change in recent years. Vegetation phenology in this region is sensitive to climate change, and currently, the relationship between the phenology of NEC and climate change remains unclear. In this study, we used a satellite-derived normalized difference vegetation index (NDVI) to obtain the temporal patterns of the land surface phenology in NEC from 2000 to 2015 and validated the results using ground phenology observations. We then explored the relationships among land surface phenology, temperature, precipitation, and sunshine hours for relevant periods. Our results showed that the NEC experienced great phenological changes in terms of spatial heterogeneity during 2000-2015. The spatial patterns of land surface phenology mainly changed with altitude and land cover type. In most regions of NEC, the start date of land surface phenology had advanced by approximately 1.0 days year-1, and the length of land surface phenology had been prolonged by approximately 1.0 days year-1 except for the needle-leaf and cropland areas, due to the warm conditions. We found that a distinct inter-annual variation in land surface phenology related to climate variables, even if some areas presented non-significant trends. Land surface phenology was coupled with climate variables and distinct responses at different combinations of temperature, precipitation, sunshine hours, altitude, and anthropogenic influence. These findings suggest that remote sensing and our phenology extracting methods hold great potential for helping to understand how land surface phenology is sensitive to global climate change.


Gram-scale synthesis of porphycenes through acid-catalyzed oxidative macrocyclizations of E/Z-mixed 5,6-diaryldipyrroethenes.
The gram-scale production of porphycene derivatives is reported. This has been achieved by acid-catalyzed ring closure of an E/Z-mixture of 5,6-diaryldipyrroethenes, resulting in the formation of meso-tetraarylporphycenes in yields of up to 80%. E/Z-isomerization of the 5,6-diaryldipyrroethenes under acidic conditions was key to proceed the effective macrocyclization.


Temporal dynamics of SARS-CoV-2 genome mutations that occurred in vivo on an aircraft.
We analyzed variations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome during a flight-related cluster outbreak of coronavirus disease 2019 (COVID-19) in Shenzhen, China, to explore the characteristics of SARS-CoV-2 transmission and intra-host single nucleotide variations (iSNVs) in a confined space. Thirty-three patients with COVID-19 were sampled, and 14 were resampled 3-31 days later. All 47 nasopharyngeal swabs were deep-sequenced. iSNVs and similarities in the consensus genome sequence were analyzed. Three SARS-CoV-2 variants of concern, Delta (n = 31), Beta (n = 1), and C.1.2 (n = 1), were detected among the 33 patients. The viral genome sequences from 30 Delta-positive patients had similar SNVs; 14 of these patients provided two successive samples. Overall, the 47 sequenced genomes contained 164 iSNVs. Of the 14 paired (successive) samples, the second samples (T2) contained more iSNVs (median: 3; 95% confidence interval [95% CI]: 2.77-10.22) than did the first samples (T1; median: 2; 95% CI: 1.63-3.74; Wilcoxon test, P = 0.021). 38 iSNVs were detected in T1 samples, and only seven were also detectable in T2 samples. Notably, T2 samples from two of the 14 paired samples had additional mutations than the T1 samples. The iSNVs of the SARS-CoV-2 genome exhibited rapid dynamic changes during a flight-related cluster outbreak event. Intra-host diversity increased gradually with time, and new site mutations occurred in vivo without a population transmission bottleneck. Therefore, we could not determine the generational relationship from the mutation site changes alone.


Association of Preoperative Physical Activity with Short- and Long-Term Outcomes in Patients Undergoing Palliative Resection for Metastatic Colorectal Cancer: An Inverse Probability of Treatment Weighting Analysis.
A lack of physical activity is a generally accepted risk factor for colorectal cancer. However, research on the effect of preoperative physical activity on postoperative and long-term outcomes is limited, especially in patients with stage IV colorectal cancer who underwent palliative surgery. Patients who underwent bowel resection for stage IV primary colorectal cancer between January 1995 and December 2016 were retrospectively enrolled. A total of 2185 patients were divided into two groups according to preoperative leisure-time weekly physical activity as assessed by metabolic equivalent of task (MET) values: MET < 12 (n = 1845) and MET ≥ 12 (n = 340). Inverse probability of treatment weighting (IPTW) was used to reduce imbalance and selection biases between the two groups. After the IPTW process, the MET < 12 group showed a higher postoperative morbidity rate (18.7% vs. 10.6%; p < 0.001) and mortality rate (2.4% vs. 0.6%; p < 0.001) than the MET ≥ 12 group. No significant difference was found in overall survival. Weekly preoperative leisure-time physical activity with MET ≥ 12 was associated with reduced short-term postoperative morbidity and mortality in patients undergoing palliative resection for metastatic colorectal cancer. However, no difference was detected in long-term survival.


Histomorphometric interpretation of bone biopsies for the evaluation of osteoporosis treatment.
Bone histomorphometry is a valuable tool in the evaluation of bone safety and the mechanism of action of drugs used in the treatment of osteoporosis. Recent studies in patients treated with anti-resorptive agents have highlighted technical issues, in particular, related to the calculation of dynamic indices of bone turnover using fluorochrome labelling. This review addresses the need for standardised approaches for overcoming these problems in order to enable valid comparison of the effects of different interventions on bone remodelling.


Anomalous lumbosacral nerve roots associated with spondylolisthesis.
Anomalies of the lumbosacral nerve roots, if unrecognized, may lead to injury of that nerve in operations on lumbar disks. Myelography rarely predicts the anomaly before operation. However, the presence of congenital skeletal defects of the lumbosacral joint should alert the surgeon to the possibility of anomalous nerve roots. Two cases of spondylolisthesis of the lumbosacral joint with with associated nerve root abnormalities are presented.


Differential stereoselectivity on metabolism of triphenylene by cytochromes P-450 in liver microsomes from 3-methylcholanthrene- and phenobarbital-treated rats.
Metabolism of triphenylene by liver microsomes from control, phenobarbital(PB)-treated rats and 3-methylcholanthrene(MC)-treated rats as well as by a purified system reconstituted with cytochrome P-450c in the absence or presence of purified microsomal epoxide hydrolase was examined. Control microsomes metabolized triphenylene at a rate of 1.2 nmol/nmol of cytochrome P-450/min. Treatment of rats with PB or MC resulted in a 40% reduction and a 3-fold enhancement in the rate of metabolism, respectively. Metabolites consisted of the trans-1,2-dihydrodiol as well as 1-hydroxytriphenylene, and to a lesser extent 2-hydroxytriphenylene. The (-)-1R,2R-enantiomer of the dihydrodiol predominated (70 to 92%) under all incubation conditions. Incubation of racemic triphenylene 1,2-oxide with microsomal epoxide hydrolase produced dihydrodiol which was highly enriched (80%) in the (-)-1R,2R-enantiomer. Experiments with 18O-enriched water showed that attack of water was exclusively at the allylic 2-position of the arene oxide, indicating that the 1R,2S-enantiomer of the oxide was preferentially hydrated by epoxide hydrolase. Thiol trapping experiments indicated that liver microsomes from MC-treated rats produced almost exclusively (greater than 90%) the 1R,2S-enantiomer of triphenylene 1,2-oxide whereas liver microsomes from PB-treated rats formed racemic oxide. The optically active oxide has a half-life for racemization of only approximately 20 s under the incubation conditions. This study may represent the first attempt to address stereochemical consequences of a rapidly racemizing intermediary metabolite.


3D facial morphometry in children with oral clefts.
The aim of this study was to characterize three-dimensional (3D) facial morphological variation of children with cleft lip and palate compared to an age- and sex-matched control group. Cross-sectional, case-controlled observational morphometric study. Subjects were 103 children aged 8 to 12 years old with cleft lip and palate-40 with unilateral cleft lip and palate, 23 with unilateral cleft lip and alveolus, 19 with bilateral cleft lip and palate, and 21 with isolated cleft palate (ICP)-and 80 sex- and age-matched control subjects. Subjects were scanned using 3D stereophotogrammetry. Thirty-nine landmarks were digitized for each scan, and the x, y, and z coordinates for each landmark were extracted. Linear and angular facial measurements were computed. Multivariate analysis of covariance was undertaken to detect significant differences in facial morphometry between the groups. Statistically significant differences (P < .05) were observed between all groups. The greatest morphometrical impact was seen in those groups where both lip and palate were affected and repaired; the group with ICP was the most similar to the control subjects. Significant differences were seen in 3D soft-tissue measurements, mainly in the nasolabial region, between the cleft groups where the lip is affected and the ICP and control groups.


Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAFV600E dual inhibitors.
Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRAFV600E and EGFR are attractive targets for many diseases treatments and have been studied extensively. In keeping with our interest in developing anticancer targeting EGFR and BRAFV600E, a novel series of 2,3-dihydropyrazino[1,2-a]indole-1,4-dione has been rationally designed, synthesized and evaluated for their antiproliferative activity against a panel of four human cancer cell lines. Compounds 20-23, 28-31, and 33 showed promising antiproliferative activities. These compounds were further tested for their inhibitory potencies against EGFR and BRAFV600E kinases with erlotinib as a reference drug. Compounds 23 and 33 exhibited equipotency to doxorubicin against the four cell lines and efficiently inhibited both EGFR (IC50 = 0.08 and 0.09 µM, respectively) and BRAFV600E (IC50 = 0.1 and 0.29 µM, respectively). In cell cycle study of MCF-7 cell line, compounds 23 and 33 induced apoptosis and exhibited cell cycle arrest in both Pre-G1 and G2/M phases. Molecular docking analyses revealed that the new compounds can fit snugly into the active sites of EGFR, and BRAFV600E kinases. Compound 23, 31 and 33 adopted similar binding orientations and interactions to those of erlotinib and vemurafenib.


