Evaluation of Root Resorption, Tooth Inclination and Changes in Supporting Bone in Class II Malocclusion Patients Treated with Forsus Appliance.
The aim of our study was to evaluate apical root resorption and changes in tooth inclinations, marginal bone height, and labio-lingual bone thickness at the mid-root and apical level in mandibular anterior teeth during the Forsus treatment using cone beam computed tomography (CBCT). CBCT scans of 16 subjects (8 males and 8 females) with Class II malocclusion (age group: 13-29 years) taken before and 6 months after the Forsus treatment were evaluated for apical root resorption, tooth inclination, marginal bone height, and thickness of bone at the mid-root and apical level in mandibular anterior teeth. There was statistically significant root resorption of central incisors (0.39 mm) and canines (0.66 mm); a decrease in the angle of inclination for all teeth; an increase in the marginal bone measurement in labial (1.31 mm) and decrease in lingual (0.93 mm) aspect at the canine region; and an increase in bone width by 0.87 mm and 0.75 mm in central and lateral incisor regions, respectively, at the mid-root level lingually. At the apex level in the canine region, bone width increased by 1.4 mm labially, while it decreased by 2.18 mm lingually; it increased significantly for incisors in the lingual region. The Forsus appliance therapy causes clinically insignificant root resorption and bone changes, and clinically significant proclination of mandibular anterior teeth. The findings of the present study aid clinicians in proper case selection and reinforce the prevention of incisor proclination while using the Forsus therapy to achieve better treatment results and stability.


Anatomic Anterior Cruciate Ligament Reconstruction Using Hamstring Tendons Restores Quantitative Pivot Shift.
It is still uncertain how surgical reconstruction of the anterior cruciate ligament (ACL) is able to restore rotatory laxity of the involved joint. The desired amount of restraint applied by the ACL graft, as compared with the healthy knee, has not been fully clarified. To quantify the ability of single-bundle anatomic ACL reconstruction using hamstring tendons in reducing the pivot-shift phenomenon immediately after surgery under anesthesia. Case series; Level of evidence, 4. An inertial sensor and image analysis were used at 4 international centers to measure tibial acceleration and lateral compartment translation of the knee, respectively. The standardized pivot-shift test was quantified in terms of the side-to-side difference in laxity both preoperatively and postoperatively with the patient under anesthesia. The reduction in both tibial acceleration and lateral compartment translation after surgery and the side-to-side difference were evaluated using the Wilcoxon signed-rank test. Alpha was set at P < .05. A total of 107 patients were recruited for the study, and data were available for 89 patients. There was a statistically significant reduction in quantitative rotatory knee laxity between preoperatively (inertial sensor, 2.55 ± 4.00 m/s2; image analysis, 2.04 ± 2.02 mm) and postoperatively (inertial sensor, -0.54 ± 1.25 m/s2; image analysis, -0.10 ± 1.04 mm) between the involved and healthy joints, as measured by the 2 devices (P < .001 for both). Postoperatively, both devices detected a lower rotatory laxity value in the involved joint compared with the healthy joint (inertial sensor, 2.45 ± 0.89 vs 2.99 ± 1.10 m/s2, respectively [P < .001]; image analysis, 0.99 ± 0.83 vs 1.09 ± 0.92 mm, respectively [P = .38]). The data from this study indicated a significant reduction in the pivot shift when compared side to side. Both the inertial sensor and image analysis used for the quantitative assessment of the pivot-shift test could successfully detect restoration of the pivot shift after anatomic single-bundle ACL reconstruction. Future research will examine how pivot-shift control is maintained over time and correlation of the pivot shift with return to full activity in patients with an ACL injury.


The sonic hedgehog signaling pathway maintains the cancer stem cell self-renewal of anaplastic thyroid cancer by inducing snail expression.
Cancer stem cells (CSCs) have been recently identified in thyroid neoplasm. Anaplastic thyroid cancer (ATC) contains a higher percentage of CSCs than well-differentiated thyroid cancer. The signaling pathways and the transcription factors that regulate thyroid CSC self-renewal remain poorly understood. The objective of this study is to use two ATC cell lines (KAT-18 and SW1736) as a model to study the role of the sonic hedgehog (Shh) pathway in maintaining thyroid CSC self-renewal and to understand its underlying molecular mechanisms. The expression and activity of aldehyde dehydrogenase (ALDH), a marker for thyroid CSCs, was analyzed by Western blot and ALDEFLUOR assay, respectively. The effect of three Shh pathway inhibitors (cyclopamine, HhAntag, GANT61), Shh, Gli1, Snail knockdown, and Gli1 overexpression on thyroid CSC self-renewal was analyzed by ALDEFLUOR assay and thyrosphere formation. The sensitivity of transfected KAT-18 cells to radiation was evaluated by a colony survival assay. Western blot analysis revealed that ALDH protein levels in five thyroid cancer cell lines (WRO82, a follicular thyroid cancer cell line; BCPAP and TPC1, two papillary thyroid cancer cell lines; KAT-18 and SW1736, two ATC cell lines) correlated with the percentage of the ALDH(High) cells as well as Gli1 and Snail expression. The Shh pathway inhibitors, Shh and Gli1 knockdown, in KAT-18 cells decreased thyroid CSC self-renewal and increased radiation sensitivity. In contrast, Gli1 overexpression led to increased thyrosphere formation, an increased percentage of ALDH(High) cells, and increased radiation resistance in KAT-18 cells. Inhibition of the Shh pathway by three specific inhibitors led to decreased Snail expression and a decreased number of ALDH(High) cells in KAT-18 and SW1736. Snail gene knockdown decreased the number of ALDH(High) cells in KAT-18 and SW1736 cells. The Shh pathway promotes the CSC self-renewal in ATC cell lines by Gli1-induced Snail expression.


Improving simultaneous and proportional control from EMG signals based on a Two-Stage Regression Structure.
A two-stage regression structure is proposed in this paper to improve simultaneous and proportional control based on electromyography (EMG) signals. Instead of considering the conventional approach with a regression model per degree of freedom (DoF), the proposed method applies a regression model per direction of each DoF: the 1st stage detects DoFs and then is used to select the direction models of the 2nd stage. By using linear regression on the data from one healthy experienced participant for 2 DoFs of his wrist, the proposed structure was evaluated offline with cross-evaluation and online with a real-time control of a cursor to hit some targets. The evaluation results showed a clear improvement of the proposed method in terms of accuracy, ability to reach the boundaries, reaction speed, accurate control and reactive control compared to the conventional approach. The potential of this structure also lies in the fact that it can use different regression methods, work for 3 DoFs and more and use the 1st stage knowledge to improve performance of the 2nd stage.


Maternal iron status influences iron transfer to the fetus during the third trimester of pregnancy.
The effect of maternal iron status on fetal iron deposition is uncertain. We used a unique stable-isotope technique to assess iron transfer to the fetus in relation to maternal iron status. The study group comprised 41 Peruvian women. Of these women, 26 received daily prenatal supplements containing iron and folate (n = 11; Fe group) or iron, folate, and zinc (n = 15; Fe+Zn group) from week 10-24 of pregnancy to 1 mo postpartum. The remaining 15 women (control group) received iron supplementation only during the final month of pregnancy. During the third trimester of pregnancy (+/- SD: 32.9 +/- 1.4 wk gestation) oral 57Fe (10 mg) and intravenous 58Fe (0.6 mg) stable iron isotopes were administered to the women, and isotope enrichment and iron-status indicators were measured in cord blood at delivery. The net amount of 57Fe in the neonates' circulation (from maternal oral dosing) was significantly related to maternal iron absorption (P < 0.005) and inversely related to maternal iron status during the third trimester of pregnancy: serum ferritin (P < 0.0001), serum folate (P < 0.005), and serum transferrin receptors (P < 0.02). Significantly more 57Fe was transferred to the neonates in non-iron-supplemented women: 0.112 +/- 0.031 compared with 0.078 +/- 0.042 mg in the control group (n = 15) and the Fe and Fe+Zn groups (n = 24), respectively (P < 0.01). In contrast, 58Fe tracer in the neonates' circulation was not significantly related to maternal iron status. The transfer of dietary iron to the fetus is regulated in response to maternal iron status at the level of the gut.


Characterization of heparin and heparan sulfate domains binding to the long splice variant of platelet-derived growth factor A chain.
Platelet-derived growth factors (PDGFs) are homo- or heterodimers of two related polypeptides, known as A and B chains. The A chain exists as two splice variants due to the alternative usage of exons 6 (PDGF-AL, longer) and 7 (PDGF-AS, shorter). Exon 6 encodes an 18-amino acid sequence rich in basic amino acid residues, which has been implicated as a cell retention signal. Several lines of evidence indicate that the retention is due to binding of PDGF-AL to glycosaminoglycans, especially to heparan sulfate. We have analyzed the saccharide domains of smooth muscle cell-derived heparan sulfate involved in this interaction. Furthermore, we have employed selectively modified heparin oligosaccharides to elucidate the dependence of the binding on different sulfate groups and on fragment length. The shortest PDGF-AL binding domain consists of 6-8 monosaccharide units. Studies using selectively desulfated heparins and heparin fragments suggest that N-, 2-O-, and 6-O-sulfate groups all contribute to the interaction. Structural comparison of heparan sulfate oligosaccharides separated by affinity chromatography on immobilized PDGF-AL showed that the bound pool was enriched in -IdceA(2-OSO3)-GlcNSO3(6-OSO3)- disaccharide units. Furthermore, analogous separation of a partially O-desulfated heparin decamer preparation, using a highly selective nitrocellulose filter-trapping system, yielded a PDGF-AL-bound fraction in which more than half of the disaccharide units had the structure -IdceA(2-OSO3)-GlcNSO3(6-OSO3)-. Our results suggest that the interaction between PDGF-AL and heparin/heparan sulfate is mediated via N-sulfated saccharide domains containing both 2-O- and 6-O-sulfate groups.


Oral bisphosphonate related osteonecrosis of the jaw: a challenging adverse effect.
Oral bisphosphonates are the most commonly prescribed antiresorptive drugs for the treatment of osteoporosis. However, there are several adverse effects associated with oral bisphosphonates including the bisphosphonate related osteonecrosis of the jaw (BRONJ). With a better understanding of this side effect, reported incidences for BRONJ in oral bisphosphonate users have increased in time. The pathogenesis of BRONJ has not been well determined. Several risk factors such as dentoalveolar surgery, therapy duration, and concomitant steroid usage have been linked to BRONJ. Conservative and surgical methods can be preferred in the treatment. Preventative measures are of great importance for the patients at high risk. In this paper, osteonecrosis of the jaw secondary to oral bisphosphonates was reviewed in order to increase awareness as well as to renew the current knowledge.


