Mutations in RNF216 do not cause 4H syndrome.
We comment on the recent publication by Ganos et al. [1] classifying a patient with non-specific white matter abnormalities, cerebellar atrophy, hypogonadotropic hypogonadism and absent lower median incisors as 4H syndrome. He had mutations in RNF216. Mutations in this gene cause Gordon-Holmes syndrome, distinct from 4H syndrome.


Comparison of complete polyprotein sequences of two isolates of salmon alphavirus (SAV) type I and their behaviour in a salmonid cell line.
Salmon pancreas disease virus is an alphavirus (family Togaviridae) affecting mainly Atlantic salmon (Salmo salar L.). Both polyprotein sequences of the Scottish isolate (SAV4640) were determined and compared with those of Irish isolate SAVF93-125. High amino acid sequence similarity (99.4 %) was found. Six amino acid deletions were found in the E2 gene of SAV4640. SAVF93-125 demonstrated a high viral load in culture despite high Mx expression. Approximately 50 % of cells infected with SAVF93-125 exhibited a cytopathic effect by day 8. SAV4640 successfully entered the cells, inducing 10,500-fold higher Mx expression at day 2 compared to SAVF93-25; however, no replication was observed based on results of the nsP1 qRT-PCR.


Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion - preliminary report.
There is little information on the relationship between growth hormone/insulin-like growth factor-I (GH/IGF-I) deficiency or IGF-I treatment on nonalcoholic fatty liver disease (NAFLD) a disorder linked to obesity and insulin resistance. To find out whether the markedly obese patients with Laron syndrome (LS) and GH gene deletion have fatty livers. We studied 11 untreated adult patients with LS (5M, 6F), five girls with LS treated by IGF-I and five adult patients with GH gene deletion (3M, 3F), four previously treated by hGH in childhood. Fatty liver was quantitatively evaluated by ultrasonography using a phase array US system (HITACHI 6500, Japan). Body adiposity was determined by DEXA, and insulin resistance was estimated by HOMA-IR using the fasting serum glucose and insulin values. Six out of 11 adult patients with LS, two out of the five IGF-I treated girls with LS and three out of five adult hGH gene deletion patients were found to have NAFLD (nonalcoholic fatty liver disease). NAFLD is a frequent complication in untreated and treated congenital IGF-I deficiency. No correlation between NAFLD and age, sex, degree of obesity, blood lipids, or degree of insulin resistance was observed.


Expression at the cell surface of native fusion protein of the Newcastle disease virus (NDV) strain Italien from cloned cDNA.
A cDNA library was constructed with poly(A)+-mRNAs from NDV-Italien infected BHK-21 cells. A clone, that hybridized to the F gene mRNA, was sequenced. A long open reading frame encodes for a protein of 553 amino acids, with a calculated molecular weight of 59,153, consisting of twelve cysteine residues and six potential glycosylation sites. The protein sequence contains a hydrophobic region at the N-terminus of F1 and a presumptive long transmembrane fragment near the C-terminus. Comparison of the F proteins from NDV strains Italien and Australia-Victoria shows that the sequences are very similar, with conservation of most cysteine residues and of the potential glycosylation sites. The F coding sequence was inserted into the genome of vaccinia virus under the control of vaccinia P7.5 transcriptional regulatory sequences. Expression of F protein was demonstrated by indirect immunofluorescence with five anti-F monoclonal antibodies known to react with conformational epitopes.


Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma.
We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1-specific CD+8 and CD4+ T cells. Metastatic melanoma patients received 3 injections of 10(6) or 10(7) DCs, delivered intradermally. Cell surface phenotype and cytokine production of the DCs used for the vaccines were tested, and indicated intermediate maturity. CD8+ T-cell responses to MART-1 27-35 were assessed by both major histocompatibility complex class I tetramer and interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) before, during, and after each vaccine and CD4+ T-cell responses to MART-1 51-73 were followed by IFN-gamma ELISPOT. We also measured antigen response breadth. Determinant spreading from the immunizing antigen MART-1 to other melanoma antigens [gp100, tyrosinase, human melanoma antigen-A3 (MAGE-A3)] was assessed by IFN-gamma ELISPOT. Twenty-three patients were enrolled and 14 patients received all 3 scheduled DC vaccines. Significant CD8+ and/or CD4+ MART-1-specific T-cell responses were observed in 6/11 and 2/4 patients evaluated, respectively, indicating that the E1-deleted adenovirus encoding the cDNA for MART-1/Melan-A (AdVMART1)/DC vaccine activated both helper and killer T cells in vivo. Responses in CD8+ and CD4+ T cells to additional antigens were noted in 2 patients. The AdVMART1-transduced DC vaccine was safe and immunogenic in patients with metastatic melanoma.


The key roles of reactive oxygen species in microglial inflammatory activation: Regulation by endogenous antioxidant system and exogenous sulfur-containing compounds.
Aberrant innate immunity in the brain has been implicated in the pathogenesis of several central nervous system (CNS) disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and depression. Except for extraparenchymal CNS-associated macrophages, which predominantly afford protection against peripheral invading pathogens, it has been reported that microglia, a population of macrophage-like cells governing CNS immune defense in nearly all neurological diseases, are the main CNS resident immune cells. Although microglia have been recognized as the most important source of reactive oxygen species (ROS) in the CNS, ROS also may underlie microglial functions, especially M1 polarization, by modulating redox-sensitive signaling pathways. Recently, endogenous antioxidant systems, including glutathione, hydrogen sulfide, superoxide dismutase, and methionine sulfoxide reductase A, were found to be involved in regulating microglia-mediated neuroinflammation. A series of natural sulfur-containing compounds, including S-adenosyl methionine, S-methyl-L-cysteine, sulforaphane, DMS, and S-alk(enyl)-l-cysteine sulfoxide, modulating endogenous antioxidant systems have been discovered. We have summarized the current knowledge on the involvement of endogenous antioxidant systems in regulating microglial inflammatory activation and the effects of sulfur-containing compounds on endogenous antioxidant systems. Finally, we discuss the possibilities associated with compounds targeting the endogenous antioxidant system to treat neuroinflammation-associated diseases.


Quantitative determination of kinins released by trypsin using enzyme-linked immunosorbent assay (ELISA) and identification by high-performance liquid chromatography (HPLC).
Rapid ELISA and HPLC procedures were developed for quantitation and identification of various natural kinins. Antibradykinin mouse monoclonal antibodies were used to determine kinin levels in the range of 20-200 ng. Bradykinin coupled to bovine serum albumin was used to coat the plates in a 3- to 4-hr ELISA. Synthetic kinin standards isoleucine-seryl-bradykinin (Ileu-Ser-BK), methionyl-lysyl-bradykinin (Met-Lys-BK), tyrosine-bradykinin (Tyr-BK) and bradykinin (BK) yielded almost identical curves with a mixture of A5 and D9 monoclonal antibodies. [Tyr5]-BK, [Tyr8]-BK and des-arginine9 bradykinin (des-Arg9-BK) showed negligible amounts of cross-reactivity. ELISA-compatible trypsin digestion developed for release of kinins from plasma of normal humans, rats and turpentine-treated rats gave values of 3.2, 6.9 and 70 micrograms/ml plasma, respectively. High performance liquid chromatography methods were developed for complete resolution of kinins on a C-18 reversed phase mu-Bondapak column before and after derivatization with phenyl isothiocyanate (PITC). The simple PITC derivatization procedure yielded good quantitation above 20 pmol. The ELISA and HPLC methods were used in a complementary fashion to assay and identify kinins in biological fluids as well as during the course of kininogen purification.


Mesenchymal stem cells attenuate ischemic acute kidney injury by inducing regulatory T cells through splenocyte interactions.
The mechanism of mesenchymal stem cell therapy in acute kidney injury remains uncertain. Previous studies indicated that mesenchymal stem cells could attenuate inflammation-related organ injury by induction of regulatory T cells. Whether regulatory T-cell induction is a potential mechanism of mesenchymal stem cell therapy in ischemic acute kidney injury and how these induced regulatory T cells orchestrate local inflammation are unknown. Here we found that mesenchymal stem cells decrease serum creatinine and urea nitrogen levels, improve tubular injury, and downregulate IFN-γ production of T cells in the ischemic kidney. In addition to the lung, mesenchymal stem cells persisted mostly in the spleen. Mesenchymal stem cells increased the percentage of regulatory T cells in the spleen and the ischemic kidney. Antibody-dependent depletion of regulatory T cells blunted the therapeutic effect of mesenchymal stem cells, while coculture of splenocytes with mesenchymal stem cells caused an increase in the percentage of regulatory T cells. Splenectomy abrogated attenuation of ischemic injury, and downregulated IFN-γ production and the induction of regulatory T cells by mesenchymal stem cells. Thus, mesenchymal stem cells ameliorate ischemic acute kidney injury by inducing regulatory T cells through interactions with splenocytes. Accumulated regulatory T cells in ischemic kidney might be involved in the downregulation of IFN-γ production.


Individualized surgical management of complete atrioventricular canal.
In a 5 year interval 46 children with complete atrioventricular canal (CAVC) required 51 operations. Thirty-two children underwent correction; nine received surgical palliation. The ages of the children undergoing correction ranged from 4 months to 14.6 years (mean 4.2 years); eight were less than 1 year old. Weights ranged from 4.1 kg to 39 kg (mean 13.5 kg); 15 weighted less than 10 kg. Ten had undergone previous palliation (seven by pulmonary artery band; three by shunt). There were no early deaths and two late deaths. One infant required mitral replacement at correction; two required subsequent mitral replacement. The ages of the children undergoing palliation ranged from 8 days to 1.34 years (mean 5.8 months); 16 were less than 1 year old. Weights ranged from 2.5 kg to 8.5 kg (mean 4.4 kg); 14 weighted less than 5 kg. Operations included pulmonary artery banding in 14, shunt creation in four, and pericardial enlargement of the right ventricular outflow tract in one. One death occurred 5 days after pulmonary artery banding in an infant with unrecognized coarctation. One late death occurred several months after the creation of a second shunt in a child with severe tetralogy of Fallot and hypoplastic pulmonary arteries. Forty-two (91%) of these children were alive at the time of this review. The outcome in these 46 patients supports individualized choice of initial operation (palliation versus correction) based upon clinical condition, weight, and associated anomalies. The pulmonary artery is banded in infants less than 4 to 5 kg; larger infants and children undergo correction primarily.


