How unique is the low oxygen response? An analysis of the anaerobic response during germination and comparison with abiotic stress in rice and Arabidopsis.
Plants face a variety of environmental stresses and have evolved molecular mechanisms to survive these challenges. One of these stresses is low oxygen conditions, which can occur under flooding conditions. Rice (Oryza sativa) is somewhat unique for its ability to tolerate and even germinate under low to no oxygen conditions. In this study, we examined global transcriptomic responses over the course of germination and in response to low oxygen and other abiotic stress in rice and Arabidopsis (Arabidopsis thaliana). Over 150 microarray datasets were analyzed in parallel to determine just how unique the low oxygen response is in rice. Comparison of aerobic germination in rice and Arabidopsis, with anaerobic germination in rice revealed conserved transcriptomic responses that are not only conserved across both species but also occur in the absence of oxygen in rice. Thus, these genes may represent functions necessary for the developmental progression of germination, whether or not oxygen is present in rice. Analysis of genes that responded differently in rice compared to Arabidopsis revealed responses specific to anaerobic germination in rice, including the down-regulation of genes encoding redox functions and up-regulation of receptor kinases. Comparison of a range of hypoxia/anoxia studies within and across Arabidopsis and rice revealed both conserved and species specific changes in gene expression (e.g., Arabidopsis specific up-regulation of WRKYs and rice specific down-regulation of heme), unveiling unique transcriptomic signatures of the low oxygen response. Lastly, a comparison of the low oxygen response with cold, salt, drought and heat stress revealed some similarity with the response to heat stress in Arabidopsis, which was not seen in rice. Comparison of these heat-responsive, abiotic stress marker genes in Arabidopsis with their rice orthologs revealed that while low oxygen may be perceived as an abiotic stress in Arabidopsis, this is not the case in rice.


Autoradiographic localization and density of [125I]ferrotransferrin binding sites in the basal ganglia of control subjects, patients with Parkinson's disease and MPTP-lesioned monkeys.
Degeneration of the nigro-striatal dopaminergic neurons occurring in Parkinson's disease is associated with an increase in iron concentrations in the substantia nigra. As this metal catalyzes the production of free radicals, and oxidative stress may participate in the cascade of events ending in cell death, this increase in iron content may be involved in dopaminergic neuronal death. The localization and number of receptors for transferrin were investigated postmortem by quantitative autoradiography of iodinated-ferrotransferrin binding in the basal ganglia from controls, parkinsonian patients and MPTP-lesioned monkeys. In human controls, specific [125i] ferrotransferrin binding-site density was highest in the putamen and the caudate nucleus, and lowest in the globus pallidus. In parkinsonian patients, it was increased in the putamen and caudate nucleus, while in MPTP-intoxicated monkeys, there was a tendency for levels to decrease in these two regions. An inverse relationship between binding density and iron content reported in the studied regions supports the assumption of a possible capture of iron at the level of dopaminergic terminals and, in parkinsonian patients, on other cellular elements as well. These results suggest an involvement of transferrin receptors in iron uptake in the striatum of patients with Parkinson's disease, with differences between the 'acute' nigro-striatal MPTP-induced degeneration syndrome and the chronic long lasting human disease.


The Association of Biochemical Hypoglycemia with the Subsequent Risk of a Severe Hypoglycemic Event: Analysis of the DCCT Data Set.
To evaluate the association of biochemical hypoglycemia with subsequent severe hypoglycemia (SH) events using the Diabetes Control and Complications Trial (DCCT) data set. The frequency of biochemical hypoglycemia (percentage of values <70 and <54 mg/dL [3.9 and 3.0 mmol/L) was assessed using DCCT blood glucose concentrations measured at a central laboratory from seven finger-stick samples (7-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. SH events required a change in mental status necessitating the involvement of another individual to provide treatment. A Poisson model accounting for repeated measures from each participant was used to assess the association of biochemical hypoglycemia frequency, computed from the 7-point finger-stick data, with the development of SH events. The risk of SH during a 3-month period was substantially higher (P < 0.001) when there was at least one hypoglycemic blood glucose value in the preceding 7-point profile, with similar results seen for both the 70 mg/dL (rate ratio = 3.0 [95% confidence interval: 2.6-3.3]) and 54 mg/dL (rate ratio = 2.7 [95% confidence interval: 2.4-3.1]) thresholds. The occurrence of biochemical hypoglycemia <70 or <54 mg/dL is associated with an increased risk of SH. For this reason as well as the deleterious effects of hypoglycemia on glucose counter-regulation and hypoglycemia awareness, cognition, quality of life, and arrhythmias, it is important in diabetes management to avoid hypoglycemic glucose levels as much as possible.


Why is "blindsight" blind? A new perspective on primary visual cortex, recurrent activity and visual awareness.
The neuropsychological phenomenon of blindsight has been taken to suggest that the primary visual cortex (V1) plays a unique role in visual awareness, and that extrastriate activation needs to be fed back to V1 in order for the content of that activation to be consciously perceived. The aim of this review is to evaluate this theoretical framework and to revisit its key tenets. Firstly, is blindsight truly a dissociation of awareness and visual detection? Secondly, is there sufficient evidence to rule out the possibility that the loss of awareness resulting from a V1 lesion simply reflects reduced extrastriate responsiveness, rather than a unique role of V1 in conscious experience? Evaluation of these arguments and the empirical evidence leads to the conclusion that the loss of phenomenal awareness in blindsight may not be due to feedback activity in V1 being the hallmark awareness. On the basis of existing literature, an alternative explanation of blindsight is proposed. In this view, visual awareness is a "global" cognitive function as its hallmark is the availability of information to a large number of perceptual and cognitive systems; this requires inter-areal long-range synchronous oscillatory activity. For these oscillations to arise, a specific temporal profile of neuronal activity is required, which is established through recurrent feedback activity involving V1 and the extrastriate cortex. When V1 is lesioned, the loss of recurrent activity prevents inter-areal networks on the basis of oscillatory activity. However, as limited amount of input can reach extrastriate cortex and some extrastriate neuronal selectivity is preserved, computations involving comparison of neural firing rates within a cortical area remain possible. This enables "local" read-out from specific brain regions, allowing for the detection and discrimination of basic visual attributes. Thus blindsight is blind due to lack of "global" long-range synchrony, and it functions via "local" neural readout from extrastriate areas.


Glutathione S-transferase gene polymorphisms and susceptibility to acute myeloid leukemia: meta-analyses.
A large body of evidence has shown the possible relevance of polymorphisms of the genes that encode glutathione S-transferase μ, π and θ (GSTM1, GSTP1 and GST1, respectively) to the susceptibility of acute myeloid leukemia, but the exact association still remains uncertain. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship. A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until 20 February 2014. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios with 95% confidence intervals were calculated to estimate the association strength using Review Manager version 5.2. Twenty-nine studies were included in the meta-analysis. The pooled analyses revealed that the GSTM1-null genotype was associated with an increased risk of acute myeloid leukemia in East Asians (P = 0.01; odds ratio = 1.22; 95% confidence interval = 1.05-1.42), and GSTT1-null genotype in Caucasians (P < 0.0001; odds ratio = 1.48; 95% confidence interval = 1.29-1.69). There was also a predilection towards the female gender for both of these polymorphisms. For GSTP1 Ile105Val polymorphism, no significant association was found under any contrast model. In addition, the presence of the double-null genotypes increased the risk of acute myeloid leukemia in both Caucasians and East Asians. This meta-analysis suggested that heritable GST status could influence the risk of developing acute myeloid leukemia.


Studies in a patient with acute leukaemia after lysergide treatment.
The second case of acute leukaemia developing after administration of lysergide is reported. The unusual bone-marrow chromosome pattern and the presence of large cells containing multiple micronucleoli suggest that this association may be causal.


The Novel Eryngii Method of Nipple Reduction for Female-to-Male Transsexuals.
Mastectomy is usually the first and most important surgical procedure in female-to-male (FTM) individuals with gender identity disorder. Nipple reduction is also important in the process of reconstructing the chest wall for a more male appearance. If the nipples remain large after a mastectomy, the results may be disappointing to many FTM transsexuals. Nipple reduction enables these individuals to go to the beach or Japanese public baths, where they may go topless in public. We therefore consider that nipple reduction is indicated for all FTM transsexuals who desire it. There are a variety of methods for the reduction of enlarged nipples for women or non-FTM patients, but only a few reports have described the process used to create masculine-appearing nipples for FTM transsexuals. We developed a novel technique called the Eryngii method for creating male-like nipples using a 4-mm diameter dermal punch knife. The name of the method refers to the Eryngii king trumpet mushroom, which the nipple resembles after the surgical process. The main strength of this method is that it permits the creation of ideal nipples without difficulty. Here we introduce the technique and discuss our history of surgical methods for nipple reduction, including improvements and elaborations.


Efficacy, safety, and tolerability of dutasteride 0.5 mg once daily in male patients with male pattern hair loss: a randomized, double-blind, placebo-controlled, phase III study.
Dutasteride (Avodart) is a dual inhibitor of both type I and type II 5 alpha reductases, and thus inhibits conversion of testosterone to dihydrotestosterone, a key mediator of male pattern hair loss. The aim of this randomized double-blind phase III study was to compare the efficacy, safety, and tolerability of dutasteride (0.5 mg) and placebo for 6 months of treatment in male patients with male pattern hair loss. A total of 153 men, 18 to 49 years old, were randomized to receive 0.5 mg of dutasteride or placebo daily for 6 months. Efficacy was evaluated by the change of hair counts, subject assessment, and photographic assessment by investigators and panels. Mean change of hair counts from baseline to 6 months after treatment start was an increase of 12.2/cm(2) in dutasteride group and 4.7/cm(2) in placebo group and this difference was statistically significant (P = .0319). Dutasteride showed significantly higher efficacy than placebo group by subject self-assessment and by investigator and panel photographic assessment. There was no major difference in adverse events between two groups. The study was limited to 6 months. This study clearly showed that 0.5 mg of dutasteride improved hair growth and was relatively well tolerated for the treatment of male pattern hair loss.