Genetic parameters for ewe productivity traits in the Columbia, Suffolk and Targhee breeds.
Estimates of repeatability and heritability were obtained for the following productivity traits of ewes: litter weight at birth (LWB) and weaning (LWW), litter size at birth (LSB), litter size alive at birth (NBA), litter size at weaning (LSW), neonatal survival rate (SRB) and preweaning survival rate (SRW). Phenotypic and genetic correlations were estimated for litter traits. The data set contained 6,394 ewe breeding records from three state stations over 10 yr on 1,731 ewes that were the progeny of 488 sires among three breeds (Columbia, Suffolk and Targhee). Pooled intra-station estimates of repeatability ranged from .11 to .22 for LWB and LWW among the three breeds. For litter size at birth, number born alive and litter size at weaning these estimates varied from .09 to .17 and for the survival traits (SRB and SRW) the variation was from .11 to .20. Intra-station estimates of heritability for the three breeds varied from .12 to .28 for LWB and LWW, and for LSB, NBA and LSW estimates varied from .05 to .35. Heritability estimates for survival traits (SRB and SRW) were low, ranging from .00 to .14. Phenotypic correlations among LWB, LWW, NBA and LSW ranged from .35 to .92 among the breed-station subclasses, with higher correlations occurring where a part-whole relationship existed. The study suggests that selection of ewes with high litter size at birth or at weaning and(or) litter weight at birth or at weaning will genetically improve total litter weight at weaning per ewe lambing.


Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function.
Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown. To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea. Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016). New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function. MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death. There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2 [IQR, 51.6-58.2] and hemoglobin A1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use. Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.


[Clinical manifestations and diagnosis of distant metastases of differentiated thyroid carcinoma after initial therapy].
We studied 58 patients with distant metastases of differentiated thyroid carcinoma diagnosed after initial therapy. Lymph node metastases were observed in 65% of the patients on initial presentation. All lymph node metastases, ninety percent of the lung metastases and only 25% of the bone metastases were asymptomatic. Radiography revealed lytic metastases in cases of bone involvement, was normal in 39.6% of the patients, and showed micrometastases in 34.5% and macrometastases in 25.8% of the patients with lung disease. Thyroglobulin (Tg) under thyroxine use was detectable in all patients without antibodies at a cut-off > 1 ng/ml, in 90% at > 5 ng/ml and in 80% at > 10 ng/ml, and after thyroxine withdrawal in 100% at a cut-off > 5 ng/ml and in 94% at > 10 ng/ml. In the case of patients with antibodies (13.8%), Tg was undetectable in half of them. Diagnostic scanning was positive in 83 and 77.6% of the patients with bone and lung metastases, respectively. After ablative therapy, the sensitivity was 100 and 93%, respectively. Eighty-five percent of patients with a negative diagnostic scan had lung metastases visible on radiographs. The determination of serum Tg is the best method in the follow-up of patients with differentiated thyroid cancer. Elevated Tg levels suggest the presence of metastases, indicating the need for ablative therapy with posttreatment scanning, which might reveal non-apparent metastases.


The morphological and biochemical effects of glibornuride on rat liver in experimental diabetes.
Glibornuride is a sulphonylurea derivative used as an oral hypoglycaemic drug in diabetics. The aim of this study was to examine the histological, ultrastructural and biochemical effects of glibornuride in streptozotocin (STZ)-treated rats. The animals were rendered diabetic by intraperitoneal injection of 65 mg/kg STZ. Fourteen days later, glibornuride was given at 5 mg/kg by gavage, daily for 28 days, to one STZ-diabetic and one control group. In the STZ-diabetic group, remarkable degenerative changes were observed. On the other hand, in the STZ-diabetic group given glibornuride, the degenerative changes decreased. In the STZ-diabetic group, blood glucose levels, serum aspartate transaminase activity, and total lipid levels increased, whereas the blood glutathione levels decreased. In contrast, in the STZ-diabetic group given glibornuride blood glucose levels, serum aspartate transaminase activity and total lipid levels decreased and blood glutathione levels increased. Significant changes in total protein levels in the serum were not observed in any group. As a conclusion, we can say that glibornuride has a protective effect against the hepatotoxicity produced by STZ-diabetes.


Adrenal Incidentaloma.
An adrenal incidentaloma is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management. The majority of patients can be reassured and discharged, but a personalized approach based upon image analysis, endocrine workup, and clinical symptoms and signs are required in every case. Adrenocortical carcinoma remains a real concern but is restricted to <2% of all cases. Functional adrenal incidentaloma lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of autonomous cortisol secretion. Modern-day surgery has improved outcomes and novel radiological and urinary biomarkers will improve early detection and patient stratification in future years to come.


[Legal responsibilities of anesthesia-resuscitation specialists for professional malpractice].
An experience of consulting at large medical insurance companies is indicative of that anesthesiology and resuscitation belong to most risky professions, which involve a possibility of inflicting an illegal damage on an insured citizen. The reasons of such a situation are as follows: a surface knowledge of the legal-and-normative aspects (which regulate the provision of medical care to citizens) by anesthesiologists and experts in resuscitation; a lack of profound erudition in the main fields of medicine and a comprehensive use of sophisticated medical instruments, which is a source of an extra danger to patients. The protection of both the doctor and the patients is an important issue under such conditions. Therefore, it is necessary to define the rights and obligations of anesthesiologists and experts in resuscitation, to master the normative acts regulating the standards of medical care and to obey strictly the fixed-by-law rights of patients.


The native language of social cognition.
What leads humans to divide the social world into groups, preferring their own group and disfavoring others? Experiments with infants and young children suggest these tendencies are based on predispositions that emerge early in life and depend, in part, on natural language. Young infants prefer to look at a person who previously spoke their native language. Older infants preferentially accept toys from native-language speakers, and preschool children preferentially select native-language speakers as friends. Variations in accent are sufficient to evoke these social preferences, which are observed in infants before they produce or comprehend speech and are exhibited by children even when they comprehend the foreign-accented speech. Early-developing preferences for native-language speakers may serve as a foundation for later-developing preferences and conflicts among social groups.


Proteomic Expression Changes in Large Cerebral Arteries After Experimental Subarachnoid Hemorrhage in Rat Are Regulated by the MEK-ERK1/2 Pathway.
Subarachnoid hemorrhage (SAH) is a serious clinical condition where leakage of blood into the subarachnoid space causes an acute rise in intracranial pressure and reduces cerebral blood flow, which may lead to delayed cerebral ischemia and poor outcome. In experimental SAH, we have previously shown that the outcome can be significantly improved by early inhibition of the MAPK/ERK kinase/extracellular signal-regulated kinase (MEK/ERK1/2) pathway. The aim of this study was to apply mass spectrometry to investigate the overall late effects of experimental SAH on cerebrovascular protein expression. SAH was induced in rats that were treated with the MEK1/2 inhibitor U0126 or vehicle. Neurological outcome was assessed using a battery of behavioral tests. Specific protein expression of large cerebral arteries was analyzed quantitatively with high-throughput tandem mass spectrometry. SAH resulted in a marked reduction of neurological scores, which was counteracted by U0126 treatment. Mass spectrometry analysis demonstrated regulation of 184 proteins after SAH, regulations that were in part prevented by U0126 treatment. Network analysis identified several protein networks including a strong structural network centered around 14-3-3. Additionally, protein networks with functions in mRNA metabolism and protein folding were identified. Treatment with U0126 inhibited cerebral vessel wall pERK1/2 expression and significantly improved outcome of the rats. In conclusion, we show that SAH induces a broad array of specific changes in the overall protein networks in cerebral artery smooth muscle cells and suggest that this is essential for understanding the vascular pathophysiology after SAH.


The HOSPITAL score as a predictor of 30 day readmission in a retrospective study at a university affiliated community hospital.
Hospital readmissions are common, expensive, and a key target of the Medicare Value Based Purchasing (VBP) program. Risk assessment tools have been developed to identify patients at high risk of hospital readmission so they can be targeted for interventions aimed at reducing the rate of readmission. One such tool is the HOSPITAL score that uses seven readily available clinical variables to predict the risk of readmission within 30 days of discharge. The HOSPITAL score has been internationally validated in large academic medical centers. This study aims to determine if the HOSPITAL score is similarly useful in a moderate sized university affiliated hospital in the midwestern United States. All adult medical patients discharged from the SIU-SOM Hospitalist service from Memorial Medical Center (MMC) from October 15, 2015 to March 16, 2016, were studied retrospectively to determine if the HOSPITAL score was a significant predictor of hospital readmission within 30 days. During the study period, 998 discharges were recorded for the hospitalist service. The analysis includes data for the 931 discharges. Patients who died during the hospital stay, were transferred to another hospital, or left against medical advice were excluded. Of these patients, 109 (12%) were readmitted to the same hospital within 30 days. The patients who were readmitted were more likely to have a length of stay greater than or equal to 5 days (55% vs. 41%, p = 0.005) and were more likely to have been admitted more than once to the hospital within the last year (100% vs. 49%, p < 0.001). A receiver operating characteristic evaluation of the HOSPITAL score for this patient population shows a C statistic of 0.77 (95% CI [0.73-0.81]), indicating good discrimination for hospital readmission. The Brier score for the HOSPITAL score in this setting was 0.10, indicating good overall performance. The Hosmer-Lemeshow goodness of fit test shows a χ (2) value of 1.63 with a p value of 0.20. This single center retrospective study indicates that the HOSPITAL score has good discriminatory ability to predict hospital readmissions within 30 days for a medical hospitalist service at a university-affiliated hospital. This data for all causes of hospital readmission is comparable to the discriminatory ability of the HOSPITAL score in the international validation study (C statistics of 0.72 vs. 0.77) conducted at considerably larger hospitals (975 average beds vs. 507 at MMC) for potentially avoidable hospital readmissions. The internationally validated HOSPITAL score may be a useful tool in moderate sized community hospitals to identify patients at high risk of hospital readmission within 30 days. This easy to use scoring system using readily available data can be used as part of interventional strategies to reduce the rate of hospital readmission.