Oral ofloxacin as treatment of malignant external otitis: a study of 17 cases.
Seventeen patients with malignant external otitis were treated with oral ofloxacin. Their mean age was 69 years. Seven of the patients were diabetic. Pseudomonas aeruginosa, sensitive to ofloxacin (Kirby-Bauer method, inhibition zone greater than or equal to 22 mm), was isolated from the external auditory canal in all patients. Ofloxacin (200 mg b.i.d.) was given to the patients for 12 to 39 days. Two patients also received additional parenteral antibiotic therapy. Subjective and objective improvement occurred in all patients during treatment, and complete resolution was documented in all patients, with one exception. Only one patient suffered recurrence 2 weeks after discontinuation of antimicrobial therapy. The results of our study suggest that oral ofloxacin is an effective treatment for malignant external otitis caused by Pseudomonas aeruginosa.


Ultrafast desorption of colloidal particles from fluid interfaces.
The self-assembly of solid particles at fluid-fluid interfaces is widely exploited to stabilize emulsions and foams, and in materials synthesis. The self-assembly mechanism is very robust owing to the large capillary energy associated with particle adsorption, of the order of millions of times the thermal energy for micrometer-sized colloids. The microstructure of the interfacial colloid monolayer can also favor stability, for instance in the case of particle-stabilized bubbles, which can be indefinitely stable against dissolution due to jamming of the colloid monolayer. As a result, significant challenges arise when destabilization and particle removal are a requirement. Here we demonstrate ultrafast desorption of colloid monolayers from the interface of particle-stabilized bubbles. We drive the bubbles into periodic compression-expansion using ultrasound waves, causing significant deformation and microstructural changes in the particle monolayer. Using high-speed microscopy we uncover different particle expulsion scenarios depending on the mode of bubble deformation, including highly directional patterns of particle release during shape oscillations. Complete removal of colloid monolayers from bubbles is achieved in under a millisecond. Our method should find a broad range of applications, from nanoparticle recycling in sustainable processes to programmable particle delivery in lab-on-a-chip applications.


Isolated ovarian vein thrombosis in COVID-19 infection.
COVID-19 (coronavirus disease-19) is associated with an increased risk for thrombosis due to endothelial dysfunction and hyperactivation of the immune system induced by the virus. Most cases of venous thromboembolism associated with COVID-19 are either pulmonary emboli or deep vein thromboses. Ovarian vein thrombosis is a rare condition most commonly seen in the postpartum period. This report describes a case of COVID-19-associated ovarian vein thrombosis in a nonpregnant woman with no evidence of underlying inherited coagulopathy.


Immunity to self and self-maintenance: what can tumor immunology teach us about ALS and Alzheimer's disease?
Mounting evidence from the last decade has shown that the immune system not only fights pathogens but also protects the body against cancer. More recently, immune surveillance has been shown to be important for maintaining the functional integrity of the central nervous system. The immune system, however, does not always prevail; tumors do grow and eventually kill their host, and devastating neurodegenerative conditions do develop. Neurodegenerative diseases, like tumors, lie dormant long before clinical symptoms appear. We propose that at this dormant stage, an ongoing competition between the local disease-causing factors and the immune system's attempts to contain them takes place. Onset of clinical symptoms occurs after disease-causing factors escape immune surveillance. Identifying the immune escape mechanisms and circumventing them soon after the emergence of clinical symptoms could lead to the development of novel therapeutic intervention for some of the most devastating neurodegenerative disorders.


Effects of fermentation products of Ganoderma lucidum on growth performance and immunocompetence in weanling pigs.
The purpose of this study was to test fermentation, for its products of a Chinese medicinal mushroom, Ganoderma lucidum, cultured by submerged fermentation for its effect on growth performance and immunocompetence in weanling piglets. In Experiment 1, 72 weanling piglets were allotted to one of four treatments receiving these fermentation products (GLF, expressed as amount of beta-glucans) at 0 (control), 50, 100, and 150 mg/kg feed for 4 weeks. The results showed that at a supplementation level of 50 mg/kg feed, GLF caused the best growth performance, the highest pseudorabies antibody titre, and a decrease of blood glucose level. It was also demonstrated that GLF up-regulated the cell-mediated immune response related cytokines (IL-2, IFN-gamma, and TNF-alpha) expression in different lymphoid tissues. After challenging with porcine circovirus (PCV) type 2 (Experiment 2), a supplementation with 50 mg GLF per kg feed also inhibited PCV-2 virus amplification, and ameliorated lymphocyte depletion in different lymphoid tissues. Conclusively, feed supplemented with GLF at 50 mg/kg could be beneficial to counteract the physiological stress in weanling piglets.


Association with pregnancy increases the risk of local recurrence but does not impact overall survival in breast cancer: A case-control study of 87 cases.
Pregnancy-associated breast cancer (PABC) constitutes 7% of all BCs in young women. The prognosis of PABC remains controversial. In this study, we evaluated the impact of the association of pregnancy with BC on the rates of overall survival (OS), disease free survival (DFS), and distant and local recurrence-free survival. We conducted a retrospective unicenter case-control study. We enrolled PABC patients treated at our institution between 1992 and 2009. For each case, 2 BC controls were matched for age and year of diagnosis. Univariate and multivariate analyses were performed to assess the parameters associated with prognosis. Eighty-seven PABC patients were enrolled and matched with 174 controls. The univariate analysis did not reveal any significant differences in OS, DFS or distant recurrence rates between the 2 groups. Pregnancy associated status, a tumor larger than T2 and neoadjuvant chemotherapy as the primary treatment were significantly associated with an increased risk of local relapse. The multivariate analysis showed that the pregnancy associated status and the tumor size were strong prognostic factors of local recurrence. Pregnancy associated status negates the prognostic value of tumor size, as both T0-T2 and T3-T4 PABC patients have the same poor prognosis as control BC patients with T3-T4 tumors. Interestingly, although PABC patients have more locally advanced tumors, they did not have a higher rate of radical surgery than the control BC patients. Pregnancy associated status is a strong prognostic factor of local relapse in BC. In PABC patients, when possible, radical surgery should be the preferred first treatment step.


Latencies obtained of the somatosensory evoked potentials of the median and tibial nerve in rhesus monkey undergoing intrauterine laminectomy to simulate myelomeningocele.
Somatosensory evoked potentials (SSEP) have been described as excellent indicators of the degree of medullar injury in degenerative and metabolic diseases of the central nervous system (CNS). The prevalence of neural tube defects (NTD) is 6 cases/10,000 live newborns worldwide. It is thought that genetic as well as environmental factors contribute to the etiology of NTD. The objective of this study was to analyze and compare the latencies obtained by means of SSEP in a clinically healthy monkey vs. rhesus monkeys with intrauterine surgery in order to simulate surgically the neural tube defect (myelomengocele) by performing an intrauterine laminectomy and in which later the defect was corrected. This study was performed using three non-human primates of the Macaca mulatta species. There were practice intrauterine surgeries in two monkeys to simulate the neurological defect produced by myelomeningocele, using the third monkey as control. For statistical methodology four monkeys were used. They were born by natural birth without any surgical manipulation. With the cesarean-obtained products, stimulation was performed of the tibial and median nerve. We observed that the hind limbs were the most affected, in particular, the left afferent of the monkey. The spinal cord was exposed to amniotic fluid, and there were no significant differences in the forelimbs. The use of SSEP provides valuable information regarding preservation of sensorial functions in a variety of experimental neurological abnormalities.


Comparison of three biological assays for the detection of toxigenic properties of Bordetella bronchiseptica associated with atrophic rhinitis.
The toxigenic properties of Bordetella bronchiseptica strains associated with clinical atrophic rhinitis were compared using three biological assays: the guinea pig skin test, the mouse spleen atrophy and the suckling mice mortality assay. Forty one sick pigs were cultured and, in 20 of them B. bronchiseptica strains were isolated. Eighteen of the strains were toxigenic by at least one test. However, positivity did not always coincide amongst assays. This discrepancy raises the possibility of either differences in sensitivity between assays or the existence of more than one toxin.


Methods for analyzing peptides and proteins on a chromatographic timescale by electron-transfer dissociation mass spectrometry.
Advancement in proteomics research relies on the development of new, innovative tools for identifying and characterizing proteins. Here, we describe a protocol for analyzing peptides and proteins on a chromatographic timescale by coupling nanoflow reverse-phase (RP) liquid chromatography (LC) to electron-transfer dissociation (ETD) mass spectrometry. For this protocol, proteins can be proteolytically digested before ETD analysis, although digestion is not necessary for all applications. Proteins <or=30 kDa can be analyzed intact, particularly if the objective is protein identification. Peptides or proteins are loaded onto a RP column and are gradient-eluted into an ETD-enabled mass spectrometer. ETD tandem mass spectrometry (MS/MS) provides extensive sequence information required for the unambiguous identification of peptides and proteins and for characterization of posttranslational modifications. ETD is a powerful MS/MS technique and does not compromise the sensitivity and speed necessary for online chromatographic separations. The described procedure for sample preparation, column packing, sample loading and ETD analysis can be implemented in 5-15 h.


Prognostic significance of MyD88 expression by human epithelial ovarian carcinoma cells.
MyD88 is an adaptor protein for TLR-4 signaling known to mediate paclitaxel resistance in epithelial ovarian carcinoma (EOC). This study examined the clinical significance of MyD88 expression in EOC. MyD88 and TLR-4 expression were examined by immunocytochemistry in 109 specimens of ovarian tissues, comprising EOC (N = 83), borderline tumors (N = 9), benign cysts (N = 9) and normal ovarian tissue (N = 8), and clinical data collected by a retrospective chart review. The correlations between MyD88 expression and clinicopathological factors and outcomes were analyzed. TLR-4 expression was detected frequently in all the ovarian tissues. Distinct MyD88 expression was showed in EOC (64 of 83, 77.1 %), in borderline tumors (5 of 9, 55.6 %) and in benign cysts (3 of 9, 33.3 %), and normal ovarian tissue showed no MyD88 expression. Positive MyD88 expression significantly correlated with shorter disease-free and overall survival for EOC (P < 0.0001 and P = 0.0031), and high MyD88 expression was significantly correlated with tumor metastasis (P = 0.0012) for EOC. Univariate and multivariate analyses revealed that MyD88 expression was an independent prognostic factor for disease-free survival and overall survival for EOC. Our data indicate that MyD88 expression is a significantly poor prognostic factor for EOC. A better understanding of the role of MyD88 expression in disease progression and outcome may be helpful for development of novel chemotherapies for patients with EOC.