Adult attachment style. I: Its relationship to clinical depression.
Although there are an increasing number of studies showing an association of adult attachment style to depressive disorder, such studies have rarely utilised epidemiological approaches with large community-based series and have relied heavily on brief self-report measurement of both attachment style and symptoms. The result is a wide inconsistency in the type of insecure style shown to relate to disorder. The present study examined adult attachment style in a high-risk community sample of women in relation to clinical depression. It utilised an interview measure of adult attachment which allowed for an assessment of both type of attachment style and the degree of insecurity of attachment. A companion paper examines its relationship with other depressive-vulnerability (Bifulco et al. 2002). Two hundred and twenty-two high-risk and 80 comparison women were selected from questionnaire screenings of London GP patient lists and intensively interviewed. A global scale of attachment style based on supportive relationships (with partner and very close others) together with attitudes to support-seeking, derived the four styles paralleling those from self-report attachment assessments (Secure, Enmeshed, Fearful, Avoidant). In order to additionally reflect hostility in the scheme, the Avoidant category was subdivided into 'Angry-dismissive' and 'Withdrawn'. The degree to which attitudes and behaviour within such styles were dysfunctional ('non-standard') was also assessed. Attachment style was examined in relation to clinical depression in a 12-month period. For a third of the series this was examined prospectively to new onset of disorder. The presence of any insecure style was significantly related to 12-month depression. However, when controls were made for depressive symptomatology at interview, only the 'non-standard' levels of Enmeshed, Fearful or Angry-dismissive styles related to disorder. Withdrawn-avoidance was not significantly related to disorder. The relationship of attachment style to clinical depression is increased by differentiating the degree of insecurity of style and differentiating hostile and non-hostile avoidance.


Glioblastoma multiforme occurring 13 years after treatment of a medulloblastoma.
Although medulloblastoma is said to be capable of astrocytic differentiation, the development of an astrocytic neoplasm in association with a medulloblastoma is extremely rare. We report the light and electron microscopic features of a supratentorial glioblastoma that occurred 13 years after radiation therapy for a cerebellar medulloblastoma. The diverse ultrastructural features of the glioblastoma may reflect the multipotentiality of the cells in medulloblastoma. An alternate interpretation is that the glioblastoma represents a radiation-induced neoplasm after therapy for a medulloblastoma.


ACTH and cortisol responses to hypotension in fetal sheep after a prior CRF injection.
To determine whether an ovine corticotropin-releasing factor (oCRF) injection modifies adrenocorticotropic hormone (ACTH) and cortisol responses to hypotension and whether the effect of any interactions between these stimuli changes across gestation, we studied chronically cannulated fetal lambs of 103-113 ("immature") and 133-139 days gestation ("mature"). Experimental groups received 500 ng/kg oCRF injections and 6 h later had arterial pressure reduced 20% for 10 min with nitroprusside. Blood samples were obtained before and after each manipulation. Controls received vehicle instead of oCRF. The oCRF increased plasma cortisol levels from 2.1 +/- 0.4 to 14.2 +/- 4.7 (SE) ng/ml in immature and 44.9 +/- 2.2 to 102.8 +/- 15 ng/ml in mature animals. In mature fetuses the oCRF did not alter plasma ACTH and cortisol increases due to hypotension. In immature animals ACTH increases were normal but cortisol increases were eliminated. This suggests that the CRF caused maximal stimulation of the adrenal gland. In older fetuses, it appears that the action of ACTH-releasing factors, secreted in response to arterial hypotension, can overcome the negative feedback effects of elevations in endogenous cortisol.


Virus-like particles and a spider mite intimately associated with a new disease of barley.
The malting barley-producing regions in Montana and Canada are threatened with a new virus-like barley disease that appears to be etiologically novel. Ultrathin sections of diseased tissue contained enveloped, filamentous virus-like particles that measured 64 nanometers by 126 to 4000 nanometers. These lengths are unique for plant viruses. Unexpectedly, the spider mite,Petrobia latens, which has never been reported to be a vector of a pathogen, was found to transmit the causal agent from diseased plants to healthy barley, while noninfective mites failed to do so unless they were allowed prior access to diseased tissue.


Deficiency of transcription factor Brn4 disrupts cochlear gap junction plaques in a model of DFN3 non-syndromic deafness.
Brn4, which encodes a POU transcription factor, is the gene responsible for DFN3, an X chromosome-linked, non-syndromic type of hearing loss. Brn4-deficient mice have a low endocochlear potential (EP), hearing loss, and ultrastructural alterations in spiral ligament fibrocytes, however the molecular pathology through which Brn4 deficiency causes low EP is still unclear. Mutations in the Gjb2 and Gjb6 genes encoding the gap junction proteins connexin26 (Cx26) and connexin30 (Cx30) genes, respectively, which encode gap junction proteins and are expressed in cochlear fibrocytes and non-sensory epithelial cells (i.e., cochlear supporting cells) to maintain the proper EP, are responsible for hereditary sensorineural deafness. It has been hypothesized that the gap junction in the cochlea provides an intercellular passage by which K+ is transported to maintain the EP at the high level necessary for sensory hair cell excitation. Here we analyzed the formation of gap junction plaques in cochlear supporting cells of Brn4-deficient mice at different stages by confocal microscopy and three-dimensional graphic reconstructions. Gap junctions from control mice, which are composed mainly of Cx26 and Cx30, formed linear plaques along the cell-cell junction sites with adjacent cells. These plaques formed pentagonal or hexagonal outlines of the normal inner sulcus cells and border cells. Gap junction plaques in Brn4-deficient mice did not, however, show the normal linear structure but instead formed small spots around the cell-cell junction sites. Gap junction lengths were significantly shorter, and the level of Cx26 and Cx30 was significantly reduced in Brn4-deficient mice compared with littermate controls. Thus the Brn4 mutation affected the assembly and localization of gap junction proteins at the cell borders of cochlear supporting cells, suggesting that Brn4 substantially contributes to cochlear gap junction properties to maintain the proper EP in cochleae, similar to connexin-related deafness.


The Impact of Health Information Technology for Early Detection of Patient Deterioration on Mortality and Length of Stay in the Hospital Acute Care Setting: Systematic Review and Meta-Analysis.
To evaluate the impact of health information technology (HIT) for early detection of patient deterioration on patient mortality and length of stay (LOS) in acute care hospital settings. We searched MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from 1990 to January 19, 2021. We included studies that enrolled patients hospitalized on the floor, in the ICU, or admitted through the emergency department. Eligible studies compared HIT for early detection of patient deterioration with usual care and reported at least one end point of interest: hospital or ICU LOS or mortality at any time point. Study data were abstracted by two independent reviewers using a standardized data extraction form. Random-effects meta-analysis was used to pool data. Among the 30 eligible studies, seven were randomized controlled trials (RCTs) and 23 were pre-post studies. Compared with usual care, HIT for early detection of patient deterioration was not associated with a reduction in hospital mortality or LOS in the meta-analyses of RCTs. In the meta-analyses of pre-post studies, HIT interventions demonstrated a significant association with improved hospital mortality for the entire study cohort (odds ratio, 0.78 [95% CI, 0.70-0.87]) and reduced hospital LOS overall. HIT for early detection of patient deterioration in acute care settings was not significantly associated with improved mortality or LOS in the meta-analyses of RCTs. In the meta-analyses of pre-post studies, HIT was associated with improved hospital mortality and LOS; however, these results should be interpreted with caution. The differences in patient outcomes between the findings of the RCTs and pre-post studies may be secondary to confounding caused by unmeasured improvements in practice and workflow over time.


Overexpression of BMI1, a polycomb group repressor protein, in bladder tumors: a preliminary report.
A Polycomb group repressor protein named BMI1 represses the genes that induce cellular senescence and cell death, and it can contribute to cancer when improperly expressed. We aimed to evaluate expression of BMI1 gene in bladder tumors. Tissue specimens containing bladder tumor were evaluated and compared with intact tissues from tumor margins and normal bladders. There were 40 tumor specimens of patients with transitional cell carcinoma of the bladder, 20 tumor-free tissues taken from the margin of the tumors, and 8 specimens from patients without tumor. Specific primers for BMI1 and B2M (as an internal control) were used for reverse transcript polymerase chain reaction technique. The production and distribution of BMI1 protein was also examined by western blotting and immunohistochemistry techniques. Polymerase chain reaction generated a 683-bp product, corresponding to the expected size of BMI1 amplified region. The identity of the amplified fragment was then confirmed by direct DNA sequencing. The mean of expression of BMI1 detected in tumor tissues was significantly higher than that in intact tissues, and there was also a significant association between the mean of gene expression and the stage of malignancy (P < .001). The expression of BMI1 at protein level was further confirmed by western blotting and immunohistochemistry. BMI1 is a potent repressor of retinoblastoma and p53 pathways, and hence, elucidating its role in tumorigenesis is very important. We reported for the first time the expression of BMI1 and its correlation with incidence and progress of bladder tumors.


Imaging brain amyloid deposition using grating-based differential phase contrast tomography.
One of the core pathological features of Alzheimer's disease (AD) is the accumulation of amyloid plaques in the brain. Current efforts of medical imaging research aim at visualizing amyloid plaques in living patients in order to evaluate the progression of the pathology, but also to facilitate the diagnosis of AD at the prodromal stage. In this study, we evaluated the capabilities of a new experimental imaging setup to image amyloid plaques in the brain of a transgenic mouse model of Alzheimer's disease. This imaging setup relies on a grating interferometer at a synchrotron X-ray source to measure the differential phase contrast between brain tissue and amyloid plaques. It provides high-resolution images with a large field of view, making it possible to scan an entire mouse brain. Here, we showed that this setup yields sufficient contrast to detect amyloid plaques and to quantify automatically several important structural parameters, such as their size and their regional density in 3D, on the scale of a whole mouse brain. Whilst future developments are required to apply this technique in vivo, this grating-based setup already gives the possibility to perform powerful studies aiming at quantifying the amyloid pathology in mouse models of AD and might accelerate the evaluation of anti-amyloid compounds. In addition, this technique may also facilitate the development of other amyloid imaging methods such as positron emission tomography (PET) by providing convenient high-resolution 3D data of the plaque distribution for multimodal comparison.