Respiratory sensitivity before and after birth.
A description is first given of respiratory activity in the fetus and its control. Evidence suggests that when the fetus makes respiratory movements, it is in a state comparable to REM sleep in the newborn and adult and that in the alternating periods of apnoea, it is in quiet sleep. It does not appear that the respiratory movements are normally regulated by chemical or reflex, e.g. Hering Breuer, inputs though they are enhanced by CO2 and depressed by hypoxia. In the apnoeic periods, breathing movements are virtually impossible to elicit by chemical or reflex means. Evidence from examination of peripheral inputs indicates that: the carotid body chemoreceptors are inhibited at receptor level, stimulation of the aortic chemoreceptors affects the circulation only and although pulmonary stretch receptors are active and are excited by inflation of the fetal lung, such inflation does not affect discharge in medullary respiratory units or phrenic nerve. Since there is no real evidence of immaturity of the respiratory system in late gestation and since chemical and most reflex inputs appear to provide an adequate stimulus, it is most probable that the periods of apnoea are caused by an inhibitory process, possibly of supra-pontine origin which acts close to medullary respiratory units and effectively inhibits the operation of the automatic component. This inhibitory process may operate periodically; or continuously and be periodically overridden in REM sleep. After birth, breathing is normally continuous and sensitive to lung inflation, CO2 and after a variable delay, to hypoxia. This may be due to the lifting of the inhibitory process allowing activation of the automatic component. However, there is evidence that even in normal, full term infants, full maturation of the automatic component is not complete until about three months of age and in the meanwhile, breathing tends to be imperfectly regulated and subject to damped oscillations when disturbed.


Canine distemper virus matrix protein influences particle infectivity, particle composition, and envelope distribution in polarized epithelial cells and modulates virulence.
In paramyxoviruses, the matrix (M) protein mediates the interaction between the envelope and internal proteins during particle assembly and egress. In measles virus (MeV), M mutations, such as those found in subacute sclerosing panencephalitis (SSPE) strains, and differences in vaccine and wild-type M proteins can affect the strength of interaction with the envelope glycoproteins, assembly efficiency, and spread. However, the contribution of the M protein to the replication and pathogenesis of the closely related canine distemper virus (CDV) has not been characterized. To this end this, we generated a recombinant wild-type CDV carrying a vaccine strain M protein. The recombinant virus retained the parental growth phenotype in VerodogSLAMtag cells, but displayed an increased particle-to-infectivity ratio very similar to that of the vaccine strain, likely due to inefficient H protein incorporation. Even though infectious virus was released only from the apical surface, consistent with the release polarity of the wild-type CDV strain, envelope protein distribution in polarized epithelial cells reproduced the bipolar pattern seen in vaccine strain-infected cells. Most notably, the chimeric virus was completely attenuated in ferrets and caused only a mild and transient leukopenia, indicating that the differences in particle infectivity and envelope protein sorting mediated by the vaccine M protein contribute importantly to vaccine strain attenuation.


Analysis of morphological characteristics of IDH-mutant/wildtype brain tumors using whole-lesion phenotype analysis.
Although IDH-mutant tumors aggregate to the frontotemporal regions, the clustering pattern of IDH-wildtype tumors is less clear. As voxel-based lesion-symptom mapping (VLSM) has several limitations for solid lesion mapping, a new technique, whole-lesion phenotype analysis (WLPA), is developed. We utilize WLPA to assess spatial clustering of tumors with IDH mutation from The Cancer Genome Atlas and The Cancer Imaging Archive. The degree of tumor clustering segmented from T1 weighted images is measured to every other tumor by a function of lesion similarity to each other via the Hausdorff distance. Each tumor is ranked according to the degree to which its neighboring tumors show identical phenotypes, and through a permutation technique, significant tumors are determined. VLSM was applied through a previously described method. A total of 244 patients of mixed-grade gliomas (WHO II-IV) are analyzed, of which 150 were IDH-wildtype and 139 were glioblastomas. VLSM identifies frontal lobe regions that are more likely associated with the presence of IDH mutation but no regions where IDH-wildtype was more likely to be present. WLPA identifies both IDH-mutant and -wildtype tumors exhibit statistically significant spatial clustering. WLPA may provide additional statistical power when compared with VLSM without making several potentially erroneous assumptions. WLPA identifies tumors most likely to exhibit particular phenotypes, rather than producing anatomical maps, and may be used in conjunction with VLSM to understand the relationship between tumor morphology and biologically relevant tumor phenotypes.


Influence of geographic origin on AIDS and serious non-AIDS morbidity/mortality during cART among heterosexual HIV-infected men and women in France.
The influence of geographic origin on the risk of severe illness and death on cART has not been explored in European countries. We studied antiretroviral-naïve heterosexual HIV-1-infected individuals enrolled in the FHDH-ANRS CO4 cohort in France who started cART between 2006 and 2011. Individuals originating from France (French natives), sub-Saharan Africa (SSA) and non-French West-Indies (NFW) were studied until 2012. Crude and adjusted rate ratios (aRR) of severe morbid events/deaths (AIDS-related and non-AIDS-related) were calculated using Poisson regression models stratified by sex, comparing each group of migrants to French natives. Among 2334 eligible men, 1379 (59.1%) originated from France, 838 (35.9%) from SSA and 117 (5.0%) from NFW. SSA male migrants had a higher aRR for non-AIDS infections, particularly bacterial infections (aRR 1.56 (95% CI 1.07-2.29), p = 0.0477), than French natives. Among 2596 eligible women, 1347 (51.9%) originated from France, 1131 (43.6%) from SSA, and 118 (4.5%) from NFW. SSA and NFW female migrants had a higher aRR for non-AIDS infections, particularly non-bacterial infections (respectively, 2.04 (1.18-3.53) and 7.87 (2.54-24.4), p = 0.0010), than French natives. We observed no other significant differences related to geographic origin as concerns the aRRs for AIDS-related infections or malignancies, or for other non-AIDS events/deaths such as cardiovascular disease, neurological/psychiatric disorders, non-AIDS malignancies and iatrogenic disorders, in either gender. Heterosexual migrants from SSA or NFW living in France have a higher risk of non-AIDS-defining infections than their French native counterparts. Special efforts are needed to prevent infectious diseases among HIV-infected migrants.


Optimization of tractography of the optic radiations.
Imaging and delineation of the optic radiations (OpRs) remains challenging, despite repeated attempts to achieve reliable validated tractography of this complex structure. Previous studies have used varying methods to generate representations of the OpR which differ markedly from one another and, frequently, from the OpR's known structure. We systematically examined the influence of a key variable that has differed across previous studies, the tractography seed region, in 13 adult participants (nine male; mean age 31 years; SD 8.7 years; range 16-47). First, we compared six seed regions at the lateral geniculate nucleus (LGN) and sagittal stratum based on the literature and known OpR anatomy. Three of the LGN regions seeded streamlines consistent with the OpR's three "bundles," whereas a fourth seeded streamlines consistent with each of the three bundles. The remaining two generated OpR streamlines unreliably and inconsistently. Two stratum regions seeded the radiations. This analysis identified a set of optimal regions of interest (ROI) for seeding OpR tractography and important inclusion and exclusion ROI. An optimized approach was then used to seed LGN regions to the stratum. The radiations, including streamlines consistent with Meyer's Loop, were streamlined in all cases. Streamlines extended 0.2 ± 2.4 mm anterior to the tip of the anterior horn of the lateral ventricle. These data suggest some existing approaches likely seed representations of the OpR that are visually plausible but do not capture all OpR components, and that using an optimized combination of regions seeded previously allows optimal mapping of this complex structure.


The role of the plant-specific ALTERED XYLOGLUCAN9 protein in Arabidopsis cell wall polysaccharide O-acetylation.
A mutation in the ALTERED XYLOGLUCAN9 (AXY9) gene was found to be causative for the decreased xyloglucan acetylation phenotype of the axy9.1 mutant, which was identified in a forward genetic screen for Arabidopsis (Arabidopsis thaliana) mutants. The axy9.1 mutant also exhibits decreased O-acetylation of xylan, implying that the AXY9 protein has a broad role in polysaccharide acetylation. An axy9 insertional mutant exhibits severe growth defects and collapsed xylem, demonstrating the importance of wall polysaccharide O-acetylation for normal plant growth and development. Localization and topological experiments indicate that the active site of the AXY9 protein resides within the Golgi lumen. The AXY9 protein appears to be a component of the plant cell wall polysaccharide acetylation pathway, which also includes the REDUCED WALL ACETYLATION and TRICHOME BIREFRINGENCE-LIKE proteins. The AXY9 protein is distinct from the TRICHOME BIREFRINGENCE-LIKE proteins, reported to be polysaccharide acetyltransferases, but does share homology with them and other acetyltransferases, suggesting that the AXY9 protein may act to produce an acetylated intermediate that is part of the O-acetylation pathway.


Subconjunctival draining minimally-invasive glaucoma devices for medically uncontrolled glaucoma.
Glaucoma is a leading cause of irreversible blindness. Subconjunctival draining minimally-invasive glaucoma devices such as the Xen gelatin implant and InnFocus stent have been introduced as a treatment to prevent glaucoma progressing.These implants provide a channel to allow aqueous humour from the anterior chamber of the eye to drain into the subconjunctival space on the surface of the eye thus reducing intraocular pressure (IOP) and mimicking the mechanism of the most commonly undertaken glaucoma surgery, trabeculectomy. To evaluate the efficacy and safety of subconjunctival draining minimally-invasive glaucoma devices in treating people with open angle glaucoma and ocular hypertension whose condition is inadequately controlled with drops. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2018, Issue 6); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 10 July 2018. We searched for randomised controlled trials (RCTs) of Xen gelatin implant or InnFocus MicroShunt to other surgical treatments (other minimally-invasive glaucoma device techniques, trabeculectomy), laser treatment or medical treatment. We also planned to include trials where these devices were combined with phacoemulsification compared to phacoemulsification alone. We planned to have two review authors independently extract data from reports of included studies using a data collection form and analyse data based on methods expected by Cochrane. Our primary outcome was mean change in IOP. Secondary outcomes included proportion of participants who were drop-free; proportion of participants who achieved an IOP of 21 mmHg or less, 17 mmHg or less or 14 mmHg or less; and proportion of participants experiencing intra- and postoperative complications. We planned to measure all outcomes in the short-term (six to 18 months), medium-term (18 to 36 months), and long-term (36 months onwards). We found no completed RCTs that met our inclusion criteria. We found one ongoing study (NCT01881425). The study compares InnFocus MicroShunt to trabeculectomy in people with primary open angle glaucoma. The primary outcome is greater than 20% IOP reduction from baseline to 12 months' follow-up. A total of 889 people aged between 40 and 85 years have been enrolled. The estimated study completion date is November 2019. There is currently no high-quality evidence for the effects of subconjunctival draining minimally-invasive glaucoma devices for medically uncontrolled open angle glaucoma. Properly designed RCTs are needed to assess the medium- and long-term efficacy and safety of this technique.