Synthesis and antimicrobial activity of some isoindolin-1-ones derivatives.
A range of N-substituted isoindolin-1-ones was prepared and their potential as novel antimicrobial agents was investigated. MIC values for active compounds were determined and reported.


Traumatic perforation of the hypopharynx in infants.
Three cases of traumatic perforation and pseudodiverticulum of the hypopharynx in newborn infants are presented. This lesion may be encountered with increasing frequency as a result of the more aggressive management of newborn infants with respiratory distress. Early recognition of this complication is essential to successful therapy. Appropriate management includes local drainage, treatment with antibiotics, and use of a nasogastric tube or gastrostomy to provide a safe route for intestinal alimentation.


Salmeterol attenuates the inflammatory response in asthma and decreases the pro-inflammatory cytokine secretion of dendritic cells.
Salmeterol is a long-acting β2-agonist that activates adenylate cyclase, causing long-lasting bronchodilation and has been used for many years to control asthma. However, little information is available about the immunoregulatory effects of salmeterol. We found that salmeterol decreases the production of pro-inflammatory cytokines in a model of allergen-challenged mice that expressed tumor-necrosis factor-alpha, interleukin-1 and interleukin-6. Dendritic cells (DCs) are antigen-presenting cells and act as sentinels in the airway. We found that salmeterol (10(-5) mol/l) reduced the inflammation caused by lipopolysaccharide (0.1 µg/ml) in activated murine bone marrow-derived DCs. Moreover, western blots demonstrated that this protective effect was mediated partially by inhibiting signaling through the nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) pathways and dramatically decreased levels of p-ERK. We suggest that salmeterol regulates the inflammation of allergen-induced asthma by modulating DCs. In conclusion, we provide evidence that DCs are the target immune cells responsible for the action of salmeterol against asthma.


Effects of repetitive transcranial magnetic stimulation over supplementary motor area in patients with schizophrenia with obsessive-compulsive-symptoms: A pilot study.
In patients with schizophrenia, obsessive-compulsive symptoms (OCS) are associated with lower rates of quality of life and polypharmacy. No previous controlled studies have tested the efficacy of repetitive transcranial magnetic stimulation (rTMS) on the treatment of OCS in this population. The present study examined the therapeutic effects of rTMS applied to the supplementary motor area (1Hz, 20min, 20 sessions) on OCS and general symptoms in patients with schizophrenia or schizoaffective disorder, and whether this intervention can produce changes in plasma levels of brain derived neurotrophic factor (BDNF). A double-blind randomized controlled trial was conducted. Active and sham rTMS were delivered to 12 patients (6 on each group). Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Brief Psychiatric Rating Scale (BPRS) scores, as well as BDNF levels, were assessed before, after, and 4 weeks after treatment. rTMS did not significantly change the outcomes after treatment and on the follow-up (Y-BOCS: Wald's X(2)=3.172; p=0.205; BPRS: X(2)=1.629; p=0.443; BDNF: X(2)=2.930; p=0.231). There seemed to be a trend towards improvement of BPRS scores 4 weeks after rTMS treatment comparing with sham (Cohen's d=0.875, with 32.9% statistical power). No side effects were reported. Future studies with larger sample sizes are needed.


Estrogen Receptors in Cell Membranes: Regulation and Signaling.
Estrogens can stimulate the development, proliferation, migration, and survival of target cells. These biological effects are mediated through their action upon the plasma membrane estrogen receptors (ERs). ERs regulate transcriptional processes by nuclear translocation and binding to specific response elements, which leads to the regulation of gene expression. This effect is termed genomic or nuclear. However, estrogens may exert their biological activity also without direct binding to DNA and independently of gene transcription or protein synthesis. This action is called non-genomic or non-nuclear. Through non-genomic mechanisms, estrogens can modify regulatory cascades such as MAPK, P13K, and tyrosine cascade as well as membrane-associated molecules such as ion channels and G-protein-coupled receptors. The recent studies on the mechanisms of estrogen action provide an evidence that non-genomic and genomic effects converge. An example of such convergence is the potential possibility to modulate gene expression through these two independent pathways. The understanding of the plasma membrane estrogen receptors is crucial for the development of novel drugs and therapeutic protocols targeting specific receptor actions.


Selection of an operation in the management of 155 cases of urethral strictures in male subjects.
A method is described for the selection of an appropriate operation in the repair of 155 male urethral strictures. A brief outline of the important aspects of the operation is presented. The patients have been followed 2 to 4 years postoperatively.


Operative management of lesions of the axillary nerve, isolated or combined with other nerve lesions.
Sixty-six surgically treated lesions of the axillary nerve were reviewed and 57 were followed up over 1 year. Patients were divided into 4 groups: isolated axillary nerve lesions (n = 23), axillary and suprascapular nerve lesions (n = 15), axillary and infraclavicular nerve/plexus lesions (n = 26), and axillary nerve lesions and lower root avulsions (n = 2). Of 34 patients operated upon within 6 months after the trauma, 24 (71%) recovered a force of M4 or M5. Of 17 patients operated upon within 1 year, 10 (59%) had M4 or M5. Of 6 patients operated upon after 1 year, only one had M4. Good shoulder function was only regained when the spinati muscles had recovered good force.


Infantile phthalate metabolism and toxico/pharmacokinetic implications within the first year of life.
Infantile development of phthalate metabolism is crucial for risk assessment of endocrine disruption and has important toxico/pharmacokinetic implications. To characterize temporal variability in urinary phthalate metabolites in infants and to examine their growth-dependent detoxification. In this cohort study, urine samples (n = 876) from 155 healthy Chinese infants were collected serially at eight time points from birth to one year old. Free and total (i.e., free plus glucuronide conjugated) phthalate metabolites (PMEs) were measured by LC/MS/MS. Time variability in PMEs and PME metabolism capacity was characterized using intraclass correlation coefficients (ICCs) and linear mixed regression models. Concentrations of most PMEs changed significantly, with ICCs ranging from 0.213 to 0.318, and trends increased significantly over time (p < 0.001), while MEHP showed fair reproducibility (ICC = 0.480). Glucuronidation increased considerably (ICC ≤ 0.250; p < 0.001) for most PMEs but not for MMP or MEHP. Ester-chain ω-/ω-1-oxidation and α-/β-oxidation patterns of MEHP steeply increased from 3 months to 8 months, where they peaked, resulting in a molar percentage of MEHP in ΣDEHP showing the inversion pattern. MEHP detoxification through oxidation of the hydrophobic ester-chain is apparently a priority for carboxyl glucuronidation in infants. Infant phthalate exposure is prevalent, but they cannot metabolize or eliminate these compounds as efficiently as adults, especially during the first 6 months of life. From an environmental biomonitoring view, age-dependent phthalate metabolism provides crucial implications for infantile ontogeny and health risk assessment within the first year of life.


A modified two-layer iteration via a boundary point approach to generalized multivalued pseudomonotone mixed variational inequalities.
Most mathematical models arising in stationary filtration processes as well as in the theory of soft shells can be described by single-valued or generalized multivalued pseudomonotone mixed variational inequalities with proper convex nondifferentiable functionals. Therefore, for finding the minimum norm solution of such inequalities, the current paper attempts to introduce a modified two-layer iteration via a boundary point approach and to prove its strong convergence. The results here improve and extend the corresponding recent results announced by Badriev, Zadvornov and Saddeek (Differ. Equ. 37:934-942, 2001).


Novel adaptive responses revealed by transcription profiling of a Synechocystis sp. PCC 6803 delta-isiA mutant in the presence and absence of hydrogen peroxide.
The isiAB genes have proven to be highly stress-responsive under a variety of environmental conditions, including iron deficiency, high salt and oxidative stress. In order to understand the function of IsiA and its importance in oxidative stress, we constructed a knock out mutant of the isiA gene and compared differential gene expression of the DeltaisiA strain in the presence and absence of H2O2. We used the full genome microarray for the cyanobacterium Synechocystis sp. PCC 6803 as previously described [Postier BL, Wang HL, Singh A, Impson L, Andrews, HL, Klahn J, Li H, Risinger G, Pesta D, Deyholos M, Galbraith DW, Sherman LA and Burnap RL (2003) BMC Genenomics 4: 23-34]. We determined that one of the main differences in DeltaisiA compared to wild-type (in the absence of peroxide) was the induction of a gene cluster (sll1693-sll1696) that encoded genes resembling pilins or general secretory proteins (Gsp). These proteins are targeted to the cytoplasmic membrane and we suggest that they may be involved in the assembly of membrane complexes, including pigment-protein complexes. The DeltaisiA strain was more resistant to H2O2 compared to the wild-type. In the presence of 1.5 mM H2O2 for 30 min, a cluster of genes that includes a peroxiredoxin was induced 7- to 8-fold and we suggest that this peroxide scavenging enzyme is responsible for the increased peroxide resistance of the DeltaisiA strain.


Early experience with bridging stent graft deployment without sheath support in branched and fenestrated endovascular aortic repair.
To assess the early experience with modified version of simplified bare-wire target vessel (SMART) technique, implying delivery of bridging stent grafts without historically established sheath support, and to compare its outcome to standard endovascular aortic repair procedures with fenestrated/branched devices. A retrospective analysis of 102 consecutive patients treated with fenestrated/branched devices from January 2020 to December 2022 was undertaken. The study population was divided into three groups-a sheath group (SG), SMART group, and nonsheath group (NSG). Primary end points were radiation exposure (dose-area product), fluoroscopy time, dose of contrast agent, operation time, and incidence of intraoperative target vessel (TV) complications and additional procedures. Freedom from secondary TV related reinterventions at the three follow-up phases were defined as secondary end points. A total of 183 TVs (38.8% visceral arteries [VA]; 56.3% renal arteries [RA]) in the SG, 36 TVs (44.4% VA, 55.6% RA) in the SMART group, and 168 TVs (47.6% VA; 50% RA) in the NSG were accessed. The mean number of fenestrations and bridging stent grafts was equally distributed in all three groups. The SMART group only included cases treated with fenestrated devices. The dose-area product was significantly lower in the SMART (median, 203 Gy × cm2; interquartile range [IQR], 179-365 Gy × cm2) and NSG (median, 340 Gy × cm2; IQR, 220-651 Gy × cm2) groups vs the SG (median, 464 Gy × cm2; IQR, 267-871 Gy × cm2; P = .007). Operation time was also significantly lower in the NSG (median, 265 minutes; IQR, 221-337 minutes) and SMART (median, 292 minutes; IQR, 234-351 minutes) groups vs the SG (median, 326 minutes; IQR, 277-375 minutes; P = .004), respectively. Intraoperative TV-related complications were most frequently observed in the SG (9/183 TVs; P = .008). This study reports the outcomes of three currently available TV stenting approaches. Previously reported SMART technique, and its modified version (NSG) proved to be a safe alternative to historically established TV stenting technique with sheath support (SG).


