[Intraocular pressure in sections with 2 microkeratomes in vitro].
The rapid integration of new technology into ophthalmologic practice, e.g. LASIK (laser in situ keratomileusis), is associated with new complications. The limitations of the new technology cannot be precisely determined. During lamellar cuts with microkeratomes intraocular pressure (IOP) elevations occur. The IOP elevation during the lamellar cut cannot be determined by conventional tonometry. We examined the IOP rise during the complete microkeratome treatment. Fresh enucleated porcine eyes were cannulated and direct IOP measurement with a Statham manometer was carried out. Thus we evaluated the IOP during the complete treatment for two differently constructed microkeratome systems. IOP elevations (mean values) between 77 mm Hg for the Corneal Shaper and 229 mm Hg for the Keratek during the vacuum phase and 140 mm Hg for the Corneal Shaper and 360 mm Hg for the Keratek during the lamellar cut were monitored. A sudden IOP decrease to-5 mm Hg was registered for the post-vacuum phase. In our opinion unphysiologic high IOP values could be dangerous for risk eyes.


Spin and wedge representations of infinite-dimensional Lie algebras and groups.
We suggest a purely algebraic construction of the spin representation of an infinite-dimensional orthogonal Lie algebra (sections 1 and 2) and a corresponding group (section 4). From this we deduce a construction of all level-one highest-weight representations of orthogonal affine Lie algebras in terms of creation and annihilation operators on an infinite-dimensional Grassmann algebra (section 3). We also give a similar construction of the level-one representations of the general linear affine Lie algebra in an infinite-dimensional "wedge space." Along these lines we construct the corresponding representations of the universal central extension of the group SL(n)(k[t,t(-1)]) in spaces of sections of line bundles over infinite-dimensional homogeneous spaces (section 5).


Phagocytosis of apoptotic cells in mammals, caenorhabditis elegans and Drosophila melanogaster: molecular mechanisms and physiological consequences.
Phagocytosis is the necessary corollary of apoptosis. It leads to the clearance of apoptotic cells by phagocytes, which can be 'professional' or 'amateur'. I review the known molecular aspects of phagocytosis of apoptotic corpses in mammals, Caenorhabditis elegans and Drosophila melanogaster from the point of view of the phagocyte and the apoptotic corpse. I highlight recent advances made in the field and discuss the physiological outcomes and consequences of this process. Indeed, phagocytosis of apoptotic cells is important in shaping or remodeling tissues to maintain their integrity and specialized functions during development and wound healing. It also contributes to the development of inflammation and/or its resolution after an injury or infection. This perhaps explains why the molecular mechanisms of phagocytosis of apoptotic cells are redundant and complex in mammals and suggests why they appear to have been mostly conserved through evolution. Caenorhabditis elegans has already proven to be useful in genetically dissecting the molecular mechanisms underlying phagocytosis of apoptotic corpses by 'amateur' neighboring cells. Drosophila melanogaster will become the model of choice in genetically dissecting the molecular mechanisms underlying phagocytosis of apoptotic cells by 'professional' phagocytes such as macrophages.


Age effects on placebo response rates in clinical trials of acute agents for migraine: pooled analysis of rizatriptan trials in adults.
This study examined the effect of age on placebo response rates in rizatriptan trials in adults. Data from eight rizatriptan adult trials involving patients treating moderate/severe migraine attacks with rizatriptan 5 mg (N = 1819), rizatriptan 10 mg (N = 2046) or placebo (N = 1322) were pooled for post hoc analysis. Logistic regression was used to model 2-h pain relief (reduction to mild or none) and 2-h pain freedom rates by treatment groups. Older patients had lower placebo response rates than younger patients; the estimated odds ratio (older vs. younger) for a 10-year age increase was 0.83 for pain relief [95% confidence interval (CI) 0.75, 0.93] and 0.81 for pain freedom (95% CI 0.68, 0.97). The response proportion vs. age trend was flat for rizatriptan 5 mg and slightly increased for rizatriptan 10 mg. The treatment-by-age interaction was significant for pain relief (P < 0.001) and pain freedom (P = 0.001), suggesting an increasing trend of treatment advantage of rizatriptan over placebo as age increased. Age appeared to be an important predictor of placebo response rate in rizatriptan trials, with older patients being less likely to respond to placebo and more likely to respond to rizatriptan.


Maximizing the rigidity of a large planar orifice air bearing.
A rotating support for a large astronomical mirror has been implemented using an opposed surface planar orifice air bearing. This bearing needs to provide rotation as free as possible of static and dynamic friction, as well as maximizing the resistance to sudden angular deviations produced by wind gusts. Information on the design of traditional bearings, namely, a cavity supplied with air under pressure through an orifice or diffuser flow restriction and closed by the moving member, has been published in detail. These traditional bearings are not suitable for the application described, due to their slow speed of response to transient changes in forces, a considerable volume of air being needed to change the pressure in the cavity. The air bearing used in this application has no cavity but consists of two flat surfaces in close proximity with air under pressure introduced at the center of one of the surfaces. The volume of air in the bearing is therefore minimized, improving the response to load change transients. The load capacity of this type bearing is reduced as the air between the bearing surfaces is not at constant pressure, but is expanding from the center point of injection to its escape at the edges. This paper indicates a quantitative method of determining the size of the air supply orifices to achieve the maximum rigidity orthogonal to the direction of motion. The approach described can also be applied to optimizing the geometry of other non-cavity air bearings.


Diabetes by Air, Land, and Sea: Effect of Deployments on HbA1c and BMI.
Service members (SMs) in the United States (U.S.) Armed Forces have diabetes mellitus at a rate of 2-3%. Despite having a chronic medical condition, they have deployed to environments with limited medical support. Given the scarcity of data describing how they fare in these settings, we conducted a retrospective study analyzing the changes in glycated hemoglobin (HbA1c) and body mass index (BMI) before and after deployment. SMs from the U.S. Army, Air Force, Navy, and Marine Corps with diabetes who deployed overseas were identified through the Military Health System (MHS) Management Analysis and Reporting Tool and the Defense Manpower Data Center. Laboratory and pharmaceutical data were obtained from the MHS Composite Health Care System and the Pharmacy Data Transaction Service, respectively. Paired t-tests were conducted to calculate changes in HbA1c and BMI before and after deployment. SMs with diabetes completed 11,325 deployments of greater than 90 days from 2005 to 2017. Of these, 474 (4.2%) SMs had both HbA1c and BMI measurements within 90 days prior to departure and within 90 days of return. Most (84.2%) required diabetes medications: metformin in 67.3%, sulfonylureas in 19.0%, dipeptidyl peptidase-4 inhibitors in 13.9%, and insulin in 5.5%. Most SMs deployed with an HbA1c < 7.0% (67.1%), with a mean predeployment HbA1c of 6.8%. Twenty percent deployed with an HbA1c between 7.0 and 7.9%, 7.2% deployed with an HbA1c between 8.0 and 8.9%, and 5.7% deployed with an HbA1c of 9.0% or higher. In the overall population and within each military service, there was no significant change in HbA1c before and after deployment. However, those with predeployment HbA1c < 7.0% experienced a rise in HbA1c from 6.2 to 6.5% (P < 0.001), whereas those with predeployment HbA1c values ≥7.0% experienced a decline from 8.0 to 7.5% (P < 0.001). Those who deployed between 91 and 135 days had a decline in HbA1c from 7.1 to 6.7% (P = 0.010), but no significant changes were demonstrated in those with longer deployment durations. BMI declined from 29.6 to 29.3 kg/m2 (P < 0.001), with other significant changes seen among those in the Army, Navy, and deployment durations up to 315 days. Most SMs had an HbA1c < 7.0%, suggesting that military providers appropriately selected well-managed SMs for deployment. HbA1c did not seem to deteriorate during deployment, but they also did not improve despite a reduction in BMI. Concerning trends included the deployment of some SMs with much higher HbA1c, utilization of medications with adverse safety profiles, and the lack of HbA1c and BMI evaluation proximal to deployment departures and returns. However, for SMs meeting adequate glycemic targets, we demonstrated that HbA1c remained stable, supporting the notion that some SMs may safely deploy with diabetes. Improvement in BMI may compensate for factors promoting hyperglycemia in a deployed setting, such as changes in diet and medication availability. Future research should analyze in a prospective fashion, where a more complete array of diabetes and readiness-related measures to comprehensively evaluate the safety of deploying SMs with diabetes.


Gastrointestinal motor function in diabetes mellitus: Relationship to blood glucose concentrations.
The application of novel investigative techniques has established that there is a high prevalence of disordered gastrointestinal motor function in patients with diabetes mellitus and has provided insights into its pathogenesis and clinical significance. Acute changes in the blood glucose concentration, even within the normal postprandial range, affect both gastrointestinal motor function and the perception of sensations arising from the gastrointestinal tract. Gastric emptying is slower during hyperglycaemia and accelerated during hypoglycaemia; the perception of gastric distension is greater during hyperglycaemia than euglycaemia. The pathways mediating the effects of the blood glucose concentration on gut motility and sensation are poorly defined. The rate of gastric emptying is an important determinant of postprandial blood glucose concentrations and there is increasing evidence that gastric emptying can be modulated therapeutically in order to optimize glycaemic control in patients with diabetes.


