Osteoblastic activity of the rabbit temporomandibular joint during distraction osteogenesis assessed by [18F]fluoride positron emission tomography.
The purpose of the study was to evaluate the effects of irradiation and hyperbaric oxygenation (HBO) on osteoblastic activity of the temporomandibular joint (TMJ) region during mandibular distraction osteogenesis. Unilateral distraction was performed on 19 rabbits, which were divided into five groups. One group served as a control group, while the others received either high- or low-dose irradiation in the TMJ region before surgery. Some of the animals were also given HBO 18 times at 2.5 ATA x 90 min preoperatively. Osteogenesis was assessed by [18F]fluoride positron emission tomography at the end of the distraction. Osteoblastic activity was higher on the distracted side in all groups, except in the high-dose irradiated group without preceding HBO. HBO increased osteogenesis on both sides after radiotherapy. It is concluded that increased osteoblastic activity reflects increased pressure on the TMJ region of the distracted side, resulting from lengthening. It seems that more remodeling is required after irradiation than without preceding radiotherapy. After radiotherapy, HBO increased osteoblastic activity.


[Analysis of clinical manifestation and genetic mutation in a child with X-linked chondrodysplasia punctata 2].
To analyze clinical manifestations and genetic mutation in a child with severe short stature and other malformations. The child has undergone history taking and physical examination. Genome DNA was extracted from peripheral blood samples of the proband and her family members. Candidate genes were captured with Agilent SureSelect and sequenced on an Illumina platform. Suspected mutation was verified by Sanger sequencing. The patient, a six-year-and-10-month old girl, presented with non-symmetrical short stature, dysmorphism, abnormalities of limbs and spine, amblyopia of left eye, and cataract of right eye, in addition with frequent respiratory infection and micturition. Laboratory testing suggested 25-hydroxy vitamin D deficiency (18.9 ng/mL). Spine X-ray showed multiple malformations with centrums. Her mother also featured short stature (138 cm). Her aunt had short stature (130 cm) and limb-length discrepancy. Her little brother was 2.5 years old, and his height was 81 cm (-3.4 SD). Exome sequencing revealed a heterozygous mutation c.184C to T (p.Arg62Trp) in the proband and her mother. The same mutation was not found in her father and brother. The patient was diagnosed with X-linked chondrodysplasia punctata 2. Mutation of the EBP gene probably underlied the disease in this family.


Efficacy and Safety of Novel Thiazolidinedione Rivoglitazone in Type-2 Diabetes a Meta-Analysis.
No meta-analysis has analyzed the safety and efficacy of rivoglitazone in type-2 diabetes (T2DM). We undertook this meta-analysis to address this knowledge gap. Electronic databases were searched for RCTs involving T2DM patients receiving rivoglitazone in the intervention arm, and placebo/active comparator in the control arm. The primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in glucose, lipids, and adverse events. From initially screened 24 articles, data from 3 RCTs (3591 patients) that fulfilled all criteria was analzsed. HbA1c was significantly lower with standard-dose (1 mg/d) [MD-0.86% (95%CI:-1.11--0.61); P < 0.01; I2 = 87%] and high-dose (1.5-2 mg/d) [MD-0.97%(95%CI:-1.03--0.90); P < 0.01; I2 = 19%] rivoglitazone compared to placebo. When compared to pioglitazone (30-45 mg/d), HbA1c lowering was comparable with standard-dose [MD 0.05%(95%CI:-0.01 - 0.11); P = 0.08; I2 = 11%], but superior with high-dose [MD -0.11%(95%CI:-0.18- -0.04); P < 0.01; I2 = 0%] rivoglitazone. Triglycerides were significantly lower with standard-dose [MD-17.95 mg/dl (95%CI:-34.23--1.66); P = 0.03; I2 = 0%] and high-dose [MD-40.41 mg/dl (95%CI:-72.90- -7.93);P = 0.01;I2 = 71%] rivoglitazone compared to placebo. Adiponectin significantly improved with standard-dose [MD 7.94 ng/ml (95%CI: 5.48-10.39); P < 0.01;I2 = 98%] and high-dose [MD 13.82 ng/ml (95%CI: 8.16-19.48); P < 0.01; I2 = 100%] rivoglitazone compared to placebo. hsCRP was significantly lower with standard-dose [MD -1.00 mg/L (95% CI: -1.20 - -0.80); P < 0.01; I2 = 6%] and high-dose [MD -1.50 mg/L (95%CI:-1.59- -1.40); P < 0.01; I2 = 0%] rivoglitazone compared to placebo. Treatment-emergent adverse events with standard-dose [Risk ratio (RR) 1.16 (95%CI: 0.84 -1.60); P = 0.38; I2 = 0%] and high-dose [RR1.34 (95%CI: 0.99-1.83); P = 0.06; I2 = 0%] rivoglitazone was comparable to placebo. Severe adverse events with standard-dose [RR1.88 (95%CI: 0.69-5.12);P = 0.22;I2 = 0%] and high-dose [RR 1.27 (95% CI: 0.45 - 3.59); P = 0.68; I2 = 0%] rivoglitazone was comparable to placebo. This meta-analysis highlights the good glycaemic efficacy and safety of both standard and high-dose rivoglitazone, and appears to be better than lobeglitazone in T2DM.


Sericin-mediated improvement of dysmorphic cardiac mitochondria from hypercholesterolaemia is associated with maintaining mitochondrial dynamics, energy production, and mitochondrial structure.
Sericin is a component protein in the silkworm cocoon [Bombyx mori Linnaeus (Bombycidae)] that improves dysmorphic cardiac mitochondria under hypercholesterolemic conditions. This is the first study to explore cardiac mitochondrial proteins associated with sericin treatment. To investigate the mechanism of action of sericin in cardiac mitochondria under hypercholesterolaemia. Hypercholesterolaemia was induced in Wistar rats by feeding them 6% cholesterol-containing chow for 6 weeks. The hypercholesterolemic rats were separated into 2 groups (n = 6 for each): the sericin-treated (1,000 mg/kg daily) and nontreated groups. The treatment conditions were maintained for 4 weeks prior to cardiac mitochondria isolation. The mitochondrial structure was evaluated by immunolabeling electron microscopy, and differential mitochondrial protein expression was determined and quantitated by two-dimensional gel electrophoresis coupled with mass spectrometry. A 32.22 ± 2.9% increase in the percent striated area of cardiac muscle was observed in sericin-treated hypercholesterolemic rats compared to the nontreatment group (4.18 ± 1.11%). Alterations in mitochondrial proteins, including upregulation of optic atrophy 1 (OPA1) and reduction of NADH-ubiquinone oxidoreductase 75 kDa subunit (NDUFS1) expression, are correlated with a reduction in mitochondrial apoptosis under sericin treatment. Differential proteomic observation also revealed that sericin may improve mitochondrial energy production by upregulating acetyl-CoA acetyltransferase (ACAT1) and NADH dehydrogenase 1α subcomplex subunit 10 (NDUFA10) expression. Sericin treatment could improve the dysmorphic mitochondrial structure, metabolism, and energy production of cardiac mitochondria under hypercholesterolaemia. These results suggest that sericin may be an alternative treatment molecule that is related to cardiac mitochondrial abnormalities.


[Convertible energy sources in Neisseria gonorrhoeae].
Availability of two major sources of convertible energy in gonococci--the intracellular pool of ATP and electrochemical potential of hydrogen ions--has been established. ATP synthesis occurs when inducing membrane potential by creation of K+ gradient with presence of valinomycin and when inducing the proton gradient. Transmembrane difference of electric potentials has been determined which changes within 103-145 mV under the increase of pH from 5.0 to 8.0, and concentration gradient of protons decreases from 80 to 47 mV. The proton-motive force value remains unchanged (183-192 mV) in the range of pH 5.0-8.0.


Relation between CYP2D6 phenotype and genotype and personality in healthy volunteers.
Our group has previously show that interindividual variability in CYP2D6 hydroxylation capacity was related to personality differences in cognitive social anxiety. Thus, we aimed to analyze whether this relationship between personality and CYP2D6 phenotype and genotype was found in a similar population of healthy volunteers from a different latitude and culture by using the same methodology. A total of 253 university students and staff from Havana Psychiatric Hospital and Calixto García Medical School in Cuba completed the Karolinska Scales of Personality (KSP), and were evaluated on debrisoquine hydroxylation capacity and CYP2D6 genotypes. KSP scores were compared between four groups, divided according to their CYP2D6 metabolic capacity: one of poor and three of extensive metabolizers. Furthermore, KSP scores were compared between another four different groups divided according to their number of CYP2D6 active genes: zero, one, two, and more than two. In Cubans, the differences in cognitive social anxiety-related personality traits across the four CYP2D6 hydroxylation capacity groups were strikingly similar to those found in Spaniards. These differences also came out to be significant for psychic anxiety (p = 0.02) and socialization (p = 0.02). The same pattern of results obtained for the subscales of psychic anxiety, socialization, psychasthenia and inhibition of aggression with regard to phenotype in both the Cuban and Spanish studies were seen with regard to CYP2D6 genotypes. Corroborating these results further strengthens evidence of the relationship between CYP2D6 metabolic capacity and personality. In this population of healthy Cuban volunteers, the CYP2D6 hydroxylation capacity was related to the degree of anxiety and socialization. These results support the postulated reduction of serotonin in CYP2D6 poor metabolizers, which may be associated with a cluster of behavioral traits (e.g., anxiety, impulsivity). Thus, research is warranted to determine CYP2D6 functional implications for interindividual differences in vulnerability to neuropsychiatric diseases and drug response.


Crystal structure of the human thioredoxin reductase-thioredoxin complex.
Thioredoxin reductase 1 (TrxR1) is a homodimeric flavoprotein crucially involved in the regulation of cellular redox homeostasis, growth, and differentiation. Its importance in various diseases makes TrxR1 a highly interesting drug target. Here we present the first crystal structures of human TrxR1 in complex with its substrate thioredoxin (Trx). The carboxy-terminal redox centre is found about 20 Å apart from the amino-terminal redox centre, with no major conformational changes in TrxR or Trx. Thus, our structure confirms that the enzyme uses a flexible C-terminal arm for electron transport to its substrates, which is stabilized by a guiding bar for controlled transfer. This notion is supported by mutational analyses. Furthermore, essential residues of the interface region were characterized both structurally and functionally. The structure provides templates for future drug design, and contributes to our understanding of redox regulatory processes in mammals.