Preliminary evidence that polymorphisms in dopamine-related transcription factors LMX1A, LMX1B and PITX3 are associated with schizophrenia.
The early development of dopaminergic pathways has been attributed importance for the aetiology of schizophrenia. Several transcription factors are involved in the survival and maturation of dopamine neurons, including LMX1A, LMX1B and PITX3. The possibility that polymorphisms in these genes may influence the development and/or the maintenance of dopaminergic neurons prompted us to investigate if five single nucleotide polymorphisms (SNPs) previously linked to Parkinson's disease are associated with this disorder. Preliminary evidence that genetic variation in LMX1A (rs6668493, rs4657411), LMX1B (rs10987386) and PITX3 (rs4919621) may increase the risk of developing schizophrenia is presented.


A role for microtubules in Plasmodium falciparum merozoite invasion.
Colchicine, a drug which poisons the polymerization of microtubules, was assayed for effects on the invasion of Plasmodium falciparum merozoites into red cells in order to investigate if merozoite microtubules have a function in invasion. Culture conditions and concentrations of colchicine were established where the maturation and rupture of schizonts was unaffected by the drug. This was judged first by light microscopy, including morphology and counts of nuclear particle numbers, then by ultrastructural studies which excluded deranged organellogenesis as a cause of merozoite failure, and finally by diachronic cultures in which both recruitment and loss of schizonts could be counted. Specific invasion inhibition was seen when 10 microM-1 mM colchicine was present. Red cells pre-incubated in colchicine and then washed showed no reduction in their extent of invasion, and neither red cell lysis, sphering nor blebbing were apparent. We conclude that intact microtubules are necessary for successful merozoite function.


A pilot study to assess the safety and efficacy of topical calcipotriol treatment in childhood psoriasis.
Childhood psoriasis is more extensive and severe compared with that of adults. Therefore an effective and safe treatment modality is needed. Although a few studies of childhood psoriasis indicate that treatment with calcipotriol is safe and effective, short-term studies cannot reflect the exact effect of calcipotriol on systemic calcium homeostasis. Our purpose was to study the long-term efficacy and safety of calcipotriol for childhood psoriasis. An uncontrolled pilot study, with long-term follow-up for as long as 106 weeks, using open-label calcipotriol ointment was conducted in 12 psoriasis patients less than 15 years of age. Response to treatment was assessed by the psoriasis area and severity index (PASI) and serum 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 levels, as well as routine laboratory analyses including serum calcium and phosphate, which were measured before and after the course of treatment. At the end of the study, the patients showed significant improvement in PASI scores compared with the baseline level. No serious side effects, including those related to calcium homeostasis, were detected. The mean values of 1,25-dihydroxyvitamin D3, however, were decreased and half of the patients had levels below the normal range. In conclusion, it is thought that calcipotriol ointment is an effective treatment modality for long-term use in childhood psoriasis. However, although not lowering serum calcium and phosphate levels, the long-term use of calcipotriol in childhood may possibly decrease the serum values of endogenous vitamin D. Therefore monitoring of vitamin D metabolites may be necessary during calcipotriol therapy. More investigative studies are needed to resolve this issue.


Liver pathology in aircrew.
The aim of this review is to determine the incidence and aetiology of fatty liver and other liver pathology in aircrew. A review of 525 fatal aircraft accidents resulted in deaths of 776 aircrew. Histology of liver, available in 423 aircrew, was reviewed and 118 found abnormal. There were 66 cases (15.6%) of fatty livers. In 11 of the fatty livers and 8 of the 52 non-fatty livers there was histopathologic evidence compatible with alcohol abuse (4.5%). The histopathologic appearances are discussed.


Synthesis, crystal structure and biological activity of 2-hydroxyethylammonium salt of p-aminobenzoic acid.
p-Aminobenzoic acid (pABA) plays important roles in a wide variety of metabolic processes. Herein we report the synthesis, theoretical calculations, crystallographic investigation, and in vitro determination of the biological activity and phytotoxicity of the pABA salt, 2-hydroxyethylammonium p-aminobenzoate (HEA-pABA). The ability of neutral and anionic forms of pABA to interact with TIR1 pocket was investigated by calculation of molecular electrostatic potential maps on the accessible surface area, docking experiments, Molecular Dynamics and Quantum Mechanics/Molecular Mechanics calculations. The docking study of the folate precursor pABA, its anionic form and natural auxin (indole-3-acetic acid, IAA) with the auxin receptor TIR1 revealed a similar binding mode in the active site. The phytotoxic evaluation of HEA-pABA, pABA and 2-hydroxyethylamine (HEA) was performed on the model plant Arabidopsis thaliana ecotype Col 0 at five different concentrations. HEA-pABA and pABA acted as potential auxin-like regulators of root development in Arabidopsis thaliana (0.1 and 0.2 mM) and displayed an agravitropic root response at high concentration (2 mM). This study suggests that HEA-pABA and pABA might be considered as potential new regulators of plant growth.


DPPH Radical Scavenging and Postprandial Hyperglycemia Inhibition Activities and Flavonoid Composition Analysis of Hawk Tea by UPLC-DAD and UPLC-Q/TOF MSE.
Hawk tea (Litsea coreana Lévl. var. Lanuginosa (Migo) Yen C. Yang & P.H. Huang), a very popular herbal tea material, has attracted more and more attention due to its high antioxidant properties and possible therapeutic effect on type II diabetes mellitus. The raw materials of Hawk tea are usually divided into three kinds: bud tea (BT), primary leaf tea (PLT) and mature leaf tea (MLT). In this study, the DPPH radical scavenging activity and the antimicrobial properties of these three kinds of Hawk tea from different regions were comparatively investigated, and a ultra-high performance liquid chromatographic coupled with a photodiode array detector (UPLC-DAD) method was employed for comparison of the three major flavonoid constituents, including hyperoside, isoquercitrin and astragalin, in different samples of Hawk tea. At the same time, the effect of methanol extract (ME) of PLT on the mouse postprandial blood glucose and the effect of ME and its different fractions (petroleum ether fraction (PE), ethyl acetate fraction (EA), n-butanol fraction (n-BuOH), and water fraction (WF)) on the activity of α-glucosidase were studied. The results showed that Hawk BT and Hawk PLT possessed the higher radicals scavenging activity than Hawk MLT, while the antibacterial activity against P. vulgaris of PLT and MLT was higher than Hawk BT. The contents of the three major flavonoid constituents in samples of Hawk PLT are higher than Hawk BT and Hawk MLT. The mouse postprandial blood glucose levels of the middle dose (0.5 g/kg) group and the high dose (1 g/kg) group with oral administration of the ME of PLT were significantly lower than the control group. What's more, the inhibitory effect of ME of PLT and its EA and n-BuOH fractions on α-glucosidase was significantly higher than that of acarbose. Rapid ultra-high performance liquid chromatography/quadrupole time-of-flight-mass spectrometry (UPLC-ESI-QTOF-MS) was used to identify the flavonoids in Hawk PLT, and a total of 20 flavonoids were identified or tentatively identified by comparing their retention times and accurate mass measurements with reference compounds or literature data. The bioactive flavonoid composition and DPPH radical scavenging activities present in different Hawk tea raw materials are quite different due to the different ontogenesis of these raw materials. Further studies on PLT showed that the substances in PLT ME could reduce the level of mouse postprandial blood glucose through inhibiting the activity of α-glucosidase.


Spinal Epidural Abscess and Strep Pharyngitis.
Spinal epidural abscesses (SEA) require prompt diagnosis to avoid devastating consequences. Here, we discuss the case of a healthy 20-year-old college student-with a recent diagnosis of strep pharyngitis-who presented with neck pain, fever, and a neurologic deficit-the most common symptoms of SEA. Magnetic resonance imaging revealed a T1-postcontrast, peripherally enhancing epidural collection from C3-T5 with associated cord compression and T3 osteomyelitis. The patient was treated with emergent skip hemilaminectomies for abscess evacuation. Surgical cultures grew Fusobacterium necrophorum, a highly unusual pathogen in SEA. It is an oral anaerobe that translocated through the mucosa in the setting of strep pharyngitis. We treated the patient with ceftriaxone for 6 weeks. The patient had a full neurologic recovery and remains without recurrence of infection 11 months postoperatively. Healthy patients without obvious risk factors may present with SEA, highlighting the need for atypical cases such as these to be brought to clinicians' attention.


[Fetal and neonatal alloimmune thrombocytopenia].
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may lead to intracranial haemorrhage (ICH) resulting in neurological damage or death. In FNAIT, transplacental maternal antibodies cause destruction of fetal platelets. Maternal immunisation occurs to fetal human platelet antigens (HPAs) inherited from the father. In the absence of screening the diagnosis often relies on a serious incident in a previous pregnancy or in a newborn sibling. Thus, a future reduction in the risk of ICH depends on prospective large trials to evaluate different diagnostic, treatment, and prevention strategies.


A Measure of Safety Behaviors for Use with Young People: Subtle Avoidance Measure for Youth.
Objective: Safety behaviors have been found to undermine successful exposure in the treatment of anxiety disorders for both adults and children. Although reliable measures of safety behaviors have been developed for use with adults, no such measure has been developed specifically for pediatric populations. In light of this limitation, the current study aimed to develop and validate a measure of the use of safety behaviors suitable for children: The Subtle Avoidance Measure for Youth (SAMY).Methods: Clinical (n = 174) and community (n = 138) young people, aged 7-13 years, provided data.Results: Both exploratory and confirmatory factor analyses supported a three-factor solution of the SAMY, which reflected checking behaviors, behaviors related to image management, and behaviors related to physical protection. The SAMY and its subscales demonstrated strong internal consistency, test-retest reliability, construct validity, and the ability to discriminate between clinical and community participants.Conclusions: Given its solid psychometric properties, the SAMY will prove useful for both research and clinical work with anxious young people.