[The national addictions survey of Mexico].
A probabilistic household survey was made with the following objectives: to estimate the prevalence of consumption of tobacco, alcohol and legal and illegal drugs; to identify attitudes and values, risk factors and problems associated with the consumption of addictive substances in a population from 12 to 65 years old, which resides in the urban areas of Mexico. This survey forms part of the National Health Surveys System, and its sample design is based on the Master Sample Framework of the National Health Surveys System, which gathered information representative of the national population and for seven regions. In the elaboration of the questionnaire indicators proposed by the World Health Organization (WHO), validated for Mexico, were used as well as previous knowledge about the topic. Thirteen thousand and five interviews were made, of which 96.7 per cent were complete and 2.6 per cent were rejected. In the group from 12 to 17 years old, 32 per cent of the men and 23 per cent of the women already consumed alcoholic drinks. The age group with the largest proportion of men who were frequent drinkers is from 30 to 39 years of age, with 36.3 per cent. For women 34.0 per cent of the frequent drinkers were found in the 40 to 49 year age group. It was found that six per cent of the population from 18 to 65 years of age is alcohol dependent, 12.5 per cent of men and less than one per cent of women. The population which smokes reaches 26 per cent of the total, with 38.3 per cent of men and 14.4 per cent of women. Forty two and four per cent of smokers are from 18 to 29 years of age. Among the daily smokers, 17 per cent were considered dependent on cigarettes. Only 4.8 per cent of the population admits having consumed some type of drug on at least one occasion, with the men from 12 to 34 years old being the age group which is most affected by the use of drugs (8.5%). Active users in the last year made up 2.1 per cent and in the last month the proportion of active users was less than one per cent. The most frequently used drug was marihuana (1%), the second used were tranquilizers (0.4%), and the third most frequently used were inhalants (glue, thinner) (0.26%). The most commonly consumed drug by male users was marihuana and by female users the most commonly used drug was stimulants.(ABSTRACT TRUNCATED AT 250 WORDS)


Differences in the purpose of exercise between hemodialysis patients who continued or dropped out of exercise programs: a multicenter cohort study.
Selecting suitable exercise goals is crucial for fostering adherence to, and maintenance of, exercise therapy. We aimed to evaluate the variance in exercise objectives between individuals who continued and those who dropped out of a 6-month intradialytic exercise program by analyzing an open-ended questionnaire administered to patients undergoing hemodialysis. The study consisted of outpatients (n = 541; mean age, 70 years) undergoing maintenance hemodialysis, who had been informed of an intradialytic exercise program and voluntarily agreed to participate. The primary outcome was the exercise purpose. The difference in exercise purpose was quantitatively analyzed between the exercise continuation and dropout groups. A co-occurrence network was created and concepts were constructed. The basic attributes were compared using chi-squared and independent t-tests. Over 6 months, 154 patients (28.5%) dropped out of the intradialytic exercise program. Concepts related to the goals of the program were: (1) physical function and condition, (2) addressing limitations, (3) maintaining daily life activities, and (4) physical condition recognition. Co-occurrence network analysis showed that the exercise continuation group established their objectives based on the health benefits of exercise, and proactively set goals rooted in comprehending their current issues and problems. The dropout group tended to perceive treatment passively as an extension of daily clinical practice, rather than actively formulating exercise objectives. The exercise objectives of those who continued the exercise program differed from those who dropped out. Patients in the exercise continuation group set more affirmative and specific exercise objectives, whereas those in the dropout group set more passive and abstract exercise objectives.


Study on detecting antibodies to Toxoplasma gondii in pooled serum of blood donors by Dot-IGSS.
To prevent post-transfusion toxoplasmosis, the sera of blood donors, per six of which were mixed as a pool, were examined for anti-Toxoplasma gondii antibiodies by Dot-immunogold silver staining (Dot-IGSS) with the single serum specimens examined simultaneously. The results showed that the sensitivity and specificity of serum pool method were 92.31% and 99.96% respectively. The consistent rate between the two methods was 99.73% and kappa value was 0.947 (p<0.01). Considering the mean infection rate of Toxoplasma gondii being 4.86% in China, if the serum pool method be adoped, with pool size k=5, a 57% reduction in the number of tests, as well as the cost of the screen, can be expected. Beside the social benefit, consequent upon the interruption of the Toxoplasma gondii infection spread through blood transfusion also can be expected.


[Endoscopic aspects of primary non-Hodgkin's lymphoma of the stomach].
The introduction of endoscopy has led to a striking improvement in the diagnosis of primary non-Hodgkin gastric lymphomas due to the possibility of viewing the lesions directly and performing histological and cytological biopsies. Endoscopic findings are however polymorphous and may present difficulties of interpretation. The aim of this study was to re-examine the endoscopic data in 40 cases (25 M and 15 F) of gastric lymphoma observed during the period 1983-1990. There were three main endoscopic findings: ulcerated lesions (55%), infiltrating lesions (40%) and polypoid lesions (5%). In 75% of cases the biopsies carried out during the course of endoscopic examination were positive for lymphoma; in 7.5% of cases histological diagnosis was made using macrobiopsies carried out using a diathermic loop whereas in 17.5% it was made during the course of laparotomy. It may be possible to make further progress towards an early diagnosis following the introduction of echoendoscopy which will allow an in-depth evaluation of lesions and the involvement of lymph node stations and nearby organs.


Spatiotemporal succession of phosphorous accumulating biofilms during the first year of establishment.
Many wastewater treatment plants are dependent on the utilization of microorganisms in biofilms. Our knowledge about the establishment of these biofilms is limited, particular with respect to biofilms involved in enhanced biological phosphorus removal (EBPR). These biofilms rely on polyphosphate-accumulating organisms (PAOs), requiring alternating oxic and anaerobic conditions for phosphorous uptake. This challenge has been solved using the Hias process, which combines moving-bed biofilm-reactor (MBBR) technology with physical transfer of biofilm-carriers from oxic to anaerobic zones. We combined biofilm fractionation with temporal analyses to unveil the establishment in the Hias process. A stable phosphorous removal efficiency of >95% was reached within 16 weeks of operation. Phosphorus removal, however, was not correlated with the establishment of known PAOs. The biofilms seemed associated with an outer microbiota layer with rapid turnover and an inner layer with a slow expansion. The inner layer showed an overrepresentation of known PAOs. In conclusion, our spatiotemporal analyses of phosphorous accumulating biofilm establishment lead to a new model for biofilm growth, while the mechanisms for phosphorous removal remain largely unresolved.


Parent reports of children's working memory, coping, and emotional/behavioral adjustment in pediatric brain tumor patients: A pilot study.
Neurocognitive problems in childhood survivors of brain tumors are well documented. Further, research has shown that problems in cognitive functioning may be associated with impairment in the use of complex strategies needed to cope with stress, including secondary control coping strategies (e.g., acceptance and cognitive reappraisal) which have been associated with fewer adjustment problems. The present study measured cognitive function, coping strategies, and adjustment in children ages 6-16 years at the time of brain tumor diagnosis and at two follow-up time-points up to 1 year post-diagnosis. In a prospective design, working memory was assessed in a total of 29 pediatric brain tumor patients prior to undergoing surgery, child self-reported coping was assessed at 6 months post-diagnosis, and parent-reported child adjustment was assessed at 12 months post-diagnosis. Significant correlations were found between working memory difficulties and secondary control coping. Secondary control coping was also negatively correlated with child attention and total problems. Regression analyses did not support secondary control coping mediating the association between working memory difficulties and child attention or total problems. These findings represent the first longitudinal assessment of the association between working memory, coping, and adjustment across the first year of a child's brain tumor diagnosis and suggest a possible role for early interventions addressing both working memory difficulties and coping in children with brain tumors.


Factors associated with short-term clinical outcomes after acute treatment of asthma in a pediatric emergency department.
Outcomes of emergency room treatment of children with asthma have not been well-documented. The purpose of this study was to describe the short-term clinical course of children aged 0-14 years after standard treatment for an acute asthma exacerbation in a pediatric emergency department, and to determine factors associated with follow-up morbidity. This was a prospective cohort study of a randomly selected sample of children with asthma who required treatment for an acute asthma exacerbation during the year 2002. A clinical chart was filled out by the attending pediatrician during the emergency department visit. Participants were interviewed by telephone at 7 and 15 days after the pediatric emergency visit. The study population included 258 children; 125 of them (48.4%) were <2 years old. Eighty-nine percent of children reported a visit with his/her primary asthma care provider during the first week after discharge from the emergency department. A total of 185 children missed 1 or more days of school, with a mean of 3.1 +/- 2.7 days (range, 1-23 days). Twenty-nine patients (11%) returned for medical care at the emergency department, 22 (8.5%) of them during the first week after discharge, and 4 (1.6%) required hospitalization. At the first follow-up control (day 7), 111 patients (43%) reported persistent symptoms and/or difficult breathing, and 157 (61%) were still using asthma medication. At the second follow-up control (day 15), 53 patients (20.5%) reported persistent respiratory symptoms, and 69 (26.7%) used asthma medication. In children >2 years of age, the percentage of patients with respiratory symptoms on day 7 was significantly lower among those who reported maintenance therapy with inhaled steroids (23.7% vs. 46%, P = 0.006). On day 7, asthma symptoms were more frequent in children <2 years of age compared to older children showed a higher percentage of asthma symptoms (50% vs. 36%, P = 0.014). Children <2 years old compared to older children also missed more days school or day nursery (4.48 +/- 4.62 days vs. 2.4 +/- 2.19 days). The short-term outcome of asthma children attended at the emergency department is worse than expected, according to rates of rehospitalization and return for medical care after discharge. Maintenance treatment with inhaled steroids favored a prompt recovery in children older than 2 years of age, whereas the short-term outcome of children aged <2 years was not influenced by any variable.