Radial buckling in the repair of retinal detachment.
Experience with external sponge buckles for the treatment of retinal detachment has led to a preference for radial placement of the sponge. More retinal holes, particularly large horseshoe breaks, can be closed effectively with radially oriented buckles than with limbus parallel ones; limbus parallel buckles often were complicated by "fish-mouthing" of the breaks and leaking radial folds. A radial orientation of the buckle averts this complication. The geometry of retinal detachment and scleral buckling reveals the origin of "fish-mouthing" and radial folds and why radially oriented buckles prevent this complication.


tiRNA-Val promotes angiogenesis via Sirt1-Hif-1α axis in mice with diabetic retinopathy.
Diabetic retinopathy (DR) is a specific microvascular complication arising from diabetes, and its pathogenesis is not completely understood. tRNA-derived stress-induced RNAs (tiRNAs), a new type of small noncoding RNA generated by specific cleavage of tRNAs, has become a promising target for several diseases. However, the regulatory function of tiRNAs in DR and its detailed mechanism remain unknown. Here, we analyzed the tiRNA profiles of normal and DR retinal tissues. The expression level of tiRNA-Val was significantly upregulated in DR retinal tissues. Consistently, tiRNA-Val was upregulated in human retinal microvascular endothelial cells (HRMECs) under high glucose conditions. The overexpression of tiRNA-Val enhanced cell proliferation and inhibited cell apoptosis in HRMECs, but the knockdown of tiRNA-Val decreased cell proliferation and promoted cell apoptosis. Mechanistically, tiRNA-Val, derived from mature tRNA-Val with Ang cleavage, decreased Sirt1 expression level by interacting with sirt1 3'UTR, leading to the accumulation of Hif-1α, a key target for DR. In addition, subretinal injection of adeno-associated virus to knock down tiRNA-Val in DR mice ameliorated the symptoms of DR. tiRNA-Val enhance cell proliferation and inhibited cell apoptosis via Sirt1/Hif-1α pathway in HRMECs of DR retinal tissues.


Handedness in Swedish 10-year-olds. Some background and associated factors.
Forty-five left-handed and 46 right-handed 10-year-old children were subjected to a limited set of neurological tests and a square tracing task. 'Pathological' handedness was diagnosed in cases showing poor performance with the non-preferred hand on the squares task. The frequency of left-handedness in the population was estimated at 9.2%. The boy : girl ratio was 1.6:1. 'Pathological' handedness was twice as common among left-handers as among right-handers. Neurological dysfunction was more common in 'pathological' handers, especially left-handers. Reduced pre-. peri- and neonatal optimality was seen in boys with 'pathological handedness'. School achievement problems and behaviour problems were much more common in left-handed boys than in other study groups. The results lend partial support for the extended pathological left-handedness model recently hypothesized by Bishop, but it is suggested that left-handedness in boys is more often a symptom of pathological shift of handedness than is left-handedness in girls.


Effect of body position on the pathogenesis of asymmetric primary open angle glaucoma.
To explore the pathogenesis of asymmetric primary open angle glaucoma (POAG) in both eyes by comparing the intraocular pressure (IOP) of patients who sleep in different positions and to investigate the relationship between IOP variations and sleep positions. One hundred and thirty-one patients with asymmetric POAG and forty-six healthy volunteers were enrolled. All participants completed a questionnaire that provided information about their sleep laterality. The cup disc ratio (C/D) and visual field defect established binocular asymmetry. The IOP of both eyes was measured using iCare parameters after the patients were asked to change body position. The "worse" and "better" eyes were identified according to the diagnosis, whereas the "dependent" and "independent" eyes were defined according to the lateral position. No significant difference in sleep laterality was observed between healthy people and patients with POAG (F=3.195, P=0.362). Among the enrolled patients, the IOP of the dependent eye was always greater than that of the independent eye in the lateral position (P<0.05). In the patients with binocular asymmetric POAG, the questionnaire clearly showed that 85.7% of left side preferences were found their left eyes to be the worse eyes and the right eyes of 71.4% patients with a right side preference were the more serious. When the asymmetric C/D ratio was greater than or equal to 0.2, the worse eye of patients with POAG and a preferred sleeping position was the dependent eye (χ2 =16.762, P=0.001). A higher IOP was measured in the dependent eye in the lateral position. The long-term tendency to choose a lateral sleeping position might lead the dependent eye to manifest more severe symptoms than the independent eye. Thus, the lateral sleeping position might be one cause of asymmetric POAG.


Postoperative subdural haematoma and pneumocephalus mimicking TIA.
An 86-year-old man presented with left hand numbness and weakness 10 days after a resection of squamous cell carcinoma of the right side of the scalp. A CT head scan identified a right-sided, hypodense subdural collection without midline shift, with associated pneumocephalus. When the images were reviewed on bony settings, minute drill holes were identified penetrating the outer tables as expected, but also the inner table of the calvarium. With this knowledge, the initial clinical diagnosis altered significantly from that of a transient ischaemic attack to a working diagnosis of a subdural haematoma as a complication of the penetrating injury to the cranium, in a patient with an elevated international normalised ratio.


Polarization effects in attosecond photoelectron spectroscopy.
We study the influence of polarization effects in streaking by combined atto- and femtosecond pulses. The polarization-induced terms alter the streaking spectrum. The conventional streaking spectrum, which maps to the vector potential of the femtosecond pulse, is modified by a contribution following the field instead. We show that polarization effects may lead to an apparent temporal shift that needs to be properly accounted for in the analysis. The effect may be isolated and studied by angle-resolved photoelectron spectroscopy from oriented polar molecules. We also show that polarization effects will lead to an apparent temporal shift of 50 as between photoelectrons from a 2p and 1s state in atomic hydrogen.


Risk of irritable bowel syndrome among asthma patients.
An association between Irritable Bowel Syndrome (IBS) and bronchial hyper-responsiveness has been suggested. Only a few studies have specifically studied the association between IBS and asthma. To estimate the incidence rate of IBS among asthma patients and to compare it with the general population. We also examined the association between use of asthma drugs, specifically corticosteroids, and IBS. Population-based cohort study using the General Practice Research Database (GPRD) in the UK. The cohort comprised a random sample of 50,000 asthma patients aged 10-79 years and a similar number of sex- and age-matched individuals free of asthma and identified from the source population. A nested case-control analysis was performed within the asthma cohort to examine the association between asthma drugs and IBS. The incidence rate of IBS in the asthma cohort was 2.5 per 1000 persons-years and 2.0 in the general population. The relative risk (RR) was 1.3 (95% CI 1.1-1.5). A medical history of neurotic and psychologic disorders, pain-related diseases and gastroenteritis were all associated with the occurrence of IBS. In the asthma cohort, current users of oral steroids presented a RR of 0.5 (95% CI 0.2-1.2) for developing IBS. The risk estimate was similar in short- and long-term users of steroids. We found a slightly increased risk of IBS in asthma patients compared to the general population and that the risk of IBS was reduced by use of oral steroids in asthma patients. Additional studies in the general population are necessary in order to confirm whether use of corticosteroids irrespective of asthma has a protective effect on the risk of IBS.


Older age becomes common late in human evolution.
Increased longevity, expressed as number of individuals surviving to older adulthood, represents one of the ways the human life history pattern differs from other primates. We believe it is a critical demographic factor in the development of human culture. Here, we examine when changes in longevity occurred by assessing the ratio of older to younger adults in four hominid dental samples from successive time periods, and by determining the significance of differences in these ratios. Younger and older adult status is assessed by wear seriation of each sample. Whereas there is significant increased longevity between all groups, indicating a trend of increased adult survivorship over the course of human evolution, there is a dramatic increase in longevity in the modern humans of the Early Upper Paleolithic. We believe that this great increase contributed to population expansions and cultural innovations associated with modernity.


[A case of cerebral syphilitic gumma mimicking a brain tumor].
We report a case of young immunocompetent woman who was presented with a left parieto-temporal mass as the first and single manifestation of syphilis. A 23 year-old woman with no significant past medical history was reffered to our hospital due to 3 month history of headache. She had a single unprotected sexual intercourse with a promiscuous man 6 month before the time of admission. Physical and neurological examinations revealed no obvious abnormalities. A brain tumor was firstly suggested according to the findings of brain magnetic resonance imaging (MRI). However, the serologic and cerebrospinal fluid test of syphilis proved to be positive, syphilitic gumma was most likely suspected. She responded dramatically to benzylpenicillin potassium. Cerebral syphilitic gumma is a rare manifestations of the neurosyphilis. Treponemal invasion of the cerebrospinal fluid occurs in approximately 25 to 60% of patients after the infection, but most cases spend asymptomatic. Cerebral gumma should be considered in differential diagnosis of any intracranial mass lesions, even in the early syphilitic stages.


Advancing the missed mutualist hypothesis, the under-appreciated twin of the enemy release hypothesis.
Introduced species often benefit from escaping their enemies when they are transported to a new range, an idea commonly expressed as the enemy release hypothesis. However, species might shed mutualists as well as enemies when they colonize a new range. Loss of mutualists might reduce the success of introduced populations, or even cause failure to establish. We provide the first quantitative synthesis testing this natural but often overlooked parallel of the enemy release hypothesis, which is known as the missed mutualist hypothesis. Meta-analysis showed that plants interact with 1.9 times more mutualist species, and have 2.3 times more interactions with mutualists per unit time in their native range than in their introduced range. Species may mitigate the negative effects of missed mutualists. For instance, selection arising from missed mutualists could cause introduced species to evolve either to facilitate interactions with a new suite of species or to exist without mutualisms. Just as enemy release can allow introduced populations to redirect energy from defence to growth, potentially evolving increased competitive ability, species that shift to strategies without mutualists may be able to reallocate energy from mutualism toward increased competitive ability or seed production. The missed mutualist hypothesis advances understanding of the selective forces and filters that act on plant species in the early stages of introduction and establishment and thus could inform the management of introduced species.


Diagnosing fetal alcohol spectrum disorder: History, challenges and future directions.
Fetal alcohol spectrum disorder (FASD) is one of the most common preventable causes of developmental disability, and is currently one of the most pressing public health concerns in Canada. FASD refers to the range of physical, mental, behavioural and learning disabilities that an individual may acquire as a result of maternal alcohol consumption. In the present paper, the history of the diagnostic approach to alcohol-related disorders over the past 35 years is reviewed. Research supporting the importance of early diagnosis for the long-term outcomes and management of individuals with FASD is presented, and challenges that have plagued efforts to efficiently diagnose individuals with FASD are discussed. Finally, the study reviews the future directions and implications regarding current diagnostic strategies.