Conditioned food aversions: principles and practices, with special reference to social facilitation.
Conditioned food aversion is a powerful experimental tool to modify animal diets. We have also investigated it as a potential management tool to prevent livestock from grazing poisonous plants such as tall larkspur (Delphinium barbeyi), white locoweed (Oxytropis sericea) and ponderosa pine (Pinus ponderosa) on western US rangelands. The following principles pertain to increasing the strength and longevity of aversions: mature animals retain aversions better than young animals; novelty of the plant is important, although aversions can be created to familiar plants; LiCl is the most effective emetic, and the optimum dose for cattle is 200 mg/kg body weight; averted animals should be grazed separately from non-averted animals to avoid the influence of social facilitation which can rapidly extinguish aversions. Social facilitation is the most important factor preventing widespread application of aversive conditioning. When averted animals see other animals eat the target food they will sample it, and if there is no adverse reaction they will continue eating and extinguish the aversion. However, if averted animals can be grazed separately, aversions will persist. Aversive conditioning may provide an effective management tool to prevent animals from eating palatable poisonous plants that cause major economic loss.


Development of recurrent pressure ulcers, risk factors in older patients: a prospective observational study.
Prevention of recurrent pressure ulcers (PU) is one of the most important challenges in wound care, furthermore, the risk factors for recurrent PUs are still not fully understood. This study aimed to explore the risk factors for recurrent PU development within two weeks, including biophysical skin properties, pro-inflammatory cytokine (tumour necrosis factor [TNF]-α) levels and bacterial species, in older patients. This prospective study was conducted in a long-term care facility with patients whose PU had healed within two months. Biophysical skin properties were evaluated by stratum corneum hydration, pH, sebum content and transepidermal water loss. TNF-α level was measured using skin blotting. Skin bacteria were collected using tape stripping and determined by species-specific gene amplification. These parameters, along with Braden scale and interface pressure, were evaluated every two weeks for a total period of eight weeks. A penalised generalised estimating equation analysis was used to determine the risk factors for recurrent PUs. In total, 20 patients were included in this study, with 57 observations. Of these, recurrent PU was seen in eight observations. Elevation of pH (p=0.049; odds ratio [OR] per 1 unit=3.91, 95% confidence interval [CI]:1.01-15.15), presence of Acinetobacter spp. (p=0.039; OR versus culture-negative=6.28, 95%CI:1.10-35.86) and higher interface pressure (p=0.008; OR per 1 mmHg=1.06, 95%CI:1.01-1.10) on the healed PU were significantly related to the development of recurrent PU. Higher pH, existence of Acinetobacter spp. and higher interface pressure on the site of the healed PU were associated with the development of recurrent PUs in older patients undergoing conservative treatments.


Allele-specific binding (ASB) analyzer for annotation of allele-specific binding SNPs.
Allele-specific binding (ASB) events occur when transcription factors (TFs) bind more favorably to one of the two parental alleles at heterozygous single nucleotide polymorphisms (SNPs). Evidence suggests that ASB events could reveal the impact of sequence variations on TF binding and may have implications for the risk of diseases. Here we present ASB-analyzer, a software platform that enables the users to quickly and efficiently input raw sequencing data to generate individual reports containing the cytogenetic map of ASB SNPs and their associated phenotypes. This interactive tool thereby combines ASB SNP identification, biological annotation, motif analysis, phenotype associations and report summary in one pipeline. With this pipeline, we identified 3772 ASB SNPs from thirty GM12878 ChIP-seq datasets and demonstrated that the ASB SNPs were more likely to be enriched at important sites in TF-binding domains. ASB-analyzer is a user-friendly tool that enables the detection, characterization and visualization of ASB SNPs. It is implemented in Python, R and bash shell and packaged in the Conda environment. It is available as an open-source tool on GitHub at https://github.com/Liying1996/ASBanalyzer .


Polyunsaturated fatty acids: do they have a role in the pathophysiology of autism?
There is now some evidence that alterations in fatty acids may play a role in the pathophysiology of autism. The aim of the present study was to examine whether autism is accompanied by abnormalities in the composition of the polyunsaturated fatty acids (PUFAs) in plasma phospholipids. The plasma phospholipid omega-3 (3) and omega-6 (6) PUFA fractions and the 3/6 ratio were measured in 16 high-functioning male youngsters with autism (age 12-18) and 22 healthy volunteers. Group mean differences were assessed by means of analysis of variance (ANOVA). In autism there was a significant increase in the fraction of C22:6-3 (docosahexaenoic acid, DHA) and an increase in the total 3/6 ratio. The results of this study suggest that an increase of the plasma phospholipid 3 PUFAs, in particular DHA, and of the total 3/6 ratio may take part in the pathophysiology of autism. One hypothesis is that an increase of 3 PUFAs may cause alterations in the serotonergic turnover and the immune response system, both known to be associated with autism. Caution must be exercised against highly concentrated 3 PUFAs supplementation.


Incidence of metastasis in circumflex iliac nodes distal to the external iliac nodes in cervical cancer.
A causal relationship between removal of circumflex iliac nodes distal to the external iliac nodes (CINDEIN) and lower leg edema has been recently suggested. The aim of this study was to elucidate the incidence of CINDEIN metastasis in cervical cancer. A retrospective chart review was carried out for 531 patients with cervical cancer who underwent lymph node dissection between 1993 and 2014. CINDEIN metastasis was pathologically identified by microscopic investigation. After 2007, sentinel lymph node biopsy was performed selectively in patients with non-bulky cervical cancer. The sentinel node was identified using (99m)Tc-phytate and by scanning the pelvic cavity with a γ probe. Two hundred and ninety-seven patients (55.9%) underwent CINDEIN dissection and 234 (44.1%) did not. The percentage of International Federation of Gynecology and Obstetrics stage IIb to IV (42.4% vs. 23.5%, p<0.001) was significantly higher in patients who underwent CINDEIN dissection than those who did not. CINDEIN metastasis was identified in 1.9% overall and in 3.4% of patients who underwent CINDEIN dissection. For patients with stage Ia to IIa disease, CINDEIN metastasis was identified in 0.6% overall and in 1.2% of patients who underwent CINDEIN dissection. Of 115 patients with sentinel node mapping, only one (0.9%) had CINDEIN detected as a sentinel node. In this case, the other three lymph nodes were concurrently detected as sentinel lymph nodes. CINDEIN dissection can be eliminated in patients with stage Ia to IIa disease. CINDEIN might not be regional lymph nodes in cervical cancer.


Local ablative therapies in oligometastatic NSCLC-upfront or outback?-a narrative review.
Patients with oligometastatic (OM) non-small cell lung cancer (NSCLC) have favorable outcomes compared to patients presenting with diffuse metastatic disease. Recent randomized trials have demonstrated safety and efficacy signals for local ablative therapies with radiotherapy, surgery, or radiofrequency ablation for OM-NSCLC patients alongside systemic therapies. However, it remains unclear whether local ablative therapy (LAT) should be offered either upfront preceding systemic therapies or following initial systemic therapies as local consolidative therapy (LCT). Establishing optimal timing of RT and systemic therapy combinations is essential to maximize efficacy while maintaining safety. Most published randomized trial evidence surrounding the benefits of LAT and systemic therapies were generated from OM-NSCLC patients receiving cytotoxic chemotherapy agents. With increasing use of novel agents such as targeted therapies (i.e., tyrosine kinase inhibitors) and immune checkpoint inhibitors in management of metastatic NSCLC patients, LAT timing may need to be modulated based on the use of specific agents. This narrative review will discuss the current evidence on either upfront LAT or LCT for OM-NSCLC based on published trials and cohort studies. We briefly explored the possible biological mechanisms of the potential clinical advantages of either approach. This review also summarized the ongoing trials incorporating both upfront LAT and LCT, and considerations for future LAT strategies.


Configuring childbirth education to survive in managed care.
Managed care plans, especially in capitated systems, have not recognized the value of childbirth education for facilitating the transition to parenthood, especially for first-time parents. Advanced practice nurses, who are the logical facilitators and teachers of such programs, have not always made cogent arguments for inclusion of childbirth education. Physicians have been embroiled in their own issues regarding managed care. The interaction of these three forces creates serious but not insurmountable constraints for providing comprehensive, cost-effective quality care for childbearing families.


Imaging findings of traumatic injuries in survivors of the 6 February 2023 earthquake in Turkey.
In the southeastern part of Turkey, two earthquakes measuring 7.7 and 7.8 on the Richter scale occurred within 9 h on 6 February 2023, causing 120,000 injuries and over 50,000 deaths. Evacuees were transferred to various secondary and tertiary hospitals as the health system and hospitals in the affected region were affected by the earthquake. Injuries were mostly caused by blunt trauma and/or prolonged bruising under rubble. The severity and pattern of traumatic injuries in earthquake victims differed from other trauma patients who were not affected by an earthquake. In addition to traumatic injuries that affected multiple body regions and systems, patients who were trapped under debris for long periods of time were also frequently found to have crush syndrome. Pulmonary thromboembolism and hypoxic-ischaemic brain injury were observed in some patients. In this review, we present the imaging findings of traumatic injuries in earthquake victims, emphasising the earthquake-related distinct injury types.


Rapid and reliable detection of α-globin copy number variations by quantitative real-time PCR.
Alpha-thalassemia is the most common human genetic disease worldwide. Copy number variations in the form of deletions of α-globin genes lead to α-thalassemia while duplications of α-globin genes can cause a severe phenotype in β-thalassemia carriers due to accentuation of globin chain imbalance. It is important to have simple and reliable methods to identify unknown or rare deletions and duplications in cases in which thalassemia is suspected but cannot be confirmed by multiplex gap-PCR. Here we describe a copy number variation assay to detect deletions and duplications in the α-globin gene cluster (HBA-CNV). Quantitative real-time PCR was performed using four TaqMan® assays which specifically amplify target sequences representing both the α-globin genes, the -α3.7 deletion and the HS-40 region. The copy number for each target was determined by the 2-ΔΔCq method. To validate our method, we compared the HBA-CNV method with traditional gap-PCR in 108 samples from patients referred to our laboratory for hemoglobinopathy evaluation. To determine the robustness of the four assays, we analyzed samples with and without deletions diluted to obtain different DNA concentrations. The HBA-CNV method identified the correct copy numbers in all 108 samples. All four assays showed the correct copy number within a wide range of DNA concentrations (3.2-100 ng/μL), showing that it is a robust and reliable method. By using the method in routine diagnostics of hemoglobinopathies we have also identified several deletions and duplications that are not detected with conventional gap-PCR. HBA-CNV is able to detect all known large deletions and duplications affecting the α-globin genes, providing a flexible and simple workflow with rapid and reliable results.