Mechanisms responsible for defective human T-lymphocyte sheep erythrocyte rosette function associated with hepatitis B virus infections.
The expression of selected lymphocyte surface-membrane markers was evaluated in 37 patients with acute viral hepatitis B, 10 of whom were studied serially through the resolving and convalescent phases of disease. Bone marrow-derived (B) lymphocytes were identified by reference to surface immunoglobulin, whereas normal thymus-derived (T) lymphocytes were assayed by their capacity to form spontaneous nonimmune rosettes with sheep erythrocytes (E rosettes, ER). During the acute and resolving phases of viral hepatitis B, the relative and absolute number of ER-positive lymphocytes was significantly reduced, whereas the number of surface immunoglobulin-positive lymphocytes and the absolute lymphocyte count remained normal. This resulted in the appearance of a third population of cells, deficient in respect to both surface immunoglobulin and ER markers. Such cells accounted for nearly 25% of peripheral blood lymphocytes, approximately 5 x 105ml blood. Depression of the number of ER-positive lymphocytes occurred at least once during the course of disease in every patient studied serially, and was observed in 55 of 67 individual assays of the 37 cases of acute viral hepatitis B. Lymphocytes from some patients reacquired ER function when cultured in fetal calf serum but not in the presence of autologous serum. Such autologous serum was capable of suppressing ER function of lymphocytes from normal donors. The extrinsic suppression of er function by a serum factor (designated as the Rosette Inhibitory Factor), was found to be time dependent, characterized by a 4-h latent period and requiring approximately 18 h for maximum attenuation of ER function. The Serum Rosette Inhibitory Factor was: (a) heat and freeze-thaw stable, (b) nondialyzable, (c) physically separable from hepatitis B surface antigen, (d) not a lymphocytotoxic antibody, and (e) had the buoyant density of a lipoprotein. This extrinsic mechanism was observed in 41.8% of patients with reduced numbers of ER-positive lymphocytes. The Rosette Inhibitory Factor was not detectable in the serum of the remaining 58.2% of the cases of acute and resolving viral hepatitis B despite the presence of reduced numbers of ER-positive lymphocytes. The lymphocytes from these cases did not reacquire ER function when cultured in the absence of autologous serum. The mechanisms responsible for the suppression of normal ER function in these cases appears to be intrinsic to the lymphocytes and not the result of a humoral factor. The T lymphocyte lineage of cells deficient in respect to ER function, whether of intrinsic or extrinsic type, was demonstrated by their capacity to form spontaneous rosettes with neuraminidase-treated sheep erythrocytes. Both intrinsic and extrinsic suppression of T lymphocyte ER function commonly occurred during the first 4 wk of acute viral hepatitis B.9 of the 10 patients followed serially continued to manifest defective ER function at 12 wk...


ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.
Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.


A study of promoter and intronic markers of ApoI/Fas gene and the interaction with Fas ligand in relapsing multiple sclerosis.
We studied the association between multiple sclerosis (MS) and a novel single nucleotide polymorphism (SNP), A/T(735)G/C, localized in intron IV of the ApoI/Fas gene, which is recognized by the restrictase MaeI. Fas-MaeI genotypes were screened in chromosomes of 215 healthy individuals and 312 relapsing MS patients of Spanish extraction. We also analyzed the interaction of this new intragenic marker with others previously associated with MS: class II HLA-DRB1*1501, Fas-MvaI and Fas ligand. The distribution of Fas-MaeI genotypes was in equilibrium in the control cohort, while a significant disequilibrium was observed in the patient group (chi(2) = 16; p = 0.0003). Fas-MaeI genotypes were statistically different in the MS and control groups, but the allele frequencies were not. Sharing of MvaI/MaeI genotypes of the promoter/intron IV region did not differ between patients and controls. We failed to find different frequencies of ApoI/Fas genotypes in the population of MS carriers of the class II HLA-DRB1*1501 allele. The case/control comparative study showed a relative risk (OR close to 1.6) of MS in individuals harboring the T and A alleles of Fas- MaeI and Fas ligand, respectively. In conclusion, our findings suggest a weak association between the intronic marker Fas-MaeI and MS and a relative interaction with Fas ligand in an MS cohort of South Spanish extraction.


Simulation of salinity effects on past, present, and future soil organic carbon stocks.
Soil organic carbon (SOC) models are used to predict changes in SOC stocks and carbon dioxide (CO(2)) emissions from soils, and have been successfully validated for non-saline soils. However, SOC models have not been developed to simulate SOC turnover in saline soils. Due to the large extent of salt-affected areas in the world, it is important to correctly predict SOC dynamics in salt-affected soils. To close this knowledge gap, we modified the Rothamsted Carbon Model (RothC) to simulate SOC turnover in salt-affected soils, using data from non-salt-affected and salt-affected soils in two agricultural regions in India (120 soils) and in Australia (160 soils). Recently we developed a decomposition rate modifier based on an incubation study of a subset of these soils. In the present study, we introduce a new method to estimate the past losses of SOC due to salinity and show how salinity affects future SOC stocks on a regional scale. Because salinity decreases decomposition rates, simulations using the decomposition rate modifier for salinity suggest an accumulation of SOC. However, if the plant inputs are also adjusted to reflect reduced plant growth under saline conditions, the simulations show a significant loss of soil carbon in the past due to salinization, with a higher average loss of SOC in Australian soils (55 t C ha(-1)) than in Indian soils (31 t C ha(-1)). There was a significant negative correlation (p < 0.05) between SOC loss and osmotic potential. Simulations of future SOC stocks with the decomposition rate modifier and the plant input modifier indicate a greater decrease in SOC in saline than in non-saline soils under future climate. The simulations of past losses of SOC due to salinity were repeated using either measured charcoal-C or the inert organic matter predicted by the Falloon et al. equation to determine how much deviation from the Falloon et al. equation affects the amount of plant inputs generated by the model for the soils used in this study. Both sets of results suggest that saline soils have lost carbon and will continue to lose carbon under future climate. This demonstrates the importance of both reduced decomposition and reduced plant input in simulations of future changes in SOC stocks in saline soils.


Clinical aspects and perinatal outcomes after cryopreservation of embryos and gametes.
Cryopreservation techniques play today a central role in assisted reproduction, as they enhance the overall efficacy of in vitro fertilization (IVF) treatments by allowing the banking of supernumerary embryos obtained in these treatments, and their later use. The transfer of frozen/thawed embryos was established nearly 30 years ago, and although it has been clinical routine for a long time, the importance of freezing embryos has been newly emphasized. As recognized downsides of IVF treatment include the high prevalence of perinatal complications due to multiple births, the recommended practice of transferring fewer embryos in the fresh IVF treatment cycle, with the goal of performing single embryo transfer and the cryostorage of remaining embryos for their later use in frozen-thawed cycles, one at a time, is currently the trend. Also of great importance, cryopreservation techniques for spermatozoa and oocytes have additionally permitted gamete storage for long-term and the implementation of several new treatment modalities for assisted reproduction. Most of these methods are applied today in clinical programs of fertility preservation and third-part reproduction, such as sperm- and egg donor programs. Use of frozen thawed sperm has been in clinical use for over 50 years and banking sperm has been routinely offered to men, usually before gonadotoxic treatments, but also in many cases, practised as a "safety policy" previously to a vasectomy. Freezing methods for women's egg have required a much longer time to achieve a comparable effective clinical standard. Only recently, with the development of vitrification of oocytes, the clinical standard was recognized and since 2013 when the label "experimental" was removed, the freezing of oocytes could be regarded as an established method, and its use extended into clinical practice for fertility preservation but also performed after personal requirements, so called, "social freezing".


Performance of Sequentially Bilateral Cochlear Implanted Children Who Speak Mandarin.
Cochlear implantation is an effective treatment for children with deafness. Although the binaural effect of bilateral cochlear implantation on sound localization and speech perception in noisy environments has been demonstrated, the outcome and performance predictors of the second cochlear implant (CI2) remain uncertain for patients receiving sequential implantation. This study evaluated the hearing performance between the first cochlear implant (CI1), CI2, and bilateral cochlear implants (CI1+2) among children with sequential bilateral cochlear implantation. This single-center retrospective study enrolled 14 children and adolescents aged 8-18 years who underwent sequential bilateral cochlear implantation with a mean interimplant interval of 8.2 years. The Mandarin Lexical Neighborhood Test (M-LNT), the Mandarin Hearing in Noise Test (M-HINT), and the Comprehensive Cochlear Implant Questionnaire (CCIQ) scores of participants were evaluated. Mann-Whitney U tests and Spearman correlation analysis were performed to analyze factors associated with CI2 performance. In the 1-year follow-up period after CI2 implantation, although the M-LNT mean score for CI2 was significantly lower than that for CI1, the M-LNT scores for CI2 and CI1+2 improved significantly over time. In a noisy environment, CI1+2 significantly outperformed CI1 in the M-HINT. The M-LNT score for CI2 was significantly associated with preoperative bimodal fitting, residual hearing of the second implanted ear, and CI2 daily-usage time. Specific to CI2, the CCIQ showed improvement 1 year after CI2 implantation. CI2 improved the hearing performance and quality of life of recipients with longer interimplant intervals, especially in noisy environments, and its efficacy was associated with preoperative bimodal fitting and regular daily use.


Generalist nematodes dominate the nemabiome of roe deer in sympatry with sheep at a regional level.
The growth of livestock farming and the recent expansion of wild ungulate populations in Europe favor opportunities for direct and/or indirect cross-transmission of pathogens. Comparatively few studies have investigated the epidemiology of gastro-intestinal nematode parasites, an ubiquitous and important community of parasites of ungulates, at the wildlife/livestock interface. In this study, we aimed to assess the influence of livestock proximity on the gastrointestinal nematode community of roe deer in a rural landscape located in southern France. Using ITS-2 rDNA nemabiome metabarcoding on fecal larvae, we analysed the gastrointestinal nematode communities of roe deer and sheep. In addition, we investigated Haemonchus contortus nad4 mtDNA diversity to specifically test parasite circulation among domestic and wild host populations. The dominant gastrointestinal nematode species found in both the roe deer and sheep were generalist species commonly found in small ruminant livestock (e.g. H. contortus), whereas the more specialised wild cervid nematode species (e.g. Ostertagia leptospicularis) were only present at low frequencies. This is in marked contrast with previous studies that found the nemabiomes of wild cervid populations to be dominated by cervid specialist nematode species. In addition, the lack of genetic structure of the nad4 mtDNA of H. contortus populations between host species suggests circulation of gastrointestinal nematodes between roe deer and sheep. The risk of contact with livestock only has a small influence on the nemabiome of roe deer, suggesting the parasite population of roe deer has been displaced by generalist livestock parasites due to many decades of sheep farming, not only for deer grazing close to pastures, but also at a larger regional scale. We also observed some seasonal variation in the nemabiome composition of roe deer. Overall, our results demonstrate significant exchange of gastrointestinal nematodes between domestic and wild ungulates, with generalist species spilling over from domestic ungulates dominating wild cervid parasite communities.