Interprofessional collaboration milestones: advocating for common assessment criteria in graduate medical education.
Milestone-based assessments of resident physicians inform critical decisions regarding resident competence and advancement. Thus, it is essential that milestone evaluations are based upon strong validity evidence and that consistent evaluation criteria are used across residency programs. A common approach to assessment of interprofessional collaboration milestones is particularly important since standardized measures of individual resident competence in interprofessional collaboration have not been established. We propose that assessments of interprofessional collaboration in graduate medical education meet common criteria, namely, these assessments should: 1) measure competency of an individual resident, 2) occur in the context of an interprofessional team, 3) be ascertained via direct observation of the resident, 4) be performed in a real-world clinical practice setting (such as a hospital ward, outpatient clinic, or operating room). We present the evidence-based rationale for these criteria and cite examples of published assessment instruments that fulfill one or more of the criteria, however further research is needed to ensure fidelity of assessments. The proposed criteria may assist residency educators as they endeavor to provide robust and consistent assessments of interprofessional collaboration milestones.


On the kinetic depth effect.
The problem of the kinetic depth effect is revisited. We study how many points in how many views are necessary and sufficient to recover structure. The constraints in the cases where the velocities of the image points are known, and the positions of the image points are known with the correspondence between them established, are different and they have to be studied separately. In the case of two projections of any number of points there are infinitely many solutions, but if we regularize the problem we get a unique solution under some assumptions. Finally, an algorithm is discussed for learning this particular kind of regularization.


Pericardial release of prostacyclin induced by bradykinin and angiotensin II: effects on coronary blood flow in the dog.
Angiotensin II and bradykinin are potent releasers of prostanoids, and it has been suggested that these prostanoids may modulate vascular tone in a number of organs. We previously showed that the pericardium is an important site of prostacyclin biosynthesis, and in this study we have investigated whether or not prostacyclin released into the pericardial fluid influences coronary blood flow. Angiotensin II and bradykinin were infused intra-aortically into anaesthetized dogs, and coronary blood flow in the circumflex artery was measured with electromagnetic probes. Krebs solution irrigating the pericardial surfaces was monitored for prostanoid release using a cascade of bioassay tissues as previously described. Angiotensin II infusions (25 ng/kg/min) increased arterial blood pressure, decreased coronary blood flow, and increased the release of a prostacyclin-like substance into the pericardial irrigating fluid. Inclusion of indomethacin (1 microgram/ml) in the pericardial irrigating fluid abolished angiotensin II-induced release of the prostacyclin-like substance from the heart, did not affect resting coronary flow, but potentiated the coronary vasoconstrictor response to intra-arterial angiotensin II. Bradykinin infusions (0.2 microgram/kg/min) also released the prostacyclin-like substance into the pericardial fluid, and caused a transient decrease in arterial pressure and increase in coronary blood flow. Inclusion of captopril (1 microgram/ml) in the irrigating fluid increased slightly the release of the prostacyclin-like substance, but did not alter the increase in coronary blood flow produced by bradykinin. Moreover, when prostacyclin release was abolished by pericardial indomethacin, the coronary vasodilator response to bradykinin was not altered. A large intravenous dose of indomethacin (5 mg/kg) increased the coronary vasoconstrictor response to angiotensin II, but, again, did not alter the vasodilator response to bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of loss control service on reported injury incidence.
A retrospective analysis evaluated the effectiveness of an insurance carrier's flexible loss control service strategy in reducing workers' compensation policyholders' reported injury and illness claims. To assess the effects of a loss control service strategy on workers' compensation claim frequency rates, on medical-only claim rates, on severity-claim rates, and on claim cost among a group of California employers. Eighty-two small- and medium-sized companies with workers' compensation policies expiring in 1999 were randomly selected from a population of policyholders assigned to loss control consultants for two or more years. Claim performance data were obtained for each company's first expired in-force policy year and its 1999 expired policy year. The retrospective design was combined with a control component based on a randomly selected comparison group of 45 companies whose first policy year with the insurer expired in 1999 and who received safety services from the loss control staff. The flexible loss control consultation service strategy was associated with lower average claim rates and costs. Companies assigned to a loss control consultant for two or more years (the "outcome group") had an average claim rate of 1.24 per $10,000 premium, compared with a rate of 1.62 in the "initial group" and a rate of 1.60 in the "comparison group." The average severity-claim rate of the outcome group was 0.32, compared with the initial-year and comparison-group means of 0.48 and 0.46, respectively. The average medical-only claim rate was 0.92, compared with the initial- and comparison-group means of 1.14 and 1.14. The outcome group's average loss ratio was over 10% lower than that of the initial and comparison groups. Statistical analysis indicated that differences among the groups' claim rates and severity-claim rates were [F=(2,206) 4.938, P=0.008] and [F=(2,206) 8.208, P<0.001], respectively. A loss control service strategy that provides service flexibility and develops partnership between employer and consultant can help reduce the frequency and severity of workers' compensation claims. Barriers to consultation service flexibility, both internal and external, should be identified and removed to enhance service efficacy.


Mesenchymal stem cells enhance GABAergic transmission in co-cultured hippocampal neurons.
Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent stem cells endowed with neurotrophic potential combined with immunological properties, making them a promising therapeutic tool for neurodegenerative disorders. However, the mechanisms through which MSCs promote the neurological recovery following injury or inflammation are still largely unknown, although cell replacement and paracrine mechanisms have been hypothesized. In order to find out what are the mechanisms of the trophic action of MSCs, as compared to glial cells, on CNS neurons, we set up a co-culture system where rat MSCs (or cortical astrocytes) were used as a feeding layer for hippocampal neurons without any direct contact between the two cell types. The analysis of hippocampal synaptogenesis, synaptic vesicle recycling and electrical activity show that MSCs were capable to support morphological and functional neuronal differentiation. The proliferation of hippocampal glial cells induced by the release of bioactive substance(s) from MSCs was necessary for neuronal survival. Furthermore, MSCs selectively increased hippocampal GABAergic pre-synapses. This effect was paralleled with a higher expression of the potassium/chloride KCC2 co-transporter and increased frequency and amplitude of mIPSCs and sIPSCs. The enhancement of GABA synapses was impaired by the treatment with K252a, a Trk/neurotrophin receptor blocker, and by TrkB receptor bodies hence suggesting the involvement of BDNF as a mediator of such effects. The results obtained here indicate that MSC-secreted factors induce glial-dependent neuronal survival and trigger an augmented GABAergic transmission in hippocampal cultures, highlighting a new effect by which MSCs could promote CNS repair. Our results suggest that MSCs may be useful in those neurological disorders characterized by an impairment of excitation versus inhibition balance.


Measurement of interstitial insulin in human muscle.
Previous measurements in lymph and adipose tissue have indicated that interstitial insulin concentrations are approximately 40% lower than in plasma. Measurements of insulin in human muscle interstitial fluid have not been performed yet. We developed a new external reference technique for calibration of microdialysis catheters in situ. This technique allows correct assessments of interstitial peptide concentrations and was employed to estimate the insulin concentration in medial quadriceps femoris muscle in 11 individuals (age: 37 +/- 3 yr; body mass index: 25.2 +/- 1.2 kg/m2) during a two-step euglycemic hyperinsulinemic clamp. At steady-state insulin and glucose infusion, plasma glucose was 5.9 +/- 0.2 mmol/l, plasma insulin was 155 +/- 17 mU/l, and interstitial muscle insulin was 67 +/- 19 mU/l (n = 9; P < 0.01). At a higher insulin infusion rate, the steady-state plasma insulin concentration was 379 +/- 58 mU/l, and interstitial insulin concentration was 180 +/- 40 mU/l (P < 0.01). The data show for the first time that high physiological and supraphysiological plasma insulin levels give 30-50% lower interstitial concentrations of insulin in the muscle. The importance of capillary delivery as a rate-limiting step for the insulin effect is suggested.


Enzymatic reactions in liposomes using the detergent-induced liposome loading method.
Microcompartmentalization is a crucial step in the origin of life. More than 30 years ago, Oparin et al. proposed models based on biochemical reactions taking place in so-called coacervates. Their intention was to develop systems with which semipermeable microcompartments could be established. In the present work we follow their intuition, but we use well-characterized bilayer structures instead of the poorly characterized coacervates. Liposomes from phospholipids can be used as microreactors but they exhibit only a modest permeability and, therefore, chemical reactions occurring inside these structures are depleted after a relatively short period. Here it is shown that even highly stable liposomes from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) can be used as semipermeable microreactors when treated with sodium cholate. Using this kind of mixed liposomes, we describe a biochemical reaction occurring inside the liposomes while the same reaction is prevented in the external medium. In addition, we show that this cholate-induced permeability of POPC bilayers can even be used to load macromolecules such as enzymes from the outside.


Racial disparities in reported prenatal care advice from health care providers.
The relationship between certain maternal behaviors and adverse pregnancy outcomes has been well documented. One method to alter these behaviors is through the advice of women's health care providers. Advice from providers may be particularly important in minority populations, who have higher rates of infant mortality and prematurity. This study examines racial disparities according to women's self-report of advice received from health care providers during pregnancy in four areas: tobacco use, alcohol consumption, drug use, and breast-feeding. Health care providers' advice to 8310 White non-Hispanic and Black women was obtained from the National Maternal and Infant Health Survey. After controlling for sociodemographic, utilization, and medical factors, Black women were more likely to report not receiving advice from their prenatal care providers about smoking cessation and alcohol use. The difference between Blacks and Whites also approached significance for breast-feeding. No overall difference was noted in advice regarding cessation of drug use, although there was a significant interaction between race and marital status. These data suggest that Black women may be at greater risk for not receiving information that could reduce their chances of having an adverse pregnancy outcome.