[Medical students' views on the use of virtual patients for teaching and assessment of clinical knowledge and reasoning].
Computerized cLinical cases ["virtual patient" (VP)] provide a useful teaching and assessment tool for clinicaL knowledge and skiLLs. However, the attitude of medical students toward this new modality needs to be evaluated. We examined students' acceptance of a web-based VP system that was deveLoped in the Technion Faculty of Medicine for teaching and assessment purposes. The VP system enables free conversation (in writing) for history taking and listing of disease symptoms. It aLso depicts images and audio-videos of heart and lung sounds, and enables users to order Laboratory and imaging tests. The system was designed to be learnt without instructors and to provide feedback online. Therefore, the process of Learning and practicing with the VP system was performed by the students at home, during their free time. At the end of the clinical introductory course to internal medicine, students (n=91) were asked to complete questionnaires and rate multiple aspects of the VP system. Student acceptance of this web-based modality was high: over 95% fully or partially accepted that the VP practice system facilitates Learning the approach to diseases they were not exposed to during the course, practicing differential diagnosis, and improving their knowledge, clinicaL skills and reasoning. A similar percentage of the students agreed that the VP exam assessed their clinical knowledge and comprehension adequately, correctly and objectively. These results document high acceptance of web-based instruction and assessment by medical students. However, many students expect that a clinical course should also include bed-side assessment.


High-resolution electrohydrodynamic bioprinting: a new biofabrication strategy for biomimetic micro/nanoscale architectures and living tissue constructs.
Electrohydrodynamic (EHD) printing is a newly emerging additive manufacturing strategy for the controlled fabrication of three-dimensional (3D) micro/nanoscale architectures. This unique superiority makes it particularly suitable for the biofabrication of artificial tissue analogs with biomimetic structural organizations similar to the scales of native extracellular matrix (ECM) or living cells, which shows great potentials to precisely regulate cellular behaviors and tissue regeneration. Here the state-of-the-art advancements of high-resolution EHD bioprinting were reviewed mainly including melt-based and solution-based processes for the fabrication of micro/nanoscale fibrous scaffolds and living tissues constructs. The related printing materials, innovations on structure design and printing processes, functionalization of the resultant architectures as well as their effects on the mechanical and biological properties of the EHD-printed structures were introduced and analyzed. The recent explorations on the EHD cell printing for high-resolution cell-laden microgel patterning and 3D construct fabrication were highlighted. The major challenges as well as possible solutions to translate EHD bioprinting into a mature and prevalent biofabrication strategy were finally discussed.


Age-specific demography in Plantago: uncovering age-dependent mortality in a natural population.
Accurate measures of age-dependent mortality are critical to life-history analysis and measures of fitness, yet these measures are difficult to obtain in natural populations. Age-dependent mortality patterns can be obscured not only by seasonal variation in environmental conditions and reproduction but also by changes in the heterogeneity among individuals in the population over time due to selection. This study of Plantago lanceolata uses longitudinal data from a field study with a large number of individuals to develop a model to estimate the shape of the baseline hazard function that represents the age-dependent risk of mortality. The model developed here uses both constant (genetics, spatial location) and time-varying (temperature, rainfall, reproduction, size) covariates not only to estimate the underlying mortality pattern but also to demonstrate that the risk of mortality associated with fitness components can change with time/age. Moreover, this analysis suggests that increasing size after reproductive maturity may allow this plant species to escape from demographic senescence.


Fast Laplace solver approach to pore-scale permeability.
We introduce a powerful and easily implemented method to calculate the permeability of porous media at the pore scale using an approximation based on the Poiseulle equation to calculate permeability to fluid flow with a Laplace solver. The method consists of calculating the Euclidean distance map of the fluid phase to assign local conductivities and lends itself naturally to the treatment of multiscale problems. We compare with analytical solutions as well as experimental measurements and lattice Boltzmann calculations of permeability for Fontainebleau sandstone. The solver is significantly more stable than the lattice Boltzmann approach, uses less memory, and is significantly faster. Permeabilities are in excellent agreement over a wide range of porosities.


[Determination of the postoperative effect on intestinal structure and myoelectric motility in rabbits: modified uncut jejunal loop versus Roux-en-Y biliodigestive anastomosis].
To evaluate influences on intestinal structure and myoelectric motility between modified uncut jejunal loop and Roux-en-Y procedures for biliodigestive anastomosis. Fifteen rabbits were randomized in modified uncut jejunal loop group, Roux-en-Y group and control group. Traced fasting slow-wave frequency (SWF) before biliodigestive diversion and 25 d postoperative (POD25) during laparotomy. Before the second laparotomy on POD21, the fasting SWF, percentage of abroad migrating myoelectric complex (MMC%), the postprandial spike potential frequency (SPF) and percentage of abroad propagation (SP%) were recorded in vivo. Compared myoelectric recordings according to parameters above. On POD90, harvested the stitched ligation of ascending loop and part of descending loop in uncut group, and biliary limb in R-Y animals, which assessed under HE, c-kit labeling immunohistochemical staining and transmission electron microscope(TEM). On POD25, SWF declined mildly in uncut group (8.4%) and markedly in R-Y group (23.8%) respectively. The difference was significant (P<0.05). Before laparotomy on POD21 when abdomen closed, between uncut and control animals, there were statistical difference in fasting SWF and postprandial SPF (P<0.05), while no significance in MMC% and SP% (P>0.05). Moreover, differences of each parameters between R-Y group and control or uncut group were markedly statistical (P<0.01). Abroad myoelectric propagation through the ligated segment can be observed in uncut animals. Meanwhile, ectopic pacemaker was detected locating in the proximal segment of the Roux limb and triggering retrograde propagation in R-Y animals. On POD90, no recanalization were observed In uncut animals. Furthermore, occluded lumen with mild atrophic mucosa under microscope and c-kit labeling cells located in the inner circular muscle layer were observed, which proven to be Interstitial cells of Cajal (ICCs) by TEM. In R-Y animals, lumen of the Roux limb dilated. There's no significant difference in c-kit labeling area between R-Y and uncut animals by image analysis system. Reductions of processes and intercellular gap junction in ICCs, and loose interconnections between ICCs and SMCS or nerve endings were observed in R-Y animals. Impaired gastrointestinal motility after the Roux-en-Y procedure may due to the aberrant interstitial cells of Cajal. Modified uncut technique reveals a reliable and effective alternative for biliodigestive reconstruction.


Effect of Early Rehabilitation on Walking Independence and Health-Related Quality of Life in Patients With Chronic Foot Wounds: A Multicenter Randomized Clinical Trial.
Rehabilitation is usually provided to patients with chronic foot wounds (CFWs) after surgery. This study aimed to assess whether early postoperative rehabilitation could maintain walking independence in hospitalized patients with CFWs. This single-blind, randomized clinical trial was performed between September 10, 2018 and March 2019, involving 60 patients who underwent both surgical procedures and rehabilitation. Participants were randomly allocated into the early rehabilitation (EG, n = 30) or the control (CG, n = 30) groups. EG received early rehabilitation immediately after surgery, while CG received late rehabilitation after wound closure. Both groups received rehabilitation sessions 5 times per week until discharge. The primary outcome was walking independence, measured via Functional Independence Measure (FIM)-gait scores. Secondary outcomes included health-related quality of life (HRQoL) using EuroQol 5 dimensions 5-level (EQ-5D-5L) and the presence of rehabilitation-related adverse events, including dehiscence of wounds and falls. Differences in intervention timing effects were analyzed using nonparametric split-plot factorial design analysis, including Fisher's exact test, Mann-Whitney U test, and Wilcoxon signed-rank test (P < .05). Out of the 60 participants, 53 patients completed the discharge follow up. Three participants (10.0%) from the EG and 4 (13.3%) from the CG dropped out due to postoperative complications unrelated to rehabilitation intervention. No rehabilitation-related adverse events were found. Participants in the EG maintained greater FIM-gait scores during hospitalization than the CG (difference, -1; P = .0001), with a difference of 0 (P = .109) at discharge. EQ-5D-5L significantly improved in both groups (EG: difference, 0.13 [P = .014], CG: difference, 0.17 [P = .0074]). The EG intervention was associated more with maintaining walking independence at discharge than CG intervention. Postoperative rehabilitation improved HRQoL without adverse events, indicating that clinicians should recommend early rehabilitation for patients with CFW to enhance walking independence.


Modulatory Role of Silver Nanoparticles and Mesenchymal Stem Cell-Derived Exosome-Modified Barrier Membrane on Macrophages and Osteogenesis.
Background: As a wound dressing and barrier membrane, surface modification of polycaprolactone (PCL) is needed in order to achieve better biological activities. Exosomes derived from mesenchymal stem cells (MSCs) hold significant tissue regeneration promise. Silver nanoparticles (Ag) have been suggested as the surface modification technique for various medical devices. Materials and Methods: Ag and human bone marrow MSC (hBMSC)-derived exosomes (MSCs-exo) were used to modify the PCL scaffold. The impact of different scaffolds on immune cells and MSC proliferation and differentiation was further evaluated. Results: MSCs-exo exhibited cup-shaped morphology with a diameter around 100 nm. MSCs-exo were enriched with exosome marker CD81 and showed good internalization into recipient cells. 200 ng/ml Ag nanoparticles and MSCs-exo were further used to modify the PCL scaffold. The internalization study further indicated a similar releasing pattern of exosomes from Ag/MSCs-exo hybrid scaffolds into RAW264.7 and hBMSCs at 12 and 24 h, respectively. Macrophages play an important role during different stages of bone regeneration. The MTT and confocal microscopy study demonstrated no significant toxicity of exosome and/or Ag hybrid scaffolds for macrophages and MSCs. Inflammatory macrophages were further used to mimic the inflammatory environment. A mixed population of elongated and round morphology was noted in the exosome and Ag hybrid group, in which the proinflammatory genes and secretion of IL-6 and TNF-α were significantly reduced. In addition, the exosome and Ag hybrid scaffolds could significantly boost the osteogenic differentiation of hBMSCs. Discussion: This study highlights the possibility of using Ag nanoparticles and MSCs-exo to modify the PCL scaffold, thus providing new insight into the development of the novel immunomodulatory biomembrane.