On the anatomy of the temporomandibular joint and the muscles that act upon it: observations on the gray whale, Eschrichtius robustus.
The temporomandibular joint and its associated musculature are described in a neonate gray whale (Eschrichtius robustus) and serve as the basis for direct anatomical comparisons with the temporomandibular region in other clades of baleen whales (Mysticeti). Members of the right whale/bowhead whale clade (Balaenidae) are known to possess a synovial lower jaw joint, while members of the rorqual clade (Balaenopteridae) have a nonsynovial temporomandibular joint characterized by a highly flexible fibrocartilaginous pad and no joint capsule. In contrast, the gray whale possesses a modified temporomandibular joint (intermediate condition), with a vestigial joint cavity lacking a fibrous capsule, synovial membrane, and articular disk. In addition, the presence of a rudimentary fibrocartilaginous pad appears to be homologous to that seen in balaenopterid mysticetes. The intrinsic temporomandibular musculature in the gray whale was found to include a multibellied superficial masseter and a single-bellied deep masseter. The digastric and internal pterygoid muscles in E. robustus are enlarged relative to the condition documented in species of Balaenoptera. A relatively complex insertion of the temporalis muscle on the dentary is documented in the gray whale and the low, knob-like process on the gray whale dentary is determined to be homologous with the prominent coronoid process of rorquals. Comparison with the anatomy of the temporomandibular musculature in rorquals reveals an increased importance of alpha rotation of the dentary in the gray whale. This difference in muscular morphology and lines of muscle action is interpreted as representing adaptations for suction feeding.


The polyadenylated RNA directing the synthesis of the rat myelin basic proteins is present in both free and membrane-bound forebrain polyribosomes.
Free and membrane-bound polyribosomes were isolated from the forebrain of actively myelinating 24-day-old rats. The poly(A)+ RNA (polyadenylated RNA) extracted from both fractions was translated in vitro in reticulocyte lysates [Hall & Lim (1981) Biochem. J. 196. 327-336] in the presence or absence of a heterologous microsomal membrane fraction from dog pancreas. The rat myelin basic proteins synthesized in vitro were isolated by CM-cellulose chromatography and by immunoprecipitation with purified anti-(myelin basic protein) antibody. The large (mol.wt. 18 500) and small (mol.wt. 16 000) myelin basic proteins were translational products of poly(A)+ RNA from both free and membrane-bound polyribosomes. The identity of the myelin basic proteins was verified by analysis of peptides generated by the cathepsin D digestion of the immunoprecipitated proteins synthesized in vitro, in comparison with authentic rat myelin basic proteins. Although several other translational products of membrane-bound polyribosomal poly(A)+ RNA were modified when microsomal membranes were present during translation, molecular weights of the myelin basic proteins themselves were unchanged. The myelin basic proteins synthesized in vitro also did not differ significantly in size from the authentic myelin basic proteins, indicating that these membrane proteins are unlikely to be synthesized as substantially larger precursor molecules. The presence of the specific mRNA species on both free and membrane-bound polyribosomes is compatible with the extrinsic location of the myelin basic proteins on the cytoplasmic surface of the myelin membrane.


Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice.
Pit1 null (Snell dwarf) and Proph1 null (Ames dwarf) mutant mice lack GH, PRL and TSH. Snell and Ames dwarf mice also exhibit reduced IGF-I, resistance to cancer and a longer lifespan than control mice. Endogenous glucose production during fasting is reduced in Snell dwarf mice compared to fasting control mice. In view of cancer cell dependence on glucose for energy, low endogenous glucose production may provide Snell dwarf mice with resistance to cancer. We investigated whether endogenous glucose production is lower in Snell dwarf mice during feeding. Inhibition of endogenous glucose production by glucose injection was enhanced in 12 to 14 month-old female Snell dwarf mice. Thus, we hypothesize that lower endogenous glucose production during feeding and fasting reduces cancer cell glucose utilization providing Snell dwarf mice with resistance to cancer. The elevation of circulating adiponectin, a hormone produced by adipose tissue, may contribute to the suppression of endogenous glucose production in 12 to 14 month-old Snell dwarf mice. We compared the incidence of cancer at time of death between old Snell dwarf and control mice. Only 18% of old Snell dwarf mice had malignant lesions at the time of death compared to 82% of control mice. The median ages at death for old Snell dwarf and control mice were 33 and 26 months, respectively. By contrast, previous studies showed a high incidence of cancer in old Ames dwarf mice at the time of death. Hence, resistance to cancer in old Snell dwarf mice may be mediated by neuroendocrine factors that reduce glucose utilization besides elevated adiponectin, reduced IGF-I and a lack of GH, PRL and TSH, seen in both Snell and Ames dwarf mice. Proteomics analysis of pituitary secretions from Snell dwarf mice confirmed the absence of GH and PRL, the secretion of ACTH and elevated secretion of Chromogranin B and Secretogranin II. Radioimmune assays confirmed that circulating Chromogranin B and Secretogranin II were elevated in 12 to 14 month-old Snell dwarf mice. In summary, our results in Snell dwarf mice suggest that the pituitary gland and adipose tissue are part of a neuroendocrine loop that lowers the risk of cancer during aging by reducing the availability of glucose.


Digoxin therapy: A persisting interest despite contrary winds.
Digoxin therapy is used to treat heart failure patients for more than 200 years. However, absence of effect on overall mortality found in the DIG study associated with frequent adverse effects due to overdosing in elderly patients with impaired renal function finally persuaded medical opinion to the weak interest of digoxin in chronic heart failure. Its image of old-fashioned drug in the mind of young cardiology generations appears widely distorted, and suffers from the absence of promotion by pharmaceutical industry, given a very low cost and a rapid arrival onto the generic market. Yet, regarding strict data from the literature, it remains a lot of positive factors in favor of the interest for digoxin: reduction of morbidity, reduction of mortality at low serum concentration <1.0 ng/ml, very low cost with favorable cost-effectiveness ratio. This article challenges some arguments for defending digoxin as another first-line therapy as well as ACE inhibitors and beta-blockers in the treatment of chronic heart failure.


Detection of common and less frequent EGFR mutations in cytological samples of lung cancer.
Lung cancer represents the leading cause of cancer death. EGFR mutations, detected in 10-40% of lung adenocarcinomas, are an essential key to therapeutic management. EGFR-activated mutations comprise mainly deletions in exon 19 and point mutations in exon 21. Although histology is the traditional method of detection, we investigated the role of cytology in EGFR mutations. A total of 774 lung cancers were studied for EGFR mutations (676 histological and 98 cytological samples), including 424 adenocarcinomas, 326 non-small cell lung carcinomas not otherwise specified, and 24 squamous cell carcinomas. We had a total of 164 (21.2%) cases of mutations. Common mutations were short in-frame deletions in exon 19 (53.7%) and single-nucleotide substitutions in exon 21 (34.1%); less frequent mutations included single-nucleotide substitutions in exon 18 (3.7%) and in-frame insertions/deletions in exon 20 (8.5%). Histologically, EGFR mutations in exons 19 and 21 occurred in 19.4% and in exons 18 and 20 in 2.2%, while the rates cytologically were 13.3% for exons 19 and 21 and 5.1% for exons 18 and 20. The sensitivity for the detection of EGFR mutations in cytological samples overlaps histology, so the use of cytological material constitutes an adequate approach for treatment selection in patients with locally advanced or metastatic lung cancer.


Guanine-nucleotide exchange factors (RAPGEF3/RAPGEF4) induce sperm membrane depolarization and acrosomal exocytosis in capacitated stallion sperm.
Capacitation encompasses the molecular changes sperm undergo to fertilize an oocyte, some of which are postulated to occur via a cAMP-PRKACA (protein kinase A)-mediated pathway. Due to the recent discovery of cAMP-activated guanine nucleotide exchange factors RAPGEF3 and RAPGEF4, we sought to investigate the separate roles of PRKACA and RAPGEF3/RAPGEF4 in modulating capacitation and acrosomal exocytosis. Indirect immunofluorescence localized RAPGEF3 to the acrosome and subacrosomal ring and RAPGEF4 to the midpiece in equine sperm. Addition of the RAPGEF3/RAPGEF4-specific cAMP analogue 8-(p-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8pCPT) to sperm incubated under both noncapacitating and capacitating conditions had no effect on protein tyrosine phosphorylation, thus supporting a PRKACA-mediated event. Conversely, activation of RAPGEF3/RAPGEF4 with 8pCPT induced acrosomal exocytosis in capacitated equine sperm at rates (34%) similar (P > 0.05) to those obtained in progesterone- and calcium ionophore-treated sperm. In the mouse, capacitation-dependent hyperpolarization of the sperm plasma membrane has been shown to recruit low voltage-activated T-type Ca(2+) channels, which later open in response to zona pellucida-induced membrane depolarization. We hypothesized that RAPGEF3 may be inducing acrosomal exocytosis via depolarization-dependent Ca(2+) influx, as RAPGEF3/RAPGEF4 have been demonstrated to play a role in the regulation of ion channels in somatic cells. We first compared the membrane potential (E(m)) of noncapacitated (-37.11 mV) and capacitated (-53.74 mV; P = 0.002) equine sperm. Interestingly, when sperm were incubated (6 h) under capacitating conditions in the presence of 8pCPT, E(m) remained depolarized (-32.06 mV). Altogether, these experiments support the hypothesis that RAPGEF3/RAPGEF4 activation regulates acrosomal exocytosis via its modulation of E(m), a novel role for RAPGEF3/RAPGEF4 in the series of events required to achieve fertilization.


Advanced Age is Not a Contraindication for Treatment With Curative Intent in Esophageal Cancer.
The objective of this study is to compare long-term outcomes between younger and older (70 y and above) esophageal cancer patients treated with curative intent. Overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free interval were compared between older (70 y and above) and younger (below 70 y) esophageal cancer patients treated between 1998 and 2013. Treatment consisted of neoadjuvant chemoradiotherapy with surgery or definitive chemoradiotherapy: 36 to 50.4 Gy in 18 to 28 fractions combined with 5-fluorouracil/cisplatin or carboplatin/paclitaxel. The study comprised 253 patients, of whom 76 were 70 years and older. Median age was 64 years (range, 41 to 83). Most patients had stage II-IIIA disease (83%). Planned treatment was neoadjuvant chemoradiotherapy with surgery for 169 patients (41 patients aged 70 y and older) and definitive chemoradiotherapy for 84 patients (31 patients aged 70 y and older). The compliance to radiotherapy was 92%, with no difference between older and younger patients. In 33 patients (13 patients aged 70 y and older) planned surgery was not performed. Median follow-up was 4.9 years. Three-year OS was 42%. The multivariable analysis showed no statistical difference in OS or in DFS comparing older and younger patients: OS (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.61-1.28), DFS (HR, 0.87; 95% CI, 0.60-1.25). Elderly showed a longer locoregional recurrence-free interval; HR, 0.53 (95% CI, 0.30-0.92; P=0.02) and a higher pathologic complete response rate (50% vs. 25%; P=0.02). Long-term outcomes of older esophageal cancer patients (70 y and above) selected for treatment with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy were comparable with the outcomes of their younger counterparts. Advanced age alone should not be a contraindication for potentially curative chemoradiotherapy-based treatment in esophageal cancer patients.