Overproduction of the cyclic AMP receptor protein of Escherichia coli and expression of the engineered C-terminal DNA-binding domain.
Overproduction of the cyclic AMP receptor protein (CRP) from Escherichia coli, up to 25% of the soluble cell protein, has been achieved in an inducible host-vector system under transcriptional control of the lambda promoter PL. This system is ideally suited for large scale production and purification of CRP. In addition, a structural gene for the DNA-binding domain of CRP has been constructed. To this end the nucleotide sequence coding for the C-terminus was fused to the sequence coding for the first 10 N-terminal amino acids and cloned into suitable vectors. Good expression was achieved using the lambda PL promoter. The gene product, beta CRP, is recognized by anti-CRP antibodies.


Biodegradation of polychlorinated biphenyls (PCBs) by the novel identified cyanobacterium Anabaena PD-1.
Polychlorinated biphenyls (PCBs), a class of hazardous pollutants, are difficult to dissipate in the natural environment. In this study, a cyanobacterial strain Anabaena PD-1 showed good resistance against PCB congeners. Compared to a control group, chlorophyll a content decreased 3.7% and 11.7% when Anabaena PD-1 was exposed to 2 and 5 mg/L PCBs for 7 d. This cyanobacterial strain was capable of decomposing PCB congeners which was conclusively proved by determination of chloride ion concentrations in chlorine-free medium. After 7 d, the chloride ion concentrations in PCB-treated groups (1, 2, 5 mg/L) were 3.55, 3.05, and 2.25 mg/L, respectively. The genetic information of strain PD-1 was obtained through 16S rRNA sequencing analysis. The GenBank accession number of 16S rRNA of Anabaena PD-1 was KF201693.1. Phylogenetic tree analysis clearly indicated that Anabaena PD-1 belonged to the genus Anabaena. The degradation half-life of Aroclor 1254 by Anabaena PD-1 was 11.36 d; the total degradation rate for Aroclor 1254 was 84.4% after 25 d. Less chlorinated PCB congeners were more likely to be degraded by Anabaena PD-1 in comparison with highly chlorinated congeners. Meta- and para-chlorines in trichlorodiphenyls and tetrachlorobiphenyls were more susceptible to dechlorination than ortho-chlorines during the PCB-degradation process by Anabaena PD-1. Furthermore, Anabaena PD-1 can decompose dioxin-like PCBs. The percent biodegradation of 12 dioxin-like PCBs by strain PD-1 ranged from 37.4% to 68.4% after 25 days. Results above demonstrate that Anabaena PD-1 is a PCB-degrader with great potential for the in situ bioremediation of PCB-contaminated paddy soils.


Home and Neighborhood Environment Predictors of Adolescents' Screen Viewing.
Nowadays, the majority of adolescents exceed the AAP guidelines for screen use and this is likely to be a risk factor for obesity. The current study aims at investigating adolescent screen viewing in the context of home and neighborhood environment. A sample of 1141 adolescents as well as their parents participated in this survey. Adolescents were asked to complete a questionnaire about time spent on screen viewing behaviors. Respectively, parents completed a questionnaire concerning environmental predictors. Almost two-thirds of the adolescents surveyed spend more than 2 hours per day on screen entertainment, with boys dealing with personal computers (PCs) and electronic games more than girls. The likelihood for an adolescent to exceed 2 hours of screen time is 3.87 times more when he has his meals in front of a TV screen on a daily basis, 1.69 times more when the TV is on, often as not on his return from school and 1.74 times more when there is a PC in the adolescent's bedroom. Certain environmental predictors influence adolescents' screen time, as a result, corrective intervention should aim at the family as a whole, as this whole shapes home environment.


Different strategies to achieve Pb-tolerance by the two Trebouxia algae coexisting in the lichen Ramalina farinacea.
Lichen thalli are permeable to airborne substances, including heavy metals, which are harmful to cell metabolism. Ramalina farinacea shows a moderate tolerance to Pb. This lichen comprises two Trebouxia phycobionts, provisionally referred to as TR1 and TR9, with distinct physiological responses to acute oxidative stress. Thus, there is a more severe decay in photosynthesis and photosynthetic pigments in TR1 than in TR9. Similarly, under oxidative stress, antioxidant enzymes and HSP70 protein decrease in TR1 but increase in TR9. Since Pb toxicity is associated with increased ROS formation, we hypothesized greater Pb tolerance in this phycobiont. Accordingly, the aim of the present study was to characterize the physiological differences in the responses of TR1 and TR9 to Pb exposure. Liquid cultures of isolated phycobionts were incubated for 7 days in the presence of Pb(NO₃)₂. Thereafter, extracellular and intracellular Pb accumulation, photosynthetic pigments, and photosynthesis (as modulated chlorophyll fluorescence) were analyzed along with the antioxidant enzymes glutathione reductase (GR), superoxide dismutase (SOD), ascorbate peroxidase (APx), and catalase (CAT), and the stress-related protein HSP70. Pb uptake increased with the amount of supplied Pb in both algae. However, while significantly more metal was immobilized extracellularly by TR9, the amount of intracellular Pb accumulation was three times higher in TR1. In neither of the phycobionts were significant effects on photosynthetic pigments or photosynthetic electron transport observed. While under control conditions GR, SOD, and APx levels were significantly higher in TR1 than in TR9, only in the latter were these enzymes induced by Pb. This resulted in quantitatively similar antioxidant activities in the two algae when exposed to Pb. In conclusion, the phycobionts of R. farinacea make use of two different strategies against stress, in which the integration of distinct anatomical and physiological features affords similar levels of Pb tolerance.


Clinical outcomes following primary percutaneous coronary intervention for ST-elevation myocardial infarction according to sex and race.
Female sex and South Asian race have been associated with poor clinical outcomes following primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) but remain understudied in large real-world series. We therefore investigated the association of sex and race with clinical outcomes following PPCI. We conducted a prospective study of all patients undergoing PPCI for STEMI between January 2009 and December 2011 at a large UK cardiac centre. Clinical characteristics and outcomes were compared according to sex and race using Chi-square test, independent samples Student's t-test and Mann-Whitney U-test. Primary and secondary outcomes were 12-month major adverse cardiovascular events (MACEs) - defined as all-cause mortality, myocardial infarction and unplanned revascularization, analysed using Cox proportional hazard models adjusting for cardiovascular risk factors. Three thousand and forty-nine patients were included. Women ( n=826) were older than men ( n=2223) (median age 69 vs. 60 years, p <0.01). Mortality (hazard ratio 1.48 (1.15-1.90)) and MACE (hazard ratio 1.40 (1.14-1.72)) were higher in women in univariable analysis. However, there were no significant sex-differences in mortality or MACE after age-stratification alone. Multivariable analysis also showed no significant differences in outcomes between sexes. South Asians ( n=297) were younger but had a higher prevalence of most risk factors than White patients ( n=2570). Mortality and MACE did not differ significantly between South Asian and White patients in univariable or multivariable analysis. MACE and mortality was not greater in women, or in South Asian patients following PPCI after adjustment for cardiovascular risk factors including age, which was most strongly associated with both outcomes.


Proteomic Identification Reveals the Role of Ciliary Extracellular-Like Vesicle in Cardiovascular Function.
Primary cilia are shown to have membrane swelling, also known as ciliary bulbs. However, the role of these structures and their physiological relevance remains unknown. Here, it is reported that a ciliary bulb has extracellular vesicle (EV)-like characteristics. The ciliary extracellular-like vesicle (cELV) has a unique dynamic movement and can be released by mechanical fluid force. To better identify the cELV, differential multidimensional proteomic analyses are performed on the cELV. A database of 172 cELV proteins is generated, and all that examined are confirmed to be in the cELV. Repressing the expression of these proteins in vitro and in vivo inhibits cELV formation. In addition to the randomized heart looping, hydrocephalus, and cystic kidney in fish, compensated heart contractility is observed in both fish and mouse models. Specifically, low circulation of cELV results in hypotension with compensated heart function, left ventricular hypertrophy, cardiac fibrosis, and arrhythmogenic characteristics, which result in a high mortality rate in mice. Furthermore, the overall ejection fraction, stroke volume, and cardiac output are significantly decreased in mice lacking cELV. It is thus proposed that the cELV as a nanocompartment within a primary cilium plays an important role in cardiovascular functions.


Pseudo-continuous transfer insensitive labeling technique.
Transfer insensitive labeling technique (TILT) was previously applied to acquire multislice cerebral blood flow maps as a pulsed arterial spin labeling (PASL) method. The magnetization transfer effect with TILT is well controlled by using concatenated radiofrequency pulses. However, use of TILT has been limited by several challenges, including slice profile errors, sensitivity to arterial transit time and intrinsic low signal-to-noise ratio (SNR). In this work, we propose to address these challenges by making the original TILT method into a novel pseudo-continuous arterial spin labeling approach, named pseudo-continuous transfer insensitive labeling technique (pTILT). pTILT improves perfusion acquisitions by (i) realizing pseudo-continuous tagging with nonadiabatic pulses, (ii) being sensitive to slow flows in addition to fast flows, and (iii) providing flexible labeling geometries. Perfusion maps during both resting state and functional tasks are successfully demonstrated in healthy volunteers with pTILT. A comparison with typical SNR values from other perfusion techniques shows that although pTILT provides less SNR than inversion-based pseudo-continuous ASL techniques, the modified sequence provides similar SNR to inversion-based PASL techniques.


Variability in inpatient serum creatinine: its impact upon short- and long-term mortality.
Long-staying medical inpatients carry a significant burden of acute and chronic illness. Prediction of their in-hospital and longer-term mortality risk is important. The aim of this study was to determine to what extent creatinine variability predicts in-hospital and 1-year mortality in inpatients. Retrospective cohort analysis. Patients were included if aged 18 years or older and if admitted for 7 days or longer. The main outcome variables were mortality in hospital and after discharge. Increasing age, the presence of heart failure and a reduced estimated glomerular filtration rate (eGFR) on admission (<60 ml/min/1.73 m(2)) all associated with death risk (both in hospital and within a year of discharge). The creatinine change was related to mortality risk for the patient whilst in hospital and within 1 year after discharge independently of these other factors. The threshold of creatinine change, above which the in-hospital mortality rose significantly was 25 µmol/l (P < 0.001). A creatinine change of >10 µmol/l predicted significantly higher mortality within a year of discharge (P < 0.001). Every 5 µmol/l change in creatinine was associated with an in-hospital mortality increase of 3% (P < 0.001) and a 1-year mortality increase of 1% (P < 0.007). Patients with a creatinine rise or fall of >10 µmol/l during admission are at higher risk of death after discharge than those with more stable creatinine. These patients therefore merit further attention that might include more focused nutritional assessment, cardiovascular risk factor management or advance care planning.