Restoration of the polyamine contents in rat hepatoma tissue-culture cells after inhibition of polyamine biosynthesis. Relationship with cell proliferation.
The restoration of the polyamine content in polyamine-deficient rat hepatoma tissue-culture (HTC) cells, after short duration of incubation in the presence of DL-alpha-difluoromethylornithine (F2MeOrn) or of (2R,5R)-6-heptyne-2,5-diamine [(2R,5R)MAP], two potent irreversible inhibitors of L-ornithine decarboxylase, has been studied in relation to cell proliferation. Both L-ornithine decarboxylase inhibitors deplete the cells of their putrescine and spermidine contents within one day after their addition to the culture medium. Thereafter, intracellular putrescine and spermidine concentrations are restored to near control values within one day when (2R,5R)MAP is removed from the medium, but remain at low levels at least for one day or longer after removal of F2MeOrn. In both conditions, spermine concentration stays at normal or above normal values and cell growth rates are unaffected. Thus, the total intracellular spermine content per culture parallels, in fact, the increase in cell number. The continuous presence of the drugs maintains the depletion of putrescine and spermidine and decreases the total intracellular spermine content of the culture to the same order of magnitude as it reduces the increase in cell numbers. These findings suggest that the antiproliferative effects of these L-ornithine decarboxylase inhibitors in HTC cells is primarily associated with the limitation of spermine biosynthesis rather than to the almost complete reduction of the putrescine and spermidine pools.


An event-related potential study of attention deficits in posttraumatic stress disorder during auditory and visual Go/NoGo continuous performance tasks.
Posttraumatic stress disorder (PTSD) is characterized by disturbances in attention, such as increased arousal and hypervigilance. This study examined the event-related potential (ERP) P3 component to target detection (Go), response inhibition (NoGo) and irrelevant nontarget stimuli during auditory and visual A-X continuous performance tasks. NoGo N2 amplitude effects were also analyzed. Participants were 23 Vietnam veterans with PTSD and 13 civilian controls. No group differences were present for N2 or P3 amplitude to Go and NoGo stimuli. The PTSD group, however, had longer P3 latency to NoGo stimuli than controls, regardless of modality. The PTSD group also had greater frontal P3 amplitude to irrelevant nontarget stimuli than controls. Significant P3 amplitude and latency findings were associated with higher hyperarousal and reexperiencing scores from the Clinician-Administered PTSD Scale. The findings suggest that attentional problems in PTSD are related to slowed central processing when response inhibition is required, and to an impaired ability to screen irrelevant information. This study provides further evidence that the attentional impairments in PTSD are not confined to trauma-related stimuli. Heightened arousal appears to enhance the attentional dysregulation seen in PTSD.


Autoimmune Liver Disease in Children with Sickle Cell Disease.
To assess the incidence, clinical features, and outcome of autoimmune liver disease (AILD) in patients with sickle cell disease (SCD). Single center retrospective review of patients with SCD with AILD referred between 1999 and 2015. Thirteen of 77 (17%) patients with SCD with hepatic dysfunction were diagnosed with AILD (median age 11, range, 3.4-16 years) with a female preponderance (77%). Acute hepatitis and insidious onset were the commonest presentations. Two patients (15%) presented with acute liver failure. In 2 patients (15%), parvovirus B19-induced transient red cell aplasia preceded the diagnosis of AILD. All patients were positive for antinuclear and/or smooth muscle autoantibodies. Six of 12 patients (50%) had cholangiopathy on cholangiogram suggesting autoimmune sclerosing cholangitis (ASC). Liver biopsy, performed in 11 patients without complications, showed interface hepatitis in 90%. Patients with AILD were treated with standard immunosuppression. After a median follow-up of 3.8 years (range, 0.2-14.3), 10 patients are alive (1 was transplanted 6.4 years after diagnosis); 2 are lost to follow-up; 1 died of subdural hemorrhage before starting treatment for AILD. Five (42%) achieved full and 4 (33%) partial biochemical remission. Ulcerative colitis, present in 4 patients (2 male patients, 3 with ASC) was diagnosed in 2 patients before and in 2 patients after the diagnosis of AILD. AILD is not uncommon in patients with SCD, affecting mainly female patients and responding satisfactorily to immunosuppressive treatment. Liver biopsy is helpful in confirming the diagnosis and can be safely performed in the absence of acute vaso-occlusive sickling episodes. Ulcerative colitis is common in the presence of ASC.


Benign Chondromyxoid Fibroma of the Iliac Crest.
A 23-year-old woman initiated a running program and after 2 months began experiencing right hip joint pain and sharp pain at the iliac crest. Following evaluation by her primary care physician, she was referred to a physical therapist. Eighteen months later, the patient had developed a bony prominence at the iliac crest that was painful to touch. She returned to see her primary care physician. Radiographs of the right hip and pelvis were completed and showed a lytic lesion that warranted additional imaging. Computed tomography and magnetic resonance imaging precontrast and postcontrast were performed, and the patient was referred to an orthopaedic oncologist. Conclusive laboratory testing determined that the tumor was a chondromyxoid fibroma J Orthop Sports Phys Ther 2018;48(2):122. doi:10.2519/jospt.2018.7551.


SOHO State of the Art Updates and Next Questions | Immunotherapeutic Options for Patients With Mantle Cell Lymphoma Who Progress on BTK Inhibitors.
Mantle cell lymphoma is a challenging subtype of B-cell non-Hodgkin lymphoma treat characterized by its aggressive nature and propensity for relapse or refractory (R/R) disease for many patients. The introduction of Bruton's tyrosine kinase inhibitors has significantly improved the outcomes for patients with R/R MCL, but a considerable proportion of patients eventually experience disease progression or develop resistance to these agents. In recent years, immunotherapeutic approaches have emerged as promising treatment options. The treatment landscape is quickly progressing with the FDA approval of CAR-T cell therapy as well as several promising bispecific antibody therapies and antibody-drug conjugates in clinical development. This review article aims to provide a comprehensive overview of the current state of immunotherapeutic options available for patients with R/R MCL.


Analysis of the promoter of the ninaE opsin gene in Drosophila melanogaster.
We have analyzed the cis-acting regulatory sequences of the ninaE gene. This gene encodes the major Drosophila melanogaster opsin, the protein component of the primary chromophore of photo-receptor cells R1-R6 of the adult eye. DNA fragments containing the start point of transcription of the ninaE gene were fused to either the Escherichia coli chloramphenicol acetyltransferase or lacZ (beta-galactosidase) gene and introduced into the Drosophila germline by P-element-mediated transformation. Expression of the E. coli genes was then used to assay the ability of various sequences from the ninaE gene to confer the ninaE pattern of expression. Fragments containing between 2.8 kb and 215 bp of the sequences upstream of the start of transcription plus the first 67 bp of the untranslated leader were able to direct nearly wild-type expression. We have identified three separable control regions in the ninaE promoter. The first, which has the properties of an enhancer element, is located between nucleotides -501 and -219. The removal of this sequence had little effect on promoter function; this sequence appears to be redundant. However, it appears to be able to substitute for the second control region which is located between nucleotides -215 and -162, and which also affects the level of output from this promoter. Removal of these two control regions resulted in a 30-fold decrease in expression; however tissue specificity was not affected. The third control region, located downstream from nucleotide -120, appears to be absolutely necessary for promoter function in the absence of the first two regulatory sequences. Examination of larvae containing fusion genes expressing beta-galactosidase suggests that the ninaE gene is also expressed in a subset of cells in the larval photoreceptor organ.


Cervical aortic arch in the pediatric population: a meta-analysis of individual patient's data.
This is the first meta-analysis to analyze all reports of published pediatric cases of cervical aortic arch (CAA) by highlighting the clinical characteristics and treatment outcomes using the reported individual data of the patients. The aim of the study is to investigate the clinical features and surgical outcomes of such a rare disease in the pediatric population. A comprehensive search was conducted in various academic databases, including PubMed, ScienceDirect, SciELO, DOAJ, and Cochrane Library, until June 2022 for case reports describing the presence of cervical aortic arch in the pediatric age. Case reports and series were included if the following criteria were met: (1) description of the cervical aortic arch; (2) patient of pediatric age; and (3) published in the English language. All other types of publications that lacked patient-specific information were excluded from the analysis. This systematic review was conducted in accordance with the PRISMA guidelines. The primary outcome measure of the analysis was early and late mortality. The literature search identified 2,272 potentially eligible articles, 72 of which met our inclusion criteria with 96 patients including the author's institutional case. At a median of 365 (90-730) days, the overall cohort registered a 7.3% (7/96) mortality rate. In the subset of patients who underwent surgery, the mortality rate was also 7.3% (4/55), and the mortality rate following surgery to treat only CAA was 2.4% (1/42). Dyspnea was identified as an independent determinant of mortality by employing the univariable Firth bias-reduced logistic regression method. Cervical aortic arch is a rare congenital heart disease that poses treatment challenges due to the high anatomical variability, diverse clinical presentations, and the presence of other concomitant diseases. The surgical treatment appears to be a safe and effective approach for resolving the symptoms, although it needs to be tailored individually for each patient. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=346826, Identifier: CRD42022346826.


Defensins in viral infections.
Defensins are antimicrobial peptides important to innate host defense. In addition to their direct antimicrobial effect, defensins modulate immune responses. Increasing evidence indicates that defensins exhibit complex functions by positively or negatively modulating infections of both enveloped and non-enveloped viruses. The effects of defensins on viral infections appear to be specific to the defensin, virus and target cell. Regulation of viral infection by defensins is achieved by multiple mechanisms. This review focuses on the interplay between defensins and viral infections, the mechanisms of action of defensins and the in vivo studies of the role of defensins in viral infections.


Expression of interleukin-2 receptor gamma chain on human neutrophils.
The interleukin-2 (IL-2) receptor gamma is an indispensable functional component of IL-2, IL-4, and IL-7 receptors, and thus, is denoted the common gamma chain, gamma c. The present study was undertaken to determine whether human polymorphonuclear neutrophils (PMNs) expressed gamma c chain. Reverse transcription-polymerase chain reaction and Northern blot analysis showed that fresh human PMN constitutively expressed a remarkable level of gamma c mRNA, which is of the size and intensity of that from the peripheral blood mononuclear cells (PBMCs). Granulocyte macrophage-colony stimulating factor, IL-2, and IL-8, which are known to activate PMN functions, failed to regulate the gamma c gene expression. Western blot analysis with a rabbit anti-gamma c polyclonal antibody identified 64-, 58-, and 50-kD gamma c bands in lysates from PMN, but only 64- and 58-kD bands from PBMCs. After the PMNs and PBMCs were treated with tunicamycin to prevent N-linked glycosylation, Western blot analysis detected a single 39-kD band, which is equal to the calculated molecular weight from the cloned cDNA. Thus, our results indicate that PMNs constitutively express high levels of gamma c and the three forms detected are caused by different glycosylation of a protein translated from a single mRNA species.