A comparison of non-contrast and contrast-enhanced MRI in the initial stage of Legg-Calvé-Perthes disease.
A prognostic indicator of outcome for Legg-Calvé-Perthes disease (LCP) is needed to guide treatment decisions during the initial stage of the disease (stage 1), before deformity occurs. Radiographic prognosticators are applicable only after fragmentation (stage II). We investigated pre- and postcontrast MRI in depicting stage I femoral head involvement. Thirty children with stage I LCP underwent non-contrast coronal T1 fast spin-echo (FSE) and corresponding postcontrast fat-suppressed T1-weighted fast spin-echo (FSE) sequences to quantify the extent of femoral head involvement. Three pediatric radiologists and one pediatric orthopedic surgeon independently measured central head involvement. Interobserver reliability of percent head involvement using non-contrasted MR images had intraclass correlation coefficient (ICC) of 0.72. Postcontrast MRI improved interobserver reliability (ICC 0.82). Qualitatively, the area of involvement was more clearly visible on contrast-enhanced MRI. A comparison of results obtained by each observer using the two MRI techniques showed no correlation. ICC ranged from -0.08 to 0.03 for each observer. Generally, greater head involvement was depicted by contrast compared with non-contrast MRI (Pearson r = -0.37, P = 0.04). Pre- and postcontrast MRI assess two different components of stage I LCP. However, contrast-enhanced MRI more clearly depicts the area of involvement.


Seasonal distribution of ultraphytoplankton and heterotrophic prokaryotes in relation to abiotic variables on the north coast of Sfax after restoration.
The Taparura project was set up to restore the north Sfax coast (Tunisia) by shutting down the northern phosphate plant responsible for chronic pollution and uncontrolled phosphogypsum dumping. The restoration effect on coastal ultraphytoplankton (<10 μm) and heterotrophic prokaryotes was investigated using conventional flow cytometry over four successive seasons during 2009-2010. Cell concentrations were generally higher than values reported for the open sea, both in the western and eastern Mediterranean basins. One striking point was that chl a concentration on the north Sfax coast was unchanged after restoration but was still one order of magnitude higher than in the Gulf of Gabès. Restoration of pH, following the shutdown of the phosphate processing plants on the north coast, appeared to reach normal levels for seawater during the study, whereas seawater acidification persisted on the south coast where plants are still in operation. The largest ultraphytoplankton biomass was from an unknown cell group, whose identity and role needs to be established.


Systematic analysis of hip-preserving treatment for early osteonecrosis of the femoral head from the perspective of bibliometrics (2010-2023).
Osteonecrosis of the femoral head (ONFH) is a serious condition that causes bone tissue death, femoral head collapse, and hip joint destruction. Early intervention through hip-preserving treatment is crucial to slow down disease progression, preserve hip joint function, and improve the quality of life of patients. We analyzed the knowledge map, research gaps, and future research directions in the field of hip-preserving treatment for early ONFH. All publications related to hip-preserving treatment for early ONFH published between 2010 and 2023 were identified from the Web of Science Core Collection and analyzed using VOSviewer 1.6.19, CiteSpace 6.2.R2, and Scimago Graphica 1.0.35. In total, 234 articles were analyzed. The results showed an exponential growth trend in the number of publications related to hip-preserving treatment for early ONFH in the past decade. China and the USA were the main contributors. International Orthopaedics published the most papers in this field, whereas Bone and Joint Surgery-American Volume had the highest average citation count per article. Several stable research topics were noted in this field, including core decompression (CD), osteotomy, bone transplantation in hip-preserving surgery, and cell therapy, which have become research hotspots in hip-preserving treatment. Hip-preserving treatment for early ONFH has received increasing attention, and research in this field is expected to grow. Stable research topics include core decompression (CD), osteotomy, bone transplantation, and cell therapy. Future research is predicted to focus on cell therapy and combination therapy, resulting in an increasing number of publications on hip-preserving treatment for early ONFH.


A vocational intervention that enhances return to work after severe acquired brain injury: A pragmatic trial.
Following a severe acquired brain injury, individuals often have low return to work rates. The Vocational Intervention Program (VIP), a partnership of Brain Injury Rehabilitation Program community rehabilitation centres with external vocational rehabilitation providers in New South Wales, Australia, was developed to facilitate a return to competitive employment for working-age people. To evaluate the efficacy of the VIP partnership model, this intervention was compared to outcomes from a health-based brain injury vocational rehabilitation centre (H-VR) or community brain injury rehabilitation centres ("treatment as usual"; TAU). A 3-arm non-randomized controlled trial was conducted among the 12 adult rehabilitation centres of the NSW Brain Injury Rehabilitation Program. The VIP arm was delivered by 6 community rehabilitation centres in partnership with 3 external private Vocational Rehabilitation providers. The H-VR arm was delivered by 1 health-based vocational rehabilitation centre and the 5 remaining centres delivered TAU. Competitive employment status ("Yes"/"No") and clinician ratings of disability and participation were collected pre- and post-intervention, and at 3-month follow-up. Multilevel models were conducted to investigate change over time by treatment arm. In total, 148 individuals with severe brain injury were included in the trial: n = 75 (VIP), n = 33 (H-VR) and n = 40 (TAU). Sixty-five people (of 108, 60%) completed the VR intervention. A significant arm-by-time interaction was found, with higher return to work rates from pre- to post-intervention in VIP and H-VR arms compared to TAU (P = 0.0002). Significant arm-by-time interactions also indicated improved work-related participation and independent living skills from pre- to post-intervention in VIP and H-VR compared to the TAU arm (P < 0.05). These improvements were maintained at 3-month follow-up. The VIP improved return to competitive employment at comparable rates to the specialist H-VR. Larger-scale adoption of the VIP model could provide significant improvements in vocational rehabilition sevices to support people in their return to work following severe brain injury. ACTRN12622000769785.


Cognition and function in Alzheimer's disease: identifying the transitions from moderate to severe disease.
Cognitive and functional decline define the transition from moderate to severe Alzheimer's disease (AD); however, specific relationships between deteriorating cognition and functional abilities are less well characterized. Such relationships are important in care planning and understanding patient needs. Objectives of this post hoc analysis of data from a multicenter randomized double-blind placebo-controlled study were to describe changes in Severe Impairment Battery (SIB) scores over 6 months in patients with moderate to severe AD (MSAD), including an assessment of donepezil treatment on SIB scores, and to potentially identify a cognitive transition point associated with predicted functional disability. The study comprised 290 patients with MSAD (standardized Mini-Mental State Examination score, 5-17) treated with donepezil 5-10 mg/day or matching placebo. Measurements were SIB, Functional Rating Scale, and Disability Assessment for Dementia. The largest decline in ability to perform basic activities of daily living (bADLs) occurred in placebo-treated patients with a baseline SIB score of approximately 70. Changes were reduced in the donepezil-treated group. This post hoc exploratory analysis suggests that a transition point between moderate and severe AD exists at a SIB score of approximately 70 and is associated with predictably declining bADLs.


Serum complement determinations in patients with quiescent systemic lupus erythematosus.
To determine whether complement component analyses during a period of inactive disease can define clinically important subgroups and predict morbidity in patients with systemic lupus erythematosus (SLE). We identified 277 patients with SLE whose disease became clinically inactive at some point after diagnosis. Serum samples were obtained at that time and tested for total complement activity (CH100) and antigenic levels of C1q, C1r, C1s, C3 and C4. Results of complement determinations were correlated with demographic characteristics and clinical findings in the followup period (mean observation period 4.25 years). We identified 25 (9%) patients with multiple complement determinations below the normal range. 24 other patients (8.5%) had a very low level of a single complement component. The group with multiple complement determinations below the normal range was much more likely than the normocomplementemic SLE controls to progress to renal insufficiency. In other respects, complement component determinations were neither reflective nor predictive of clinical course. In this group of patients with inactive SLE, complement component analyses did not generally correlate with longterm outcome; however, multiple low complement component determinations during disease quiescence was associated with increased risk of renal insufficiency.


[What our patients want and need to know about generalized anxiety disorder].
Persons with generalized anxiety disorder often do not seek treatment, and if they do, it is more often for the somatic symptoms (muscle tension, insomnia) or for a secondary depression than because of the cardinal feature of generalized anxiety disorder: worry. The worry aspect becomes apparent when the patient is proposed to try anxiolytic medication. The physician will then need to be prepared to answer many questions regarding the potential hazards and benefits of such medication. These patients tend to have a sceptical attitude, having informed themselves on websites that display claims that are based on anything from evidence-based scientific guidelines to distorted, erroneous and unfounded allegations. Which are the frequent questions that worried patients pose to the physician before accepting anxiolytic pharmacotherapy? Having seen anxious patients in my practice during 25 years, and having conducted several clinical trials of anxiolytics I have put together evidence-based answers in plain language to these questions in this paper.


Free-to-total leptin ratio in maternal plasma is constant throughout human pregnancy.
To clarify the mechanism of leptin resistance during pregnancy, we measured plasma leptin concentrations, free to total leptin ratio (percent free leptin) and soluble leptin receptor concentrations in pregnant women, and compared the results with those in non-pregnant women. We collected plasma samples from 23 non-pregnant and 31 pregnant women in the third trimester. Plasma samples from 5 pregnant women were collected longitudinally in each trimester. Plasma leptin concentrations in pregnant women in the second trimester (17.4 +/- 3.2 ng/ml) were higher than those in the first trimester of pregnancy (11.0 +/- 2.8 ng/ml, n = 5), as previously reported. However, percent free leptin did not change significantly throughout pregnancy. Percent free leptin correlated with total leptin concentrations (ng/ml) in non-pregnant women (r = 0.727, P < 0.0001), but not in women in the third trimester of pregnancy (r = 0.006). Constant percent free leptin during pregnancy despite increased leptin concentrations indicates increased leptin binding capacity in pregnant women, that might partly contribute to the establishment of leptin resistance. On the other hand, soluble leptin receptor concentrations showed significant negative correlation with BMI and plasma leptin concentrations in pregnant women (r = -0.470, P < 0.01 and r = -0.493, P < 0.01, respectively) but not in non-pregnant women. These data suggest the possibility that soluble leptin receptor is a minor component of leptin binding capacity in the plasma of pregnant women.