Tuberculosis: an unusual presentation.
Patient with tuberculosis may present with atypical, unusual or complex features. The reported case is of 31 years lady admitted with fever, breathlessness and features of cardiac failure. She was detected to have right lower lung consolidation, minimal bilateral pleural effusion, features suggestive of sub-acute pericarditis and subsequent chest x-ray revealed miliary mottling as well. Later on Acid Fast Bacilli were detected in sputum and pleural fluid. Clinicians need to keep complex presentation of TB in mind to manage the case at its earlier stage to avoid residual complication.


Noninvasive Respiratory Support.
Mechanical ventilation is associated with increased survival of preterm infants but is also associated with an increased incidence of chronic lung disease (bronchopulmonary dysplasia) in survivors. Nasal continuous positive airway pressure (nCPAP) is a form of noninvasive ventilation that reduces the need for mechanical ventilation and decreases the combined outcome of death or bronchopulmonary dysplasia. Other modes of noninvasive ventilation, including nasal intermittent positive pressure ventilation, biphasic positive airway pressure, and high-flow nasal cannula, have recently been introduced into the NICU setting as potential alternatives to mechanical ventilation or nCPAP. Randomized controlled trials suggest that these newer modalities may be effective alternatives to nCPAP and may offer some advantages over nCPAP, but efficacy and safety data are limited.


Voluntary wheel running: patterns and physiological effects in mice.
Exercise can prevent and improve the pathophysiology of diseases and promote healthy aging. Thus, understanding the mechanisms that regulate the beneficial effects of exercise may lead to the development of new strategies to enhance quality of life and to counteract chronic diseases. Voluntary wheel running is an interesting model to study the effects of exercise in mice. Compared to forced treadmill exercise, voluntary wheel running presents several advantages such as: 1) running pattern is similar to natural running behavior of mice; 2) it is performed under non-stressed conditions, according to the rhythmicity of the animal; 3) it does not require direct interference from the researcher, and can be easily applied in long-term studies. Mice run spontaneously when given access to running wheels, for a total distance of ∼4 to 20 km per day and a total activity time of ∼3 to 7 hours a day. Hence, voluntary wheel running can result in robust endurance-like adaptation in skeletal and cardiac muscles and protect from sarcopenia. However, due to the lack of control over exercise parameters in voluntary exercise models, it is important for the researcher to understand the patterns and variability of wheel running in mice, as well as the factors that can affect voluntary running activity. Overall, voluntary wheel running in mice is a very interesting approach to study the chronic adaptation to exercise, analyze the effects of exercise, and test exercise capacity in different experimental models.


Effects of online palliative care training on knowledge, attitude and satisfaction of primary care physicians.
The Spanish Palliative Care Strategy recommends an intermediate level of training for primary care physicians in order to provide them with knowledge and skills. Most of the training involves face-to-face courses but increasing pressures on physicians have resulted in fewer opportunities for provision of and attendance to this type of training. The effectiveness of on-line continuing medical education in terms of its impact on clinical practice has been scarcely studied. Its effect in relation to palliative care for primary care physicians is currently unknown, in terms of improvement in patient's quality of life and main caregiver's satisfaction. There is uncertainty too in terms of any potential benefits of asynchronous communication and interaction among on-line education participants, as well as of the effect of the learning process.The authors have developed an on-line educational model for palliative care which has been applied to primary care physicians in order to measure its effectiveness regarding knowledge, attitude towards palliative care, and physician's satisfaction in comparison with a control group.The effectiveness evaluation at 18 months and the impact on the quality of life of patients managed by the physicians, and the main caregiver's satisfaction will be addressed in a different paper. Randomized controlled educational trial to compared, on a first stage, the knowledge and attitude of primary care physicians regarding palliative care for advanced cancer patients, as well as satisfaction in those who followed an on-line palliative care training program with tutorship, using a Moodle Platform vs. traditional education. 169 physicians were included, 85 in the intervention group and 84 in the control group, of which five were excluded. Finally 82 participants per group were analyzed. There were significant differences in favor of the intervention group, in terms of knowledge (mean 4.6; CI 95%: 2.8 to 6.5 (p = 0.0001), scale range 0-33), confidence in symptom management (p = 0.02) and confidence in terms of communication (p = 0.038). Useful aspects were pointed out, as well as others to be improved in future applications. The satisfaction of the intervention group was high. The results of this study show that there was a significant increase of knowledge of 14%-20% and a significant increase in the perception of confidence in symptom management and communication in the intervention group in comparison with the control group that received traditional methods of education in palliative care or no educational activity at all. The overall satisfaction with the intervention was good-very good for most participants.This on-line educational model seems a useful tool for palliative care training in primary care physicians who have a high opinion about the integration of palliative care within primary care. The results of this study support the suggestion that learning effectiveness should be currently investigated comparing different Internet interventions, instead of Internet vs. no intervention.


The usual treatment of trigeminal autonomic cephalalgias.
Trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, and rhinorrhea (SUNCT). Conventional pharmacological therapy can be successful in the majority of trigeminal autonomic cephalalgias patients. Most cluster headache attacks respond to 100% oxygen inhalation, or 6 mg subcutaneous sumatriptan. Nasal spray of sumatriptan (20 mg) or zolmitriptan (5 mg) are recommended as second choice. The bouts can be brought under control by a short course of corticosteroids (oral prednisone: 60-100 mg/day, or intravenous methylprednisolone: 250-500 mg/day, for 5 days, followed by tapering off the dosage), or by long-term prophylaxis with verapamil (at least 240 mg/day). Alternative long-term preventive medications include lithium carbonate (800-1600 mg/day), methylergonovine (0.4-1.2 mg/day), and topiramate (100-200 mg/day). As a rule, paroxysmal hemicrania responds to preventive treatment with indomethacin (75-150 mg/day). A short course of intravenous lidocaine (1-4 mg/kg/hour) can reduce the flow of attacks during exacerbations of SUNCT. Lamotrigine (100-300 mg/day) is the preventive drug of choice for SUNCT. Gabapentin (800-2700 mg/day), topiramate (50-300 mg/day), and carbamazepine (200-1600 mg/day) may be of help.


Emotion regulation during threat: Parsing the time course and consequences of safety signal processing.
Improved understanding of fear inhibition processes can inform the etiology and treatment of anxiety disorders. Safety signals can reduce fear to threat, but precise mechanisms remain unclear. Safety signals may acquire attentional salience and affective properties (e.g., relief) independent of the threat; alternatively, safety signals may only hold affective value in the presence of simultaneous threat. To clarify such mechanisms, an experimental paradigm assessed independent processing of threat and safety cues. Participants viewed a series of red and green words from two semantic categories. Shocks were administered following red words (cue+). No shocks followed green words (cue-). Words from one category were defined as safety signals (SS); no shocks were administered on cue+ trials. Words from the other (control) category did not provide information regarding shock administration. Threat (cue+ vs. cue-) and safety (SS+ vs. SS-) were fully crossed. Startle response and ERPs were recorded. Startle response was increased during cue+ versus cue-. Safety signals reduced startle response during cue+, but had no effect on startle response during cue-. ERP analyses (PD130 and P3) suggested that participants parsed threat and safety signal information in parallel. Motivated attention was not associated with safety signals in the absence of threat. Overall, these results confirm that fear can be reduced by safety signals. Furthermore, safety signals do not appear to hold inherent hedonic salience independent of their effect during threat. Instead, safety signals appear to enable participants to engage in effective top-down emotion regulatory processes.


EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients.
Standardized conditions to distinguish subpopulations of colorectal cancer (CRC) patients more and less sensitive to cetuximab therapy remain undefined. We retrospectively analyzed epidermal growth factor receptor (EGFR) copy number by fluorescence in situ hybridization (FISH) in paraffin-embedded tumor blocks from 85 chemorefractory CRC patients treated with cetuximab. Results were analyzed according to different score systems previously reported in colorectal and lung cancers. The primary end point of the study was identification of the EGFR FISH score that best associates with response rate (RR). Using receiver operating characteristic (ROC) analysis, the cut-off that best discriminated responders versus nonresponders to cetuximab was a mean of 2.92 EGFR gene copies per cell. This model showed sensitivity of 58.6% [95% confidence interval (CI) = 47.1-70.1) and specificity of 93.3% (95% CI = 80.6-100). EGFR FISH-positive patients (N = 43, 50.6%) had significantly higher RR (P = 0.0001) and significantly longer time to disease progression (P = 0.02) than EGFR FISH negative (N = 42, 49.4%). Other scoring systems resulted less accurate in discriminating patients with the highest likelihood of response to cetuximab therapy. CRC patients with high EGFR gene copy number have an increased likelihood to respond to cetuximab therapy. Prospective clinical trials with a careful standardization of assay conditions and pattern interpretation are urgently needed.


Urease operon and urease activity in commensal and disease-causing nontypeable Haemophilus influenzae.
The ure operon was significantly more prevalent in Haemophilus influenzae isolates causing otitis media and chronic obstructive pulmonary disease (COPD)-associated bronchitis than in those from throats of healthy individuals (97% versus 78.1%, P < 0.001). Strains lacking the ure operon are over 8 times more likely to be from the throat than either otitis media or COPD isolates.