Sex pheromone of the dogwood borer, Synanthedon scitula.
The sex pheromone of female dogwood borers (DWB) Synanthedon scitula (Harris) (Lepidoptera: Sesiidae) was determined to be an 88:6:6 ternary blend of (Z,Z)-3,13-octadecadienyl acetate (Z,Z-3,13-ODDA), (E,Z)-2,13-octadecadienyl acetate (E,Z-2,13-ODDA), and (Z,E)-3,13-octadecadienyl acetate (Z,E-3,13-ODDA) by gas chromatography-electroantennographic detection (GC-EAD) and gas chromatography-mass spectrometry (GC-MS). The major sex pheromone component, Z,Z-3,13-ODDA, was attractive as a single component. A blend of Z,Z-3,13-ODDA with 1-3% of E,Z-2,13-ODDA (binary blend) was more attractive than the single component. A third component, Z,E-3,13-ODDA, was sometimes observed in GC-EAD analyses, and enhanced attraction to the binary blend in some field bioassays. Lures containing 1 mg of binary and ternary blends attracted 18 and 28 times more male DWB moths, respectively, than caged virgin females in field trials. Attraction was strongly antagonized by addition of as little as 0.5% of E,Z-3,13-octadecadienyl acetate (E,Z-3,13-ODDA). In a period of 12 wk in 2004, more than 60,000 males were captured in sticky traps baited with synthetic pheromone blends in six apple orchards in Virginia, West Virginia, and North Carolina. Lure longevity trials showed that approximately 76% of the pheromone remained in rubber septum lures after 12 wk in the field.


Zinc mesoporphyrin induces rapid and marked degradation of the transcription factor Bach1 and up-regulates HO-1.
Heme oxygenase 1 (HO-1) is the first and rate-controlling enzyme in heme degradation. Bach1 is a mammalian transcriptional repressor of HO-1. To understand how zinc mesoporphyrin (ZnMP) induces the expression of HO-1, we investigated the effects of ZnMP on Bach1 mRNA and protein levels in human hepatoma Huh-7 cells by quantitative RT-PCR and Western blots. We found that ZnMP markedly up-regulated HO-1 mRNA and protein levels, and rapidly and significantly decreased Bach1 protein levels by increasing degradation of Bach1 protein [half life (t(1/2)) from 19 h to 45 min], whereas ZnMP did not influence Bach1 mRNA levels. The proteasome inhibitors, epoxomicin and MG132, significantly inhibited degradation of Bach1 by ZnMP in a dose-dependent fashion, indicating that the degradation of Bach1 by ZnMP is proteasome-dependent. Purified Bach1 C-terminal fragment bound heme, but there was no evidence for binding of ZnMP to the heme-binding region of Bach1. In conclusion, ZnMP produces profound post-transcriptional down-regulation of Bach1 protein levels and transcriptional up-regulation of HO-1. Our results indicate that ZnMP up-regulates HO-1 gene expression by markedly increasing Bach1 protein degradation in a proteasome-dependent manner.


Parents' perspectives on the quality of life of adolescents with cerebral palsy: trajectory, choices and hope.
Quality of life (QoL) is an important outcome of health interventions for children and youth with cerebral palsy (CP). When planning interventions it is fundamental to understand what constitutes a good QoL, a subjective construct, and what factors are important to consider from both parents' and children's perspectives. We used a grounded theory methodology to explore parents' perspectives on the factors that are important for the QoL of their adolescents with CP. Fourteen parents were interviewed using a purposeful sampling strategy, followed by theoretical sampling until saturation was reached. Parents reflected on several important aspects of their children's QoL. In particular, they described how their trajectories as parents of a child with a disability have contributed to their adolescents' current well-being. Over time, parents' hopes for a cure were transformed into hopes for their child's happiness. This trajectory was influenced by the adolescents' intrinsic characteristics and the parents' strategies to overcome challenges and was informed by the parents' and their children's ability to make choices in pursuit of their preferences. Adolescents' and parents' accounts should be considered when planning interventions for adolescents with disabilities. It is important to consider parents' personal characteristics, experiences and the strategies that have been proven to be efficacious in improving their children's QoL and to understand their need to make choices relating to participation and accessibility in order to promote QoL for this at-risk population. Implications for Rehabilitation Parents' trajectory on raising a child with a disability is important for understanding adolescents' QoL. Parents' characteristics and environmental factors influence adolescents' well-being. Hope and choice experiences by parents of children with CP are important for their children's QoL. Transition from pediatric to adult services are required to address disability-related aspects as well as adolescent needs for intimacy, sexuality and planning for their future during adolescence.


Local brainstem glucose utilization in the squirrel monkey.
The 2-deoxy-D-[14C]-glucose method for the measurement of local cerebral glucose utilization (LCGU) in individual brain nuclei and regions has been applied to the squirrel monkey (Saimiri sciureus). The determinations were conducted in five conscious, lightly restrained adult, female, Colombian squirrel monkeys. Local glucose utilization in brainstem structures (LBGU) was highest in nuclei involved in auditory and vestibular functions and in some nuclei involved in general motor activity. The values for glucose utilization (mumoles/100 g/min) were generally lower than in comparable structures reported by other authors in the rat and slightly lower than those in the macaque monkey. In the Beagle dog the values for "medulla" are markedly lower than for most individual structures in the squirrel monkey medulla, about equal in the inferior colliculus and appreciably higher in the superior colliculus.


The sensitivity to methylnitrosourea-induced T-cell leukemogenesis in mice is modified by the injection of hydrocortisone.
T-cell leukemias were induced in adult BDF1 mice by a single i.v. injection of methylnitrosourea (MNU). Leukemogenesis was delayed by a single or repeated injections of hydrocortisone (HC) after MNU and also when HC was given one day before MNU. Enhancement of leukemogenesis was seen in experiments with 10 and 14 days' intervals between HC and MNU. The T-cell subset composition of the thymus after HC treatment was studied at these time intervals, but a specific target cell for the action of MNU, reduced one day after HC and increased in number during the thymic regeneration at 10 and 14 days could not be defined. HC did not prohibit the toxic action of MNU as measured by hemopoietic stem cell numbers in the femur.


Treatment of squamous cell carcinoma of the posterior pharyngeal wall: Radiotherapy versus surgery.
Treatment strategy in squamous cell carcinoma (SCC) of the posterior pharyngeal wall is still being debated. We performed a retrospective analysis according to delivered treatment. One hundred eighty patients were treated between 1997 and 2011. Eighty-nine patients (49.4%) received surgery +/- radiotherapy (RT), whereas 91 (50.6%) received definitive RT +/- chemoradiotherapy (RT/CRT). Five-year overall survival (OS) was 33.4%. There was a significant 5-year OS benefit in surgical treatment versus RT/CRT (43% vs 24.1%; p = .002). Multivariate analysis showed that current smokers, T3 to T4 classification, well-differentiated SCC, and nonsurgical treatment were associated with reduced OS. Subgroup analysis showed significant survival benefit of surgical treatment compared with RT/CRT in patients with T1 to T2 but not in T3 to T4 disease. Surgical management translated into a survival benefit, even in early T classification. These results should be interpreted with caution for selection bias. Surgery remains the standard of care in localized posterior pharyngeal wall SCC. Primary CRT should be considered for nonoperable disease. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1722-E1729.


[Non-tumoral vascular disorders of the lung in the adulthood].
Non-tumoral vascular disorders of the lung are multiple, even if cases diagnosed in the adulthood are rare. They include congenital or acquired conditions, which related symptoms, if present, are non specific. This explains why their diagnosis is challenging and usually delayed. Surgery is the cornerstone of their treatment, although interventional radiology represents currently a less invasive alternative option for some of them.


Primary Rhinoplasty Combined with Pyriform Aperture Augmentation in Asians.
To explore a pyriform aperture augmentation method that is suitable for Asian patients with mid-face concavity, we designed a novel prosthesis to perform pyriform aperture augmentation. Three different rhinoplasty schemes are designed according to the degree of mid-face concavity: (1) simple implantation around the pyriform aperture, (2) implantation around the pyriform aperture and augmentation rhinoplasty is performed concurrently, and (3) implantation around pyriform aperture combined with nasal extension technique. Comprehensive rhinoplasty with pyriform aperture augmentation can substantially improve the aesthetic relationship between nasal and facial areas. This technique is suitable for comprehensive rhinoplasty of Asian patients with mid-face concavity.


Bio-nanoconjugates of lithocholic acid/IR 780 for ROS-mediated apoptosis and optoacoustic imaging applications in breast cancer.
A new lithocholic acid/IR 780 conjugate (LIC) was designed and synthesized for theranostic applications in triple-negative breast cancer. Lithocholic acid is an antitumor biomacromolecule and acts via multiple molecular targets. IR 780 iodide is a fluorescent NIR organic dye researched as a photothermal agent in cancer therapy. A combined conjugate, LIC can have wide applications as a Photothermal/chemotherapeutic and imaging agent in cancer therapy. LIC was characterized and evaluated for its photothermal cytotoxic effect in breast cancer cell lines. Further, to improve the bioavailability of the LIC, a polymeric (PLGA) nanosystem was developed and characterized. The resultant lithocholic acid/IR 780 polymeric nanoconjugates (LIPNCs) were well taken up by the cells and are evident by the inherent red fluorescence of LIC. The LIPNCs also exhibited commendable heat generation when exposed to NIR light (808 nm). The in-vitro anti-cancer studies of LIPNCs also revealed a significant NIR light-based photothermal efficacy (cytotoxic dose 0.75 μM) when compared to the free conjugate (LIC) or the parent moieties. Further cell-based fluorescent and molecular assays showed that LIPNCs induced ROS-mediated apoptotic cell death concurrently being physiologically biocompatible. In-vitro photoacoustic imaging of the LICs exhibited signals comparable to free IR780 dye. Future in vivo studies with LIPNCs or LIC may prove beneficial for developing a promising translational system for its wide application in image-guided cancer theranostics.


The largest hoplophonine and a complex new hypothesis of nimravid evolution.
Nimravids were the first carnivorans to evolve saberteeth, but previously portrayed as having a narrow evolutionary trajectory of increasing degrees of sabertooth specialization. Here I present a novel hypothesis about the evolution of this group, including a description of Eusmilus adelos, the largest known hoplophonine, which forces a re-evaluation of not only their relationships, but perceived paleoecology. Using a tip-dated Bayesian analysis with sophisticated evolutionary models, nimravids can now be viewed as following two paths of evolution: one led to numerous early dirk-tooth forms, including E. adelos, while the other converged on living feline morphology, tens of millions of years before its appearance in felids.