Validation of Sentinel Lymph Node Biopsy Technique Using Dual Tracer Technique in Post Lumpectomy Early Breast Cancer Patients.
Sentinel lymph node biopsy (SLNB) is the gold standard for the evaluation of axilla in clinically node-negative early breast cancers. There is limited data on the role and efficacy of the same in the post lumpectomy scenario. This prospective interventional study was conducted over 1 year on 30 post lumpectomy pT1/2 cN0 patients. SLNB was performed by preoperative lymphoscintigram using technetium-labeled human serum albumin followed by intraoperative blue dye injection. Sentinel nodes were identified based on blue dye uptake and gamma probe and sent for intra operative frozen section. Completion axillary nodal dissection was performed in all cases. The primary end point was sentinel node identification rate and accuracy of nodal frozen section. Sentinel node identification rate was 86.7% (n = 26/30) for scintigraphy alone and 96.7% (n = 29/30) using combined method. Average sentinel nodal yield/patient was 3.6 (range 0-7). Maximum yield was seen for hot and blue nodes (1.86). Sensitivity (n = 9/9) and specificity (n = 19/19) of frozen section were 100% with a false negative rate of 0% (0/19). Demographic factors such as age, body mass index, laterality, quadrant, biology, grade, and pathological T stage had no impact on the identification rate. Sentinel lymph node using dual tracer has a high identification rate and a low false negative rate post lumpectomy. Age, body mass index, laterality, quadrant, grade, biology, and pathological T size had no impact on the identification rate.


Bioassay for homogeneous parasporal crystal of Bacillus thuringiensis using the tobacco hornworm, Manduca sexta.
A method for determining the toxicity of Bacillus thuringiensis subsp. kurstaki parasporal crystal to the tabocco hornworm, Manduca sexta, is described. The use of both mortality and weight loss data have provided a highly sensitive and reproducible bioassay that can be used to compare relative toxicities of crystals from other subspecies as well as toxic components contained therein.


Endogenous retrovirus expression in stimulated murine lymphocytes. Identification of a new locus controlling mitogen induction of a defective virus.
Germ line DNA from all strains of mice contains numerous endogenous retroviruses. One of these viruses, a virus with xenotropic host range is induced from lymphocytes of most strains by treatment with B cell mitogens. Virus induction is amplified by 5-bromo-2'-deoxyuridine (BrdU) treatment. We report here studies of the genetic control of retrovirus induction from lymphocytes in crosses between BALB/cTif mice and noninducible 129/Rrj mice. We identify a novel locus, Bdv-1, which controls the expression of a reverse transcriptase-positive, defective retrovirus in BALB/cTif lymphocytes. In addition, we confirm previous reports that xenotropic virus is controlled by a locus, Bxv-1, mapping to chromosome 1. The two loci are nonlinked and respond differently to inducing stimuli. Bxv-1 is induced mainly by BrdU and only marginally by mitogen; in contrast, Bdv-1 is induced by mitogen and BrdU has little effect. The induction of these two loci is discussed with respect to B cell differentiation.


Detection of Intact Transcription Factors in Human Neutrophils.
The crucial contribution of neutrophils to innate immunity extends well beyond their traditional role as professional phagocytes. Indeed, it is now well established that neutrophils generate a plethora of inflammatory cytokines and chemokines that are profoundly involved in the onset and evolution of the inflammatory reaction. Several recent studies have shown that neutrophils can represent an important source of inflammatory cytokines in pathophysiological settings. The inflammatory and immunomodulatory cytokines produced by neutrophils are generally encoded by immediate-early response genes, which in turn depend on the activation of transcription factors such as those belonging to the nuclear factor κB (NF-κB) and signal transducers and activators of transcription (STAT) families. We have shown in the past that the expression of such factors is induced in neutrophils stimulated by physiological agonists. However, the detection of intact (i.e., undegraded) transcription factors in neutrophils requires special precautions and a specially designed protocol, due to the huge amounts of endogenous proteases present in these cells. This protocol is the focus of this chapter.


The spine and spinal cord during neurosurgical operations: real-time ultrasonography.
Intraoperative ultrasound scanning of the spinal cord and spine was performed during 36 operations in 35 patients. The technique allows neurosurgeons to evaluate an operative procedure during the operation. Effectiveness of shunt placement in syringomyelia can be detected and the completeness of tumor or disk removal can be determined. Precise locations for biopsy of intramedullary lesions can be made. Periodic motion of the spinal cord at the cardiac rate was also detected. This motion was usually due to transmitted pulsations from the anterior spinal artery and appeared to be most pronounced when the artery was compressed between a mass and the spinal cord. This finding refutes the commonly held idea that spinal cord motion implies that the cord is free within the thecal sac.


Efficacy and safety of rivaroxaban in extreme elderly patients with atrial fibrillation: Analysis of the Shikoku Rivaroxaban Registry Trial (SRRT).
The Shikoku Rivaroxaban Registry Trial (SRRT) is a retrospective survey of the use of rivaroxaban for stroke prevention in elderly patients in Shikoku, Japan. The SRRT enrolled 1339 patients from 8 hospitals. Patients were divided into two groups according to their age, the extreme elderly group (453 patients aged ≧80 years) and the control group (886 patients aged <80 years). In the extreme elderly group, 41.5% of the patients had low body weight (<50kg) and 65.1% had abnormal renal function (creatinine clearance <50ml/min). The mean CHADS2, CHA2DS2-VASc, and HAS BLED scores were 2.7, 4.4, and 2.3, respectively. There were 333 (73.5%) patients who met the dosing criteria, and of these patients, 81.2% received rivaroxaban 10mg daily. Thromboembolic events occurred in 4 patients (0.94%/person year) and intracranial hemorrhage occurred in 4 patients (0.89%/person year). The incidence of these events was not significantly different from the control group. In addition, all patients with cerebral infarction had been treated with a smaller dose of rivaroxaban than recommended by the dosing criteria, suggesting that dosing criteria should be adhered to. These results suggest that rivaroxaban is effective and safe in extreme elderly patients with atrial fibrillation.


Somatic gene mutations in vivo as indicated by the 6-thioguanine-resistant T-lymphocytes in human blood.
The clonal and the autoradiographic assays for 6-thioguanine-resistant (TGr) T-lymphocytes (T-Lys) in human blood are reviewed. Studies of TGr colonies recovered from clonal assays show that the mutant T-Lys (i) are either helper (T4) or suppressor (T8) cells, (ii) possess stable TGr phenotypes, (iii) are deficient in hypoxanthine guanine phosphoribosyltransferase (HPRT), and (iv) have structural alterations in the hprt gene. TGr T-Ly mutant frequencies (Mfs) determined by clonal assays are of the order of 10(-6)-10(-5) for normal adults. Autoradiographically determined variant frequencies (Vfs) are also in this range for normal adults when lymphocytes are cryopreserved before study to remove 'phenocopies'. Cancer exposed to potentially mutagenic treatments have elevated TGr T-Ly Vfs. Comparative clonal and autoradiographic assays of the same blood samples give generally similar results when allowances are made for potential sources of error in each assay. The TGr T-Ly system is presented for human specific-locus mutagenicity monitoring.


Effects of N-alcohols on potassium conductance in squid giant axons.
The effect of bath application of several short chain N-alcohols on voltage-dependent potassium conductance has been studied in intact giant axons of Loligo forbesi under voltage-clamp conditions. All tested alcohols (methanol, ethanol, propanol, butanol, heptanol and octanol) were found to depress potassium conductance only at concentrations much larger than those necessary to reduce sodium conductance. The efficacy of the different molecules was correlated with the carbon-chain length. In all cases the effects were found to be at least partly reversible. Low concentrations of propanol (100 mM) or heptanol (1 mM) were found to increase potassium conductance whereas higher concentrations had the usual depressing effect. The two alcohols were found to induce a slow inactivation of the potassium conductance. A detailed analysis of the time course of the turning-on of the potassium current for various pulse potentials in the presence of TTX revealed that, for membrane potential values more positive than -20 mV, the time constant of activation was reduced in the presence of propanol or heptanol. The delay which separates the change in potential and the turning-on of the potassium current, which was systematically analysed for different pulse and prepulse potential values, was increased by the two alcohols, the curve relating this delay to prepulse potential being shifted towards larger (positive) delays. This high degree of complexity in the effects on potassium conductance suggests that the alcohol molecules modify several more or less independent mechanisms associated with the turning-on of the potassium current.


Role of HER2 in Prognosis of Salivary Duct Carcinoma: A Systematic Review and Meta-Analysis.
Salivary duct carcinoma (SDC) is a rare, aggressive malignancy with a poor prognosis. These tumors frequently stain positive for HER2/ErbB2, but data on the prognostic significance of HER2 status in SDC are mixed. We sought to determine whether HER2 status affects survival outcomes in SDC. PubMed, Embase, and Web of Science databases were searched from inception to October 2020. Eligibility was restricted to studies reporting HER2/ErbB2 overexpression in histologically confirmed de novo SDC or SDC ex pleomorphic adenoma, with corresponding overall (OS) and disease-free (DFS) survival measures. Separate multivariable and univariable meta-analyses were performed using random-effects models. Statistical heterogeneity was estimated by Cochran's Q and I2 tests. Funnel plots were generated and Egger's test was used to assess for publication bias. The risk of bias was assessed with the Newcastle-Ottawa Scale. Of 183 unique citations, 14 studies of 663 patients were included. Most included studies determined HER2 status according to ASCO/CAP guidelines. The univariable meta-analysis did not reveal an effect between HER2 status and OS (HR 1.09, 95% CI 0.84-1.42). In the multivariable analysis, HER2 positivity was associated with a HR of 1.49 for OS (95% CI 0.96-2.30). Fewer studies reported data for DFS than OS, with no relationship between HER2 status and DFS found on multivariable or univariable meta-analyses. In patients with salivary duct carcinoma, HER2 positivity was not found to be associated with worse overall survival. This information may be useful when counseling patients and considering treatment options. Laryngoscope, 133:476-484, 2023.