Musashi2 promotes the development and progression of pancreatic cancer by down-regulating Numb protein.
Musashi2-Numb interaction plays a vital role in the progression of myeloid leukemia. However, its potential role in solid cancers has rarely been reported. We investigated the coordinate function of Musashi2-Numb in the development of pancreatic cancer (PC) in vitro and vivo. Both Musashi2 protein and mRNA levels were higher in PC tissues than that in paired normal pancreas (P<0.05). Musashi2 overexpression and Numb positive expression were positively and negatively associated with tumor size and UICC stage, respectively (P<0.05). Multivariate analysis identified Musashi2 and Numb as adverse and favorable independent indicators for the survival of PC patients. Moreover, patients with high Musashi2 expression combining with negative Numb expression had a significantly worse overall survival (P=0.001). The negative relationship between Musashi2 and Numb was found at both PC tissue and cell levels. These two endogenous proteins can be co-immunoprecipitated from PC cell lines, and Musashi2 silence up-regulated Numb protein in vitro and vivo. Meanwhile, its silence decreased cell invasion and migration in vitro and inhibited the growth of subcutaneous tumors and the frequency of liver metastasis in vivo. However, Numb knockdown significantly reversed the decrease of cell invasion and migration induced by Musashi2 silence. Musashi2 promotes the development and progression of pancreatic cancer by down-regulating Numb protein. The interaction of Musashi2-Numb plays a significant role in the development and progression of PC.


The limitations of ancestral state reconstruction and the evolution of the ascus in the Lecanorales (lichenized Ascomycota).
Ancestral state reconstructions of morphological or ecological traits on molecular phylogenies are becoming increasingly frequent. They rely on constancy of character state change rates over trees, a correlation between neutral genetic change and phenotypic change, as well as on adequate likelihood models and (for Bayesian methods) prior distributions. This investigation explored the outcomes of a variety of methods for reconstructing discrete ancestral state in the ascus apex of the Lecanorales, a group containing the majority of lichen-forming ascomycetes. Evolution of this character complex has been highly controversial in lichen systematics for more than two decades. The phylogeny was estimated using Bayesian Markov chain Monte Carlo inference on DNA sequence alignments of three genes (small subunit of the mitochondrial rDNA, large subunit of the nuclear rDNA, and largest subunit of RNA polymerase II). We designed a novel method for assessing the suitable number of discrete gamma categories, which relies on the effect on phylogeny estimates rather than on likelihoods. Ancestral state reconstructions were performed using maximum parsimony and maximum likelihood on a posterior tree sample as well as two fully Bayesian methods. Resulting reconstructions were often strikingly different depending on the method used; different methods often assign high confidence to different states at a given node. The two fully Bayesian methods disagree about the most probable reconstruction in about half of the nodes, even when similar likelihood models and similar priors are used. We suggest that similar studies should use several methods, awaiting an improved understanding of the statistical properties of the methods. A Lecanora-type ascus may have been ancestral in the Lecanorales. State transformations counts, obtained using stochastic mapping, indicate that the number of state changes is 12 to 24, which is considerably greater than the minimum three changes needed to explain the four observed ascus apex types. Apparently, the ascus in the Lecanorales is far more apt to change than has been recognized. Phylogeny corresponds well with morphology, although it partly contradicts currently used delimitations of the Crocyniaceae, Haematommataceae, Lecanoraceae, Megalariaceae, Mycoblastaceae, Pilocarpaceae, Psoraceae, Ramalinaceae, Scoliciosporaceae, and Squamarinaceae.


Scanning gate imaging of a disordered quantum point contact.
Scanning gate microscopy (SGM) is a novel technique that has been used to image characteristic features related to the coherent electron flow in mesoscopic structures. For instance, SGM has successfully been applied to study peculiar electron transport properties that arise due to small levels of disorder in a system. The particular case of an InGaAs quantum well layer in a heterostructure, which is dominated by a quasi-ballistic regime, was analyzed. A quantum point contact fabricated onto this material exhibits conduction fluctuations that are not expected in typical high-mobility heterostructures such as AlGaAs/GaAs. SGM revealed not only interference patterns corresponding to specific conductance fluctuations but also mode-dependent resistance peaks corresponding to the first and second quantum levels of conductance (2e(2)/h) at zero magnetic field. On the other hand, clear conductance plateaus originating from the integer quantum Hall effect were observed at high magnetic fields. The physical size of incompressible edge channels was estimated from cross-sectional analysis of these images.


Transport across the cell-membrane dictates nanoparticle fate and toxicity: a new paradigm in nanotoxicology.
The toxicity of metallic nanoparticles (MNPs) has been fully ascertained, but the mechanisms underlying their cytotoxicity remain still largely unclear. Here we demonstrate that the cytotoxicity of MNPs is strictly reliant on the pathway of cellular internalization. In particular, if otherwise toxic gold, silver, and iron oxide NPs are forced through the cell membrane bypassing any form of active mechanism (e.g., endocytosis), no significant cytotoxic effect is registered. Pneumatically driven NPs across the cell membrane show a different distribution within the cytosol compared to NPs entering the cell by active endocytosis. Specifically, they exhibit free random Brownian motions within the cytosol and do not accumulate in lysosomes. Results suggest that intracellular accumulation of metallic nanoparticles into endo-lysosomal compartments is the leading cause of nanotoxicity, due to consequent nanoparticle degradation and in situ release of metal ions.


Robotic Placement of the FENIX Continence Restoration System in a Patient with Previous Radiation to the Pelvis: A Case Report.
Fecal incontinence (FI) is a disabling problem affecting women. Conservative treatment includes dietary modification, antimotility agents, and pelvic floor physical therapy. If conservative medical management is unsuccessful, surgical intervention may be required. Surgical options include rectal sphincteroplasty, bulking agent injection, radiofrequency anal sphincter remodeling, and sacral nerve stimulation therapy. Recently, a new therapy for FI, the FENIX Continence Restoration System (Torax Medical, Inc., Shoreview, MN), has become available. The FENIX device is placed through a perineal incision; however, pelvic radiation and previous anal carcinoma are both contraindications. We report the case of a 62-year-old woman with FI after anal carcinoma. Treatment included surgery, chemotherapy, and pelvic radiation. Initially, she was treated with conservative therapy and sacral nerve stimulation, which were only partially effective. A physical examination showed perineal skin changes consistent with previous radiation, which increased the patient's risk of infection and a nonhealing wound. Therefore, a robotic approach was used to place the FENIX device and improve the patient's quality of life. Our case sets a precedent for expanding the treatment options of FI in patients with previous pelvic radiation and using a robotic approach for the placement of the FENIX device.


A new application of molecularly imprinted materials.
We have studied the possibility of shifting a thermodynamically unfavourable enzymatic equilibrium towards product formation via the addition of a highly specific adsorbent. The commercially interesting enzymatic condensation of Z-L-aspartic acid with L-phenylalanine methyl ester to the sweetener aspartame was chosen as the model system. Extremely stable and specific adsorbents for the product Z-L-Asp-L-Phe-OMe (Z-aspartame) were prepared using the emerging technique of molecular imprinting. A considerable increase (40%) in the yield of product was obtained when such adsorbents were present during the enzymatic reaction. The message of this investigation is that the use of such specific, sterilizable adsorbents should be considered for enzymatic processes to increase the yield. Finally, the direct isolation of a product formed by the retrieval of the adsorbents carrying the product can be envisaged, especially if the adsorbents are magnetic.


Non spiral and spiral (helical) flow patterns in stenoses. In vitro observations using spin and gradient echo magnetic resonance imaging (MRI) and computational fluid dynamic modeling.
Physiological blood flow patterns are themselves poorly understood despite their impact on arterial disease. Stable spiral (helical) laminar flow (SLF) has been observed in normal subjects. The purpose of the present study is to develop a method of magnetic resonance (MR) flow pattern visualization and to analyze spiral and non-spiral flow patterns with and without luminal narrowing in vitro. The flow conditions were then modeled using computational fluid dynamics (Star-CD). Laminar integrity was examined in a flow-rig using spin and gradient echo magnetic resonance imaging (MRI) in non-stenosed and stenosed conduits in the presence of non-spiral and spiral flow. No difference was observed in a non-stenosed conduit between non-spiral and spiral flow. In the presence of a stenosis spiral flow preserves flow velocity coherence whereas non-spiral flow increasingly lost coherence beginning proximal to the stenosis. Computational fluid dynamic modeling of the in vitro experiment showed marked differences between the 2 flow patterns. Non-spiral flow produced greater inwardly directed forces just beyond the stenosis and greater outward pressures at more distal sites. The near wall turbulent energy was up to 700% less with spiral flow over non-spiral flow beyond the stenosis. Spiral flow appears to offer clear flow profile stabilizing advantages over non-spiral flow, by significantly reducing the turbulence caused by a stenosis. Spiral flow also produces lower forces acting on the vessel wall.


GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors.
Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; αMβ2), expressed on both MDSCs and TAMs. However, inhibition or blockade of CD11b/CD18 has had limited success in clinical trials to date, likely since saturation of CD11b requires doses that are not clinically tolerable with the agents tested so far. Interestingly, activation of CD11b with leukadherin-1 was found to reduce macrophage and neutrophil migration in animal models of inflammatory conditions. Preclinical studies with GB1275, a salt form of leukadherin-1, demonstrated that activation of CD11b improves the antitumor immune response and enhances the response to immunotherapy in mouse models of pancreatic adenocarcinoma, breast cancer and lung cancer. Based on the promising results from preclinical studies, a phase 1/2 clinical study (NCT04060342) of GB1275 in patients with advanced solid tumor types known to be resistant or less likely responsive to immuno-oncology therapies, including pancreatic, breast, prostate, and microsatellite-stable colorectal cancer, is ongoing. In this review, we examine targeting MDSCs as a therapeutic approach in cancer therapy, with a special focus on GB1275 preclinical studies laying the rationale for the phase 1/2 clinical study.