Risk factors for inpatient mortality among children with severe acute malnutrition in Zimbabwe and Zambia.
Malnutrition underlies 45% of deaths in children under-5 years annually. Children hospitalised with complicated severe acute malnutrition (SAM) have unacceptably high mortality. We aimed to identify variables from early hospital admission (baseline factors) independently associated with inpatient mortality in this cohort to identify those most at risk. Observational study of 745 children aged 0-59 months admitted with complicated SAM at three hospitals in Zimbabwe/Zambia. Children underwent anthropometry and clinical assessment by a study physician within 72 h of enrolment, and caregivers provided sociodemographic data. Children were followed-up daily until discharge/death. A multivariable survival analysis identified the baseline factors independently associated with mortality. 70/745 (9.4%) children died in hospital. Age between 6-23 months [aHR 6.53, 95%CI 2.24-19.02], higher mid-upper arm circumference [aHR 0.73, 95%CI 0.59-0.89], presence of oedema [aHR 2.22, 95%CI 1.23-4.05], shock [aHR 8.18, 95%CI 3.79-17.65], sepsis [aHR 3.13, 95%CI 1.44-6.80], persistent diarrhoea [aHR 2.27, 95%CI 1.18-4.37], lack of a toilet at home [aHR 4.35, 95%CI 1.65-11.47], and recruitment at one Harare site [aHR 0.38, 95%CI 0.18-0.83] were all independently associated with inpatient mortality. Oedematous children had a significantly higher birthweight [2987 g vs 2757 g, p < 0.001] than those without oedema; higher birthweight was weakly associated with mortality [aHR 1.50 95%CI 0.97-2.31]. Children with oedema, low MUAC, baseline infections, shock and lack of home sanitation had a significantly increased risk of inpatient mortality following hospitalisation for complicated SAM. Children with high-risk features may require additional care. A better understanding of the pathophysiology of SAM is needed to identify adjunctive interventions.


Antiretroviral Therapy Use Was Not Associated with Stillbirth or Preterm Birth in an Analysis of U.S. Medicaid Pregnancies to Persons with HIV.
Using a U.S. based, nationally representative sample, this study compares stillbirth and preterm birth outcomes between women living with HIV (WWH) who did and did not use antiretroviral therapy (ART) during pregnancy, additionally assessing ART duration and regimen type. Using 2001 to 2012 Medicaid Analytic eXtract (MAX) data from the 14 states with the highest prevalence of HIV. We estimated two, propensity score matched, multivariate logistic regression models for both outcomes of stillbirth and preterm birth: (1) any ART use and (2) the number of months on ART during pregnancy for ART users, adjusting for patient-level covariates. Only 34.6% of pregnancies among WWH had a history of ART use and among those, the proportions of stillbirth and preterm birth were 0.9% and 7.9%, respectively. Any ART use was not significantly associated with either outcome of stillbirth (marginal effects [MEs]: 0.06%, 95% confidence interval [CI]: -0.17 to 0.28) or preterm birth (ME: -0.12%, 95% CI: -0.79 to 0.55). For ART users, duration of ART was not significantly associated with either outcome. Black race was a strong independent predictor in both models (stillbirth: 0.80% and 0.84%, preterm birth: 4.19% and 3.76%). Neither protease inhibitor (PI) nor boosted PI regimens were more strongly associated with stillbirth or preterm birth than nucleoside reverse transcriptase inhibitor-based regimens. ART use during pregnancy was low during this period. Our findings suggest that ART use and ART regimen are not associated, positively or negatively, with stillbirth or preterm birth for mothers with Medicaid. Additionally, our findings highlight a persisting need to address disparities in these outcomes for Black women.


Airborne ultrasound pulse amplification based on acoustic resonance switching.
Airborne ultrasound radiation pressure, a nonlinear effect that appears as a static force in mid-air in the presence of strong ultrasound, has recently been applied in novel scientific and industrial fields. However, the output power of an ultrasound transducer remains low mainly due to the significant mismatch in acoustic impedance between a solid diaphragm and air. To circumvent this fundamental challenge, we propose to emit amplified airborne ultrasound pulses by instantaneously releasing stored acoustic energy into free-space. Specifically, we implement an acoustic cavity with a mechanically rotating shutter covering its open top. Once the acoustic cavity is fully charged, the stored energy is released by opening the shutter. By developing a choke structure that reduces leakage of the stored energy, we generate ultrasound pulses with 2.5 times higher peak power than the input continuous waves at 40 kHz. This preliminary result has a great potential to generate high-power ultrasound pulses using a conventional air-coupled transducer by separating the storage and radiation process, thus circumventing the fundamental limitation brought by impedance mismatch.


Control of food-borne infections and intoxications.
Most food-borne diseases are caused by microorganisms that initially contaminate the living plant or animal or recontaminate the food during handling or processing. Control measures are intended to (1) prevent microorganisms from contaminating food and involve all hygienic production measures (raw material, premises, equipment, cleaning and disinfection, personnel); (2) prevent microorganisms both from growing or forming toxins, e.g. through chilling, freezing or other processes that do not destroy microbes, such as reduction of aw or pH; (3) eliminate microorganisms, e.g. through thermal processing. Integrated systems for control of the microbiology and hygiene of foods aim at a gradual or stepwise reduction of health hazards at all stages of production and processing until final operations. As a further development of HACCP (Hazard Analysis Critical Control Point), other systems such as the LISA (Longitudinally Integrated Safety Assurance) concept, include also the primary stages of harvesting. With respect to food animals, this clearly involves veterinary control of the livestock as an initial stage of food production. As with salmonellosis, the implementation of control systems is helpful in reducing risks at particular critical points. However, isolated measures do not solve the problem as a whole and cannot meet the demands of consumer protection. At least in the case of salmonellosis a global strategy of control is needed which requires political decisions from the relevant public health bodies.


Superficial and medium-depth chemical peels.
The use of chemicals for facial rejuvenation has been explored since ancient times. A sound knowledge of skin anatomy and wound healing is important for understanding the principles of chemical peeling. Chemical peels are classified according to the depth of skin resurfacing produced. The main clinical indications in the cosmetic field are photoaging, dyschromias, and acne scars, which are classified according to the histologic depth of the clinical changes. Proper patient selection, skin priming, and postpeel care are of utmost importance in ensuring a satisfactory outcome. Chemical peels are combined with other rejuvenating treatments for best results in photoaging.


Pretreatment cortisol levels predict posttreatment outcomes among older adults with depression in cognitive behavioral therapy.
Previous studies suggest that individuals with elevated levels of cortisol (the "stress hormone") could be particularly resistant to treatment for depression. However, most of these studies have been conducted in the context of antidepressant medications, and no study has examined pretreatment cortisol levels as a predictor of treatment outcomes among older adults with depression in cognitive-behavioral therapy (CBT), despite the relevance of this population for such a research question. The current study includes 54 older adults with depression who provided salivary cortisol samples at baseline and completed measures of depression at pretreatment and posttreatment, following a 12-week course of CBT. Structural equation modeling results suggest that those with higher daily outputs of cortisol and flatter diurnal slopes were less likely to benefit from CBT-a finding which if replicated could have important implications for clinical practice and future research.


Bombarding cancer: biolistic delivery of therapeutics using porous Si carriers.
A new paradigm for an effective delivery of therapeutics into cancer cells is presented. Degradable porous silicon carriers, which are tailored to carry and release a model anti-cancer drug, are biolistically bombarded into in-vitro cancerous targets. We demonstrate the ability to launch these highly porous microparticles by a pneumatic capillary gene gun, which is conventionally used to deliver cargos by heavy metal carriers. By optimizing the gun parameters e.g., the accelerating gas pressure, we have successfully delivered the porous carriers, to reach deep targets and to cross a skin barrier in a highly spatial resolution. Our study reveals significant cytotoxicity towards the target human breast carcinoma cells following the delivery of drug-loaded carriers, while administrating empty particles results in no effect on cell viability. The unique combination of biolistics with the temporal control of payload release from porous carriers presents a powerful and non-conventional platform for designing new therapeutic strategies.


Interleukin 1 regulates the expression of osteopontin mRNA by osteoblasts.
Osteopontin is a matrix protein which belongs to the integrin superfamily and is involved in cell adhesion. In the present study, we examined the regulation of the mRNA expression of osteopontin by interleukin 1 alpha (IL-1 alpha) in osteoblasts. IL-1 alpha greatly increased the steady-state level of osteopontin mRNA in both a mouse osteoblastic cell line (MC3T3-E1) and mouse primary osteoblast-like cells. The increase in the osteopontin mRNA expression by IL-1 alpha was dose-dependent at a range of 0.004-0.2 nM. This was most likely due to an increase in the transcriptional rate, not to an increase in the stability of osteopontin mRNA. The in vitro nuclear transcription experiment showed that IL-1 alpha-treated MC3T3-E1 cells increased the synthesis of osteopontin mRNA. Besides IL-1 alpha, tumor necrosis factor alpha (TNF-alpha), lipopolysaccharides (LPS) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) increased the osteopontin mRNA expression in both the clonal osteoblasts (MC3T3-E1) and the primary osteoblast-like cells. In response to such bone-resorbing agents, primary osteoblast-like cells expressed osteopontin mRNA much more strongly than primary fibroblast-like cells isolated from mouse calvaria. Both IL-1 alpha and 1 alpha,25(OH)2D3 greatly increased the production of 68 and 62 kDa phosphoproteins in conditioned media of MC3T3-E1 cell cultures, which probably correspond to osteopontin. These results suggest that osteopontin plays an important role in bone remodeling, in particular bone resorption.


Synthesis and preliminary evaluation of neoglycopolymers carrying multivalent N-glycopeptide units.
In the present study, for the discovery of uncharacterized glycan-binding receptors or lectin-like receptors in plants, we developed neoglycopolymers to which three types of N-glycopeptides are conjugated; the first with plant complex type N-glycan (M3FX), the second with high-mannose type N-glycan (M8), and the third with animal complex type N-glycan (NeuAc2Gal2GN2M3). Three types of Asn-oligosaccharide (Asn-M3FX, Asn-M8, or Asn-NeuAc2Gal2GN2M3) were prepared from storage glycoproteins of Ginkgo biloba seeds, Vigna angularis seeds, and egg yolk glycopeptides from actinase digests of each glycoproteins or glycopeptide. Neoglycopolymers were synthesized such that the α-amino groups of Asn-oligosaccharide were coupled to the carboxyl groups of poly-γ-L-glutamic acid (γ-L-PGA) with 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM). The resulting neoglycopolymers were purified through a combination of gel-filtration and reverse-phase HPLC. The incorporation of N-glycans into γ-L-PGA (mol%) was estimated through amino acid composition analysis after acid hydrolysis. The incorporation rates of Asn-M3FX, Asn-M8, and Asn-NeuAc2Gal2GN2M3 into γ-L-PGA were 15.4%, 8.6%, and 11.1%, indicating that nearly 890, 500, and 640 molecules of N-glycans were conjugated with γ-L-PGA, respectively. Furthermore, we confirmed that the neoglycopolymer carrying the multivalent high-mannose type N-glycans is a useful tool for rapid purification of mannose-binding protein, Concanavalin A, from jack bean extract.