Remote ischemic perconditioning protects the liver from ischemia-reperfusion injury.
Ischemia-reperfusion (IR)-induced injury is a frequent sequel of major liver resections. IR injury after prolonged surgical interventions could be the source of increased risk of postoperative morbidity and mortality. Hepatoprotective effects of this new feasible method called remote ischemic perconditioning (RIPER) were investigated in our rat model of IR injury. Male Wistar rats underwent ischemia for 60 min on two-thirds of their livers, followed by 1, 6, and 24 h of reperfusion (n = 72, 8 per group). During liver ischemia, but before reperfusion, rats in the treated groups received four cycles of brief infrarenal aortic clamping as perconditioning. Liver microcirculation was monitored by laser Doppler flowmeter parallel with mean arterial pressure measurements. Liver tissue injury and redox homeostasis were investigated. Furthermore, serum tumor necrosis factor alpha (TNF-α) levels were measured. In the RIPER group, compared with the IR group, serum transaminase levels were significantly lower after each reperfusion period (alanine aminotransferase: 1 h, P < 0.001; 6 h, P < 0.05; 24 h, P < 0.01 and aspartate aminotransferase: 1 h, P < 0.001; 6 h, P < 0.05; 24 h, P < 0.05). Reperfusion microcirculatory parameters significantly improved in the perconditioned group compared with those in the IR group (reperfusion area: P = 0.005; maximal plateau: P = 0.0002). Regarding TNF-α levels, significant differences were detected between the two IR injured groups (RIPER versus IR: 1 h, 34.3 ± 12.8 pg/mL versus 205.7 ± 60.9 pg/mL, P < 0.001; 6 h, 60.6 ± 11.7 pg/mL versus 110.4 ± 21.6 pg/mL, P < 0.05). Results of the histologic assessment and redox state measurements also showed favorable changes. Our team firstly reported the protective effects of RIPER on liver morphology, redox homeostasis, and microcirculation and proposed the changes of TNF-α expression.


Loss of proprioception or motor control is not related to functional ankle instability: an observational study.
Is loss of proprioception or loss of motor control related to functional ankle instability? Are proprioception and motor control related? Is there any difference in proprioception or motor control between ankles with different severity of functional ankle instability? Cross-sectional, observational study. Twenty people aged between 18 and 40 years with functional ankle instability associated with a history of ankle sprain more than one month prior. Twenty age-matched controls with no functional ankle instability or history of ankle sprain. Functional ankle instability was classified using the Cumberland Ankle Instability Tool, proprioception at the ankle was measured as movement detection at three velocities, and motor control was measured using the Landing Test and the Hopping Test. There was little if any relation between proprioception (r = 0.14 to 0.03, 95% CI 0.40 to 0.25) or motor control (r = 0.08 to 0.07, 95% CI 0.35 to 0.20) and functional ankle instability. There was also little if any relation between proprioception and motor control except for a low correlation between movement detection at 0.1 deg/s and the Landing Test (r = 0.35, 95% CI 0.09 to 0.58). Furthermore, there was no difference between the ankles with or without functional ankle instability in proprioception or motor control. By greater than one month after ankle sprain, loss of proprioception does not make a major contribution to functional ankle instability.


Traumatic inferior shoulder dislocation: a review of management and outcome.
Traumatic inferior shoulder dislocation (ISD) is rare, estimated to occur in 0.5% of all shoulder dislocations. We describe the demographics, natural history and outcome of this injury. The aim of the study is to provide a summary of the demographics, clinical presentation, management and outcome of patients who suffer ISD METHODS: We conducted a systematic review of the English language literature on ISD using PubMed, Medline, CINHAL, Cochrane Database and Evidence-Based Medicine Reviews. Articles were examined independently by two of the authors and data were extracted using a standard form. Descriptive statistics were performed. 199 patients were identified, from 101 articles. Mean age was 44 years (range 13-94 years). All cases were caused by trauma, with falls accounting for 44% of all cases. There were three reported cases (2%) of open dislocations and 29 cases (15%) of bilateral ISD. Proximal humerus and scapular fractures were reported in 39 and 8% of patients, respectively. Neurological injury after dislocation was noted in 58 patients (29%). Vascular injury was noted in 20 patients (10%), which included axillary arterial injury in 19 patients and an upper limb deep vein thrombosis in one patient. Follow-up data were available for 107 patients (54%), with an average duration of 2.7 years (1 week-32 years). Avascular necrosis (AVN) was noted between 8 weeks and 2 years after initial injury in three patients (1.5%). Clinical and radiographic assessment of ISD is key to diagnosis and successful reduction. Patients can be treated with shoulder immobilisation for 2-3 weeks. In the setting of ongoing pain or instability, further imaging should be performed. The outcome of ISD is generally favourable.


Risk of Severe Influenza Among Adults With Chronic Medical Conditions.
Severe influenza illness is presumed more common in adults with chronic medical conditions (CMCs), but evidence is sparse and often combined into broad CMC categories. Residents (aged 18-80 years) of Central and South Auckland hospitalized for World Health Organization-defined severe acute respiratory illness (SARI) (2012-2015) underwent influenza virus polymerase chain reaction testing. The CMC statuses for Auckland residents were modeled using hospitalization International Classification of Diseases, Tenth Revision codes, pharmaceutical claims, and laboratory results. Population-level influenza rates in adults with congestive heart failure (CHF), coronary artery disease (CAD), cerebrovascular accidents (CVA), chronic obstructive pulmonary disease (COPD), asthma, diabetes mellitus (DM), and end-stage renal disease (ESRD) were calculated by Poisson regression stratified by age and adjusted for ethnicity. Among 891 276 adults, 2435 influenza-associated SARI hospitalizations occurred. Rates were significantly higher in those with CMCs compared with those without the respective CMC, except for older adults with DM or those aged <65 years with CVA. The largest effects occurred with CHF (incidence rate ratio [IRR] range, 4.84-13.4 across age strata), ESRD (IRR range, 3.30-9.02), CAD (IRR range, 2.77-10.7), and COPD (IRR range, 5.89-8.78) and tapered with age. Our findings support the increased risk of severe, laboratory-confirmed influenza disease among adults with specific CMCs compared with those without these conditions.


Microencapsulation of stem cells to study cellular interactions.
Microencapsulation is a technique used in both controlled delivery of materials over time as well as preservation of these materials while delivery is occurring. The range of materials able to be encapsulated is variable, from drugs to living cells. The latter is described here. Electrospray microencapsulation applies a high-voltage field, through which a polymeric material is extruded. A gelling bath, comprising a cross-linking material, is used to create a stable hydrogel containing secondary substances intended for delivery. Control of extrusion parameters, such as flow rate and voltage, allows for specification of diameter and pore sizes of the microcapsules.


Pedoenvironmental indicators of soil in Western Amazonia, Brazil.
This study aimed to ascertain what soil attributes may be an indicator of natural and anthropic pedogenic changes in top grassland (TG), low grassland (LG), ecotone zone (EZ), and forest (F) in Western Amazonia. Twenty samples of the diagnostic horizons were collected from the studied pedoenvironments: TG (A 0.0-14 and Bi 0.30-0.66 m); LG (A 0.0-0.15 and Cg1 0.27-0.80 m); EZ (A 0.0-0.15 and Bi 0.32-0.50 m); and forest (F) (A1 0.0-0.15 and Bt1 0.67-0.10 m). Sand, silt, clay, particle density (PD),soil bulk density (BD),saturated soil hydraulic conductivity, calcium (Ca), magnesium (Mg), exchangeable aluminum (Al3+), potassium (K), sodium (Na), phosphorus (P), pH in water and KCl, and organic matter (OM) contents were calculated and submitted to variance analysis. LG is more related to OM and clay than SHC value. These same attributes characterized TG. EZ is highlighted by its higher values and relationship with Al and K. It was concluded that for TG, LG, EZ, and F top soil layers, 28% of natural and anthropic changes can be identified based on sand, clay, pH in KCl, and OM data; on the other hand, subsurface 23% of determinations can be attributed to pH in H2O, Al, Na, and sand.


Fatigue estimation using voice analysis.
In the present article, we present a means to remotely and transparently estimate an individual's level of fatigue by quantifying changes in his or her voice characteristics. Using Voice analysis to estimate fatigue is unique from established cognitive measures in a number of ways: (1) speaking is a natural activity requiring no initial training or learning curve, (2) voice recording is a unobtrusive operation allowing the speakers to go about their normal work activities, (3) using telecommunication infrastructure (radio, telephone, etc.) a diffuse set of remote populations can be monitored at a central location, and (4) often, previously recorded voice data are available for post hoc analysis. By quantifying changes in the mathematical coefficients that describe the human speech production process, we were able to demonstrate that for speech sounds requiring a large average air flow, a speaker's voice changes in synchrony with both direct measures of fatigue and with changes predicted by the length of time awake.


[Carotid body tumors and their operative problems (author's transl)].
Exstirpation of a neck tumor as an outpatient procedure became troublesome (bleeding). The surgeon had not realised the nature of the tumor.


Occupational therapy for patients with acute lung injury: factors associated with time to first intervention in the intensive care unit.
Very early occupational therapy intervention in the intensive care unit (ICU) improves patients' physical recovery. We evaluated the association of patient, ICU, and hospital factors with time to first occupational therapy intervention in ICU patients with acute lung injury (ALI). We conducted a prospective cohort study of 514 consecutive patients with ALI from 11 ICUs in three hospitals in Baltimore, MD. Only 30% of patients ever received occupational therapy during their ICU stay. Worse organ failure, continuous hemodialysis, and uninterrupted continuous infusion of sedation were independently associated with delayed occupational therapy initiation, and hospital study site and admission to a trauma ICU were independently associated with earlier occupational therapy. Severity of illness and ICU practices for sedation administration were associated with delayed occupational therapy. Both hospital study site and type of ICU were independently associated with timing of occupational therapy, indicating modifiable environmental factors for promoting early occupational therapy in the ICU.


Time-lapse monitoring: An adjunct tool to select embryos for preimplantation genetic testing.
The goal for the present study was to investigate the effect of aneuploidy on embryo morphokinetics events in a time-lapse imaging (TLI) system incubator. This retrospective cohort study was performed in a private university-affiliated in vitro fertilization center, between 2019 March and December 2020. Kinetic data were analyzed in 935 embryos, derived from 316 patients undergoing intracytoplasmic sperm injection cycle with preimplantation genetic testing (PGT) for aneuploidy, individually cultured in a TLI incubator until Day 5 of development. Timing of morphokinetic variables, the incidences of multinucleation, and Known Implantation Data Score (KIDScore)-Day 5 were compared between euploid (n = 352) and aneuploid embryos (n = 583). Aneuploid embryos showed significantly longer timing to complete specific morphokinetic parameters compared to euploidy embryos. Euploidy embryos also showed a significantly higher KIDScore when compared with the aneuploidy ones. Our evidence suggests that TLI monitoring may be an adjunct approach to select embryos for PGT; however, cautious investigation is still needed.