Characterization of asymmetric fluorogenic phosphonates as probes for developing organophosphorus hydrolases with broader stereoselectivity.
Organophosphorus hydrolases (OPH) such as mammalian plama paraoxonase (PON1) detoxify asymmetric toxic organophosphorus (OP) nerve agents by preferentially hydrolyzing the less toxic P(+) optical isomer. In order to develop new OPHs with broader stereoselectivity we have prepared a series of asymmetric fluorogenic organophosphonates (Flu-OPs). Such Flu-OPs may serve as molecular probes for screening large libraries of OP hydrolases during directed evolution. Flu-OPs were prepared as methylphosphonates (MPs) diesters containing either ethyl (E), isopropyl (I), cyclohexyl (C) or pinacolyl (P) groups that are structural congeners of the nerve agents VX, sarin, cyclosarin and soman, respectively. The second ester bond was formed with fluorescent moieties that are either 3-cyano-4-methyl-7-hydroxy coumarin (MeCyC) or 1,3-dichloro-7-hydroxy 9,9-dimethyl-9H-acridin-2-one (DDAO). To further characterize the Flu-OPs as surrogates of their respective nerve agents, we have studied the reactivation of Flu-OP-inhibited AChE using 2-PAM and toxogonin (TOX). AChE was 90-95% inhibited by all Flu-OPs (0.36-0.9(M) and then was reactivated by either 2-PAM or TOX. TOX caused a more rapid reactivation than 2-PAM with the following rank order; EMP>IMP>CMP. TOX was also shown to be a better reactivator than 2-PAM for AChE inhibited by the nerve agents VX and cyclosarin. PMP-AChE could not be reactivated by either TOX or 2-PAM, similarly to aging of PMP-AChE formed by inhibition with soman. Racemic CMP-MeCyC was used for screening two new PON1 variants from a neutral library of PON1. These multiple mutation variants include replacement of active site amino acid residues. Neither mutation in these new variants appeared in PON1 variants previously discovered by directed evolution using symmetric Flu-OP. Detoxification rate of cylcosarin by these new PON1 variants was rather slow indicating the need to further screen PON1 clones using optically active Flu-OPs. Therefore, we have separated enzymatically the P(-) enantiomer of CMP-MeCyC and determined its 98% purity using chiral HPLC.


[Eating disorders in adolescents - what to look for?].
Increase in the incidence and prevalence of Eating Disorders have made it increasingly important that Health Care Professionals be familiar with the early detection and appropriate management of this group of disorders. To characterize an adolescent population followed in Adolescent Medicine office visit of Pediatric Department in Leiria's Hospital with Eating Disorders for type of disorder, presence of alert signs and symptoms and risk factors for an early detection of disease. Retrospective analytic study conducted by consulting clinical processes and first office visit questionnaires of adolescent population followed for Eating Disorders, between August 2005 and April 2008. Criteria of Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition were considered to define Eating Disorder type. Twenty two adolescents were included, with 20 girls. Five adolescents met all Anorexia Nervosa criteria and two met all Bulimia Nervosa criteria. The other 15 were included in Eating Disorder Not Otherwise Specified. All samples showed intense fear of gaining weight and 20 adolescents a disturbed body image. All adolescents confessed having restrictive eating attitudes, half had compensatory behaviors and four assume having recurrent episodes of binge eating. Almost all revealed some type of somatic complaint and 19 showed psychological symptoms. One third of this population had personal history of obesity/overweight. Most adolescents presented weight lost when observed in the first office visit. Six adolescents showed body weight under 85% of that expected. One third of postmenarche adolescents suffered from secondary amenorrhea. Half of adolescents reported dysfunctional family and one quarter had separate parents; eight adolescents had family history of mental illness. Most adolescents were included in the diagnosis of Eating Disorder Not Otherwise Specified, according with other studies in this age. This fact implies that in practice the suspicion of an Eating Disorder in an adolescent should not be restricted to the meeting of other categories criteria. For an early detection, relevance should be given to aspects like a weight loss even without an abnormal body mass index, an inappropriate eating attitude, a dissatisfaction with body image, associated with a multiplicity of psychosomatic complaints, in a dysfunctional family environment.


On meta-analytic assessment of surrogate outcomes.
We discuss the strengths and weaknesses of the meta-analytic approach to estimating the effect of a new treatment on a true clinical outcome measure, T, from the effect of treatment on a surrogate response, S. The meta-analytic approach (see Daniels and Hughes (1997) 16, 1965-1982) uses data from a series of previous studies of interventions similar to the new treatment. The data are used to estimate relationships between summary measures of treatment effects on T and S that can be used to infer the magnitude of the effect of the new treatment on T from its effects on S. We extend the class of models to cover a broad range of applications in which the parameters define features of the marginal distribution of (T, S). We present a new bootstrap procedure to allow for the variability in estimating the distribution that governs the between-study variation. Ignoring this variability can lead to confidence intervals that are much too narrow. The meta-analytic approach relies on quite different data and assumptions than procedures that depend, for example, on the conditional independence, at the individual level, of treatment and T, given S (see Prentice (1989) 8, 431-440). Meta-analytic calculations in this paper can be used to determine whether a new study, based only on S, will yield estimates of the treatment effect on T that are precise enough to be useful. Compared to direct measurement on T, the meta-analytic approach has a number of limitations, including likely serious loss of precision and difficulties in defining the class of previous studies to be used to predict the effects on T for a new intervention.


Optimal location of a single distal interlocking screw in intramedullary nailing of distal third femoral shaft fractures.
This biomechanical study was done to determine the effect of the level of a single distal screw in a static intramedullary (IM) femoral nail on the stability of fixation of a fracture in the distal third of the femur. Fifteen composite fiberglass femora were osteotomized transversely in the distal third of the femur. A Grosse-Kempf nail was implanted into the femurs, which were divided into three groups of five specimens. Single screw distal nail locking was varied distal to the osteotomy site for each group at 2.5, 5.0, and 7.5 centimeters, respectively. All instrumented femurs were mounted on a servohydraulic testing machine and fitted with transducers to measure axial, rotational, and bending displacements. Specimens were cyclically loaded (one hertz) in simultaneous torsion (moment: +/- 10 newton-meters) and axial compression (amplitude: 2,000 newtons) for 500 cycles with a 250-pound abductor force. Data from linear and rotational transducers were sampled at 100 hertz for five cycles before cycling, every 100 cycles of loading, and immediately after cycling. Custom computer software was developed to convert transducer signals into static and dynamic measurements of axial motion (in millimeters), rotation (in degrees), and angulation (in degrees). Osteotomy site dynamic rotation increased significantly in specimens locked at 7.5 centimeters when compared with the 2.5-centimeter group. There was minimal difference between the stability of the 5.0-centimeter and 7.5-centimeter groups. There was no significant change in position at the fracture site before or after cyclic loading with respect to axial shortening, rotation, or bending. Both dynamic axial and angular displacements were also unaffected by screw position. The location of a single distal interlocking screw in static IM nail fixation of distal third femur fractures can significantly affect rotational stability but not axial or angular fixation.


The Impact of Knee Injury History on Health-Related Quality of Life in Adolescent Athletes.
Current evidence suggests that, despite returning to full participation, physically active adults with a previous knee injury experience lower health-related quality of life (HRQOL) than those with no knee injury history. It is unknown if this relationship is present in adolescent athletes. To determine the impact of knee injury history on HRQOL in adolescent athletes who were medically cleared for full participation. Cross-sectional. Athletic training clinics. A convenience sample of 183 adolescent athletes, who were medically cleared for full participation, were grouped by self-report of a previous knee injury: positive knee injury history (HIS; n = 36, age = 15.7 [1.4] y, height = 168.0 [11.9] cm, and weight = 71.8 [11.9] kg) and no knee injury history (NO-HIS; n = 147, age = 15.5 [1.4] y, height = 166.0 [10.5] cm, and weight = 67.6 [14.6] kg). Participants completed the Pediatric International Knee Documentation Committee form and Pediatric Quality of Life Inventory during their preparticipation examination. Generalized linear models were used to compare group differences for the total and subscale scores of the Pediatric International Knee Documentation Committee and Pediatric Quality of Life Inventory. Main effects of injury group indicated that the HIS group reported significantly lower scores than the NO-HIS group for the Pediatric International Knee Documentation Committee total score (P < .001; HIS = 79.2 [21.7], NO-HIS = 95.8 [8.6]) and for the Pediatric Quality of Life Inventory total (P = .001; HIS = 85.7 [10.9], NO-HIS = 90.9 [7.3]), physical functioning (P = .002; HIS = 86.7 [13.6], NO-HIS = 92.1 [8.2]), school functioning (P = .01; HIS = 80.6 [12.4], NO-HIS = 86.8 [12.2]), and social functioning (P = .01; HIS = 89.3 [12.4], NO-HIS = 94.6 [8.9]) scores. No group differences were reported for the emotional functioning subscale (P = .13; HIS = 85.7 [17.7], NO-HIS = 89.7 [13.1]). No interactions or main effects of sex were reported (P > .05). Our findings suggest that, despite returning to full sport participation, adolescent athletes with a previous knee injury generally experience lower HRQOL than their peers with no knee injury history, specifically for knee-specific HRQOL, physical functioning, school functioning, and social functioning. Our results are similar to previous findings reported in college athletes and military cadets.