Otologic Findings Based on no Complaints in a Pediatric Examination.
Introduction the otological evaluation is highly significant in those branches of medicine in which the general evaluation of the patient is conducted by general practitioners and pediatricians. Objectives To investigate the otologic findings and their incidences in the sample, which consisted of patients who presented to the pediatric outpatient clinic with non-otologic complaints. Methods Patients, aged between 2 and 16 years, who had neither otorhinolaryngological complaints nor history of surgery by the otolaryngology (ear, nose and throat, ENT) department were included in the present study. The findings detected in the external auditory system and in the tympanic membranes as well as the otorhinolaryngologists' otologic examination findings of the referred patients were recorded from the files of each patient along with the applied medical and surgical treatments, and diagnostic investigations. Results Of a total of 973 patients evaluated, 129 (13.2%) were referred to the ENT outpatient clinic due to any otologic pathology. In the otorhinolaryngological examinations, false positivity was detected in 12 (1.2%) patients, and pathological findings were detected in 117 (12%) patients who received the following diagnoses: 68 (6.9%) had otitis media with effusion(OME); 37 (3.8%) had cerumen impactions; 8 (0.8%) had acute otitis media (AOM); 2 (0.2%) had ticks in the external auditory canal; 2 (0.2%) had a retraction pocket in tympanic membrane; 1 (0.1%) had unilateral central dry perforation of the tympanic membrane; and 1(0.1%) had congenital cholesteatoma. Conclusion Any complications and sequelae that may develop due to any pathologies and predominantly infections can be prevented by an early diagnosis, which can be made by means of a simple examination, performed merely with an otoscope. Pediatricians and general practitioners should be in close contact with otorhinolaryngologists regarding the pathologies they identify.


One hundred million years of skin feeding? Extended parental care in a Neotropical caecilian (Amphibia: Gymnophiona).
Maternal dermatophagy, the eating of maternal skin by offspring, is an unusual form of parental investment involving co-evolved specializations of both maternal skin and offspring dentition, which has been recently discovered in an African caecilian amphibian. Here we report the discovery of this form of parental care in a second, distantly related Neotropical species Siphonops annulatus, where it is characterized by the same syndrome of maternal and offspring specializations. The detailed similarities of skin feeding in different caecilian species provide strong evidence of its homology, implying its presence in the last common ancestor of these species. Biogeographic considerations, the separation of Africa and South American land masses and inferred timescales of amphibian diversification all suggest that skin feeding is an ancient form of parental care in caecilians, which has probably persisted in multiple lineages for more than 100 Myr. These inferences support the hypotheses that (i) maternal dermatophagy is widespread in oviparous direct-developing caecilians, and (ii) that viviparous caecilians that feed on the hypertrophied maternal oviduct evolved from skin-feeding ancestors. In addition to skin-feeding, young S. annulatus were observed to congregate around, and imbibe liquid exuded from, the maternal cloacal opening.


Clinical courses and changes of pancreatic beta-cell function in young-onset diabetics: report of two cases.
Accurate classification of diabetes in some young patients is difficult but clearly of importance in deciding the appropriate treatment. We report the different clinical courses and beta-cell function changes in 2 young-onset diabetics. In the beginning, each of them was considered to be a patient with insulin-dependent diabetes mellitus (IDDM) and was treated with insulin. Then, treatment was shifted from insulin to oral hypoglycemic agents (OHA) because each patient's beta-cell function was comparable to that of patients with non-insulin-dependent diabetes mellitus (NIDDM). In case 1, the patient's glycemic control and beta-cell function progressively deteriorated and finally insulin therapy was required. In case 2, the patient was continuously treated with OHA. Although his blood glucose was not well-controlled, his beta-cell function had been well-preserved. Recently he achieved near-normoglycemia by improving his diet and OHA compliance. Clearly, case 1 was a slowly progressive Type 1 DM patient and case 2 was a young Type 2 DM patient. This classification was further supported by the finding that the patient in case 1 had human leukocyte antigen (HLA)-DR3, but the patient in case 2 did not.


A carboxypeptidase inhibitor from the tick Rhipicephalus bursa: isolation, cDNA cloning, recombinant expression, and characterization.
A novel proteinaceous metallo-carboxypeptidase inhibitor, named tick carboxypeptidase inhibitor (TCI), was isolated from the ixodid tick Rhipicephalus bursa and N-terminally sequenced. The complete cDNA encoding this protein was cloned from tick mRNA by reverse transcription-PCR and rapid amplification of cDNA ends techniques. The full-length TCI cDNA contains an open reading frame coding for a precursor protein of 97 amino acid residues that consists of a predicted signal peptide of 22 residues and of mature TCI, a 75-residue cysteine-rich protein (12 Cys). The deduced amino acid sequence shows no homology to other known proteins; the C terminus, however, resembles those of other protein metallo-carboxypeptidase inhibitors, suggesting a common mechanism of inhibition. Recombinant TCI expressed in Escherichia coli is fully functional and inhibits carboxypeptidases of the A/B subfamily with equilibrium dissociation constants in the nanomolar range. Structural analyses by circular dichroism and nuclear magnetic resonance indicate that TCI is a protein strongly constrained by disulfide bonds, unusually stable over a wide pH range and highly resistant to denaturing conditions. As a tight binding inhibitor of plasma carboxypeptidase B, also known as thrombin-activatable fibrinolysis inhibitor, recombinant TCI stimulates fibrinolysis in vitro and thus may have potential for applications to prevent or treat thrombotic disorders.


Oral poliovirus vaccine evolution and insights relevant to modeling the risks of circulating vaccine-derived polioviruses (cVDPVs).
The live, attenuated oral poliovirus vaccine (OPV) provides a powerful tool for controlling and stopping the transmission of wild polioviruses (WPVs), although the risks of vaccine-associated paralytic polio (VAPP) and circulating vaccine-derived poliovirus (cVDPV) outbreaks exist as long as OPV remains in use. Understanding the dynamics of cVDPV emergence and outbreaks as a function of population immunity and other risk factors may help to improve risk management and the development of strategies to respond to possible outbreaks. We performed a comprehensive review of the literature related to the process of OPV evolution and information available from actual experiences with cVDPV outbreaks. Only a relatively small fraction of poliovirus infections cause symptoms, which makes direct observation of the trajectory of OPV evolution within a population impractical and leads to significant uncertainty. Despite a large global surveillance system, the existing genetic sequence data largely provide information about transmitted virulent polioviruses that caused acute flaccid paralysis, and essentially no data track the changes that occur in OPV sequences as the viruses transmit largely asymptomatically through real populations with suboptimal immunity. We updated estimates of cVDPV risks based on actual experiences and identified the many limitations in the existing data on poliovirus transmission and immunity and OPV virus evolution that complicate modeling. Modelers should explore the space of potential model formulations and inputs consistent with the available evidence and future studies should seek to improve our understanding of the OPV virus evolution process to provide better information for policymakers working to manage cVDPV risks.


Impact of climate changes from Middle Miocene onwards on evolutionary diversification in Eurasia: insights from the mesobuthid scorpions.
The aridification from Middle Miocene onwards has transformed the Asian interior into an arid environment, and the Pleistocene glacial-interglacial oscillations exerted further ecological impact. Therefore, both aridification and glaciation would have considerably influenced the evolution of many mid-latitude species in temperate Asia. Here, we tested this perspective by a phylogeographic study of the mesobuthid scorpions across temperate Asia using one mitochondrial and three nuclear genes. Concordant mitochondrial and nuclear gene trees were obtained, which are consistent with species tree inferred using a Bayesian approach. The age of the most recent common ancestor (MRCA) of all the studied scorpions was estimated to be 12.49 Ma (late Middle Miocene); Mesobuthus eupeus diverged from the clade composing Mesobuthus caucasicus and Mesobuthus martensii in early Late Miocene (10.21 Ma); M. martensii diverged from M. caucasicus at 5.53 Ma in Late Miocene. The estimated MRCA ages of M. martensii and the Chinese lineage of M. eupeus were 2.37 and 0.68 Ma, respectively. Central Asia was identified as the ancestral area for the lineage leading to M. martensii and M. caucasicus and the Chinese lineage of M. eupeus. The ancestral habitat of the genus Mesobuthus is likely to have been characterized by an arid environment; a shift towards more humid habitat occurred in the MRCA of M. martensii and a lineage of M. caucasicus, finally leading to the adaptation of M. martensii to humid environment. Our data strongly support the idea that the stepwise intensified aridifications from Mid-Miocene onwards drove the diversification of mesobuthid scorpions, and suggest that M. martensii and M. eupeus observed today in China originated from an ancestral lineage distributed in Central Asia. Both the colonization and the ensuing evolution of these species in East Asia appear to have been further moulded by Quaternary glaciations.


Nucleotide sequence analysis of the linked left and right hand terminal regions of adenovirus type 5 DNA present in the transformed rat cell line 5RK20.
A peculiar phenomenon is observed in several adenovirus type 2 or 5 (Ad2 or Ad5) transformed cell lines: the right hand and left hand terminal regions of the viral genome present in the viral DNA insertions of these cell lines are found to be linked together. A large part of the viral DNA insertion present in the Ad5 transformed rat cell line 5RK20 has been cloned in the lambda vector Charon21A, including the segment containing the linked terminal regions. Sequence analysis of the linkage region showed a perfect homology with the Ad5 DNA sequence and a direct linkage of basepair (bp) 63 of the left hand end of the viral genome to bp 108 of the right hand end. No cellular or rearranged viral sequences were present. Our findings suggest that the joining of viral sequences into the cellular genome.