Acinic cell carcinoma in Northern Ireland: a 10-year review.
12 cases of acinic cell carcinoma diagnosed in Northern Ireland from 1942 to 1982 on which there was at least 10 years' follow-up were reviewed, by pooling cases from all regional pathology laboratories. Clinical findings at presentation were established from case notes, together with details of eventual clinical outcome. Sections were examined to determine tumour size, morphological pattern and cytological constitution, the presence or absence of cytological atypia, mitotic activity, lymphocytic and desmoplastic responses, and to assess for infiltrative margins and adequacy of excision. The tumours arose in 8 females and 4 males, aged 22 to 86 years at presentation. Eleven tumours were in the parotid, one in the soft palate. Two patients suffered local recurrence, both more than 7 years after diagnosis. Five patients had regional lymph node metastasis, four at presentation. No patient suffered haematogenous metastasis or died of tumour. Of the features examined, incomplete excision increased the risk of local recurrence. While numbers are small, the acinic cell carcinoma in Northern Ireland is an unpredictable low-grade malignant tumour which is capable of recurrence and metastasis. Adequate excision at presentation appears to be the most appropriate therapy.


Carnitine deficiency with cardiomyopathy presenting as neonatal hydrops: successful response to carnitine therapy.
A small-for-date infant presented at birth with severe non-immune hydrops, cardiac failure, metabolic acidosis and hypoglycaemia. Ultrasonography disclosed a cardiomyopathy. Initial therapy consisting of artificial ventilation, inotropes and diuretics resulted in partial disappearance of oedema without significant improvement in cardiac function. Episodes of hypoglycaemia recurred despite continuous glucose infusions. Total serum carnitine from cord blood was 1.65 nmoles/ml and was undetectable on day 20. Oral DL-carnitine supplements resulted in normoglycaemia, dramatic improvement in cardiac function and restoration of serum carnitine levels to normal values. The infant was thereafter maintained on carnitine therapy. Follow-up over 1 year showed moderate growth retardation and normal developmental milestones. In order to account for such a severe neonatal presentation of carnitine deficiency, a combination of defective pre- and postnatal carnitine supply with an inborn error of carnitine handling is considered. The present case illustrates the need for evaluation of carnitine status in fetuses and neonates presenting with hydrops associated with cardiac failure.


Retracted: Efficacy Investigation of TACE Combined with Lenvatinib and Sintilimab in Intermediate-Stage Hepatocellular Carcinoma.
[This retracts the article DOI: 10.1155/2022/6957580.].


Performance of different colorectal cancer screening strategies: a long-term passive follow-up population-based screening program in Beijing, China.
We aimed to assess the performance of the risk assessment questionnaire and fecal immunochemical test (FIT) in a population-based colorectal cancer (CRC) screening program to provide timely evidence for tailored screening strategies in China. This analysis was conducted using data from Beijing Cancer Screening Prospective Cohort Study (BCSPCS). A risk assessment questionnaire and FIT were selected as the primary screening methods, and participants with any positive results were referred to undergo a diagnostic colonoscopy. From 2015 to 2020, 148,636 Beijing residents aged 40-69 years were invited from designated communities, with 147,807 finishing the risk assessment questionnaire and 115,606 (78.2%) completing the FIT. Among the 42,969 (29.1%) high-risk CRC participants, 23,824 (55.4%) underwent colonoscopy. One year after enrollment, all subjects were linked to the Beijing Cancer Registry (BCR) database and 241 cases of CRC were confirmed. The CRC incidence rate was 58.2/100,000 for the low-risk arm and 418.9/100,000 for the high-risk arm. For participants who underwent colonoscopy, 91 CRC cases were detected, with a detection rate of 91.9% and 63.7% of them were early-stage cases. Furthermore, the sensitivities of utilizing the risk assessment questionnaire alone, FIT alone, combined risk assessment questionnaire and FIT were 75.7%, 50.1%, and 95.1%, and the specificities were 75.3%, 87.3%, and 70.7%, respectively. The Beijing CRC screening program can effectively detect early-onset CRC; however, the compliance with colonoscopy still needs to be improved.


Role of Natural Products in Developing Novel Anticancer Agents: A Perspective.
Cancer is a heterogeneous disease and is one of the significant health issues, especially in public health systems around the world. Natural products and their structural derivatives with outstanding chemical diversity have been investigated for potential anti-cancer agents. Many natural products revealing potential anti-cancer properties such as cytotoxicity, proliferation inhibition, induced apoptosis, retard metastasis, suppressing angiogenesis, and improved chemotherapy have been isolated from various plants and herbs. Several promising lead molecules have been identified recently; a few are in the clinical trial stage. This short communication summarises the role of natural products and their analogs in anti-cancer drug developments, especially plant, marine and microbial-based anti-cancer agents.


A microtiter plate assay for protein kinase C.
We report the development of a microtiter plate assay for protein kinase C. Reaction components and enzyme samples (protein kinase C purified by phosphatidylserine/cholesterol affinity or DEAE-Sephacel ion-exchange chromatography) were added to wells of a 96-well microtiter plate. The assay was started by the addition of [gamma-32P]ATP with a repeating pipet. After a 3-min incubation at 30 degrees C the wells were sampled six at a time with a 12-channel pipet and spotted onto phosphocellulose filter paper rectangles which were washed with tap water and acetone and counted for radioactivity. The microtiter plate method was more rapid than but gave results similar to those of a standard assay performed in plastic test tubes individually incubated in a 30 degrees C water bath. The microtiter plate procedure gave an intraassay (within one plate) variation of less than 9% and an interassay (between plates) variation of less than 5%. It was linear with time of incubation for 20 min and with amount of enzyme. This method can be used to expedite the assaying of column chromatography fractions for protein kinase C (and other kinase) activity.


The involvement of protein TNFSF18 in promoting p-STAT1 phosphorylation to induce coronary microcirculation disturbance in atherosclerotic mouse model.
The inflammation of coronary endothelium was critically involved in the pathogenesis of atherosclerosis. The purpose of the study was to reveal the roles of TNFSF18 in promoting p-STAT1 phosphorylation to induce disturbance of coronary microcirculation in atherosclerotic mouse model. This study was dividedly transfected TNFSF18 inhibitor, small interfering-TNFSF18 plasmid (si-TNFSF18) and a blank vector plasmid into atherosclerotic mouse model. Results showed that the coronary vascular lumen was narrowed and crescent plaques were adhered to the coronary vessel wall in atherosclerotic mouse model. However, the accumulation of microthrombus in coronary artery and vascular crescent plaques were evidently reduced with the antagonistic TNFSF18. Besides, the inflammatory cytokines TNF-α, TNF-β and IL-1β were abundant in mouse model, and TNFSF18 inhibition decreased the secretion of cytokines. Meanwhile, the amount of Th1 cells were also reduced after transfected with TNFSF18 inhibitor and si-TNFSF18 plasmid compared with the mouse model transfected with blank vector plasmid. Moreover, the protein TNFSF18 was highly expressed in the cytoplasm and p-STAT1 was located in cell nucleus of the mouse model coronary vascular tissues. Consistently, the proteins TNFSF18, p-STAT1, VCAM1, ICAM1, ITGAD and ITGB3 were significantly expressed in atherosclerotic mouse model, while antagonistic TNFSF18, conversely, decreased the proteins' expression. Taken together, this study indicated that the coronary endothelial inflammation triggered TNFSF18 expression, which promoted p-STAT1 phosphorylation to activate the proteins VCAM1, ICAM1, ITGAD and ITGB3, thus exacerbating coronary microcirculation disorder in atherosclerotic mouse model.


An La-related protein controls cell cycle arrest by nuclear retrograde transport of tRNAs during diapause formation in Artemia.
In eukaryotes, tRNA trafficking between the nucleus and cytoplasm is a complex process connected with cell cycle regulation. Such trafficking is therefore of fundamental importance in cell biology, and disruption of this process has grave consequences for cell viability and survival. To cope with harsh habitats, Artemia has evolved a special reproductive mode to release encysted embryos in which cell division can be maintained in a dormancy state for a long period. Using Artemia as a peculiar model of the cell cycle, an La-related protein from Artemia, named Ar-Larp, was found to bind to tRNA and accumulate in the nucleus, leading to cell cycle arrest and controlling the onset of diapause formation in Artemia. Furthermore, exogenous gene expression of Ar-Larp could induce cell cycle arrest in cancer cells and suppress tumor growth in a xenograft mouse model, similar to the results obtained in diapause embryos of Artemia. Our study of tRNA trafficking indicated that Ar-Larp controls cell cycle arrest by binding to tRNAs and influencing their retrograde movement from the cytoplasm to the nucleus, which is connected to pathways involved in cell cycle checkpoints. These findings in Artemia offer new insights into the mechanism underlying cell cycle arrest regulation, as well as providing a potentially novel approach to study tRNA retrograde movement from the cytoplasm to the nucleus.


Temporal trends of halogenated and organophosphate contaminants in striped dolphins from the Mediterranean Sea.
PBDEs, HBCD, novel DBDPE, PBEB and HBB, dechloranes, OPFRs and natural MeO-PBDEs were monitored in muscle of striped dolphins (Stenella coeruleoalba) from the Mediterranean Sea collected in three time periods (1990, 2004-2009 and 2014-2018). PBDEs levels decreased about 60% in under three decades, from 5067 ± 2210 to 2068 ± 2642ngg-1 lw, evidencing the success of their ban. Most PBDEs were found in all the samples, with BDE-47, -99, -154, -100 and -153 as the main contributors. Found in 71.4% of the samples, α-HBCD was stable through time and usually <LOQ. DBDPE concentrations decreased by 89% from 1990 to 2004-2009 and have remained stable since. HBB occurred rarely and decreased by 94% to a current few ngg-1 lw. Dec 602 was the main dechlorane with stable concentrations around 1200 ngg-1 lw, but a declining trend might have started in the last years. OPFRs concentrations were stable and showed the highest concentrations of all FRs in 2014-2018: 6253 ± 11,293ngg-1 lw. TBOEP and TNBP contributed to most of the OPFR concentration, the former with decreasing levels by 96%. MeO-PBDEs showed mean concentrations between 600 and 700ngg-1 lw in all periods. Non-targeted analysis allowed the identification and semi-quantification of additional chlorinated pollutants, such as polychlorinated terphenyls (PCTs) (levels decreasing by 81% to a current 770 ngg-1 lw mean) and polychlorinated diphenyl ethers (PCDEs) (decreasing by 83% to a current 3200ngg-1 lw) in Mediterranean marine mammals for the first time.