Organizational Readiness Tools for Global Health Intervention: A Review.
The ability of non-governmental organizations, government agencies, and corporations to deliver and support the availability and use of interventions for improved global public health depends on their readiness to do so. Yet readiness has proven to be a rather fluid concept in global public health, perhaps due to its multidimensional nature and because scholars and practitioners have applied the concept at different levels such as the individual, organization, and community. This review concerns 30 publically available tools created for the purpose of organizational readiness assessment in order to carry out global public health objectives. Results suggest that these tools assess organizational capacity in the absence of measuring organizational motivation, thus overlooking a key aspect of organizational readiness. Moreover, the tools reviewed are mostly untested by their developers to establish whether the tools do, in fact, measure capacity. These results suggest opportunities for implementation science researchers.


An Analysis of Scalable GPU-Based Ray-Guided Volume Rendering.
Volume rendering continues to be a critical method for analyzing large-scale scalar fields, in disciplines as diverse as biomedical engineering and computational fluid dynamics. Commodity desktop hardware has struggled to keep pace with data size increases, challenging modern visualization software to deliver responsive interactions for O(N3) algorithms such as volume rendering. We target the data type common in these domains: regularly-structured data. In this work, we demonstrate that the major limitation of most volume rendering approaches is their inability to switch the data sampling rate (and thus data size) quickly. Using a volume renderer inspired by recent work, we demonstrate that the actual amount of visualizable data for a scene is typically bound considerably lower than the memory available on a commodity GPU. Our instrumented renderer is used to investigate design decisions typically swept under the rug in volume rendering literature. The renderer is freely available, with binaries for all major platforms as well as full source code, to encourage reproduction and comparison with future research.


Use of ultrasound in the reproductive management of dairy cattle.
The significant decrease in fertility observed in dairy cattle during the last few decades and increasing requirements by the farmers have made a regular control of reproduction indispensable to urgently identify and solve potential problems affecting reproductive efficiency. Traditionally, the main diagnostic methods used for reproductive control in cattle included rectal palpation, inspection of vaginal discharge and vaginoscopy. Since the 1990 s, the use of ultrasound (US) has become a common diagnostic method as a result of the new advances made in the development of US scans: smaller size, high level of autonomy, high image quality and accessible prices. Ultrasound improves accuracy in the diagnoses of stages of the oestrous cycle, ovarian and uterine pathologies, and pregnancy diagnosis. In addition, it facilitates the diagnosis of alterations during pregnancy (embryo mortality, foetal malformations, etc.) and helps determining foetal sex from day 55 of pregnancy.


Streptomyces lunalinharesii 235 prevents the formation of a sulfate-reducing bacterial biofilm.
Streptomyces lunalinharesii strain 235 produces an antimicrobial substance that is active against sulfate reducing bacteria, the major bacterial group responsible for biofilm formation and biocorrosion in petroleum reservoirs. The use of this antimicrobial substance for sulfate reducing bacteria control is therefore a promising alternative to chemical biocides. In this study the antimicrobial substance did not interfere with the biofilm stability, but the sulfate reducing bacteria biofilm formation was six-fold smaller in carbon steel coupons treated with the antimicrobial substance when compared to the untreated control. A reduction in the most probable number counts of planktonic cells of sulfate reducing bacteria was observed after treatments with the sub-minimal inhibitory concentration, minimal inhibitory concentration, and supra-minimal inhibitory concentration of the antimicrobial substance. Additionally, when the treated coupons were analyzed by scanning electron microscopy, the biofilm formation was found to be substantially reduced when the supra-minimal inhibitory concentration of the antimicrobial substance was used. The coupons used for the biofilm formation had a small weight loss after antimicrobial substance treatment, but corrosion damage was not observed by scanning electron microscopy. The absence of the dsrA gene fragment in the scraped cell suspension after treatment with the supra-minimal inhibitory concentration of the antimicrobial substance suggests that Desulfovibrio alaskensis was not able to adhere to the coupons. This is the first report on an antimicrobial substance produced by Streptomyces active against sulfate reducing bacteria biofilm formation. The application of antimicrobial substance as a potential biocide for sulfate reducing bacteria growth control could be of great interest to the petroleum industry.


Identification of a Novel Glycosyltransferase Prognostic Signature in Hepatocellular Carcinoma Based on LASSO Algorithm.
Although many prognostic models have been developed to help determine personalized prognoses and treatments, the predictive efficiency of these prognostic models in hepatocellular carcinoma (HCC), which is a highly heterogeneous malignancy, is less than ideal. Recently, aberrant glycosylation has been demonstrated to universally participate in tumour initiation and progression, suggesting that dysregulation of glycosyltransferases can serve as novel cancer biomarkers. In this study, a total of 568 RNA-sequencing datasets of HCC from the TCGA database and ICGC database were analysed and integrated via bioinformatic methods. LASSO regression analysis was applied to construct a prognostic signature. Kaplan-Meier survival, ROC curve, nomogram, and univariate and multivariate Cox regression analyses were performed to assess the predictive efficiency of the prognostic signature. GSEA and the "CIBERSORT" R package were utilized to further discover the potential biological mechanism of the prognostic signature. Meanwhile, the differential expression of the prognostic signature was verified by western blot, qRT-PCR and immunohistochemical staining derived from the HPA. Ultimately, we constructed a prognostic signature in HCC based on a combination of six glycosyltransferases, whose prognostic value was evaluated and validated successfully in the testing cohort and the validation cohort. The prognostic signature was identified as an independent unfavourable prognostic factor for OS, and a nomogram including the risk score was established and showed the good performance in predicting OS. Further analysis of the underlying mechanism revealed that the prognostic signature may be potentially associated with metabolic disorders and tumour-infiltrating immune cells.


Prognostic Relevance and Function of MSX2 in Colorectal Cancer.
Colorectal cancer patients with diabetes had the high risks of total mortality. High expression of MSX2 is related to development of diabetes. There are few reports about the clinical implications and function of MSX2 in colorectal cancer (CRC). The purpose of this study is to investigate the relationship between the expression of MSX2 and clinical relevance and discover the possible mechanism of MSX2 in the development of CRC. Compared with adjacent tissues, the expression of MSX2 was higher in tumor tissues in both mRNA and protein levels (P < 0.01). Kaplan-Meier survival analysis showed that high mRNA expression of MSX2 was associated with short survival time (P = 0.013). Chi-squared test analysis indicated that MSX2 expression was related to tumor size (P = 0.04), tumor locus (P = 0.025), clinical stage (P < 0.001), tumor invasion (P = 0.003), lymphatic metastasis (P = 0.01), and distant metastasis (P = 0.033). In vitro experiments demonstrated that knockdown of MSX2 expression attenuated cell proliferation and invasion, promoted cell cycle arrest and apoptosis, and inactivated Akt phosphorylation. In conclusion, MSX2 played a crucial role in the progression of CRC and may be a potential novel prognostic factor and therapeutic target for CRC therapy. Our work may provide certain enlightenment for investigating the mechanism of MSX2 in the process of diabetes.


Identifying a Lung Stem Cell Subpopulation by Combining Single-Cell Morphometrics, Organoid Culture, and Transcriptomics.
Single-cell RNA sequencing is a valuable tool for dissecting cellular heterogeneity in complex systems. However, it is still challenging to estimate the proliferation and differentiation potentials of subpopulations within dormant tissue stem cells. Here, we established a new single-cell analysis method for profiling the organoid-forming capacity and differentiation potential of tissue stem cells to disclose stem cell subpopulations by integrating single-cell morphometrics, organoid-forming assay, and RNA sequencing, a method named scMORN. To explore lung epithelial stem cells, we initially developed feeder-free culture system, which could expand all major lung stem cells, including basal, club, and alveolar type 2 (AT2) cells, and found that club cells contained a subpopulation, which showed better survival rate and high proliferation capacity and could differentiate into alveolar cells. Using the scMORN method, we discovered a club cell subpopulation named Muc5b+ and large club (ML-club) cells that efficiently formed organoids than other club or AT2 cells in our feeder-free organoid culture and differentiated into alveolar cells in vitro. Single-cell transcriptome profiling and immunohistochemical analysis revealed that ML-club cells localized at the intrapulmonary proximal airway and distinct from known subpopulations of club cells such as BASCs. Furthermore, we identified CD14 as a cell surface antigen of ML-club cells and showed that purified CD14+ club cells engrafted into injured mouse lungs had better engraftment rate and expansion than other major lung stem cells, reflecting the observations in organoid culture systems. The scMORN method could be adapted to different stem cell tissues to discover useful stem-cell subpopulations.


Chondrocyte death in mechanically injured articular cartilage--the influence of extracellular calcium.
Calcium is thought to be an important regulator of chondrocyte death associated with articular cartilage injury. Our objective was to determine the influence of extracellular calcium on chondrocyte death following mechanical injury. Using a surgically relevant model of sharp mechanical injury (with a scalpel) and confocal laser scanning microscopy (CLSM), in situ chondrocyte death was quantified within the full thickness of articular cartilage as a function of medium calcium concentration and time (2.5 h and 7 days). Exposure of articular cartilage to calcium-free media (approximately 0 mM) significantly reduced superficial zone chondrocyte death after mechanical injury compared with exposure to calcium-rich media (2-20 mM, ANOVA at 2.5 h, p = 0.002). In calcium-rich media, although the extent of chondrocyte death increased with increasing medium calcium concentration, cell death remained localized to the superficial zone of articular cartilage over 7 days (ANOVA, p < 0.05). However, in calcium-free media, there was an increase in chondrocyte death within deeper zones of articular cartilage over 7 days. The early (within hours) chondroprotective effect in calcium-free media suggests that the use of joint irrigation solutions without added calcium may decrease chondrocyte death from mechanical injury during articular surgery. The delayed (within days) increase in chondrocyte death in calcium-free media supports the use of calcium supplementation in media used during cartilage culture for tissue engineering or transplantation.