Wine drinking and epithelial ovarian cancer risk: a meta-analysis.
Wine has been the focus in the prevention of epithelial ovarian cancer (EOC) development because resveratrol abundant in wine has anti-carcinogenic properties. However, epidemiologic results have been heterogenous in the chemopreventive effect of wine on the development of EOC. Thus, we performed a meta-analysis for comparing EOC risk between wine and never drinkers using previous related studies. After extensive search of the literature between January 1986 and December 2008, we analyzed 10 studies (3 cohort and 7 case control studies) with 135,871 women, who included 65,578 of wine and 70,293 of never drinkers. In all studies, there was no significant difference in EOC risk between wine and never drinkers (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.92 to 1.38; random effects). When we performed re-analysis according to the study design, 3 cohort and 7 case control studies showed that there were also no significant differences in EOC risk between wine and never drinkers, respectively (OR, 1.44 and 1.04; 95% CI, 0.74 and 2.82 and 0.88 to 1.22; random effects). In sub-analyses using 2 case-control studies, EOC risk was not different between former and never drinkers (OR, 1.12; 95% CI, 0.87 to 1.44; fixed effect), and between current and former drinkers (OR, 0.74; 95% CI, 0.41 to 1.34; random effects). Although resveratrol, abundantly found in wine, is a promising naturally occurring compound with chemopreventive properties on EOC in preclinical studies, this meta-analysis suggests the epidemiologic evidence shows no association between wine drinking and EOC risk.


Chelidonium majus crude extract induces activation of peripheral blood mononuclear cells and enhances their cytotoxic effect toward HeLa cells.
The aim of the study was to examine the immunomodulatory effect of crude Chelidonium majus L ethanolic extract on ex vivo harvested peripheral blood mononuclear cells (PBMNCs). PBMNCs were isolated by density gradient centrifugation. The PBMNC cytotoxicity assay was performed with HeLa tumor cells as target cells. MTT assay was used to estimate the proliferation effect of extract and cytotoxic efficiency of treated PBMNCs. Flow cytometric analysis was used for immunophenotyping. Treatment induced moderate proliferative response, perturbation in PBMNC ratios, and the emergence of some unconventional subpopulations. The percentage ratio of double positive CD4+ and CD8+ T lymphocytes and monocytes, ratio of T and B lymphocytes expressing CD14, and percentage of NK cells expressing CD57 increased after treatment, indicating activation of PBMNC subpopulations. Cytotoxic activity against HeLa cells was enhanced. Activation of PBMNCs and enhancement of their cytotoxic effect toward HeLa cells indicate the immunostimulatory effect of Ch. majus ethanolic extract.


Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and ethanol.
Venlafaxine is a new antidepressant with a unique mode of action. Because many patients taking antidepressant therapy may self-medicate with ethanol, this study was undertaken to assess the possible pharmacokinetic and pharmacodynamic interactions between venlafaxine and ethanol. This randomized, double-blind, placebo-controlled, two-period crossover study was conducted with 16 healthy men. Multiple doses of venlafaxine (50 mg every 8 hours) or placebo were administered for 7 days. On days 5 and 7 a single dose of 0.5 g/kg of ethanol or a placebo solution was administered in a randomized fashion. Pharmacokinetic data indicated that ethanol administration did not affect the disposition of venlafaxine or O-desmethylvenlafaxine. Similarly, venlafaxine administration did not affect the pharmacokinetic disposition of ethanol. Ethanol produced its expected effects on the eight psychometric tests administered. Venlafaxine produced small effects on the results of the Digit Symbol Substitution Test, the Divided Attention Reaction Time, and the Profile of Mood States. No pharmacodynamic interaction was detected between venlafaxine and ethanol.


[Significance of the isoantigen A2 and immune anti-A1 antibodies in transfusiology].
The paper gives data on the frequency of A2 and A2B blood groups in the blood samples of 3590 donors and patients and on the carriage of irregular anti-A1 antibodies. To define the belonging of anti-A1 antibodies to various classes of immunoglobulins, their resistance and temperature optimum, at which the antibodies showed the highest activity, the authors examined the irregular anti-A1 antibodies-containing sera from 43 subjects with A2 and A2B blood groups. The necessity of identifying the carriage of irregular anti-A1 antibodies is determined by the fact that there may be posttransfusion reactions or complications in recipients, the carriers of such antibodies, who are transfused donor red blood cells containing the antigen A1. The risk of the development of such events is particularly great when anti-A1 antibodies are active at 37 degrees C and belong to the IgG class, i.e. they are immune; transfusion to a recipient is carried out during surgery under artificial hypothermia (below 28 degrees C). The red blood cells (A2 or A2B) from a donor having the same group should be selected for recipients having an A2 or A2B blood groups, respectively, and immune anti-A1 antibodies; if the latter are absent, in accordance with the instruction, there may be a selection of other-group donor red blood cells: 0 group red blood cells to recipients with A2 blood group and 0 or B group red blood cells to recipients with A2B blood group. An individual selection should be without fail made for the compatibility of bloods from a donor and a recipient in salt tests (at 4-8, 20-22, and 37 degrees C) and indirect Coombs' test. When plasma components (fresh frozen plasma, native plasma and its concentrate) are transfused to recipients with A2 and A2B blood groups having immune anti-A1 antibodies, one should use the same plasma group--A and AB, respectively.


Surface anatomy of the middle division of the facial nerve: Zuker's point.
The anatomy of the facial nerve and its branches has been well documented. The course of the extratemporal facial nerve, its anatomical planes, and the surface landmarks of the temporal division and marginal mandibular division are well known. However, the surface landmark of the middle division of the facial nerve has not been studied to date. Eighteen hemifacial dissections in 10 fresh human cadavers were performed through a preauricular face-lift incision. An 18-gauge needle with brilliant green dye was used to mark the nerve through the skin before dissection. The exact location of the middle division branches of the facial nerve was documented in relation to the transcutaneous marking. The middle division branches of the facial nerve were found to lie at a mean of 2.3 mm from the tattooed point, with a range of 0 to 6 mm. A nerve branch was found directly tattooed by the needle seven of 18 times, inferior to the tattoo five of 18 times, and superior to the tattoo six of 18 times. The zygomatic/buccal motor branch that innervates the zygomaticus major muscle can be reliably found at the midway point on a line drawn from the root of the helix and the lateral commissure of the mouth. This study will help guide surgeons to the middle division of the facial nerve as it applies to facial surgery.


[Associated factors for prediabetes in patients with human immunodeficiency virus].
HIV disease was transformed from a fatal condition to one with metabolic complications. In Mexico City, the associated factors for prediabetes in this population are unknown; investigating it is relevant to improve their quality of life. To determine the risk association factors for prediabetes in people living with HIV. Cross-analytical, retrospective study. Records of patients living with HIV were reviewed, exposure factors and fasting glucose concentration were recorded. Patients from 18 to 65 years of age were included, on co-formulated antiretroviral treatment, without adjustment of antiretroviral treatment in the last two years, with a BMI of 18.5-40 kg/m2. 148 patients were included, 68 presented prediabetes. The factors with risk association that were identified are: age over 60 years (OR 9.48, 95% CI 1.68-40.13), treatment with Efavirenz/Tenofovir/Emtricitabine (OR 9.28, 95% CI 2.55-33.74) and treatment time antiretroviral older than 12 months (OR 2.53, 95% CI .912-7.041). The prevalence of prediabetes in people living with HIV is 46%. The main associated factor was the consumption of Atripla. This study has clinical relevance since it will allow the implementation of prevention, diagnosis and treatment strategies for prediabetes in order to reduce associated morbidity and mortality.


Magnetic field observations during the ulysses flyby of jupiter.
The Jovian flyby of the Ulysses spacecraft presented the opportunity to confirm and complement the findings of the four previous missions that investigated the structure and dynamics of the Jovian magnetosphere and magnetic field, as well as to explore for the first time the high-latitude dusk side of the magnetosphere and its boundary regions. In addition to confirming the general structure of the dayside magnetosphere, the Ulysses magnetic field measurements also showed that the importance of the current sheet dynamics extends well into the middle and outer magnetosphere. On the dusk side, the magnetic field is swept back significantly toward the magnetotail. The importance of current systems, both azimuthal and field-aligned, in determining the configuration of the field has been strongly highlighted by the Ulysses data. No significant changes have been found in the internal planetary field; however, the need to modify the external current densities with respect to previous observations on the inbound pass shows that Jovian magnetic and magnetospheric models are highly sensitive to both the intensity and the structure assumed for the current sheet and to any time dependence that may be assigned to these. The observations show that all boundaries and boundary layers in the magnetosphere have a very complex microstructure. Waves and wave-like structures were observed throughout the magnetosphere; these included the longest lasting mirror-mode wave trains observed in space.


Osmotic adaptation by gram-negative bacteria: possible role for periplasmic oligosaccharides.
The cyclic (1----2)-beta-D-glucans produced by species of Agrobacterium and Rhizobium resemble the membrane-derived oligosaccharides of Escherichia coli in their periplasmic localization, intermediate size, and (1----2)-beta-D-glucan backbones. The regulation of the biosynthesis of cyclic (1----2)-beta-D-glucan by Agrobacterium tumefaciens is now shown to parallel the osmotic regulation of membrane-derived oligosaccharide biosynthesis in Escherichia coli. This result suggests a general role for periplasmic oligosaccharides in the osmotic adaptation of Gram-negative bacteria as ecologically diverse as enteric and soil bacteria.