Prevalence of hepatitis C virus infection in asymptomatic anti-HIV1 negative pregnant women and their children.
The prevalence of hepatitis C virus (HCV) infection was studied prospectively in pregnant women in France and their children by detection of anti-HCV with second-generation ELISA (ELISA2). In ELISA2-positive women, anti-HCV was detected with second- and third-generation RIBA (RIBA2 and RIBA3) and serum HCV RNA was detected with PCR. Among 670 women, anti-HIV1-negative, 26 (3.9%) were positive with ELISA2. RIBA2 was positive in 13 and HCV RNA was found in 10. Ten ELISA2-positive women had a further evaluation with assessment of HCV infection in their children. Among the 10 children born to the index pregnancy, only one was positive with ELISA2 and RIBA2 but negative with RIBA3 and PCR; the nine other children were ELISA2, RIBA2, RIBA3, and PCR negative. All 26 siblings (2-16 years old), of whom 14 were born to PCR-positive mothers, were ELISA2 and RIBA2 negative. We conclude that among anti-HIV1-negative pregnant women with normal serum ALT levels, the prevalence of HCV infection is relatively high but the risk for mother-to-infant transmission of HCV seems to be low.


A randomized controlled trial to evaluate the effectiveness of a novel mouth rinse in patients with gingivitis.
This single-center, randomized controlled trial aimed to determine the effectiveness of a novel, biofilm-disrupting, mouth rinse that combines Cetylpyridinium chloride (CPC) and essential oils in preventing re-accumulation of supragingival plaque and supragingival microbiome in patients with gingivitis after dental prophylaxis. One hundred eighteen participants were randomly assigned in a 1:1 ratio to receive twice-daily test mouth rinse (59) or carrier rinse control (59) for 12 weeks after dental prophylaxis. In a per-protocol analysis that included patients who completed the intervention, the treatment group (39) had significantly lower supragingival plaque scores at 6 and 12 weeks compared to the control group (41; p = 0.022). Both groups showed similar improvement in gingivitis score, but neither group had improvement in bleeding score or probing depth. Thirty-eight (29%) patients did not complete the study due to loss of follow-up (17) or early discontinuation of the assigned intervention (21). Microbiome sequencing showed that the treatment rinse significantly depleted abundant and prevalent members of the supragingival plaque microbiome consortium. Among patients with gingivitis, the novel mouth rinse significantly reduced re-accumulation of supragingival plaque following dental prophylaxis by depleting supragingival plaque microbiome. However, long-term adherence to the rinse may be limited by adverse effects ( ClinicalTrials.gov number, NCT03154021).


Effects of prostaglandins E1 and E2 on activity in laryngeal and pharyngeal afferent fibers.
Prostaglandins (PG) E1 and E2 were applied topically to the receptive fields of feline laryngeal and pharyngeal sensory receptors, while action potentials were recorded from single - or few-fiber preparations of the superior laryngeal nerve. When initially dissolved in ethanol, PGs stimulated these sensory receptors. If ethanol was not used as a solvent for the PGs they did not stimulate the sensory receptors. Similarly, local application of dilute (0.025%, v/v) solutions of ethanol alone excited the receptors, whereas phosphate buffer alone did not. Thus PGE1 and PGE2 do not themselves stimulate sensory receptors in the larynx and pharynx. These findings suggest that irritant properties of PGEs on upper airways are attributable to the ethanol used as a solvent.


Laser technology in orthopedics: preliminary study on low power laser therapy to improve the bone-biomaterial interface.
Low Power Laser (LPL) seems to enhance the healing of bone defects and fractures. The effect of LPL in other orthopedic areas such as osteointegration of implanted prosthetic bone devices is still unclear. In the present study, 12 rabbits were used to evaluate whether Ga-Al-As (780 nm) LPL stimulation has positive effects on osteointegration. Hydroxyapatite (HA) cylindrical nails were drilled into both distal femurs of rabbits. From postoperative day 1 and for 5 consecutive days, the left femura of all rabbits were given LPL treatment (Laser Group-LG) with the following parameters: 300 Joule/cm2, 1 Watt, 300 Hertz, pulsating emission, 10 minutes. The right femura were sham-treated (Control Group-CG). At 4 and 8 weeks after implantation, histologic and histomorphometric investigations evaluated bone-biomaterial-contact. Histomorphometry showed a higher degree of osteointegration at the HA-bone interface in the LG Group at 4 (p < 0.0005) and 8 weeks (p < 0.001). These preliminary positive results seem to support the hypothesis that LPL treatment can be considered a good tool to enhance the bone-implant interface in orthopedic surgery.


Fos expression in the vestibular brainstem: what one marker can tell us about the network.
Fos inducible transcription factor expression in rodent brains (rats and gerbils) during manipulations of vestibular input is reviewed. Stimuli included centripetal hypergravity, unilateral labyrinth lesion or semicircular canal plugging, rotational axis cross-coupling (Coriolis forces), high and low rotational vestibulo-ocular reflex gain adaptation, translabyrinth galvanic stimulation, pharmacological manipulation, and combinations thereof. Each type of stimulation elicited unique but partially redundant response patterns in the vestibulo-olivo-cerebellar (VOC) network that reflect the origin and interaction of the labyrinth inputs. On the basis of these patterns, a trained observer can predict what the animal experienced during testing; the patterns of VOC Fos expression reveal a trace of recent genomic activity. Based on principal component analysis, VOC network modules associated with lesion recovery, spatial representation and the calibration of gravity, and optokinetic influences are proposed. Probable and possible gene targets of the Fos protein are also reviewed.


Reduction of the long-term use of proton pump inhibitors by a patient-oriented electronic decision support tool (arriba-PPI): study protocol for a randomized controlled trial.
Proton pump inhibitors (PPIs) are increasingly being prescribed, although long-term use is associated with multiple side effects. Therefore, an electronic decision support tool with the aim of reducing the long-term use of PPIs in a shared decision-making process between general practitioners (GPs) and their patients has been developed. The developed tool is a module that can be added to the so-called arriba decision support tool, which is already used by GPs in Germany in routine care. In this large-scale cluster-randomized controlled trial we evaluate the effectiveness of this arriba-PPI tool. The arriba-PPI tool is an electronic decision support system that supports shared decision-making and evidence-based decisions around the long-term use of PPIs at the point of care. The tool will be evaluated in a cluster-randomized controlled trial involving 210 GP practices and 3150 patients in Germany. GP practices will be asked to recruit 20 patients aged ≥ 18 years regularly taking PPIs for ≥ 6 months. After completion of patient recruitment, each GP practice with enrolled patients will be cluster-randomized. Intervention GP practices will get access to the software arriba-PPI, whereas control GPs will treat their patients as usual. After an observation period of six months, GP practices will be compared regarding the reduction of cumulated defined daily doses of PPI prescriptions per patient. Our principal hypothesis is that the application of the arriba-PPI tool can reduce PPI prescribing in primary care by at least 15% compared to conventional strategies used by GPs. A positive result implies the implementation of the arriba-PPI tool in routine care. German Clinical Trials Register, DRKS00016364. Registered on 31 January 2019.


Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma.
Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL , Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application.


Engineering d-amino acid containing novel protease inhibitors using catalytic site architecture.
The mechanism of proteolysis by serine proteases is a reasonably well-understood process. Typically, a histidine residue acting as a general base deprotonates the catalytic serine residue and the hydrolytic water molecule. We disclose here, the use of an unnatural d-amino acid as a strategic residue in P1 position, designed de novo based on the architecture of the protease catalytic site to impede the catalytic histidine residue at the stage of acyl-enzyme intermediate. Several probe molecules containing d-homoserine or its derivatives at P1 position are evaluated. Compounds 1, 6, and 8-10 produced up to 57% loss of activity against chymotrypsin. More potent and specific inhibitors could be designed with structure optimization as this strategy is completely general and can be used to design inhibitors against any serine or cysteine protease.


Familiar Stranger: Ecological Genomics of the Model Saprotroph and Industrial Enzyme Producer Trichoderma reesei Breaks the Stereotypes.
The filamentous fungus Trichoderma reesei (Hypocreales, Ascomycota) has properties of an efficient cell factory for protein production that is exploited by the enzyme industry, particularly with respect to cellulase and hemicellulase formation. Under conditions of industrial fermentations it yields more than 100g secreted protein L(-1). Consequently, T. reesei has been intensively studied in the 20th century. Most of these investigations focused on the biochemical characteristics of its cellulases and hemicellulases, on the improvement of their properties by protein engineering, and on enhanced enzyme production by recombinant strategies. However, as the fungus is rare in nature, its ecology remained unknown. The breakthrough in the understanding of the fundamental biology of T. reesei only happened during 2000s-2010s. In this review, we compile the current knowledge on T. reesei ecology, physiology, and genomics to present a holistic view on the natural behavior of the organism. This is not only critical for science-driven further improvement of the biotechnological applications of this fungus, but also renders T. reesei as an attractive model of filamentous fungi with superior saprotrophic abilities.


Possible regulation of microtubules through destabilization of tubulin.
Chaperones and folding cofactors are known to mediate posttranslational folding of nascent tubulin, thus forming functional dimers. Based on sequence likeness, a novel protein similar to cofactor E, E-like protein (El), was identified. In overexpression experiments El, similar to a subset of folding factors (i.e. cofactors D and E), appears to disrupt functional dimers and target them for destruction by the proteasome. El apparently does not interact with microtubules directly and has no function in the tubulin folding pathway. Suppression of El expression seems to increase the cellular content of stable, posttranslationally modified microtubules by an unknown mechanism. Degradation of functional tubulin dimers as well as the alteration of the cellular content of stable microtubules through El might regulate the distribution and organization of organelles in vivo.