In-vitro and in-silico anti-HSV-1 activity of a marine steroid from the jellyfish Cassiopea andromeda venom.
In this study, we investigated the potential in vitro anti-HSV-1 activities of the Cassiopea andromeda jellyfish tentacle extract (TE) and its fractions, as well as computational work on the thymidine kinase (TK) inhibitory activity of the identified secondary metabolites. The LD50, secondary metabolite identification, preparative and analytical chromatography, and in silico TK assessment were performed using the Spearman-Karber, GC-MS, silica gel column chromatography, RP-HPLC, LC-MS, and docking methods, respectively. The antiviral activity of TE and the two purified compounds Ca2 and Ca7 against HSV-1 in Vero cells was evaluated by MTT and RT-PCR assays. The LD50 (IV, mouse) values of TE, Ca2, and Ca7 were 104.0 ± 4, 5120 ± 14, and 197.0 ± 7 (μg/kg), respectively. They exhibited extremely effective antiviral activity against HSV-1. The CC50 and MNTD of TE, Ca2, and Ca7 were (125, 62.5), (25, 12.5), and (50, 3.125) μg/ml, respectively. GC-MS analysis of the tentacle extract revealed seven structurally distinct chemical compositions. Four of the seven compounds had a steroid structure. According to the docking results, all compounds showed binding affinity to the active sites of both thymidine kinase chains. Among them, the steroid compound Pregn-5-ene-3,11-dione, 17,20:20,21 bis [methylenebis(oxy)]-, cyclic 3-(1,2-ethane diyl acetal) (Ca2) exhibited the highest affinity for both enzyme chains, surpassing that of standard acyclovir. In silico data confirmed the experimental results. We conclude that the oxosteroid Ca2 may act as a potent agent against HSV-1.


Disease processes may be reflected by correlations among tissue kallikrein proteases but not with proteolytic factors uPA and PAI-1 in primary ovarian carcinoma.
In epithelial ovarian cancer, the high mortality rate is usually ascribed to late diagnosis, since these tumors commonly lack early-warning symptoms, but tumor-associated biomarkers useful for prognosis or therapy response prediction are in short supply. However, members of the tissue kallikrein serine protease family, the serine protease uPA and its inhibitor PAI-1, are associated with tumor progression of ovarian cancer. Therefore, we used ELISA to determine uPA, PAI-1, and tissue kallikreins hK5-8, 10, 11, and 13 in extracts of 142 primary tumor tissue specimens from ovarian cancer patients and studied the strength of association between protein expression levels of these tumor tissue-associated factors. uPA, PAI-1, hk5, and hk8 were related to FIGO stage; hK5 expression was higher in FIGO III/IV than in FIGO I/II patient tissues. PAI-1 and hk5 differed significantly according to nuclear grading; expression of hK5 was higher in G3 than in G1/2 tumors. Associations between uPA, PAI-1, and the tissue kallikreins were weak. There were strong pairwise correlations within the cluster of tissue kallikreins hK5, 6, 7, 8, 10, and 11, but their bivariate distributions depended on nuclear grading. These results support the notion that several tissue kallikreins are co-expressed in ovarian cancer patients, substantiating the existence of a steroid hormone-driven tissue kallikrein cascade in this disease.


Turning Doctoral Students into Faculty in Gerontological Social Work: The AGESW Experience.
Developing faculty interested in aging may help social work meet the needs of our growing aging population. However, doctoral students need a variety of supports to complete PhDs and become gerontological social work faculty. This study explored one program's role in supporting the development of social work doctoral students to faculty in gerontology. An e-mail invitation was sent to all former participants (2010-2016 cohorts) of the Association for Gerontology Education in Social Work (AGESW) Pre-Dissertation Fellows Program (PDFP). The 38-question online survey consisted of Likert-type scales, multiple answers, and one open-ended question per section about the program's impacts on their academic career development in teaching, research, mentoring, and support. Forty-five respondents, representing all six cohorts, completed the survey. More than half reported that the PDFP contributed to their ability to publish their research (64.4%, n = 29), grow their professional network (86.7%, n = 39, and teach (55.5%, n = 25). Doctoral programs provided different experiences than the PDFP, including mentoring, methodological training, professional development, networking, and peer support. Results suggest the PDFP provides content recipients value that supplements instruction received in their institutions. The program's ability to connect students to each other and to national leaders enhances their career development and socialization into academic roles.


A Randomized Controlled Trial of Parent-Child Psychotherapy Targeting Emotion Development for Early Childhood Depression.
Clinical depression in children as young as age 3 has been validated, and prevalence rates are similar to the school-age disorder. Homotypic continuity between early and later childhood depression has been observed, with alterations in brain function and structure similar to those reported in depressed adults. These findings highlight the importance of identifying and treating depression as early as developmentally possible, given the relative treatment resistance and small effect sizes for treatments later in life. The authors conducted a randomized controlled trial of a dyadic parent-child psycho-therapy for early childhood depression that focuses on enhancing the child's emotional competence and emotion regulation. A modified version of the empirically tested parent-child interaction therapy with a novel "emotion development" module (PCIT-ED) was compared with a waiting list condition in a randomized controlled trial in 229 parent-child dyads with children 3-6.11 years of age. Both study arms lasted 18 weeks. Children in the PCIT-ED group had lower rates of depression (primary outcome), lower depression severity, and lower impairment compared with those in the waiting list condition (Cohen's d values, >1.0). Measures of child emotional functioning and parenting stress and depression were significantly improved in the PCIT-ED group. The findings from this randomized controlled trial of a parent-child psychotherapy for early childhood depression suggest that earlier identification and intervention in this chronic and relapsing disorder represents a key new pathway for more effective treatment. Manualized PCIT-ED, administered by master's-level clinicians, is feasible for delivery in community health settings.


Streptococcus zooepidemicus infection in sheep.
Fibrinous pericarditis, fibrinous pleuritis and pneumonia associated with Streptococcus zooepidemicus were observed in two lambs in a small flock of sheep. These lesions were reproduced in lambs inoculated intratracheally with Streptococcus zooepidemicus. Clinical signs included pyrexia, serous to mucopurulent nasal discharge, dyspnea and depression followed by death in six to seven days. Histologically the tissue changes were characterized by an acute inflammatory response involving bronchioles and alveoli, fibrinous pleuritis and fibrinous pericarditis.


Clinical efficacy of endovascular radiofrequency ablation in the treatment of portal vein tumor thrombus of primary hepatocellular carcinoma.
The objective of this study is to investigate the clinical efficacy and safety of Habib™ VesOpen, a new intravascular radiofrequency ablation (RFA) catheter in percutaneous puncture of portal vein tumor thrombus (PVTT) in patients with primary hepatocellular carcinoma. Collected data of patients with primary hepatocellular carcinoma with portal vein trunk or main branch who were treated by the RFA of portal vein tumor ablation with Habib™ VesOpen, a new intravascular RFA catheter. The postoperative success rate, complications, liver and kidney function, alpha-fetoprotein (AFP), portal vein patency, and tumor thrombus were analyzed, and the survival status of patients was analyzed by Kaplan-Meier survival analysis, and the COX proportional hazards regression model was used to analyze the factors influencing the clinical prognosis of patients. All the 44 patients were operated successfully without complications such as vascular perforation, infection, liver abscess, and intraperitoneal hemorrhage. The liver function index, alanine aminotransferase, aspartate aminotransferase, and serum albumin (ALB) were significantly different before and after surgery at 2 weeks and 4 weeks after operation (P < 0.05); AFP before and after surgery, the difference was statistically significant (P < 0.05). Doppler ultrasonography showed blood flow through the original portal vein after 4 weeks of surgery; enhanced computed tomography examination or magnetic resonance examination on the abdomen suggested patients with varying degrees of tumor thrombosis or disappearance after 8 weeks of surgery. The overall survival time was 284.72 ± 27.20 days (95% confidence interval: 231.42-338.02 days). The cumulative survival rates of 90, 180, and 360 days were 97.7%, 72.7%, and 17.2%, respectively. Cox multivariate regression analysis showed that tumor size and the size of ALB before RFA treatment was an independent factor in the prognosis of hepatocellular carcinoma with PVTT ablation (P < 0.05). The use of Habib™ VesOpen intravascular RFA catheter percutaneous puncture of the portal vein tumor RFA has positive clinical effect which is safe and reliable, expected to become one of the effective means in treatment of primary hepatocellular carcinoma with PVTT.


[Determination of the accessible surface of lysozyme and human serum albumin molecules by the total tritium labeling method].
Amino acids composing an accessible surface of lysozyme and human serum albumin (HSA) globules were determined by the total tritium labelling method. A good correlation between our data on the distribution of the tritium label for the lysozyme molecule and X-ray data on the tertiary structure for this macromolecule was received. Lysozyme was used as a standard for determining the accessible surface of the globule albumin. It was shown that the accessible surface of the albumin globule is substantially more hydrophobic (average accessible surface area of hydrophobic amino acids is 130 A2 in HSA and 20 A2 in lysozyme) than in lysozyme. The HSA molecule is characterized by high values of: the accessible surface area, the ratio of extended area to the folded one, and the surface roughness index. These data indicate that the HSA molecule is less compactly packed than lysozyme.


Overexpression, purification and helix-destabilizing properties of Epstein-Barr virus ssDNA-binding protein.
The Epstein-Barr virus (EBV) ssDNA-binding protein (SSB) encoded by the BALF2 gene is one of the essential replication proteins in the lytic phase of EBV DNA replication. In order to obtain the amount of EBV SSB required for characterization, a recombinant baculovirus containing the complete sequence of the BALF2 open reading frame under the control of the baculovirus polyhedrin promoter was constructed. Insect cells infected with the recombinant virus produced a protein of 130 kDa, recognized by anti-BALF2 protein-specific polyclonal antibody. The overexpressed EBV SSB was purified homogeneously from the cytosolic fraction of the recombinant virus-infected cells. The purified protein displaced short DNA strands from their complementary sequences in the single-stranded form of M13. The helix-destabilizing activity was neutralized by the anti-BALF2 protein-specific antibody. Maximum unwinding occurred at EBV SSB concentrations exceeding saturation level of the DNA substrate. The DNA unwinding reaction mediated by the EBV SSB was highly cooperative and extremely rapid. The reaction displayed no directionality and required neither ATP nor MgCl2, two essential cofactors for DNA helicase activity. The helix-destabilizing property of the EBV SSB may function to melt out secondary structures on the ssDNA template, thereby facilitating the movement of the EBV DNA polymerase.