Megavoltage radiotherapy effects on organs of the reticuloendothelial system.
To study the uptake capacity of cells from the reticuloendothelial system after irradiation with high-energy X-rays. Eighteen male Wistar rats were distributed in three groups: group A (n = 6): control, unirradiated animals studied alongside animals from group B; group B (n = 6) and group C (n = 6): animals irradiated and studied after 24 and 48 hours, respectively. The rats were anesthetized and placed on a 10 MV linear accelerator. Next, they were irradiated in the abdominal region, with 8 Gy. Twenty-four (groups A and B) and 48 hours later (group C), a colloidal carbon solution (1 mL/kg) was intravenously injected in the tail vein. Fifty minutes later, the spleens and livers were withdrawn and prepared to be studied. Kupffer cells and splenic macrophages containing carbon pigments were counted in an optical microscope. Arithmetic means were calculated for each group and compared among them. X-rays were associated with a reduced number of Kupffer cells containing colloidal carbon, proliferation and enlargement of biliary ducts, hypoplasia, and hepatocyte necrosis. In the irradiated spleen, the colloidal carbon uptake was concentrated in the marginal zone around the white pulp, with an inexpressive uptake of pigments by macrophages from white and red pulps. The X-rays in the rat abdomen are associated with a reduction in the Kupffer cells uptake of colloidal carbon, hepatocyte disorders, bile duct proliferation, and splenic uptake of colloidal carbon concentrated in the marginal zone.


[Tommaso Campailla: dream stuff and the hypochondria of an eclectic].
Born on 7th April 1668 in Modica, Ciceronian 'Agrum Motucanum', the Modican county of Chiaramontes and Chiabreras, Tommaso Campailla, a poet and a physician, is mostly known as the author of a philosophical poem in octaves--Adam or the Created World. In his 1727 Problemi naturali [Natural Problems], his essay Del disordinato discorso dell'uomo [On Man's Disorderly Discourse] distinguishes itself by its intellectual wit on both the speculative and the experimental research aspects. He formulates concepts on the darkness which often reason has to fare through; he substantializes the body/soul syncretic dimension, and underlines how this disrupts the perfect bodily mechanism. His observations are born in a scientific and historical period which was absorbed within an iatromechanical scenario of which they are reliable proofs and physiological foundations. If on the one hand he reduces the spiritual (psychical) stance to a physical one, on the other hand he gives substance to his questioning his own inner torments, his own hypochondriac being. He died of apoplexy aged 72, on 7th February 1740.


A Review of the Historical Evolution, Biomechanical Advantage, Clinical Applications, and Safe Insertion Techniques of Cervical Pedicle Screw Fixation.
Cervical spine instrumentation is evolving with an aim of stabilizing traumatic and non-traumatic cases of the cervical spine with a beneficial reduction, better biomechanical strength, and a strong construct with minimal intraoperative, as well as immediate and late postoperative complications. The evolution from interspinous wiring till cervical pedicle screws has changed the outlook in treating the cervical spine pathologies with maximum 3D stability, decreasing the duration of postoperative immobilization and hospital stay. Some complications associated with the use of cervical pedicle screw can be catastrophic. This review article discusses the morphometry of cervical pedicle; indications, biomechanical superiority, tricks, and pitfalls of cervical pedicle screw; complications and technical advancements in targeting safe surgery; and future directions of cervical pedicle screw instrumentation.


Reliability of Telephone and Videoconference Methods of Cognitive Assessment in Older Adults with and without Dementia.
Telephone and videoconference administration of cognitive tests introduce additional sources of variance compared to in-person testing. Reviews of test-retest reliability have included mixed neurocognitive and psychiatric populations with limited consideration of methodological and statistical contributions. We reviewed reliability estimates from comparison studies of older adults with and without dementia, considering test-retest analyses and study methods. Medline, Embase, PsycINFO, and Web of Science were systematically searched from 1 January 2000 to 9 June 2020 for original articles comparing telephone or videoconference administered cognitive instruments to in-person administration in older adults with and without dementia or mild cognitive impairment. Of 4,125 articles, 23 were included: 11 telephone (N = 2 dementia cohorts) and 12 videoconference (N = 4 dementia cohorts). Telephone administered subtest scores trended in the same direction as in-person with comparable means. Person-level data were scarce. Data on dementia was only available for MMSE, with resulting subtle modality bias. MMSE, SMMSE, Letter Fluency, and HVLT-R in healthy to mild-moderate Alzheimer's disease were particularly reliable for videoconference administration. Other tests show promise but require more observations and comprehensive analyses. Most studies used high-speed stable videoconferencing hardware resulting in a lack of ecological validity for home administration. Remote administration is often consistent with in-person administration but variable and limited at the person/test level. Improved statistical design and inclusion of dementia related cohorts in telephone studies is recommended. Reliability evidence is stronger for videoconferencing but with limited applicability to home administration and severe dementia. Improved reporting of administrative procedures is recommended.


Self-regulatory processes defend against the threat of death: Effects of self-control depletion and trait self-control on thoughts and fears of dying.
Nine studies (N = 979) demonstrated that managing the threat of death requires self-regulation. Both trait and state self-control ability moderated the degree to which people experienced death-related thought and anxiety. Participants high (vs. low) in self-control generated fewer death-related thoughts after being primed with death, reported less death anxiety, were less likely to perceive death-related themes in ambiguous scenes, and reacted with less worldview defense when mortality was made salient. Further, coping with thoughts of death led to self-regulatory fatigue. After writing about death versus a control topic, participants performed worse on several measures of self-regulation that were irrelevant to death. These results suggest that self-regulation is a key intrapsychic mechanism for alleviating troublesome thoughts and feelings about mortality.


Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk.
Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling. We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation. All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power-with the exception of isolated rare inherited pathogenic variants -does not yet reach a threshold that would typically be considered actionable for reproductive decision-making. Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study.


Potential for bisphosphonate treatment in Legg-Calve-Perthes disease.
The observation that the pathogenesis of femoral head deformity in Legg-Calve-Perthes disease (LCPD) relates to bone resorption without subsequent coupled bone formation leads quickly to the hypothesis that antiresorptive agents may provide a useful adjunctive avenue for therapy. Robust bone catabolism in the absence of anabolism can only lead to femoral head deformity. The published data on bisphosphonate use in models of LCPD was reviewed. Multiple animal studies support the further investigation of bisphosphonates and other anticatabolic agents in LCPD. Clinical data is only now starting to be gathered on the basis of animal and safety data.Rodent studies of traumatic and spontaneous osteonecrosis confirm that femoral head shape can be preserved by systemic bisphosphonate administration. Large animal piglet studies also show better preservation of the femoral head shape with systemic and local bisphosphonate administration, and also illustrate that systemic therapy requires initial revascularization of the necrotic head before its distribution within the head-a potential drawback of systemic therapy. Timing of effective dosing is likely to be very important. If the goal of treatment is to prevent deformity, then the window of therapy may be limited to an early stage of the disease before the significant collapse of the head.Although limiting bone resorption and preserving femoral head shape with bisphosphonates or other anticatabolic drugs may be of use, anabolic stimulation to speed up healing and new bone formation may also be desirable. Physical factors such as weight relief and activity modification may be important as the mechanical properties of the necrotic femoral head are significantly compromised during healing. The inflammatory nature of early LCPD is likely to also play a role in pathogenesis. These factors cannot be addressed by the use of antiosteoclastic therapy alone. Further basic science and clinical studies are required to clarify the role of bisphosphonates as adjunctive therapy in LCPD.


Percutaneous mitral valve repair with the MitraClip: early results from the MitraClip Asia-Pacific Registry (MARS).
Percutaneous MitraClip therapy has been shown to be safe and efficacious in mitral regurgitation (MR). Our aim was to describe early outcomes in patients from the Asia- Pacific region. The MitraClip Asia-Pacific Registry (MARS) includes data from eight different centres in five countries in the Asia-Pacific region. The primary efficacy outcome was reduction in MR to ≤2+ at 30 days. The safety outcome was 30-day freedom from major adverse events (MAE), defined as the composite of death, myocardial infarction, non-elective cardiac surgery, renal failure, transfusion of ≥2 units of blood, ventilation for >48 hours, septicaemia, and new onset atrial fibrillation. A total of 142 patients underwent the MitraClip procedure from February 2011 to October 2013. Fifty-three point five percent (76) of patients had functional MR, 45.8% (65) had degenerative MR and 0.7% (1) had mixed MR. The acute procedural success rate was 93.7% (133). Thirty-one point seven percent of the patients were in NYHA Class I-II at baseline, compared to 82.1% at 30 days (p<0.001). Zero percent (0) of the patients had ≤2+ MR at baseline compared to 76.8% (109) at 30 days (p<0.001). Results from the Asia-Pacific region show that the MitraClip procedure is effective in reducing mitral regurgitation and has favourable short-term safety outcomes.


Spontaneous emergence of multiple drug resistance in tuberculosis before and during therapy.
The emergence of drug resistance in M. tuberculosis undermines the efficacy of tuberculosis (TB) treatment in individuals and of TB control programs in populations. Multiple drug resistance is often attributed to sequential functional monotherapy, and standard initial treatment regimens have therefore been designed to include simultaneous use of four different antibiotics. Despite the widespread use of combination therapy, highly resistant M. tb strains have emerged in many settings. Here we use a stochastic birth-death model to estimate the probability of the emergence of multidrug resistance during the growth of a population of initially drug sensitive TB bacilli within an infected host. We find that the probability of the emergence of resistance to the two principal anti-TB drugs before initiation of therapy ranges from 10(-5) to 10(-4); while rare, this is several orders of magnitude higher than previous estimates. This finding suggests that multidrug resistant M. tb may not be an entirely "man-made" phenomenon and may help explain how highly drug resistant forms of TB have independently emerged in many settings.


Rabies virus glycoprotein analogs: biosynthesis in Escherichia coli.
The surface of rabies virus is composed of an approximately 60,000 dalton glycoprotein, in which most of the antigenic and immunogenic determinants of the virus reside. We have constructed plasmids for the direct expression in Escherichia coli of the mature full length rabies glycoprotein gene and also for the expression of a glycoprotein gene which has been truncated to exclude the coding region for a hydrophobic, possibly transmembrane, domain of the protein. Escherichia coli harboring the plasmids synthesize analog proteins which conform by several biochemical and antigenic criteria to rabies glycoprotein.