[The high-frequency electroencephalogram: the results and outlook].
At present, the significance of high-frequency (HF) components in brain electrical activity (EA) is widely discussed in literature. In particular, the gamma range of human EEG is considered as one of the indices of cognitive activity. In the paper a review is presented of the author's own data concerning the functional estimation of low-voltage HF components of the neocortical EA recorded in the broad band (1-100, 1-256 Hz) in the course of instrumental conditioning in dogs. Three different techniques of EA analysis were used in the study: 1) fast Fourier transformation (FFT) of EA in a broad band, 2) developed by us alternative method of non-harmonic expansion of the EEG curves taking into account their shape, 3) factor analysis of the EA spectral densities. Combination of these techniques allowed us to obtain some novel evidence indicative of high informativity of the HF fluctuations. Spatial cortical localization of the HF components of the EA is much more expressed in comparison with the traditional 1-30 Hz range. Results of factor analysis suggest functional heterogeneity of the HF band. Obtained data open new ways for researches concerning the phenomena of the functional mosaics in the neocortex as one of fundamental mechanisms in brain activity organization.


Comparing potentially avoidable hospitalization rates related to ambulatory care sensitive conditions in Switzerland: the need to refine the definition of health conditions and to adjust for population health status.
Regional rates of hospitalization for ambulatory care sensitive conditions (ACSC) are used to compare the availability and quality of ambulatory care but the risk adjustment for population health status is often minimal. The objectives of the study was to examine the impact of more extensive risk adjustment on regional comparisons and to investigate the relationship between various area-level factors and the properly adjusted rates. Our study is an observational study based on routine data of 2 million anonymous insured in 26 Swiss cantons followed over one or two years. A binomial negative regression was modeled with increasingly detailed information on health status (age and gender only, inpatient diagnoses, outpatient conditions inferred from dispensed drugs and frequency of physician visits). Hospitalizations for ACSC were identified from principal diagnoses detecting 19 conditions, with an updated list of ICD-10 diagnostic codes. Co-morbidities and surgical procedures were used as exclusion criteria to improve the specificity of the detection of potentially avoidable hospitalizations. The impact of the adjustment approaches was measured by changes in the standardized ratios calculated with and without other data besides age and gender. 25% of cases identified by inpatient main diagnoses were removed by applying exclusion criteria. Cantonal ACSC hospitalizations rates varied from to 1.4 to 8.9 per 1,000 insured, per year. Morbidity inferred from diagnoses and drugs dramatically increased the predictive performance, the greatest effect found for conditions linked to an ACSC. More visits were associated with fewer PAH although very high users were at greater risk and subjects who had not consulted at negligible risk. By maximizing health status adjustment, two thirds of the cantons changed their adjusted ratio by more than 10 percent. Cantonal variations remained substantial but unexplained by supply or demand. Additional adjustment for health status is required when using ACSC to monitor ambulatory care. Drug-inferred morbidities are a promising approach.


HDL functions and their interaction in patients with ST elevation myocardial infarction: a case control study.
Recent studies emphasize the importance of HDL function over HDL cholesterol measurement, as an important risk for cardiovascular diseases (CVD). We compared the HDL function of patients with acute coronary syndrome (ACS) and healthy controls. We measured cholesterol efflux capacity of HDL using THP-1 macrophages labelled with fluorescently tagged (BODIPY) cholesterol. PON1 activities toward paraoxon and phenyl acetate were assessed by spectrophotometric methods. We recruited 150 ACS patients and 110 controls. The HDL function of all patients during acute phase and at six month follow-up was measured. The mean age of the patients and controls was 51.7 and 43.6 years respectively. The mean HDL cholesterol/apolipoprotein A-I levels (ratio) of patients during acute phase, follow-up and of controls were 40.2 mg/dl/ 112.5 mg/dl (ratio = 0.36), 38.3 mg/dl/ 127.2 mg/dl (ratio = 0.30) and 45.4 mg/dl/ 142.1 mg/dl (ratio = 0.32) respectively. The cholesterol efflux capacity (CEC) of HDL was positively correlated with apolipoprotein A-I levels during acute phase (r = 0.19, p = 0.019), follow-up (r = 0.26, p = 0.007) and of controls (r = 0.3, p = 0.0012) but not with HDL-C levels (acute phase: r = 0.07, p = 0.47; follow-up: r = 0.1, p = 0.2; control: r = 0.02, p = 0.82). Higher levels of cholesterol efflux capacity, PON1 activity and apolipoprotein A-I were associated with lower odds of development of ACS. We also observed that low CEC is associated with higher odds of having ACS if PON1 activity of HDL is also low and vice versa. ACS is associated with reduced HDL functions which improves at follow-up. The predicted probability of ACS depends upon individual HDL functions and the interactions between them.


[Relation between QT dispersion and reperfusion in acute myocardial infarct].
QT dispersion (QTd) represents the parameter of the expanded heterogeneity of myocard of ventricles. The aim of this study was to examine the dynamics of changes of QTd during the first 5 days of the acute myocardial infarction (AMI) in dependence to noninvasively estimated success of thrombolytic therapy. Thirty six patients with AMI were included in the study. All patients were treated with alteplaze according to rapid protocol. QTd (QTc max-QTc min) was measured immediately after the reception (0 min), after the thrombolytic therapy (90 min) and since the 2nd to the 5th day of the hospitalization. Reperfusion was estimated on the basis of electrocardiographic and biohumoral parameters. In the group of 36 patients, 22 male and 11 female, both parameters of the reperfusion were not compatible in 3 patients. The other 23 patients had the reperfusion, while 10 patients did not have it. At the reception there was no significant difference of QTd between the group with reperfusion (79 +/- 34 ms) and the group without reperfusion (65 +/- 19 ms). After receiving alteplase, the average QTd in the group with reperfusion was 67 +/- 31 ms, which was not shorter in relation to the group without reperfusion (70 +/- 23 ms). Since the 2nd day of AMI, significantly smaller QTd in pa-patients with reperfusion was not registered compared with the patients without the reperfusion (54 +/- 17 vs. 73 +/- 20 ms), whereas since the 3rd day the difference became significant (46 +/- 16 vs. 87 +/- 24 ms). On the 4th day it was 43 +/- 12 vs. 78 +/- 21 ms, and on the 5th day it was 38 +/- 11 vs. 62 +/- 23 ms. On the 1st day significant difference of QTd between the groups with and without reperfusion was not registered in the group of patients with anterior AMI (0 min: 97 +/- 47 vs. 72 +/- 16; 90 min: 68 +/- 47 vs. 72 +/- 20) whereas on the 2nd day it became statistically significant (51 +/- 15 vs. 74 +/- 20 on the 2nd day, 51 +/- 20 vs. 88 +/- 24 on the 3rd day, 46 +/- 10 vs. 81 +/- 19 on the 4th day and 40 +/- 8 vs. 69 +/- 22 ms on the 5th day. In the group of patients with inferolateral AMI, only on the 3rd day significant difference of QTd between the group with and the group without reperfusion was registered (43 +/- 14 vs. 69 +/- 29 ms), while in all other measuring it was not registered (0 min: 69 +/- 22 vs. 42 +/- 9; 90 min: 67 +/- 20 vs. 67 +/- 41; 55 +/- 19 vs. 60 +/- 25 on the 2nd day; 41 +/- 14 vs. 51 +/- 6 on the 4th day and 51 +/- 12 vs. 37 +/- 8 ms on the 5th day). Qt dispersion was of significantly shorter duration in patients with the successfully performed reperfusion in relation to the patients without the reperfusion. In patients with the anterior AMI, QTd was significantly different in patients with in relation to the patients without the reperfusion in distinction with the patients with inferolateral AMI.


The placenta. Not just a conduit for maternal fuels.
The placenta is a specialized organ of exchange that provides nutrients to and excretes waste products from the fetus. The exchange of nutrients between placenta and fetus involves three major mechanisms: 1) direct transfer of nutrients from the maternal to the fetal plasma, 2) placental consumption of nutrients, and 3) placental conversion of nutrients to alternate substrate forms. Although direct transfer has been considered the primary means by which placental-fetal exchange controls the supply of nutrients to the fetus and thereby fetal metabolism and growth, the considerable metabolic activity of the placenta provides a large and fundamentally important contribution to both the quality and quantity of nutrient substrates supplied to the fetus; e.g., placental O2 and glucose consumption rates approach or even exceed those of brain and tumor tissue. Other placental metabolic activities include glycolysis, gluconeogenesis, glycogenesis, oxidation, protein synthesis, amino acid interconversion, triglyceride synthesis, and chain lengthening or shortening of individual fatty acids. Thus, consideration of the metabolism of the placenta is essential for a more complete understanding of how the placenta regulates nutrient transfer to the fetus, fetal energy balance, and fetal growth.


Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells.
Human neutrophils stimulated with phorbol myristate acetate were able to destroy suspensions or monolayers of cultured human endothelial cells. Neutrophil-mediated cytotoxicity was related to phorbol myristate acetate concentration, time of incubation and neutrophil number. Cytolysis was prevented by the addition of catalase, while superoxide dismutase had no effect on cytotoxicity. The addition of the heme-enzyme inhibitors, azide or cyanide, markedly stimulated neutrophil-mediated damage while exogenous myeloperoxidase failed to stimulate cytolysis. Neutrophils isolated from patients with chronic granulomatous disease did not destroy the endothelial cell targets while myeloperoxidase-deficient neutrophils successfully mediated cytotoxicity. Endothelial cell damage mediated by the myeloperoxidase deficient cells was also inhibited by catalase but not superoxide dismutase. The addition of purified myeloperoxidase to the deficient cells did not stimulate cytotoxicity. Glucose-glucose oxidase, an enzyme system capable of generating hydrogen peroxide, could replace the neutrophil as the cytotoxic mediator. The addition of myeloperoxidase at low concentrations of glucose oxidase did not increase cytolysis, but at the higher concentrations of glucose oxidase it stimulated cytotoxicity. The destruction of endothelial cells by the glucose oxidase-myeloperoxidase system was inhibited by the addition of hypochlorous acid scavengers. In contrast, neutrophil-mediated cytolysis was not effectively inhibited by the hypochlorous acid scavengers. Based on these observations, we propose that human neutrophils can destroy cultured human endothelial cells by generating cytotoxic quantities of hydrogen peroxide.