Lessons Learned on a High-Altitude Expedition to Mount Kilimanjaro.
High-altitude expeditions expose teams to particular medical, environmental, and social challenges that can have unintended and severe consequences for crew members. In June 2017, the 9-d Equal Playing Field (EPF) expedition to Mount Kilimanjaro to set a world record for the highest-altitude soccer match ever played demonstrated the variety of challenges that may arise during these types of trips. This trip included a full-length soccer match at 5714 m (18,746 ft), leading to additional challenges for expedition members participating in the athletic event. The EPF medical team identified the challenges that occurred during the expedition and documented the methods used to resolve these challenges in real time. From the challenges faced during the expedition, we describe the lessons learned for future expeditions to Mount Kilimanjaro and other high-altitude environments. Challenges arose with medical tent visibility, medical disqualification, underreporting of medical events, and acute pain management, while anticipated challenges with interpersonal conflict did not occur. The rigorous preparation and anticipation by the EPF medical team prior to expedition departure may have helped mitigate this conflict as well as prevented unintended severe medical events from occurring.


Morphological and electrophysiological examination of olfactory sensory neurons during the early developmental prolarval stage of the sea lamprey Petromyzon marinus L.
This study examined olfactory sensory neuron morphology and physiological responsiveness in newly hatched sea lamprey, Petromyzon marinus L. These prolarvae hatch shortly after neural tube formation, and stay within nests for approximately 18 days, before moving downstream to silty areas where they burrow, feed and pass to the larval stage. To explore the possibility that the olfactory system is functioning during this prolarval stage, morphological and physiological development of olfactory sensory neurons was examined. The nasal cavity contained an olfactory epithelium with ciliated olfactory sensory neurons. Axons formed aggregates in the basal portion of the olfactory epithelium and spanned the narrow distance between the olfactory epithelium and the brain. The presence of asymmetric synapses with agranular vesicles within fibers in the brain, adjacent to the olfactory epithelium suggests that there was synaptic connectivity between olfactory sensory axons and the brain. Neural recordings from the surface of the olfactory epithelium showed responses following the application of L-arginine, taurocholic acid, petromyzonol sulfate (a lamprey migratory pheromone), and water conditioned by conspecifics. These results suggest that lampreys may respond to olfactory sensory input during the prolarval stage.


Patient experience and repeatability of measurements made with the Pentacam HR in patients with keratoconus.
To investigate whether the repeatability of measurements with the Pentacam HR in patients with keratoconus is improved by patients gaining more experience of the measurement situation. Such an improvement could enhance the accuracy with which progressive keratoconus can be detected. Four replicate measurements were performed on Day 0 and on Day 3. Parameters commonly used in the diagnosis of progressive keratoconus were included in the analysis, namely the flattest central keratometry value (K1), the steepest central keratometry value (K2), the maximum keratometry value (Kmax), and the parameters A, B and C from the Belin ABCD Progression Display. In addition, quality parameters used by the Pentacam HR to assess the quality of the measurements were included, namely the analysed area (front + back), 3D (front + back), XY, Z, and eye movements. Neither the diagnostic parameters nor the quality parameters showed any statistically significant improvement on Day 3 compared to Day 0. The quality parameter "eye movements" deteriorated significantly with increasing Kmax. Gaining experience of the measurement situation did not increase the accuracy of the measurements. Further investigations should be performed to determine whether the increasing number of eye movements with increasing disease severity has a negative effect on the repeatability of the measurements.


Study on the absolute configuration and biological activity of rotenoids from the leaves and twigs of Millettia pyrrhocarpa Mattapha, Forest & Hawkins, sp. Nov.
M. pyrrhocarpa is a new plant in the Fabaceae: Faboideae family that is found in Thailand. A literature search revealed that the Milletia genus is rich in bioactive compounds possessing a wide range of biological activities. In this study, we aimed to isolate novel bioactive compounds and to study their bioactivities. The hexane, ethyl acetate, and methanol extracts from the leaves and twigs of M. pyrrhocarpa were isolated and purified using chromatography techniques. These extracts and pure compounds were tested in vitro for their inhibitory activities against nine strains of bacteria, as well as their anti-HIV-1 virus activity and cytotoxicity against eight cancer cell lines. Three rotenoids, named 6aS, 12aS, 12S-elliptinol (1), 6aS, 12aS, 12S-munduserol (2), dehydromunduserone (3), and crude extracts were evaluated for antibacterial, anti-HIV, and cytotoxic activities. It was found that compounds 1-3 inhibited the growth of nine strains of bacteria, and the best MIC/MBC values were obtained at 3/ > 3 mg/mL. The hexane extract showed anti-HIV-1 RT with the highest %inhibition at 81.27 at 200 mg/mL, while 6aS, 12aS, 12S-elliptinol (1) reduced syncytium formation in 1A2 cells with a maximum EC50 value of 4.48 μM. Furthermore, 6aS, 12aS, 12S-elliptinol (1) showed cytotoxicity against A549 and Hep G2 cells with maximum ED50 values of 2.27 and 3.94 μg/mL. This study led to the isolation of constituents with potential for medicinal application, providing compounds (1-3) as lead compounds against nine strains of bacteria. The hexane extract showed the highest %inhibition of HIV-1 virus, Compound 1 showed the best EC50 in reducing syncytium formation in 1A2 cells, and it also showed the best ED50 against human lung adenocarcinoma (A549) and human hepatocellular carcinoma (Hep G2). The isolated compounds from M. pyrrhocarpa offered significant potential for future medicinal application studies.


Current Guidelines for Postoperative Treatment and Follow-Up of Well-Differentiated Thyroid Cancer.
Well-differentiated thyroid cancer is increasing in incidence but the disease-specific mortality remains very low. The only effective adjuvant treatment is radioactive iodine ablation. Guidelines regarding the use and dosage of radioactive iodine depend on pathologic features of the primary and metastatic tumor that define risk. Long-term treatment includes thyroid-stimulating hormone suppression and surveillance with serum thyroglobulin and radiologic assessment for nodal recurrence.


[Biological Age as a Method for Systematic Assessment of Ontogenetic Changes in the State of an Organism].
Aging is a common feature of living and nonliving systems as a disturbance of the structure of the system accumulating with age. The only cause of aging of a living system, which is capable of renewal, is the insufficiency of renewal. The latter manifests itself as two global mechanisms of aging: the genetically determined nonrenewal of a number of structures that can only die with age (stochastic aging) and the regulatory reduction in the rate of self-renewal of living structures. The regulatory reduction in cellular self-renewal (cell growth and division) is most important. At the same chronological age, the degree of aging of the organism in general, as well as individual organs, cells, and systems of the organism, may be different, reflecting the concept of biological age (BA)--an indicator of the level of development, changes, or deterioration of a structure or function of an element of the organism, a functional system, or the organism as a whole. It is expressed in units oftime by relating the values of biomarkers defining the processes of aging with the standard average statistical dependences of changes in these biomarkers with the chronological age. The concept of BA is directly related to the concept of viability of the organism, which is determined by the sum (integral) of viabilities of its parts (in practice, the residual functional resource). For quantitative characterization of aging in general, the index of integrated biological age is used. To give a detailed characterization, the partial biological ages are used, which reflect the aging of different systems of the organism, as well as a number of indices reflecting its functional and psychological possibilities. The contribution of pathological processes to BA is also taken into account. In addition, the amount of retained adaptive reserves in the physical and nervous and mental aspects, the risk factors, and the factors of longevity should be determined. For this purpose, it is necessary to take into account the family history (hereditary factors) and the individual history (acquired factors). The use ofthe BA determination method by doctors in clinical practice stimulates the development of preventive medicine, which is important to improve both the individual health and the quality of life. The BA determination method is also the main tool for testing the effectiveness of tools and methods of geroprophylaxis.


High-throughput ovarian follicle counting by an innovative deep learning approach.
The evaluation of the number of mouse ovarian primordial follicles (PMF) can provide important information about ovarian function, regulation of folliculogenesis or the impact of chemotherapy on fertility. This counting, usually performed by specialized operators, is a tedious, time-consuming but indispensable procedure.The development and increasing use of deep machine learning algorithms promise to speed up and improve this process. Here, we present a new methodology of automatically detecting and counting PMF, using convolutional neural networks driven by labelled datasets and a sliding window algorithm to select test data. Trained from a database of 9 millions of images extracted from mouse ovaries, and tested over two ovaries (3 millions of images to classify and 2 000 follicles to detect), the algorithm processes the digitized histological slides of a completed ovary in less than one minute, dividing the usual processing time by a factor of about 30. It also outperforms the measurements made by a pathologist through optical detection. Its ability to correct label errors enables conducting an active learning process with the operator, improving the overall counting iteratively. These results could be suitable to adapt the methodology to the human ovarian follicles by transfer learning.


Minimum 6-year outcomes for interstitial cystitis treated with sacral neuromodulation.
Interstitial cystitis is a multifaceted medical condition consisting of pelvic pain, urgency, and frequency. Can sacral neuromodulation be successfully utilized for the medium term of ≥ 6 years in interstitial cystitis patients for whom standard drug therapies have failed? In our observational, retrospective, case-controlled review (January 2002-March 2004), we sought to discern whether neuromodulation could be successfully implemented with acceptable morbidity rates in interstitial cystitis patients. Thirty-four female patients underwent stage 1 and 2 InterStim placements under a general anesthetic. Simple means and medians were analyzed. Mean pre-op/post-op pelvic pain and urgency/frequency scores were 21.61 ± 8.6/9.22 ± 6.6 (p < 0.01), and mean pre-op/post-op visual analog pain scale (VAPS) were 6.5 ± 2.9/2.4 ± 1.1 (p < 0.01). Median age was 41 ± 14.8 years with a mean follow-up of 86 ± 9.8 months. With a minimum 6-year follow-up we determined that sacral neuromodulation provides adequate improvement for the symptoms of recalcitrant interstitial cystitis.