Microscopic Cracks Modulate Nucleation and Solid-State Crystallization Tendency of Amorphous Celecoxib.
Drugs have been classified as fast, moderate, and poor crystallizers based on their inherent solid-state crystallization tendency. Differential scanning calorimetry-based heat-cool-heat protocol serves as a valuable tool to define the solid-state crystallization tendency. This classification helps in the development of strategies for stabilizing amorphous drugs. However, microscopic characteristics of the samples were generally overlooked during these experiments. In the present study, we evaluated the influence of microscopic cracks on the crystallization tendency of a poorly water-soluble model drug, celecoxib. Cracks developed in the temperature range of 0-10 °C during the cooling cycle triggered the subsequent crystallization of the amorphous phase. Nanoindentation study suggested minimal differences in mechanical properties between samples, although the cracked sample showed relatively inhomogeneous mechanical properties. Nuclei nourishment experiments suggested crack-assisted nucleation, which was supported by Raman data that revealed subtle changes in intermolecular interactions between cracked and uncracked samples. Celecoxib has been generally classified as class II, i.e., a drug with moderate crystallization tendency. Interestingly, classification of amorphous celecoxib may change depending on the presence or absence of cracks in the amorphous sample. Hence, subtle events such as microscopic cracks should be given due consideration while defining the solid-state crystallization tendency of drugs.


Prevalence of Coronary Artery Calcification on Pre-Atrial Fibrillation Ablation CT Pulmonary Venograms and its Impact on Selection for Statin Therapy.
Atherosclerotic cardiovascular disease (ASCVD) shares many risk factors with atrial fibrillation (AF). Obtaining computed tomography images of the pulmonary veins (CTPV) before AF ablation procedures is common and can incidentally detect coronary artery calcification (CAC). The purpose of this study was to investigate the prevalence of CAC on pre-ablation CTPV, the frequency of CAC reporting on CTPV reports, and its impact on statin therapy among patients hospitalized for AF procedures. We retrospectively evaluated consecutive patients undergoing CTPV and AF procedures from October 2016 to December 2017 in a single-center tertiary hospital. The patients' demographic and clinical characteristics were analyzed. The CAC presence on CTPV was visually assessed. The severity was classified qualitatively. The statin therapy status was evaluated using the patient's admission and discharge medication lists. A total of 638 subjects were included in our study, with 34.5% female. The mean age was 63.3 ± 10.8 years. CAC was detected in 70.1% of all patients, and in 58.1% of patients without a history of ASCVD. When present, CAC was documented in 92.6% of the clinical CTPV reports. While coronary artery atherosclerosis was present in a majority of AF patients, and its presence was widely reported, it was not associated with increased statin therapy at discharge.


[Concentrational changes of mannose-binding proteins in blood plasma during noncomplicated pregnancy and in blood plasma of pregnant women with some infections].
Value of mannose-binding proteins was determined in plasma of pregnant women with no complications and also in pregnant women with some infections using affinitive chromatography. It was found that the concentration of mannose-binding proteins in blood plasma of women equals 0.152+/-0.025 mg/ml. The concentration of mannose-binding proteins in blood plasma increase during the consecutive trimesters of noncomplicated pregnancy. In the first trimester it equals 0.198+/-0.032 mg/ml, in the second 0.257+/-0.027 mg/ml and in the third trimester 0.345+/-0.034 mg/ml. We also found that the concentration of mannose-binding proteins in blood plasma of pregnant woman suffering with chlamydial infection equals 1.025+/-0.115 mg/ml, and in blood plasma of pregnant woman suffering with cytomegalovirus infection 1.278+/-0.144 mg/ml. The obtained data confirm a hypothesis of increased activity of innate immune system during pregnancy. Also according to this results complications accompanied by chlamydial and cytomegalovirus infections during pregnancy is the result of increasing activity of mannose-binding proteins.


Virtual reality training for cataract surgery operating performance in ophthalmology trainees.
Cataract surgery is the most common incisional surgical procedure in ophthalmology and is important in ophthalmic graduate medical education. Although most ophthalmology training programs in the United States (US) include virtual reality (VR) training for cataract surgery, comprehensive reviews that detail the impact of VR training on ophthalmology trainee performance are lacking. To assess the impact of VR training for cataract surgery on the operating performance of postgraduate ophthalmology trainees, measured by operating time, intraoperative complications, postoperative complications, supervising physician ratings, and VR simulator task ratings. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), Ovid MEDLINE, Embase.com, PubMed, LILACS, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 14 June 2021. We included randomized controlled trials (RCTs) comparing VR training to any other method of training, including non-VR simulation training (e.g., wet laboratory training), didactics training, or no supplementary training in postgraduate ophthalmology trainees. We used standard Cochrane methodology. Primary outcomes were operating times in the operating room and intraoperative complications. Secondary outcomes were operating times in simulated settings, simulator task ratings, and supervising physician ratings, either in the operating room or simulated settings. We included six RCTs with a total of 151 postgraduate ophthalmology trainees ranging from 12 to 60 participants in each study. The included studies varied widely in terms of geography: two in the US, and one study each in China, Germany, India, and Morocco. Three studies compared VR training for phacoemulsification cataract surgery on the Eyesi simulator (VRmagic, Mannheim, Germany) with wet laboratory training and two studies compared VR training with no supplementary training. One study compared trainees who received VR training with those who received conventional training for manual small incision cataract surgery on the HelpMeSee simulator (HelpMeSee, New York, NY). Industry financially supported two studies. All studies had at least three domains judged at high or unclear risks of bias. We did not conduct a meta-analysis due to insufficient data (i.e., lack of precision measurements, or studies reported only P values). All evidence was very low-certainty, meaning that any estimates were unreliable. The evidence for the benefits of VR training for trainees was very uncertain for primary outcomes. VR-trained trainees relative to those without supplementary training had shorter operating times (mean difference [MD] -17 minutes, 95% confidence interval [CI] -21.62 to -12.38; 1 study, n = 12; very low-certainty evidence). Results for operating time were inconsistent when comparing VR and wet laboratory training: one study found that VR relative to wet laboratory training was associated with longer operating times (P = 0.038); the other reported that two training groups had similar operating times (P = 0.14). One study reported that VR-trained trainees relative to those without supplementary training had fewer intraoperative complications (P < 0.001); in another study, VR and conventionally trained trainees had similar intraoperative complication rates (MD -8.31, 95% CI -22.78 to 6.16; 1 study, n = 19; very low-certainty evidence). For secondary outcomes, VR training may have similar impact on trainee performance compared to wet laboratory and greater impact compared to no supplementary training, but the evidence was very uncertain. One study reported VR-trained trainees relative to those without supplementary training had significantly reduced operating time in simulated settings (P = 0.0013). Another study reported that VR-trained relative to wet laboratory-trained trainees had shorter operating times in VR settings (MD -1.40 minutes, 95% CI -1.96 to -0.84; 1 study, n = 60) and similar times in wet laboratory settings (MD 0.16 minutes, 95% CI -0.50 to 0.82; 1 study, n = 60). This study also found the VR-trained trainees had higher VR simulator ratings (MD 5.17, 95% CI 0.61 to 9.73; 1 study, n = 60). Results for supervising physician ratings in the operating room were inconsistent: one study reported that VR- and wet laboratory-trained trainees received similar supervising physician ratings for cataract surgery (P = 0.608); another study reported that VR-trained trainees relative to those without supplementary training were less likely to receive poor ratings by supervising physicians for capsulorhexis construction (RR 0.29, 95% CI 0.15 to 0.57). In wet laboratory settings, VR-trained trainees received similar supervising physician ratings compared with wet laboratory-trained trainees (MD -1.50, 95% CI -6.77 to 3.77; n = 60) and higher supervising physician ratings compared with trainees without supplementary training (P < 0.0001). However, the results for all secondary outcomes should be interpreted with caution because of very low-certainty evidence. AUTHORS' CONCLUSIONS: Current research suggests that VR training may be more effective than no supplementary training in improving trainee performance in the operating room and simulated settings for postgraduate ophthalmology trainees, but the evidence is uncertain. The evidence comparing VR with conventional or wet laboratory training was less consistent.


Modified checklist for autism in toddlers: cross-cultural adaptation and validation in Spain.
Early detection and treatment have been shown to be effective in reducing disability severity caused by Autistic Spectrum Disorders (ASDs). As Spanish pediatricians have no detection tool, the Modified Checklist for Autism in Toddlers (M-CHAT) was first translated into and culturally adapted to Spanish. Validity and reliability studies were carried out in two different geographical areas of Spain, where M-CHAT was administered to two different samples, namely: 2,480 high- and low-risk children; and 2,055 low-risk children. The results obtained were similar to those yielded by the original M-CHAT studies. Differences were found in positive predictive value, due to the low ASD frequency observed in this study. M-CHAT is still being studied in a large population-based screening program in Spain.


Impact of Obstructive Sleep Apnea Treatment on Cardiovascular Disease Associated Mortality and Morbidity: A Systematic Review.
The association between untreated obstructive sleep apnea (OSA) and cardiovascular disease (CVD) is well known. In this literature review, we aim to review the existing literature on treatment effects of OSA and its impact on CVD morbidity and mortality, stratified by gender. We systematically reviewed PubMed, Medline, and Scopus per PRISMA guidelines and included 25 studies in the final review. Primary outcomes were CVD-associated morbidity and mortality. Out of 25 studies, 10 were meta-analysis, 8 observational, and 7 randomized controlled trials. The treatment modality was continuous positive airway pressure (CPAP) in 23 studies, noninvasive positive pressure ventilation, and oral appliance therapy in 2. Secondary prevention of CVD was the endpoint in 23 studies. A total of 165,775 participants between 45 and 75 years of age, 60%-90% males, and the average Epworth Sleepiness Scale (ESS) score was 5-9. CV outcomes included myocardial infarction, angina, heart failure (HF), acute coronary syndrome (ACS), coronary artery disease (CAD), ischemic heart disease, cardiomyopathy, atrial fibrillation (AF), and hypertension. In 4 studies, CPAP was associated with a reduction in CVD mortality, and 10 studies showed improvement in morbidity. Our review of literature did not show consistent benefits in CV outcomes in OSA patients. We identified many potential research areas, especially the lack of studies demonstrating dose-dependent effect of OSA treatment on CV outcomes, especially when stratified by severity of OSA and gender. Larger prospective studies with longer follow-up will be helpful to study these parameters.