Carbon exchanges and their responses to temperature and precipitation in forest ecosystems in Yunnan, Southwest China.
Forest ecosystems play an increasingly important role in the global carbon cycle. However, knowledge on carbon exchanges, their spatio-temporal patterns, and the extent of the key controls that affect carbon fluxes is lacking. In this study, we employed 29-site-years of eddy covariance data to observe the state, spatio-temporal variations and climate sensitivity of carbon fluxes (gross primary productivity (GPP), ecosystem respiration (Reco), and net ecosystem carbon exchange (NEE)) in four representative forest ecosystems in Yunnan. We found that 1) all four forest ecosystems were carbon sinks (the average NEE was -3.40tCha-1yr-1); 2) contrasting seasonality of the NEE among the ecosystems with a carbon sink mainly during the wet season in the Yuanjiang savanna ecosystem (YJ) but during the dry season in the Xishuangbanna tropical rainforest ecosystem (XSBN), besides an equivalent NEE uptake was observed during the wet/dry season in the Ailaoshan subtropical evergreen broad-leaved forest ecosystem (ALS) and Lijiang subalpine coniferous forest ecosystem (LJ); 3) as the GPP increased, the net ecosystem production (NEP) first increased and then decreased when the GPP>17.5tCha-1yr-1; 4) the precipitation determines the carbon sinks in the savanna ecosystem (e.g., YJ), while temperature did so in the tropical forest ecosystem (e.g., XSBN); 5) overall, under the circumstances of warming and decreased precipitation, the carbon sink might decrease in the YJ but maybe increase in the ALS and LJ, while future strength of the sink in the XSBN is somewhat uncertain. However, based on the redundancy analysis, the temperature and precipitation combined together explained 39.7%, 32.2%, 25.3%, and 29.6% of the variations in the NEE in the YJ, XSBN, ALS and LJ, respectively, which indicates that considerable changes in the NEE could not be explained by variations in the temperature and precipitation. Therefore, the effects of other factors (e.g., CO2 concentration, N/P deposition, aerosol and other variables) on the NEE still require extensive research and need to be considered seriously in carbon-cycle-models.


Detection limits for ferrimagnetic particle concentrations using magnetic resonance imaging based proton transverse relaxation rate measurements.
A clinical magnetic resonance imaging (MRI) system was used to measure proton transverse relaxation rates (R2) in agar gels with varying concentrations of ferrimagnetic iron oxide nanoparticles in a field strength of 1.5 T. The nanoparticles were prepared by coprecipitation of ferric and ferrous ions in the presence of either dextran or polyvinyl alcohol. The method of preparation resulted in loosely packed clusters (dextran) or branched chains (polyvinyl alcohol) of particles containing of the order of 600 and 400 particles, respectively. For both methods of particle preparation, concentrations of ferrimagnetic iron in agar gel less than 0.01 mg ml(-1) had no measurable effect on the value of R2 for the gel. The results indicate that MRI-based R2 measurements using 1.5 T clinical scanners are not quite sensitive enough to detect the very low concentrations of nanoparticulate biogenic magnetite reported in human brain tissue.


Enhanced error-related brain activity in children predicts the onset of anxiety disorders between the ages of 6 and 9.
Considering that anxiety disorders frequently begin before adulthood and often result in chronic impairment, it is important to characterize the developmental pathways leading to the onset of clinical anxiety. Identifying neural biomarkers that can predict the onset of anxiety in childhood may increase our understanding of the etiopathogenesis of anxiety, as well as inform intervention and prevention strategies. An event-related potential (ERP), the error-related negativity (ERN), has been proposed as a biomarker of risk for anxiety and has previously been associated with anxiety in both adults and children. However, no previous study has examined whether the ERN can predict the onset of anxiety disorders. In the current study, ERPs were recorded while 236 healthy children, approximately 6 years of age, performed a go/no-go task to measure the ERN. Three years later, children and parents came back to the lab and completed diagnostic interviews regarding anxiety disorder status. Results indicated that enhanced error-related brain activity at age 6 predicted the onset of new anxiety disorders by age 9, even when controlling for baseline anxiety symptoms and maternal history of anxiety. Considering the potential utility of identifying early biomarkers of risk, this is a novel and important extension of previous work.


In vivo regulation of the Escherichia coli araC promoter.
The ara pC promoter is known to be derepressed about fivefold for 20 to 30 min after the addition of arabinose. This transient derepression was studied by using araC::Mu lac insertions and araC-lacZ gene fusions. In strains containing increased levels of araC protein, the pC promoter became progressively less derepressible, but the ara pBAD promoter remained normally inducible. Repression of pC was reestablished 20 min after induction in araB mutants, but did not occur in arabinose-transport-deficient mutants. Finally, mutant araCc proteins which normally do not repress pC did so in the presence of arabinose.


Core-Shell and Hollow Particles of Carbon and SiC Prepared from Hydrochar.
The applications of silicon carbide (SiC) include lightweight materials with thermal shock resistance. In this study, core-shell C-SiC particles were synthesized by compacting and rapidly heating a hydrochar from glucose by using strong pulsed currents and infiltration of silicon vapor. Hollow particles of SiC formed on removing the carbon template. In contrast to related studies, we detected not only the pure 3C polytype (β-SiC) but also significant amounts of the 2H or the 6H polytypes (α-SiC) in the SiC.


[Nerve fibre bundle defects in a pre-chiasmal lesion].
Prechiasmal lesions of the visual pathway are produced by visual field defects that either affect only one eye or, if both eyes are affected, they are clearly different. Typically, the defects respect the vertical meridian. This report of a case shows that the classical nerve fibre bundle defect must be taken into consideration for differential diagnosis. In a 67-year-old patient, a meningeoma of the sphenoid was diagnosed that had spread into the optic canal. Examination of the visual field showed an inferior altitudinal nerve fibre bundle defect. Apparently the retinal pattern of nerve fibres remains intact even when approaching the optic chiasm. Nerve fibre bundle defects are therefore sometimes found in prechiasmal lesions and should be considered for differential diagnosis (e. g., in the case of a suspected low tension glaucoma).


Analysis of Mitochondrial Transfer in Direct Co-cultures of Human Monocyte-derived Macrophages (MDM) and Mesenchymal Stem Cells (MSC).
Mesenchymal stem/stromal cells (MSC) are adult stem cells which have been shown to improve survival, enhance bacterial clearance and alleviate inflammation in pre-clinical models of acute respiratory distress syndrome (ARDS) and sepsis. These diseases are characterised by uncontrolled inflammation often underpinned by bacterial infection. The mechanisms of MSC immunomodulatory effects are not fully understood yet. We sought to investigate MSC cell contact-dependent communication with alveolar macrophages (AM), professional phagocytes which play an important role in the lung inflammatory responses and anti-bacterial defence. With the use of a basic direct co-culture system, confocal microscopy and flow cytometry we visualised and effectively quantified MSC mitochondrial transfer to AM through tunnelling nanotubes (TNT). To model the human AM, primary monocytes were isolated from human donor blood and differentiated into macrophages (monocyte derived macrophages, MDM) in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF), thus allowing adaptation of an AM-like phenotype (de Almeida et al., 2000; Guilliams et al., 2013). Human bone-marrow derived MSC, were labelled with mitochondria-specific fluorescent stain, washed extensively, seeded into the tissue culture plate with MDMs at the ratio of 1:20 (MSC/MDM) and co-cultured for 24 h. TNT formation and mitochondrial transfer were visualised by confocal microscopy and semi-quantified by flow cytometry. By using the method we described here we established that MSC use TNTs as the means to transfer mitochondria to macrophages. Further studies demonstrated that mitochondrial transfer enhances macrophage oxidative phosphorylation and phagocytosis. When TNT formation was blocked by cytochalasin B, MSC effect on macrophage phagocytosis was completely abrogated. This is the first study to demonstrate TNT-mediated mitochondrial transfer from MSC to innate immune cells.


Effect of a health maintenance organization on physiologic health. Results from a randomized trial.
In a previous comparison of persons between 14 and 62 years of age randomly assigned to receive care through a fee-for-service system (n = 784) or through a health maintenance organization (HMO) (n = 738) in Seattle, Washington, persons in the HMO had much lower hospital expenditures and admissions, more bed days, a higher prevalence of serious symptoms, and less satisfaction with care. We report an examination of 20 additional health status measures. Our results are consistent with a hypothesis of no differences in health status measures between the two systems. In addition, a comparison of nine health practices between the systems also indicated no overall differences. Most physiologic measures and health practices for a typical person were not affected by care received through the fee-for-service system or the HMO. However, we are less certain of this result in specific subgroups, such as persons of lower income initially at elevated risk, because confidence intervals are necessarily wider. We conclude that the cost savings achieved by this HMO through lower hospitalization rates were not reflected in lower levels of health status.


[Results of 10 years of use of lincomycin (1966-1976) in the clinics of the N. N. Priorov Central Research Institute of Traumatology and Orthopedics].
During 10 years 1063 patients were treated with lincomycin used parentally or orally at the N. N. Priorov Central Research Institute of Traumatology and Orthopedy. The doses and the rate of its use depended on the state of the patient, its age and weight. Lincomycin was used for the treatment of patients with osteomyelitis or purulent wound infection, as well as for prophylaxis of suppuration. The drug was used for a long period of time under conditions of the same hospital, and it was shown that it remained up to the present days highly effective in therapy of infections and especially bone infections caused by staphylococci sensitive to it. The 10-year study of staphylococcal sensitivity to lincomycin revealed an insignificant increase in the development of resistance to it. The paper presents data on the importance of adequate surgical interventions in addition to the antibiotic therapy in cases with bone infections. A possibility of lincomycin combined use with other antibiotics and gentamicin or kanamycin in particular was shown. Complications, such as diarrhea and urticaria were registered in 11 patients.