Changes in serum phosphorus level in patients with severe burns: A prospective study.
The second most abundant mineral in the body, phosphorus (P), is absorbed in the small intestine after ingestion enhanced by 1,25-dihydroxy vitamin D, and its excretion is exclusively regulated by the kidney. It is clinically significant, aside from its disturbance in burn ICU patient's P mechanism. The increasing rate of morbidity and mortality among the patients can be associated with severe hypophosphatemia. The current study aimed at investigating the changes in serum P levels in the early period after burns, the relationship between serum P level and TBSA (total body surface area) of burn, and the impact of hypophosphatemia on patients' clinical outcomes. The current prospective, observational study was conducted on 137 patients hospitalized in the burn intensive unit (BICU) of Velayat Sub-specialty Burn and Plastic Surgery Center from December 2015 to May 2017. According to the TBSA percentage, the patients were divided into three groups. The level of serum P was determined in the 1st, 3rd, 5th, 7th, and 9th days of hospital stay and before discharge. To evaluate the trend of P changes in the sixtime-points, the average changes along with 95% confidence intervals (CI) were used for multivariate analysis of variance with repeated measures (repeated measures ANOVA). A P-value of 0.05 or less was considered statistically significant. The analyses were performed using SPSS software, version 19 (SPSS Inc.). Totally, 137 patients (70% male, mean age 32 ± 21years, and TBSA 32.6 ± 14%) were included in the study. The overall incidence of hypophosphatemia was 75.1%. Hypophosphatemia developed as early as 1.66 ± 0.136 (95%CI: 1.4-1.9) days after injury. The highest decrease in the serum P level was observed on the 3rd and 5th days after burn as 2.78 mg/dL and 2.85 mg/dL, respectively (P-value = 0.001). A correlation was observed between TBSA and serum P level. The mean serum P level decreased with increasing the percentage of burns. There was a correlation between serum P level and mortality; therefore, a decrease in serum P level increased the patient's mortality rate (P < 0.05). The current study highlighted that hypophosphatemia is often observed in patients with burn injuries during their hospitalization. It is potentially beneficial to identify patients at risk of hypophosphatemia. Therefore, it is suggested that P level be assessed regularly in patients with burn injuries for the timely initiation of P replacement therapy.


High temperature noble gas thermometry in Lake Kivu, East Africa.
Due to their biological and chemical inertness, noble gases in natural waters are widely used to trace natural waters and to determine ambient temperature conditions during the last intensive contact with the atmosphere (equilibration). Noble gas solubilities are strong functions of temperature, with higher temperatures resulting in lower concentrations. Thus far, only common environmental conditions have been considered, and hence investigated temperatures have almost never exceeded 35 °C, but environmental scenarios that generate higher surface-water temperatures (such as volcanism) exist nonetheless. Recently published measurements of noble gas concentrations in Lake Kivu, which sits at the base of the Nyiragongo volcano in East Africa, unexpectedly show that the deep waters are strongly depleted in noble gases with respect to in-situ conditions, and so far no quantitative explanation for this observation has been provided. We make use of recently published noble gas solubility data at higher temperatures to investigate our hypothesis that unusually high equilibration temperatures could have caused the low measured noble gas concentrations by applying various approaches of noble gas thermometry. Noble gas concentration ratios and least squares fitting of individual concentrations indicate that the data agrees best with the assumption that deep water originates from groundwater formed at temperatures of about 65 °C. Thus, no form of degassing is required to explain the observed noble gas depletion: the deep water currently contained in Lake Kivu has most probably never experienced a large scale degassing event. This conclusion is important as limnic eruptions were feared to threaten the lives of the local population.


Ectopic hepatic tissue misdiagnosed as a tumor of lung.
The ectopic or accessory liver lobe is an uncommon congenital anatomic abnormality. It is considered to be the outcome of an abnormal development of liver tissue during embryologic period. In some cases, it may be secondary to a trauma or a surgical operation. Literature reports only anecdotal cases; there are not series. The most common localization is the abdominal cavity, but very rarely it can also be found in the thoracic cavity. In most cases, preoperative correct diagnosis is very difficult because it is unlikely to consider this rare condition in course of differential diagnosis. Most cases are misdiagnosed, and patients undergo surgical intervention with suspect of lung lesion. Some times the intrathoracic accessory lobe is an intraoperative incidental finding. In this report, we present the case of a young female patient who underwent surgical treatment for a suspect pulmonary lesion that at histological examination resulted to be an intrathoracic accessory hepatic lobe.


Insights into mesoporous MCM-41-supported titania decorated with CuO nanoparticles for enhanced photodegradation of tetracycline antibiotic.
In this research, tetracycline photodegradation under UV light was investigated over bare TiO2 and a series of MCM-41 supported CuO-TiO2 heterojunctions varying in CuO content with the intent of exploring the effect of MCM-41 presence and especially, CuO addition. Several techniques including XRD, FESEM, EDX, DRS, BET, and PL were applied to characterize the physicochemical and photophysical properties of synthesized nanocomposites. It was found that the co-existence of MCM-41 and CuO enhances the surface dispersion of Ti species, leading to less number of agglomerates and smaller particle size of TiO2, which it promoted photophysical properties and reinforced the interaction of surface species with the support and thereby, the photosite leachings were lessened. However, the excessive loadings alleviate the synergetic effect of CuO due to the significant decrease of surface area, the appearance of more number of agglomerations, and surface coverage of MCM-41. The results revealed that CuO addition not only enhances the photocatalytic activity of TiO2/MCM-41 but also makes it reusable in further experiments. It was also observed that the highest photodegradation of tetracycline was obtained over TiO2-CuO/MCM-41 nanocomposite containing 5 wt% CuO. It is attributed to less electron-hole recombination, appropriate band gap, smaller number of agglomerations, and more uniform dispersion of photosites. Following the obtained results, a possible reaction mechanism was also proposed.


Coping as a mechanism linking stressful life events and mental health problems in adolescents.
Although stressful life events represent an etiologic factor of mental health problems in adolescents, few studies have been conducted to address mechanisms linking the stress-psychopathology relation. The present study was designed to examine coping as a mediate factor on the relationship between stressful life events and symptoms of anxiety and depression. The participants were 13 512 students from eight cities of China, who participated in a school-based survey. Data were collected by a questionnaire comprising coping, stressful life events, anxiety, and depressive symptoms. As a model, a series of regression equations were used to examine whether coping mediated the association between stressful life events and symptoms of anxiety and depression. Each dimension of stressful life events showed significant correlation with anxiety, depression and coping (all P<0.001). In the model to analyze mediate effects, all standardized coefficients (β) were significant (all P<0.01), indicating marked mediator effects. Furthermore, negative coping might account for more mediate effects than positive coping on this relationship. Coping partially mediated the relationship between stressful life events and mental health during adolescence. This study highlighted an important public health priority for preventive interventions targeting stress-related psychopathology, and for further promoting adolescents' mental health.


Study on supramolecular complexing ability vis-à-vis estimation of pKa of substituted sulfonamides: dominating role of Balaban index (J).
The supramolecular complexing ability vis-à-vis pKa estimation of a large series of 43 sulfonamides was made using a series of molecular descriptors including topological indices. The set of topological indices chosen also contains Balaban (J) and a variety of Balaban type indices: J, Jz, Jm, Jv, Jc, and Jp. The results have shown that the most discriminating Balaban index (J) in multi-parametric regression analysis combined with indicator parameters yields excellent models and also establishes the superiority of the J index over other Balaban type indices. The statistics is improved when one of the indicator parameters is replaced by molar volume (MV). The results are discussed critically using a variety of statistics.


Reconstructing 1D Fe Single-atom Catalytic Structure on 2D Graphene Film for High-Efficiency Oxygen Reduction Reaction.
The ordinary intrinsic activity and disordered distribution of metal sites in zero/one-dimensional (0D/1D) single-atom catalysts (SACs) lead to inferior catalytic efficiency and short-term endurance in the oxygen reduction reaction (ORR), which restricts the large-scale application of hydrogen-oxygen fuel cells and metal-air batteries. To improve the activity of SACs, a mild synthesis method was chosen to conjugate 1D Fe SACs with 2D graphene film (Fe SAC@G) that realized a composite structure with well-ordered atomic-Fe coordination configuration. The product exhibits outstanding ORR electrocatalytic efficiency and stability in 0.1 M KOH aqueous solution. DFT-D computational results manifest the intrinsic ORR activity of Fe SAC@G originated from the newly-formed FeN4 -O-FeN4 bridge structure with moderate adsorption ability towards ORR intermediates. These findings provide new ways for designing SACs with high activity and long-term stability.


Health care worker hand contamination at critical moments in outpatient care settings.
The delivery of health care in outpatient settings has steadily increased over the past 40 years. The risk of infection in these settings is considered to be low. However, the increasing severity of illness and complexity of care in outpatient settings creates a need to reexamine the transmission of pathogens in this setting. Seventeen health care workers from 4 wound care facilities were sampled during 46 patient care encounters to determine the presence of health care-associated pathogens (ie, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, multidrug-resistant Acinetobacter species, and Clostridium difficile) on their hands at key moments of care. Health care workers acquired at least 1 pathogen on their hands during 28.3% of all patient care encounters. Hands sampled before a clean or aseptic procedure and hands sampled after body fluid exposure risk were each contaminated in 17.4% of instances. Hand contamination occurred in 19.6% of instances where health care workers wore gloves during care compared with 14.6% when health care workers were ungloved. Contamination of health care workers' hands presents a significant risk of pathogen transmission in outpatient settings. Gloving education, hand hygiene solutions at the point of care, and hand hygiene surveillance are important solutions for reducing transmission of pathogenic organisms.


Sphero-echinocytosis of human red blood cells caused by snake, red-back spider, bee and blue-ringed octopus venoms and its inhibition by snake sera.
It was found that bee (Apis mellifera) venom, red-back spider (Latrodectus mactans) venom, blue-ringed octopus (Hapalochlaena maculosa) venom, ten different snake venoms, phospholipase A2 and four snake toxins caused sphero-echinocytosis of human red blood cells at 200 ng/ml. Most venoms and toxins lost the ability to deform human red blood cells when their components of less than mol. wt 10,000 were applied. In a number of cases the sphero-echinocytotic effect was also inhibited by blood sera of Notechis scutatus and Pseudonaja textilis.