Challenges and success in periodontal plastic surgery.
To truly understand a field of study, one must delve into its past and examine the challenges and successes that have shaped its current practices. In the case of periodontal plastic surgery, recognizing how challenges induced changes over the last 70 years-from the 1950s to today-is essential to fully comprehend its evolution. This editorial provides a perspective on the field, highlighting the interrelationships between influential surgical techniques and advancements in research methodology. With each event building upon the last, the evolution of periodontal plastic surgery is a story of scientific progress and ongoing research, fostering a sense of community and shared knowledge.


Brucella abortus Senses the Intracellular Environment through the BvrR/BvrS Two-Component System, Which Allows B. abortus To Adapt to Its Replicative Niche.
Brucella abortus is a facultative extracellular-intracellular pathogen belonging to a group of Alphaproteobacteria that establishes close interactions with animal cells. This bacterium enters host cells in a membrane-bound compartment, avoiding the lysosomal route and reaching the endoplasmic reticulum through the action of the type IV secretion system, VirB. In this work, we demonstrate that the BvrR/BvrS two-component system senses the intracellular environment to mount the transcriptional response required for intracellular life adaptation. By combining a method to purify intracellularly extracted bacteria with a strategy that allows direct determination of BvrR phosphorylation, we showed that upon entrance to host cells, the regulatory protein BvrR was activated (BvrR-P) by phosphorylation at aspartate 58. This activation takes place in response to intracellular cues found in early compartments, such as low pH and nutrient deprivation. Furthermore, BvrR activation was followed by an increase in the expression of VjbR and VirB. The in vitro activation of this BvrR-P/VjbR/VirB virulence circuit rescued B. abortus from the inhibition of intracellular replication induced by bafilomycin treatment of cells, demonstrating the relevance of this mechanism for intracellular bacterial survival and replication. All together, our results indicate that B. abortus senses the transition from the extracellular to the intracellular milieu through BvrR/BvrS, allowing the bacterium to transit safely to its replicative niche. These results serve as a working model for understanding the role of this family of two-component systems in the adaptation to intracellular life of Alphaproteobacteria.


Evaluation of pathogenesis caused in cattle and guinea pig by a Mycobacterium bovis strain isolated from wild boar.
In many regions of the world, wild mammals act as reservoir of Mycobacterium bovis, a situation that prevents the eradication of bovine tuberculosis. In order to observe whether a strain isolated from a wild boar, previously tested as highly virulent in a mice model, is also virulent in cattle, we performed cattle experimental inoculation with this strain Groups of Friesian calves were either infected with the wild boar strain M. bovis 04-303 or with the bovine strain NCTC10772 as a control. We found that antigen-specific IFN-γ release in whole blood samples occurred earlier in animals infected with M. bovis 04-303. Both M. bovis strains resulted in a positive skin test, with animals infected with the wild boar isolate showing a stronger response. These results and the presence of more severe organ lesions, with granuloma and pneumonic areas in cattle demonstrate that the wild boar isolate is more virulent than the NCTC10772 strain. Additionally, we tested the infectivity of the M. bovis strains in guinea pigs and found that M. bovis 04-303 had the highest pathogenicity. M. bovis strains isolated from wild boars may be pathogenic for cattle, producing TB lesions.


Diagnosis and management of metatarsal fractures.
Patients with metatarsal fractures often present to primary care settings. Initial evaluation should focus on identifying any conditions that require emergent referral, such as neurovascular compromise and open fractures. The fracture should then be characterized and treatment initiated. Referral is generally indicated for intra-articular or displaced metatarsal fractures, as well as most fractures that involve the first metatarsal or multiple metatarsals. If the midfoot is injured, care should be taken to evaluate the Lisfranc ligament. Injuries to this ligament require referral or specific treatment based on severity. Nondisplaced fractures of the metatarsal shaft usually require only a soft dressing followed by a firm, supportive shoe and progressive weight bearing. Stress fractures of the first to fourth metatarsal shafts typically heal well with rest alone and usually do not require immobilization. Avulsion fractures of the proximal fifth metatarsal tuberosity can usually be managed with a soft dressing. Proximal fifth metatarsal fractures that are distal to the tuberosity have a poorer prognosis. Radiographs should be carefully examined to distinguish these fractures from tuberosity fractures. Treatment of fractures distal to the tuberosity should be individualized based on the characteristics of the fracture and patient preference. Nondisplaced fractures of the proximal portion of metatarsals 1 through 4 can be managed acutely with a posterior splint followed by a molded, non-weight-bearing, short leg cast. If radiography reveals a normal position seven to 10 days after injury, progressive weight bearing may be started, and the cast may be removed three to four weeks later.


Mixotrophy in Pyroleae (Ericaceae) from Estonian boreal forests does not vary with light or tissue age.
In temperate forests, some green plants, namely pyroloids (Pyroleae, Ericaceae) and some orchids, independently evolved a mode of nutrition mixing photosynthates and carbon gained from their mycorrhizal fungi (mixotrophy). Fungal carbon is more enriched in 13C than photosynthates, allowing estimation of the proportion of carbon acquired heterotrophically from fungi in plant biomass. Based on 13C enrichment, mixotrophic orchids have previously been shown to increase shoot autotrophy level over the growth season and with environmental light availability. But little is known about the plasticity of use of photosynthetic versus fungal carbon in pyroloids. Plasticity of mixotrophy with leaf age or light level (estimated from canopy openness) was investigated in pyroloids from three Estonian boreal forests. Bulk leaf 13C enrichment of five pyroloid species was compared with that of control autotrophic plants along temporal series (over one growth season) and environmental light gradients (n=405 samples). Mixotrophic 13C enrichment was detected at studied sites for Pyrola chlorantha and Orthilia secunda (except at one site for the latter), but not for Chimaphila umbellata, Pyrola rotundifolia and Moneses uniflora. Enrichment with 13C did not vary over the growth season or between leaves from current and previous years. Finally, although one co-occurring mixotrophic orchid showed 13C depletion with increasing light availability, as expected for mixotrophs, all pyroloids responded identically to autotrophic control plants along light gradients. A phylogenetic trend previously observed is further supported: mixotrophy is rarely supported by 13C enrichment in the Chimaphila + Moneses clade, whereas it is frequent in the Pyrola + Orthilia clade. Moreover, pyroloid mixotrophy does not respond plastically to ageing or to light level. This contrasts with the usual view of a convergent evolution with orchids, and casts doubt on the way pyroloids use the carbon gained from their mycorrhizal fungi, especially to replace photosynthetic carbon.


Epstein-Barr virus infection and the pathogenesis of malignant lymphomas.
EBV is associated with an ever increasing number of human malignancies, which illustrates the importance of understanding how the virus contributes to tumorigenesis. Recent work has identified as set of EBV latent proteins that are indispensable for B cell transformation in vitro, and possible mechanisms of action are beginning to emerge for some of these proteins. In addition to viral gene expression, host factors appear to be involved in the development of virus associated tumours. Firstly, virus specific immunity is important for preventing the outgrowth of EBV associated tumours. Disturbances of EBV specific immunosurveillance can occur as a consequence of systemic immunosuppression or due to local factors, some of which may directly or indirectly result from the expression of EBV genes. Secondly, the phenotype of virus infected cells seems to be important. Thus, many EBV associated tumours appear to arise from cell types that do not represent a "physiological" target for the virus and thus may not be adapted to establishing asymptomatic persistent EBV infection. Furthermore, the function of transformation associated viral gene products may vary according to the cellular phenotype.


Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA).
The C-5 substituted 2,4-diaminoquinazoline RG3039 (compound 1), a member of a chemical series that was identified and optimized using an SMN2 promoter screen, prolongs survival and improves motor function in a mouse model of spinal muscular atrophy (SMA). It is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS), but the mechanism whereby DcpS inhibition leads to therapeutic benefit is unclear. Compound 1 is a dibasic lipophilic molecule that is predicted to accumulate in lysosomes. To understand if the in vivo efficacy is due to DcpS inhibition or other effects resulting from the physicochemical properties of the chemotype, we undertook structure based molecular design to identify DcpS inhibitors with improved physicochemical properties. Herein we describe the design, synthesis, and in vitro pharmacological characterization of these DcpS inhibitors along with the in vivo mouse CNS PK profile of PF-DcpSi (compound 24), one of the analogs found to be efficacious in SMA mouse model.


Ophidiomycosis surveillance of snakes in Georgia, USA reveals new host species and taxonomic associations with disease.
Ophidiomycosis (snake fungal disease) is caused by the fungus Ophidiomyces ophiodiicola and threatens snake health worldwide. It has been documented throughout the eastern United States and severe cases have recently been reported in Georgia, USA. To evaluate disease distribution and prevalence in this state, 786 free-ranging snakes were examined for skin lesions consistent with ophidiomycosis and swabbed to detect O. ophiodiicola DNA using qPCR. Sampled snakes represented 34 species and 4 families; 27.5% had skin lesions, 13.3% were positive for O. ophiodiicola DNA, and 77.8% of the qPCR positive individuals had skin lesions. This is the first report of O. ophiodiicola in five of the 22 species that were qPCR positive. Multinomial logistic regression modeling indicated that Drymarchon couperi had a higher relative risk of apparent ophidiomycosis (lesions present and qPCR positive), and the best models predicting qPCR result and ophidiomycosis category included individual factors and excluded temporal and spatial factors. Phylogeny-based bipartite network analysis showed that Nerodia erythrogaster, Nerodia taxispilota, and D. couperi had the highest prevalence of apparent ophidiomycosis; this category was more prevalent in the subfamily Colubrinae and less prevalent in Natricinae. These results provide important information about ophidiomycosis epidemiology, which has implications for snake conservation.


Direct Synthesis of Ultrathin Pt Nanowire Arrays as Catalysts for Methanol Oxidation.
High-performance electrocatalysts are of critical importance for fuel cells. Morphological modulation of the catalyst materials is a rare but feasible strategy to improve their performance. In this work, Pt nanowire arrays are directly synthesized with a template-less wet chemical method. The effects of surface functionalization and the reduction kinetics are revealed to be vital to the nanowire growth. The growth mechanism of the Pt nanowires is studied. By adjusting the concentration of the organic ligands, Pt nanowire arrays with tunable surface roughness can be obtained on various substrate surfaces. Such arrays avoid the contact resistance of randomly packed particles and allow open diffusion channels for reactants and products alike, making them excellent electrocatalysts for the methanol oxidation reaction. In particular, Pt nanowire arrays with rough surface have a mass activity of 1.24 A mgPt -1 at 1.12 V (vs Ag/AgCl), 3.18-fold higher than that of the commercial Pt/C catalysts. It also shows more resistant against poisoning, as indicated by the higher If /Ib ratio (2.06), in comparison to the Pt/C catalysts (1.30).