Inferring generation-interval distributions from contact-tracing data.
Generation intervals, defined as the time between when an individual is infected and when that individual infects another person, link two key quantities that describe an epidemic: the initial reproductive number, [Formula: see text], and the initial rate of exponential growth, r. Generation intervals can be measured through contact tracing by identifying who infected whom. We study how realized intervals differ from 'intrinsic' intervals that describe individual-level infectiousness and identify both spatial and temporal effects, including truncating (due to observation time), and the effects of susceptible depletion at various spatial scales. Early in an epidemic, we expect the variation in the realized generation intervals to be mainly driven by truncation and by the population structure near the source of disease spread; we predict that correcting realized intervals for the effect of temporal truncation but not for spatial effects will provide the initial forward generation-interval distribution, which is spatially informed and correctly links r and [Formula: see text]. We develop and test statistical methods for temporal corrections of generation intervals, and confirm our prediction using individual-based simulations on an empirical network.


[Effect of occupation on health behavior and biological cardiovascular risk factors].
Within the framework of the second survey of MONICA-Switzerland (cantons of Vaud and Fribourg; canton of Tessin), the data of 683 working men were analysed to examine the relation between occupation and cardiovascular risk factors. For this purpose, lifestyle factors (smoking, nutritional habits, physical activity, alcohol intake) as well as blood pressure and serum lipoprotein concentrations were compared among 17 different occupational groups. Furthermore, every occupational group was ranked, based on the medians of the mentioned dependent variables. A strong relationship between socioeconomic status (recorded as number of years of schooling completed) and an index for healthy lifestyle was found. However, in some occupational groups a major discrepancy between socioeconomic status respectively lifestyle and measured cardiovascular risk factors (blood pressure, lipoprotein concentrations) was observed. It is therefore hypothesized that unknown occupational factors adversely affect blood pressure and serum lipoproteins for example in physicians, managers and executives whereas the contrary--beneficial effect of unknown occupational factors--is true for example for drivers and bricklayers.


Alzheimer's disease protein Abeta1-42 does not disrupt isolated synaptic vesicles.
Synaptic vesicles are central to neurotransmission and cognition. Studies of the Alzheimer's disease (AD) associated peptide, amyloid beta (Abeta), suggest that it has the potential to non-specifically solubilize or permeabilize membranes and that it has detergent and pore-forming properties. Damage to the membrane or integrity of synaptic vesicles could compromise its function. We test the hypothesis that the intact synaptic vesicle is a direct site of attack by Abeta1-42 in AD pathology by examining the properties of individual isolated vesicles exposed to Abeta1-42. In particular, we compared the rate of leakage of dye molecules from synaptic vesicles, the rate of proton permeation across the membrane of the vesicle, and the rate of active proton transport into the vesicle interior in the presence and absence of Abeta1-42. From these experiments, we conclude that isolated synaptic vesicles are not disrupted by Abeta1-42.


Inadequacies in service delivery for the diagnosis and treatment of vaginitis and vaginosis in Nairobi, Kenya.
Vulvovaginal candidiasis (VVC), a common cause of vaginitis, affects 75% of women in their lifetime. In Kenya, vaginitis/VVC is managed using the vaginal discharge syndrome guidelines. We assessed how frequently healthcare workers consider the diagnosis of vaginitis/VVC in symptomatic women, and adherence to the syndromic guidelines, outpatient records at Nairobi City County health facilities, of non-pregnant symptomatic females aged ≥15 years were abstracted. Descriptive statistics were applied, and analysis of determinants of practice determined using multivariable logistic regression models. Of 6,516 patients, 4,236 (65%) (inter-facility range 11-92%) had vaginitis of which 1,554 (37%) were considered VVC (inter-facility range 0-99%). Vaginitis was associated with facility, adjusted odds ratio (aOR) 2.80 (95% confidence interval (CI) 1.64-4.76) and aOR 0.03 (95% CI 0.02-0.04); and month, aOR 0.33 (95% CI 0.25-0.43). Vaginal examination was in 53% (inter-facility range 0-98%). Adherence to syndromic treatment was 56% (inter-facility range 0-83%), better with older patients (aOR 7.73, 95% CI 3.31-18.07). Vaginitis and VVC are commonly diagnosed in symptomatic patients in Nairobi; adherence to the syndromic guidelines is low and differs across the health facilities. Interventions to improve adherence are needed.


Outcomes for individuals turned down for living kidney donation.
A better understanding of the consequences of being turned down for living kidney donation could help transplant professionals to counsel individuals considering donation. In this exploratory study, we used survey instruments and qualitative interviews to characterize nonmedical outcomes among individuals turned down for living kidney donation between July 1, 2010 and December 31, 2013. We assembled a comparator group of kidney donors. Among 83 turned-down donors with contact information at a single center, 43 (52%) participated in the study (median age 53 years; 53% female; 19% black). Quality of life, depression, financial stress, and provider empathy scores were similar between individuals turned down for donation (n = 43) and donors (n = 128). Participants selected a discrete choice response to a statement about the overall quality of their lives; 32% of turned-down donors versus 7% of donors (P < 0.01) assessed that their lives were worse after the center's decision about whether they could donate a kidney. Among turned-down donors who reported that life had worsened, 77% had an intended recipient who was never transplanted, versus 36% among individuals who assessed life as the same or better (P = 0.02). In interviews, the majority of turned-down donors reported emotional impact, including empathy, stress, and other challenges, related to having someone in their lives with end-stage kidney disease. Generic instruments measuring quality of life, depression, financial stress, and provider empathy revealed no significant differences between kidney donors and turned-down donors. However, qualitative interviews revealed preliminary evidence that some turned-down donors experienced emotional consequences. These findings warrant confirmation in larger studies.


Differentiation of Autoimmune Pancreatitis from Pancreatic Cancer Remains Challenging.
Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis. Whilst being corticosteroid responsive, AIP often masquerades radiologically as pancreatic neoplasia. Our aim is to appraise demographic, radiological and histological features in our cohort in order to differentiate AIP from pancreatic malignancy. Clinical, biochemical, histological and radiological details of all AIP patients 1997-2016 were analysed. The initial imaging was re-reviewed according to international guidelines by three blinded independent radiologists to evaluate features associated with autoimmune pancreatitis and pancreatic cancer. There were a total of 45 patients: 25 in type 1 (55.5%), 14 type 2 (31.1%) and 6 AIP otherwise not specified (13.3%). The median (IQR) age was 57 (51-70) years. Thirty patients (66.6%) were male. Twenty-six patients (57.8%) had resection for suspected malignancy and one for symptomatic chronic pancreatitis. Three had histologically proven malignancy with concurrent AIP. Two patients died from recurrent pancreatic cancer following resection. Multidisciplinary team review based on radiology and clinical history dictated management. Resected patients (vs. non-resected group) were older (64 vs. 53, p = 0.003) and more frequently had co-existing autoimmune pathologies (22.2 vs. 55.6%, p = 0.022). Resected patients also presented with less classical radiological features of AIP, which are halo sign (0/25 vs. 3/17, p = 0.029) and loss of pancreatic clefts (18/25 vs. 17/17, p = 0.017). There were no differences in demographic features other than age. Despite international guidelines for diagnosing AIP, differentiation from pancreatic cancer remains challenging. Resection remains an important treatment option in suspected cancer or where conservative treatment fails.


The dynamics of eukaryotic replication initiation: origin specificity, licensing, and firing at the single-molecule level.
Eukaryotic replication initiation is highly regulated and dynamic. It begins with the origin recognition complex (ORC) binding DNA sites called origins of replication. ORC, together with Cdc6 and Cdt1, mediate pre-replicative complex (pre-RC) assembly by loading a double hexamer of Mcm2-7: the core of the replicative helicase. Here, we use single-molecule imaging to directly visualize Saccharomyces cerevisiae pre-RC assembly and replisome firing in real time. We show that ORC can locate and stably bind origins within large tracts of non-origin DNA and that Cdc6 drives ordered pre-RC assembly. We further show that the dynamics of the ORC-Cdc6 interaction dictate Mcm2-7 loading specificity and that Mcm2-7 double hexamers form preferentially at a native origin sequence. Finally, we demonstrate that single Mcm2-7 hexamers propagate bidirectionally, monotonically, and processively as constituents of active replisomes.


Tuberculosis remains a public health problem in Romania.
Tuberculosis (TB) remains a major public health problem in Romania, which has the highest TB incidence in the European Union. We undertook a retrospective study to describe changing trends in the main epidemiological indicators of TB in Romania from 1995 to 2016. Data were obtained from the Marius Nasta Institute of Pneumology, Bucharest, official data published by the National Center for Public Health Statistics and Informatics in Health Statistics Yearbooks, the European Health For All database and the World Health Organization 2017 global TB report. Overall TB notifications in Romania declined after 2002, from 142.2 to 74/100 000 in 2016. For new TB cases, the incidence declined after 2002, from 118.9 to 54.5/100 000 in 2016. After peaking in 2002, at 23.3/100 000, the notification rate of relapses declined to 11.8/100 000 in 2014, but almost doubled the following year. The number of multidrug-resistant TB cases decreased from 624 in 2009 to 530 in 2012, but then increased to 670 in 2015. The number of extensively drug-resistant TB cases tripled between 2012 and 2015, from 22 to 68 cases. Although the decline in TB nationwide after 2002 confirms the effectiveness of control measures, the current TB burden in Romania remains very high by European standards.