Hormonal content of plasma and endometrium of women taking oral contraceptives.
A total of 134 women were studied, 75 of whom were using cyclic steroid contraception (ethinyl estradiol, 0.05 mg plus norgestrel, 0.5 mg) and 59 of whom had normal ovaulatory cycles. By radioimmunoassay techniques simultaneous determinations were made of total estrogens (TE) and progesterone (P) in both plasma and endometrium and of FSH and LH in plasma, covering all days of the pseudomenstrual and true menstrual cycles. As expected, the ovulating women showed a midcycle peak of plasma TE and an increase in plasma P thereafter, while no cyclic variations were observed in the treated group. Correlations of endometrial concentrations of TE and P with plasma FSH and LH levels are discussed. In 13 of the 75 treated women elevations of endometrial P concentrations were present, presumably demonstrating the "escape phenomenon." The possible future value of endometrial hormone determinations is suggested.


Focal FDG Uptake in Lung Parenchyma Without Structural Alterations on CT.
Transient visualization of a FDG avid abnormality in the lungs without any structural lesion is reported in a case of iatrogenic pulmonary microembolism.


Ribbon synapses of the mammalian retina contain two types of synaptic bodies--ribbons and spheres.
The present paper reports that the synaptic bodies of the retinal ribbon synapses in rat, guinea pig, golden hamster and mouse are a heterogeneous population of organelles. In addition to the well-known synaptic ribbons sensu stricto which consist of a platelike electron-dense central structure surrounded by electron-lucent synaptic vesicles, there are what is termed synaptic spheres, in which the core is not platelike, but round to oval. In rat retinae procured at day, ribbons outnumbered spheres by a factor of 4. At night spheres were not seen in photoreceptor cells. Spheres, like ribbons, may lie some distance from the synaptic site, perhaps indicating transit from their site of origin to the synapse. At night ribbons are longer than at daytime. In addition to the previously described connecting stalks between synaptic vesicles and the electron-dense ribbons, the presence of filamentous stalks between adjacent synaptic vesicles is described. The latter stalks, depending on their presence or absence, may influence the position of the synaptic vesicles in relation to the synaptic body and/or the presynaptic membrane. It is concluded that the plasticity of retinal synapses cannot be fully appreciated unless the temporal changes of ribbons, spheres and the connecting stalks are taken into consideration.


[Survey of caries status of 5-year-old children in Shanghai in 1995].
To determine the caries status of 5-year-old children in Shanghai. Use multistage sampling method,stratified sampling and simple random sampling methods. 2 132 5-year-old children were chosen and their DMFTs were examined. Two thirds were done in three downtown districts and the rest in three suburb counties. Each gender occupies half. DMFT in downtown and suburb was 3.46 and 7.37, respectively. Caries prevalence was 71.13% and 92.56%, respectively.The percentage of filling in DMFT was 14.79% and 3.24%, respectively. All this three indices proved to be significantly different between downtown and suburb. It is indicated that caries prevalence of deciduous teeth should be lowered both in downtown and suburb areas. Filling percentage should be improved urgently, especially in suburbs. The preventive means should focus on suburbs as well.


Anti-oxidant activity in measles.
Measles leads to serious complications, especially in developing countries. Our aim was to evaluate the effect of oxidative stress on the enzymatic and non-enzymatic anti-oxidant status in children with measles. Levels of superoxide dismutase, glutathione peroxidase, catalase, ceruloplasmin, albumin, total bilirubin and uric acid were studied in 17 children with measles and 29 healthy controls. There was a statistically significant difference between the groups for all parameters. All of the anti-oxidant activities except for albumin level were increased in the study group. Both enzymatic and nonenzymatic anti-oxidant defence systems were affected in measles.


Evaluation of potential adverse events following COVID-19 mRNA vaccination among adults aged 65 years and older: Two self-controlled studies in the U.S.
Our near-real-time safety monitoring of 16 adverse events (AEs) following COVID-19 mRNA vaccination identified potential elevation in risk for six AEs following primary series and monovalent booster dose administration. The crude association with AEs does not imply causality. Accordingly, we conducted robust evaluation of potential associations. We conducted two self-controlled case series studies of COVID-19 mRNA vaccines (BNT162b2 and mRNA-1273) in U.S. Medicare beneficiaries aged ≥ 65 years. Adjusted incidence rate ratio (IRRs) and 95 % confidence intervals (CIs) were estimated following primary series doses for acute myocardial infarction (AMI), pulmonary embolism (PE), immune thrombocytopenia (ITP), disseminated intravascular coagulation (DIC); and following monovalent booster doses for AMI, PE, ITP, Bell's Palsy (BP) and Myocarditis/Pericarditis (Myo/Peri). The primary series study included 3,360,981 individuals who received 6,388,542 primary series doses; the booster study included 6,156,100 individuals with one monovalent booster dose. The AMI IRR following BNT162b2 primary series and booster was 1.04 (95 % CI: 0.91 to 1.18) and 1.06 (95 % CI: 1.003 to 1.12), respectively; for mRNA-1273 primary series and booster, 1.01 (95 % CI: 0.82 to 1.26) and 1.05 (95 % CI: 0.998 to 1.11), respectively. The hospital inpatient PE IRR following BNT162b2 primary series and booster was 1.19 (95 % CI: 1.03 to 1.38) and 0.86 (95 % CI: 0.78 to 0.95), respectively; for mRNA-1273 primary series and booster, 1.15 (95 % CI: 0.94 to 1.41) and 0.87 (95 % CI: 0.79 to 0.96), respectively. The studies' results do not support that exposure to COVID-19 mRNA vaccines elevate the risk of ITP, DIC, Myo/Peri, and BP. We did not find an increased risk for AMI, ITP, DIC, BP, and Myo/Peri and there was not consistent evidence for PE after exposure to COVID-19 mRNA primary series or monovalent booster vaccines. These results support the favorable safety profile of COVID-19 mRNA vaccines administered in the U.S. elderly population.


Akt isoforms in vascular disease.
The mammalian serine/threonine Akt kinases comprise three closely related isoforms: Akt1, Akt2 and Akt3. Akt activation has been implicated in both normal and disease processes, including in development and metabolism, as well as cancer and cardiovascular disease. Although Akt signalling has been identified as a promising therapeutic target in cancer, its role in cardiovascular disease is less clear. Importantly, accumulating evidence suggests that the three Akt isoforms exhibit distinct tissue expression profiles, localise to different subcellular compartments, and have unique modes of activation. Consistent with in vitro findings, genetic studies in mice show distinct effects of individual Akt isoforms on the pathophysiology of cardiovascular disease. This review summarises recent studies of individual Akt isoforms in atherosclerosis, vascular remodelling and aneurysm formation, to provide a comprehensive overview of Akt function in vascular disease.


Postoperative hypocalcemia in patients who did or did not undergo parathyroid autotransplantation during thyroidectomy: a comparative study.
Permanent hypoparathyroidism is a recognized complication of thyroidectomy. Apart from preservation of parathyroid glands in situ by meticulous dissection, parathyroid autotransplantation (PTHAT) has been performed increasingly to avoid permanent hypoparathyroidism. From January 1995 to October 1997, PTHAT was performed routinely for devascularized or inadvertently removed glands in 98 (36%) of 271 patients undergoing thyroidectomy. Potential risk factors and the impact of PTHAT on postoperative hypocalcemia were studied. Postoperative hypocalcemia occurred in 40 patients (14.8%), whereas 5 patients (1.8%) had permanent hypocalcemia during a median follow-up of 9 months. The incidence of transient hypocalcemia (n = 35) was higher in patients who underwent PTHAT (21.4%) than in patients who did not undergo PTHAT (8.1%) (P < .01). Permanent hypocalcemia occurred only in patients who did not undergo PTHAT. None of the 21 patients who had postoperative hypocalemia after PTHAT had permanent hypoparathyroidism compared with 26% (5/19) of patients who did not undergo PTHAT (P = .018). When the resected thyroid gland was examined for parathyroid tissue, the incidence of positive identification was higher in patients who did not undergo PTHAT (13%) than in patients who did undergo PTHAT (4%) (P = .015). Patients with postoperative hypocalcemia after PTHAT have virtually no risk of having permanent hypoparathyroidism. A more careful examination of the resected thyroid tissue can help to identify inadvertently removed parathyroid glands for autotransplantation.


The role of Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis in vivo and in vitro.
The molecular mechanisms underlying arsenic-induced neurotoxicity have not been completely elucidated. Our study aimed to determine the role of the Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis. Pathological and molecular biological tests were performed on the cerebral cortex of arsenic-exposed rats and SH-SY5Y neuroblastoma cells. Arsenic induced apoptosis in the cortical neurons, which corresponded to abnormal ultrastructural changes. Mechanistically, arsenic activated the Fas-FasL-FADD signaling pathway and the downstream caspases both in vivo and in vitro. ZB4 treatment reversed the apoptotic effects of arsenic on the SHSY5Y cells. Taken together, arsenic induces neurotoxicity by activating the Fas-FasL-FADD signaling pathway.


Predicting resting energy expenditure in patients with musculoskeletal deformities.
The aim of this study was to assess the validity of the commonly used equations (Harris-Benedict (HB), Schofield (S) and equations based on midarm circumference (MAC) and midarm muscle circumference (MAMC) in predicting resting energy expenditure (REE) in a population of patients with musculoskeletal deformities. 20 kyphoscoliotic patients (15 female (F); 5 male (M); mean age 59.6 years) and 10 controls (7 F; 3M; 59.8 years) were studied. REE measured by indirect calorimetry (IC) with a ventilated canopy system (Deltatrac metabolic monitor) was not significantly different between patients and controls (Mean (SD) REE (MJ/24 h): 5.48 (1.1); controls: 5.28(0.8)). In patients with deformities the Schofield equation gave values which were closest to measured REE (mean difference and limits of agreement IC vs S: 0.098 MJ/24 h; -0.822 and 1.018). The Harris-Benedict equation using height (Ht) and armspan (AS) in lieu of height also gave acceptable results (IC vs HB (Ht): 0.34; -0.638 and 1.318; IC vs HB (AS): 0.255; -0.683 and 1.253). Equations based on MAC and MAMC compared poorly (IC vs MAC equation: 0.398; -1.530 and 2.326; IC vs MAMC equation 0.687; -0.911 and 2.285). On regression analysis the equation REE = 0.295 (MAMC) + 0.0483 (AS) -0.0324 (age) -6.25 predicted REE best in the patient population (r(2) = 0.861).