Genetic spatial structure in a butterfly metapopulation correlates better with past than present demographic structure.
The Glanville fritillary butterfly (Melitaea cinxia) has been studied in the Aland Islands in Finland since 1991, where it occurs as a classic metapopulation in a large network of 4000 dry meadows. Much ecological work has been conducted on this species, but population genetic studies have been hampered by paucity of suitable genetic markers. Here, using single nucleotide polymorphisms and microsatellites developed for the Glanville fritillary, we examine the correspondence between the demographic and genetic spatial structures. Given the dynamic nature of the metapopulation, the current genetic spatial structure may bear a signal of past changes in population sizes and past patterns of gene flow rather than reflect the current demographic structure or landscape structure. We analyse this question with demographic data for 10 years, using the Rand index to assess the similarity between the genetic, demographic, and landscape spatial structures. Our results show that the current genetic spatial structure is better explained by the past rather than by the current demographic spatial structure or by the spatial configuration of the habitat in the landscape. Furthermore, current genetic diversity is significantly explained by past metapopulation sizes. The time lag between major demographic events and change in the genetic spatial structure and diversity has implications for the study of spatial dynamics.


An unusual cause of urinothorax.
Urinothorax is a rare complication of blunt renal trauma, ureteral instrumentation or ureteral surgery. A leakage from the urinary tract causes urinoma, a retroperitoneal collection of fluid, which can lead to urinothorax. We report a patient with solitary kidney who underwent extracorporeal shock wave lithotripsy (ESWL) for nephrolithiasis. Four days after ESWL, she had right-sided pleural effusion which demonstrated as urinothorax. Urinoma occurring after ESWL, as in our case, is a situation that has not been reported before as a cause of urinothorax. Urinothorax should be taken into consideration in patients with pleural effusion who recently underwent ESWL.


Can Maternal Autoantibodies Play an Etiological Role in ASD Development?
Autism spectrum disorder (ASD) is a heterogeneous condition with multiple etiologies and risk factors - both genetic and environmental. Recent data demonstrate that the immune system plays an important role in prenatal brain development. Deregulation of the immune system during embryonic development can lead to neurodevelopmental changes resulting in ASD. One of the potential etiologic factors in the development of ASD has been identified as the presence of maternal autoantibodies targeting fetal brain proteins. The type of ASD associated with the presence of maternal autoantibodies has been referred to as maternal antibodies related to ASD (MAR ASD). The link between maternal autoantibodies and ASD has been demonstrated in both clinical studies and animal models, but the exact mechanism of their action in the pathogenesis of ASD has not been clarified yet. Several protein targets of ASD-related maternal autoantibodies have been identified. Here, we discuss the role of microtubule-associated proteins of the collapsin response mediator protein (CRMP) family in neurodevelopment and ASD. CRMPs have been shown to integrate multiple signaling cascades regulating neuron growth, guidance or migration. Their targeting by maternal autoantibodies could change CRMP levels or distribution in the developing nervous system, leading to defects in axon growth/guidance, cortical migration, or dendritic projection, which could play an etiological role in ASD development. In addition, we discuss the future possibilities of MAR ASD treatment.


[2 types of neurons differing in their plastic properties: study of ionic mechanisms].
Plasticity ionic mechanisms of 2 types of neurones identified in the brain of snail Helix pomatia: habituating and non-habituating to rhythmic intracellular stimulation by DC pulses were studied. It has been shown that the development of habituation is due to entering of Ca2+ into the cell and by its activation of Ca-dependent K-conductivity of the membrane, leading to hyperpolarization, decrease of input resistance and elimination of spike response to stimulation. Depression of Ca-dependent K-conductivity by quinine totally blocks the ability of the neurons to habituate to stimulation. The data obtained on non-habituating neurons testify that their non-habituation to intracellular stimulation results from their absence or weak manifestation of Ca-dependent K-conductivity in their membrane. Ca2+ entering non-habituating cells during electrical stimulation may have depolarizing and facilitating effects.


Synthesis of Single-Handed Helical Spiro-Conjugated Ladder Polymers through Quantitative and Chemoselective Cyclizations*.
We report the unprecedented synthesis of one-handed helical spiro-conjugated ladder polymers with well-defined primary and secondary structures, in which the spiro-linked dibenzo[a,h]anthracene fluorophores are arranged in a one-handed twisting direction, through quantitative and chemoselective acid-promoted intramolecular cyclizations of random-coil precursor polymers composed of chiral 1,1'-spirobiindane and achiral bis[2-(4-alkoxyphenyl)ethynyl]phenylene units. Intense circular dichroism (CD) and circularly polarized luminescence (CPL) were observed, whereas the precursor polymers exhibited negligible CD and CPL activities. The introduction of 2,6-dimethyl substituents on the 4-alkoxyphenylethynyl pendants is of key importance for this simple, quantitative, and chemoselective cyclization. This strategy is applicable to the defect-free precise synthesis of other varieties of fully π-conjugated molecules and coplanar ladder polymers that have not been achieved before.


Histochemical changes in gastric mucosubstances in patients with acute and chronic ulcer disease.
The several types of epithelial cells in human gastric mucosa produce different mucosubstances. The surface epithelium largely forms a neutral mucosubstance except that in about two-thirds of the specimens the deep foveolar cells produce a slight to moderate amount of a mucosubstance apparently containing sulfate esters and carboxyl groups. Mucous neck cells often exhibit a neutral mucosubstance but in about onehalf of the stomachs reveal a slight to moderate reactivity indicative of sulfated mucosubstance. Chief cells contain a sulfated mucosubstance with unique histochemical properties. Mast cells vary widely in prevalence but those in the gastric mucosa appear depleted of stored mucosubstances when compared with those in the gastric submucosa or the esophagus. The sulfated mucosubstance normally abundant in human as in canine chief cells appears consistently depleted in patients with stress ulcer or hemorrhagic gastritis. In addition, mucus often appears depleted in the surface epithelium and interstitial edema is present in the superficial mucosa of these patients. These findings appear consistent with the view that biosynthetic activity in chief cells and surface epithelial cells is impaired perhaps secondary to shock-induced circulatory changes in gastric mucosa of patients with stress ulcer or hemorrhagic gastritis.


Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers.
We previously reported that natural killer cell stimulatory factor (NKSF), a heterodimeric lymphokine purified from the conditioned medium of human B lymphoblastoid cell lines, induces interferon gamma (IFN-gamma) production from resting peripheral blood lymphocytes (PBL) and synergizes with interleukin 2 in this activity. In this study, we show that human NKSF induces IFN-gamma production from both resting and activated human PBL and from freshly isolated murine splenocytes. Human T and NK cells produce IFN-gamma in response to NKSF, but resting PBL require the presence of nonadherent human histocompatibility leukocyte antigens DR+ (HLA-DR+) accessory cells to respond to NKSF. The mechanism(s) by which NKSF induces IFN-gamma production results in accumulation of IFN-gamma mRNA, is insensitive to cyclosporin A, and synergizes with those mediated by phytohemagglutinin, phorbol diesters, anti-CD3 antibodies, and allogeneic antigens, but not by Ca2+ ionophores. The ability of NKSF to directly induce IFN-gamma production and to synergize with other physiological IFN-gamma inducers, joined with the previously described ability to enhance lymphocyte cytotoxicity and proliferation, indicates that this lymphokine is a powerful immunopotentiating agent.


Phosphatidylinositol metabolism and polyoma-mediated transformation.
The effect of polyoma middle-sized tumor antigen (MTAg) on phosphatidylinositol metabolism has been characterized in vivo and in vitro using polyoma-transformed and polyoma-infected cells. Cells infected with transformation-competent polyoma virus exhibit increased levels of inositol phospholipids and the second messenger inositol trisphosphate. MTAg or pp60c-src immunoprecipitates from MTAg-transformed cells contain an activity that phosphorylates phosphatidylinositol and phosphatidylinositol 4-phosphate. This activity is induced in parallel with MTAg when the MTAg synthesis is regulated by hormonal or heavy metal inducers. Immunoprecipitates from one class of polyoma mutants defective in transformation have a reduced level of associated phosphatidylinositol kinase activity in vitro yet are capable of tyrosine phosphorylation on exogenous protein substrates at rates comparable to wild-type virus. Thus, for these mutants, phosphatidylinositol kinase activity is more tightly correlated with transformation than is protein kinase activity. These results suggest that alterations in phosphatidylinositol metabolism by MTAg play a role in transformation by polyoma virus.


Engineered Human Dendritic Cell Exosomes as Effective Delivery System for Immune Modulation.
Exosomes (exos) contain molecular cargo of therapeutic and diagnostic value for cancers and other inflammatory diseases, but their therapeutic potential for periodontitis (PD) remains unclear. Dendritic cells (DCs) are the directors of immune response and have been extensively used in immune therapy. We previously reported in a mouse model of PD that custom murine DC-derived exo subtypes could reprogram the immune response toward a bone-sparing or bone-loss phenotype, depending on immune profile. Further advancement of this technology requires the testing of human DC-based exos with human target cells. Our main objective in this study is to test the hypothesis that human monocyte-derived dendritic cell (MoDC)-derived exos constitute a well-tolerated and effective immune therapeutic approach to modulate human target DC and T cell immune responses in vitro. MoDC subtypes were generated with TGFb/IL-10 (regulatory (reg) MoDCs, CD86lowHLA-DRlowPDL1high), E. coli LPS (stimulatory (stim) MoDCs, CD86highHLA-DRhighPDL1low) and buffer (immature (i) MoDCs, CD86lowHLA-DRmedPDL1low). Exosomes were isolated from different MoDC subtypes and characterized. Once released from the secreting cell into the surrounding environment, exosomes protect their prepackaged molecular cargo and deliver it to bystander cells. This modulates the functions of these cells, depending on the cargo content. RegMoDCexos were internalized by recipient MoDCs and induced upregulation of PDL1 and downregulation of costimulatory molecules CD86, HLADR, and CD80, while stimMoDCexos had the opposite influence. RegMoDCexos induced CD25+Foxp3+ Tregs, which expressed CTLA4 and PD1 but not IL-17A. In contrast, T cells treated with stimMoDCexos induced IL-17A+ Th17 T cells, which were negative for immunoregulatory CTLA4 and PD1. T cells and DCs treated with iMoDCexos were immune 'neutral', equivalent to controls. In conclusion, human DC exos present an effective delivery system to modulate human DC and T cell immune responses in vitro. Thus, MoDC exos may present a viable immunotherapeutic agent for modulating immune response in the gingival tissue to inhibit bone loss in periodontal disease.