Hyperactivation of nuclear receptor coactivators induces PERK-dependent cell death.
Nuclear receptor coactivators (NCOAs) function as coactivators for nuclear receptors as well as several other transcription factors and potentiate their transcriptional activity. NCOAs play an important role in biology of hormone-dependent and -independent cancers. MCB-613 is a recently described, small molecule stimulator of NCOAs and anti-neoplastic compound that leads to the death of tumour cells due to increased cellular stress. In the present study we investigated the molecular mechanism of MCB-613-induced cell death. We report that absence of NCOA3 leads to compromised activation of PERK signalling pathway during unfolded protein response (UPR). We found that chemical and genetic inhibition of NCOA3 attenuated the expression of PERK at mRNA and protein level. We show that loss of NCOA3 renders cells hypersensitive to UPR induced cell death. Our results show that MCB-613 induced cell death is attenuated in NCOA3 knockout HeLa cells and MCB-613 leads to enhanced PERK signalling in wild-type HeLa cells. The knockdown of PERK provides resistance to MCB-613 mediated cell death while knockdown of XBP1 and ATF6 have no such effect. Our results suggest that hyperstimulation of NCOA3 by MCB-613 induces cell death by evoking constitutive PERK signalling. Taken together our results point to NCOA3 as an important determinant in regulating cell fate during ER stress, with too little and too much NCOA3 both producing deleterious effects.


Perioperative issues due to long-standing lung collapse during repair of a large ascending aortic aneurysm.
Acute lung collapse during open-heart surgery may potentially lead to problems such as inadequate gas exchange, increased pulmonary vascular resistance, increased afterload to the right ventricle, and difficulty in weaning from cardiopulmonary bypass (CPB). Therefore, expansion of the lungs is ensured prior to separation from CPB. We report the inability to manually expand a chronically collapsed lung during the repair of ascending aortic aneurysm. The collapsed lung did not pose difficulty in separation from CPB and in blood gas management during the perioperative period. We discuss perioperative management issues in such situations.


A Longitudinal Study of Adherence to the Mediterranean Dietary Pattern and Metabolic Syndrome in a Non-Mediterranean Population.
Adherence to the Mediterranean diet (MedDiet) has been proposed to reduce the risk of metabolic syndrome (MetS), but the association of the diet on MetS in non-Mediterranean populations remains unclear. The aim of this study was to investigate whether adherence to the MedDiet is related to the incident MetS and its components during a 3-year follow-up among Iranian adults. Longitudinal associations between the MedDiet and MetS components were investigated on 2241 adults, aged 18 - 74 years, without type 2 diabetes selected from participants of the Tehran lipid and glucose study (TLGS). The association between the MedDiet and MetS incidence was also examined in 1661 participants, free of Mets at baseline. Adherence to the MedDiet was assessed using the traditional Mediterranean diet score (MDS) and a recently posteriori adaptation of the MDS of Sofi et al. (Sofi-MDS). MetS was defined according to the recent interim consensus. After adjusting for potential confounders, neither higher MDS nor higher Sofi-MDS were significantly associated with the mean values of MetS components and the risk of metabolic abnormalities incidence after 3 years follow-up. During the 3 years of follow-up, 246 developed MetS were identified. In multivariable model, the adjusted odds ratio (OR) of developing MetS did not differ significantly in participants with the highest tertile of the MDS (OR (95% CI): 0.88 (0.62 - 1.23)) or sofi-MDS (OR (95% CI):1.12 (0.77 - 1.62)) compared to those in the lowest tertiles. Adherence to the MedDiet, according to MDS and Sofi-MDS, may not predict MetS components and MetS incidence after 3 years of follow-up in Iranian adult populations.


Discovery of Novel Potent Covalent Glutathione Peroxidase 4 Inhibitors as Highly Selective Ferroptosis Inducers for the Treatment of Triple-Negative Breast Cancer.
Glutathione peroxidase 4 (GPX4) is a promising target to induce ferroptosis for the treatment of triple-negative breast cancer (TNBC). We designed and synthesized a novel series of covalent GPX4 inhibitors based on RSL3 and ML162 by structural integration and simplification strategies. Among them, compound C18 revealed a remarkable inhibitory activity against TNBC cells and significantly inhibited the activity of GPX4 compared to RSL3 and ML162. Moreover, it was identified that C18 could notably induce ferroptosis with high selectivity by increasing the accumulation of lipid peroxides (LPOs) in cells. Further study demonstrated that C18 covalently bound to the Sec46 of GPX4. Surprisingly, C18 exhibited an outstanding potency of tumor growth inhibition in the MDA-MB-231 xenograft model with a TGI value of 81.0%@20 mg/kg without obvious toxicity. Overall, C18 could be a promising GPX4 covalent inhibitor to induce ferroptosis for the treatment of TNBC.


Tachycardia increases NADPH oxidase activity and RyR2 S-glutathionylation in ventricular muscle.
We have shown previously that electrically induced tachycardia effectively produces myocardial preconditioning. Among other effects, tachycardia increases calcium release rates in microsomal fractions enriched in sarcoplasmic reticulum (SR) isolated from dog cardiac ventricular muscle. Here, we report that preconditioning tachycardia increased twofold the NADPH oxidase activity of isolated SR-enriched microsomal fractions, measured as NADPH-dependent generation of superoxide anion and hydrogen peroxide. Tachycardia also augmented the association of rac1 and the NADPH oxidase cytosolic subunit p47(phox) to the microsomal fraction, without modifying the content of the membrane integral subunit gp91(phox). Microsomes from control animals displayed endogenous S-glutathionylation of cardiac ryanodine receptors (RyR2); in microsomal fractions isolated after tachycardia RyR2 S-glutathionylation levels were 1.7-fold higher than in controls. Parallel in vitro experiments showed that NADPH produced a transient increase in calcium release rates and enhanced 1.6-fold RyR2 S-glutathionylation in control microsomes but had marginal or no effects on microsomes isolated after tachycardia. Catalase plus superoxide dismutase, and the NADPH oxidase inhibitors apocynin and diphenyleneiodonium prevented the in vitro stimulation of calcium release rates and RyR2 S-glutathionylation induced by NADPH, suggesting NADPH oxidase involvement. Conversely, addition of reducing agents to vesicles incubated with NADPH markedly inhibited calcium release and prevented RyR2 S-glutathionylation. We propose that tachycardia stimulates NADPH oxidase activity, which by enhancing RyR2 redox modifications such as S-glutathionylation, would contribute to sustain faster calcium release rates during conditions of increased cardiac activity. This response may be an important component of tachycardia-induced preconditioning.


[Surgical treatment for locally advanced lung cancer; therapeutic response of induction chemotherapy and postoperative chemotherapy].
The current chemotherapy has been able to give us many options to treat for lung cancer and recent studies have showed that perioperative chemotherapy may improve survival. In this study, we compared 2 groups with locally advanced lung cancers (stage III, T3N0M0, inclusive of ipsilateral PM2, D1 and D2) ; group A, which had been treated by chemotherapy for downstaging prior to surgery (n = 23), and group B, which had been treated by surgery alone (n = 48). The postoperative 3- and 5-year overall survival rates analyzed using the Kaplan-Meier method were 64.7 and 29.4% for group A, 32.5 and 10% for group B, respectively. And there was a significant difference between 2 groups. Further on patients with pN2, 3-year survival rate was 60% for group A and 36.7% for group B. In view of the progress of chemotherapy, even if the locally advanced lung cancer, which may be suspected of invasion to pulmonary artery, pulmonary vein and central bronchus, is not classified as T4, a patient with it should be performed an induction chemotherapy for downstaging and an operation for complete resection of the tumor and preserving lung function.


Stability and flexibility in the structure of the hyperthermophile DNA-binding protein Sac7d.
Sac7d is a chromatin protein from the hyperthermophile Sulfolobus acidocaldarius that severely kinks duplex DNA with negligible change in protein structure. In previous work, the overall stability of Sac7d has been well-characterized with a global analysis of the linkage of folding, protonation, and anion binding. We extend that work here with NMR measurements of global stability as well as the distribution of stability and flexibility in the solution structure. Native state amide hydrogen exchange has been used to identify the most-protected core amide protons which exchange through global unfolding. The pH and temperature dependence of stability defined by native state exchange is in excellent agreement with the free energy surface determined by a linkage analysis of the dependence of folding on pH, salt, and temperature. These results confirm that the deltaC(P) obtained from a Kirchhoff analysis of DSC data (i.e., deltaH vs Tm) is incorrect, and an accurate description of the protein stability curve for Sac7d requires a measure of the thermodynamic contributions of protonation and anion binding. Amide hydrogen exchange, along with generalized order parameters determined by 15N relaxation data, demonstrates considerable variation in stability throughout the structure with some of the least stable regions occurring at the N- and C-termini. The most stable and inflexible region of the backbone occurs primarily in the DNA-binding beta-sheet which is responsible for bending DNA.


A phenomenological perspective on preceptorship in the intergenerational context.
Pairing a student with an experienced nurse through preceptorship is an approach to teaching/learning that promotes critical thinking, cultivates practical wisdom, and facilitates competence. Frequently, nursing students are of a different generation than their assigned preceptors and differences in worldviews and expectations can impact upon the success of preceptorship. A phenomenological study, guided by van Manen's approach to human science research, was conducted to explore preceptorship within this intergenerational context. Data were generated using unstructured interviews with a purposive sample of seven preceptors and seven students recruited from an undergraduate nursing program. The findings reveal three main themes: being affirmed, being challenged, and being on a pedagogical journey. The findings of this study have the potential to enhance generational understanding in the pedagogical context and foster a teaching/learning culture in the clinical practice setting inclusive of divergent generational expectations.


c-Jun expression in single cells and preneoplastic foci induced by diethylnitrosamine in B6C3F1 mice: comparison with the expression of pi-class glutathione S-transferase.
Expression of the oncogene product c-Jun was examined and compared with that of class pi glutathione S-transferase (GST-II) during chemical hepatocarcinogenesis in female and male mice. A single i.p. injection of diethylnitrosamine (DEN) (10 mg/kg) was administered to B6C3F1 mice and livers were immunohistochemically investigated with anti-c-Jun and anti-GST-II antibodies at various time points thereafter. In females, almost all foci detected by hematoxylin and eosin staining were positive for c-Jun 3, 6, 9 and 11 months after the DEN administration. Seventy-one and 82% of c-Jun-positive foci at 9 and 11 months respectively, were also positive for GST-II, while this was the case for only 15% at 6 months. In males almost all foci were also positive for c-Jun at 3 and 6 months, but 23% of foci were negative at 9 months. Unlike the foci in females, 96 and 79% of those in males expressing c-Jun were negative for GST-II at 6 and 9 months respectively. Both GST-II expression in foci of females and its lack in those of males were highly correlated with c-Jun expression. Furthermore, single cells expressing c-Jun were also observed in both sexes at 3 months and thereafter, but not at 2 or 4 weeks. Alterations in the numbers of c-Jun-positive single cells, minifoci and foci followed sequentially revealed the number of such single cells to decrease, while foci increased, the sum being relatively constant. On the other hand, while a large number of GST-II-positive single cells were detected in female livers 2 and 4 weeks after the DEN administration, they markedly decreased thereafter, suggesting that the majority were unlikely to give rise to foci. Thus, c-Jun may be a better positive marker not only for preneoplastic foci, but also putative precursor single cells in both female and male mice and therefore be useful for analysis of hepatocarcinogenic processes.


Differential ANG II generation in plasma and tissue of mice with decreased expression of the ACE gene.
We utilized mice with homozygous disruption of angiotensin-converting enzyme (ACE) (-/-), mice with heterozygous deletion of ACE (+/-), and wild-type mice (+/+) to test the hypothesis that genetic variation in ACE modulates tissue and plasma angiotensin (ANG) II concentrations. With the use of ANG I as substrate, kidney, heart, and lung ACE activity was reduced 80% in -/- mice compared with +/+ mice. However, ANG II concentrations and ANG II-to-ANG I ratios in the kidney, heart, and lung did not differ among genotypes. In contrast, plasma ANG II concentrations in -/- mice were <2 fmol/ml, whereas plasma ANG I concentrations were extremely high (765 fmol/ml). Chymase activity was increased 14-fold in the kidney (P < 0.05) and 1.5-fold in the heart (P < 0.05) of -/- versus +/+ mice but did not differ among genotypes in the lung. ANG II formation from enzymes other than ACE and chymase contributed <2% of total ANG II formation in all genotypes. These data suggest that ACE is essential to ANG II formation in the vascular space, whereas chymase may provide an important mechanism in maintaining steady-state ANG II levels in tissue.


Designing Probes for Immunodiagnostics: Structural Insights into an Epitope Targeting Burkholderia Infections.
Structure-based epitope prediction drives the design of diagnostic peptidic probes to reveal specific antibodies elicited in response to infections. We previously identified a highly immunoreactive epitope from the peptidoglycan-associated lipoprotein (Pal) antigen from Burkholderia pseudomallei, which could also diagnose Burkholderia cepacia infections. Here, considering the high phylogenetic conservation within Burkholderia species, we ask whether cross-reactivity can be reciprocally displayed by the synthetic epitope from B. cenocepacia. We perform comparative analyses of the conformational preferences and diagnostic performances of the corresponding epitopes from the two Burkholderia species when presented in the context of the full-length proteins or as isolated peptides. The effects of conformation on the diagnostic potential and cross-reactivity of Pal peptide epitopes are rationalized on the basis of the 1.8 Å crystal structure of B. cenocepacia Pal and through computational analyses. Our results are discussed in the context of designing new diagnostic molecules for the early detection of infectious diseases.


[Tumors of the upper urinary tract in patients following bladder tumors: multicentric locations or seeding? Apropos of 14 cases].
The occurrence of upper urinary tract tumors has been studied in 479 patients followed for bladder cancer: The incidence rate is low (2.9%) but increases with time (mean: 58 months). Some patients are more exposed: those who underwent repeated transurethral resections of Ta-T1 multifocal bladder carcinoma. Retrograde and voiding cystourethrogram seems to be useful to select a group "at risk" during the follow-up of patients with bladder tumors treated by endoscopic resection: a yearly excretory urography for upper urinary tract survey should then be performed.


Alternated intra-arterial and intravitreal chemotherapy for advanced intraocular retinoblastoma: preliminary successful results without systemic chemotherapy.
To describe the efficacy of intravitreal chemotherapy (IViC) preceded by intra-arterial chemotherapy (IAC) for the treatment of advanced stage retinoblastoma. This non-comparative interventional case series retrospectively reviewed the medical records of six patients who presented within months of each other with unilateral retinoblastoma, Reese-Ellsworth stage Vb/D of ABC classification in the affected eye. After clinical and ophthalmoscopic evaluation, they underwent MRI to exclude local and CNS dissemination. The IAC was given to treat retinal masses and intravitreal injections to treat vitreous seeding. Patients had received two cycles (six infusions) of IAC, and from six up to ten melphalan injections into the vitreous, with an interval of 7-10 days between them. From one to four intravitreal injections were performed for partial remission or consolidation. No permanent complications of procedures have been reported. All patients underwent to bimonthly MRI examination, during treatment and every 3 months for 1 year after last injection, to exclude orbital dissemination. Successful control (100 %) of tumor masses and vitreous seeds was achieved in all cases at 12 months follow-up. Complications were posterior lens opacity, acute ischemic papillitis, partial CVR thrombosis, hypotonia (case 1), partial vitreous hemorrhage (case 4). No complications appeared in cases 2, 3, 5, and 6. No intraocular or orbital tumor recurrence or retinoblastoma metastases (follow-up range, 12-33 months) were observed. Sequential IAC and intravitreal melphalan for advanced retinoblastoma allowed to provide retinal and vitreous seed control.


Different patterns of hydrophobic protein storage in different forms of neuronal ceroid lipofuscinosis (NCL, Batten disease).
Since the discovery of mitochondrial ATP synthase subunit c storage in different forms of neuronal ceroid lipofuscinosis (NCL, Batten disease), it has been found that other hydrophobic proteins also accumulate in different forms. Costorage of subunit c of vacuolar ATPase is observed in "mnd/mnd" mice and in English Setters, Border Collies and Tibetan Terriers. A small amount is stored in the ovine disease and none in the human late-infantile disease. It is a storage body matrix component. An additional 8 kDa component immunoreactive to vacuolar ATPase subunit c antibodies is found in brain-derived storage bodies. The sphingolipid activator proteins, SAPs A and D, are stored in the human infantile disease and a form in Miniature Schnauzer dogs, but neither of the c subunits are. These results suggest two classes of NCL, the subunit c-storing diseases, related by a series of lesions in a subunit c-turnover pathway, and the SAP-storing diseases.


[Body image and the experience of illness--experience of women with breast cancer].
This phenomenological study aimed at problematizing the living body as experienced by American women who suffered from breast cancer and underwent chemotherapy. Forty-eight interviews were collected from 18 women over a period of six months for another study. A secondary analysis was performed. It centered on the following three questions: 1. How do bodily changes impact on the women's embodied self-understanding? 2. How does bodily subjection to medical treatments illuminate professional and self's relationships to the body? and 3. What kind of knowledge about the body and the illness do the women express? 1. Central in the patients' accounts were experiences of "I cannot" (any more) or "I can" (again). 2. Illness and bodily subjection to medical interventions influenced the women's relationship with their body. Five different patterns of "I"-body-relationships are described. They varied between "I"-body-oneness and "I"-body distance. 3. The women expressed varying levels of knowledge as they talked about bodily experiences and the illness. Vernacular concepts, medical concepts and complex medical knowledge were expressed. The paper emphasizes the existential importance of "I can" or "I cannot" experiences.


Menometrorrhagia of the puberty: therapy with Clomiphene (Clomiphene and puberal menometrorrhagia).
The authors administrated the Clomiphene, in different doses, to 8 patients among 27 observed. These patients were checked for a long time by basal body temperature and in some cases, measuring total urinary estrogens and pregnandioluria. The therapy was administrated in 38 cicles of the 163 cicles observed. This drug got evident results on flux duration, less significant results on the cicle length. The Clomiphene produced ovulatory cicles in 58 per cent of the cases, against 7 per cent of spontaneous ovulatory cicles of the same patients. The drug effect is better in the cases with normo or moderate hypo or hyper estrogenism, not so good in the cases with a remarcable hypoestrogenism. The therapy with Clomiphene did not produce any inconvenient. The results got were put in comparison with those of the other drug (Ciclophenile) and the superiority of Clomiphene was confirmed.


EPR spin trapping of oxygen radicals in plants: a methodological overview.
We present a brief account of the difficulties involved in detection of oxygen free radicals in plants and give a rationale for using the EPR spin trapping technique in such studies. Comparative analysis of characteristics of different spin traps is given, having in mind their suitability in trapping oxygen-centered free radicals. Certain technical aspects of EPR experiments related to successful trapping of free radicals are discussed. Previous studies of trapping of oxygen radicals in plants are reviewed in terms of how efficient the experimental approach employed has been in their detection and how this influences conclusions about the mechanisms of their production. In addition, we analyze the potential of spin labels in the analysis of free radical production in plants and demonstrate that the combination of EPR spin traps and spin labels is extremely efficient for this purpose.


[Ultrastructural changes in the spermatozoa of sheep infected with Brucella ovis].
The semen was studied of four rams of the Mutton Merino, Suffolk, "Kavkazki Merino* breeds and a local crossbred race, affected with infectious epididymitis and having semen deteriorated to a various extent, in order to establish the changes in the ultrastruct of spermatozoa through electron microscopy. The following conclusions were drawn on the basis of the results obtained: 1. The changes caused by Brucella ovis infection in such cases are chiefly concentrated in the head of spermatozoa. Detachment and rupture of the plasmalemma are observed along with the separation of the acrosome and galea capitis, swelling of the nuclear membrane, granulation and break-up of the nuclear matter. 2. The neck of spermatozoa where fast disintegration of the connective substance between it and the head and the complete separation of head and body take place, is slightly resistant. 3. The leucocytes in the semen phagocytize both Brucella organisms and a great number of spermatozoa (autophagocytosis of spermatozoa on a mass scale). The ultrastructure of the spermatozoa breaks up, and the leucocytes are ysed.