Aspartate transport in synaptosomes from rat brain.
Active transport of aspartate by neuronal synapses has been studied using preparations of synaptosomes from rat forebrain. The maximal accumulation of labeled D-aspartate [( Asp]i/[Asp]o) was observed to increase as the second power of the transmembrane electrical potential (measured by the potassium ion concentration gradient [( K+]i/[K+]o], which indicates that aspartate is transported with a net charge of +2. The aspartate gradient also increased as the second power of the sodium ion gradient, indicating that two Na+ are transported inward with each aspartate. Measurement of total intra- and extrasynaptosomal aspartate (L-aspartate) and the specific activities of each after adding labeled D-aspartate shows the presence of two intrasynaptosomal pools, a rapidly exchanging pool in which the L-aspartate is dependent on [Na+] and [K+] in the same manner as described for D-aspartate and a slowly exchanging pool essentially insensitive to [Na+] and [K+]. Maximal activation of uptake with 50 microM aspartate causes an alkalinization of the external medium which suggests that H+ is taken up with the aspartate (or OH- is ejected) to neutralize the negative charge of aspartate at physiological pH values. The data are consistent with the transport process being: Asp- + H+ + 2Na+ o = Asp- + H+ + 2Nai+. These stoichiometries can explain the energetics of both in vitro and in vivo uptake of aspartate by the high affinity, [Na+]- and [K+]-dependent system.


Fast T2-mapping with snapshot flash imaging.
It has been shown recently that quantitative T2-maps may be measured by acquisition of a series of at least eight T2-weighted SNAPSHOT FLASH images. These measurements require a relaxation delay of 10-15 s after each T2-weighted image for the complete relaxation of the spin system. This results in long measuring times. The method presented in this paper allows a considerable reduction of the measuring time by combining the T2-sequence with a fast T1-measurement. Quantitative T1- and T2-maps may be acquired simultaneously in less than 30 s. The method was tested in a phantom experiment. In an in vivo application, relaxation times of different tissues in the abdomen of a rat were measured.


Vesical transmigration of an intrauterine contraceptive device: A rare case report and literature review.
Displacement of an intrauterine contraceptive device (IUD) is a rare and serious complication of IUD insertion. Theoretically, it can migrate to anywhere in the pelvic and abdominal cavity. However, it is not usual for an IUD to migrate to the bladder. In this case report, we reported a patient with chronic urinary symptoms caused by the migration of an IUD into the bladder. The displacement of the IUD led to contraception failure and IUD retention in the bladder for 5 years. Pelvic ultrasonography (US), radiography, and cystoscopy examinations confirmed the migration of IUD in bladder. The patient underwent cystoscopy. The MCu IUD was successfully removed without any complications. Our study demonstrated that a missing IUD should be followed up and removed early to avoid possible serious complications.


Suture fixation of dislocated endothelial grafts.
To share the experience of suturing the displaced endothelial grafts in three patients who developed this complication following a posterior endothelial keratoplasty. Prospective evaluation of three patients who underwent surgical revision by suture fixation for dislocated endothelial graft. The surgeries were performed immediately after noting the complication during the post-op visits and were followed up for 6 months. Assessments at follow-up visits include visual acuity, pachymetry, endothelial cell count, topography, and corneal slit-lamp digital photography. No significant postoperative complications were encountered in any of the three eyes after graft suturing. The vision was worse than hand movements in all, following the graft dislocation and this improved to an average of 20/50 at 6-month post-op. In two of the three eyes the endothelial cell count reduced from 2600 cells preoperatively to 1251 and 988 cells, respectively. Mean topographic astigmatism after the suture removal was 2.4 D. Suture fixation of early endothelial graft dislocation seems to be a good alternative in dislocated endothelial discs as it provides a good refractive and visual outcome, instead of converting it to a standard full-thickness penetrating keratoplasty.


Natural hybridization between Ixodes ricinus and Ixodes persulcatus ticks evidenced by molecular genetics methods.
The recently shown phenomenon of natural hybridization between Ixodes persulcatus and Ixodes pavlovskyi ticks (Kovalev et al., 2015) stimulated similar studies in the sympatric zones of other tick species. In the present paper, 265 Ixodes ricinus and I. persulcatus ticks from Estonia were subjected to a search for interspecific hybrids based on nuclear (ITS2) and mitochondrial (cox1) markers as well as morphological features. Surprisingly, only 72.1% of ticks morphologically identified as I. ricinus actually were I. ricinus both at nuclear and mitochondrial markers, while the accuracy of morphological species identification for I. persulcatus was 99.3%. Among ticks morphologically identified as I. ricinus, 24.6% turned out to be interspecific hybrids and 3.3% were I. persulcatus. Generally, about 11% of the individuals studied were shown to be interspecific hybrids with different levels of nuclear DNA introgression. The analysis of hybrid populations proved the mating pair female I. ricinus×male I. persulcatus to form hybrids more efficiently, then female I. persulcatus×male I. ricinus. The same trend can be observed for backcrosses preferentially mating with I. ricinus. Hybridization between I. ricinus and I. persulcatus proved the existing view about their reproductive isolation to be untenable. Interspecific hybridization occurring between both closely (I. persulcatus and I. pavlovskyi) and more distantly (I. ricinus and I. persulcatus) related Ixodes species could introduce novel alleles that modify vector competence, host use or the ability to exploit diverse microhabitats.


Spatiotemporal Cadence of Macrophage Polarisation in a Model of Light-Induced Retinal Degeneration.
The recruitment of macrophages accompanies almost every pathogenic state of the retina, and their excessive activation in the subretinal space is thought to contribute to the progression of diseases including age-related macular degeneration. Previously, we have shown that macrophages aggregate in the outer retina following damage elicited by photo-oxidative stress, and that inhibition of their recruitment reduces photoreceptor death. Here, we look for functional insight into macrophage activity in this model through the spatiotemporal interplay of macrophage polarisation over the course of degeneration. Rats were exposed to 1000 lux light damage (LD) for 24 hrs, with some left to recover for 3 and 7 days post-exposure. Expression and localisation of M1- and M2- macrophage markers was investigated in light-damaged retinas using qPCR, ELISA, flow cytometry, and immunohistochemistry. Expression of M1- (Ccl3, Il-6, Il-12, Il-1β, TNFα) and M2- (CD206, Arg1, Igf1, Lyve1, Clec7a) related markers followed discrete profiles following light damage; up-regulation of M1 genes peaked at the early phase of cell death, while M2 genes generally exhibited more prolonged increases during the chronic phase. Moreover, Il-1β and CD206 labelled accumulations of microglia/macrophages which differed in their morphological, temporal, and spatial characteristics following light damage. The data illustrate a dynamic shift in macrophage polarisation following light damage through a broad swathe of M1 and M2 markers. Pro-inflammatory M1 activation appears to dominate the early phase of degeneration while M2 responses appear to more heavily mark the chronic post-exposure period. While M1/M2 polarisation represents two extremes amongst a spectrum of macrophage activity, knowledge of their predominance offers insight into functional consequences of macrophage activity over the course of damage, which may inform the spatiotemporal employment of therapeutics in retinal disease.


Chitin hydrolysis assisted by cell wall degrading enzymes immobilized of Thichoderma asperellum on totally cinnamoylated D-sorbitol beads.
In this study, cell wall degrading enzymes produced by Thrichoderma asperellum (TCWDE) were immobilized on totally cinnamoylated D-sorbitol (TCNSO) beads and used for chitin hydrolysis. In order to optimize immobilization efficiency, the reaction time was varied from 2 to 12 h and reactions were conducted in the presence or absence of Na2SO4. Immobilized enzymes were analysed concerning to thermal and operational stability. Immobilization in presence of Na2SO4 was 54% more efficient than immobilization in absence of salt. After optimization, 32% of the total enzyme offered was immobilized, with 100% of bounding efficiency, measured as the relation between protein and enzyme immobilized. Free and TCNSO-TCWDE presented very similar kinetics with maximum hydrolysis reached at 90 min of reaction. Thermal stability of both free and TCNSO-TCWDE was similar, with losses in activity after 55 °C. Moreover, free and TCNSO-TCWDE retained 100% activity after 3h incubation at 55 °C. TCNSO-TCWDE were used in a bath-wise reactor during 14 cycles, producing 1825 μg of N-acetylglucosamine (NAG) maintaining 83% of initial activity.


Sodium chloride stimulates the biomass and astaxanthin production by Haematococcus pluvialis via a two-stage cultivation strategy.
A major challenge facing by astaxanthin industrialization is the low productivity and high production costs. This study established a two-stage cultivation strategy based on the application of NaCl to improve the production of biomass and astaxanthin by Haematococcus pluvialis. During the first growth stage, 12.5 mg L-1 NaCl led to a remarkable enhancement in biomass, which was 1.28 times compared with the control. Moreover, 2 g L-1 NaCl stimulated the astaxanthin content from 12.18 mg g-1 to 25.92 mg g-1 during the second induction stage. Simultaneously, salinity stress application increased the lipids and GABA contents, as well as the levels of Ca2+ and carotenogenic genes' expression, but suppressed the contents of carbohydrate and protein and high-light induced-ROS. This study proposed a simple and convenient strategy for efficient coproduction of biomass and astaxanthin and provides insights into the underlying mechanism of astaxanthin biosynthesis in H. pluvialis induced by salinity stress.


Defining the gap in heart failure treatment in patients with cardiac implantable electronic devices.
The use of guideline-directed medical therapy (GDMT) is poorly described in patients with heart failure and reduced ejection fraction (HFrEF) with cardiac resynchronization therapy (CRT) and/or implantable cardioverter defibrillators (ICDs). To define the eligibility, uptake, dose, contraindications, and barriers to uptake of contemporary medical therapy in this population. Retrospective analysis of consecutive adults with ICD and/or CRT attending two Canadian tertiary centre device clinics between 1 March and 31 May 2021. From 1005 device clinic consultations, 227 (22.6%) patients with HFrEF and CRT and/or ICD were included. GDMT eligibility was high: beta-blockers (99.6%), mineralocorticoid receptor antagonists (MRA) (89.0%), angiotensin receptor-neprilysin inhibitors (ARNI) (84.6%), and sodium-glucose cotransporter-2 inhibitors (SGLT2I) (87.7%). Contraindications were rare: beta-blockers (0.4%), MRA (11.0%), ARNI (15.4%), and SGLT2I (12.3%). Uptake of GDMT was high for beta-blockers (97.4%) but low for other medications: MRA (63.0%), ARNI (46.7%), SGLT2I (22.9%). Except for SGLT2I (84.6%) and beta-blockers (57.9%), less than one-half of patients were prescribed target-doses of MRA (10.5%), and ARNI (47.7%). Of the visits, GDMT was already optimal in 16%, electrophysiologists acted in 33% (21% prescribed, 7% ordered investigations, 5% referred to heart function services), and in the remaining visits, optimization was either deferred to another cardiologist (20%) or no plan was mentioned (25%), besides other reasons (4%). Despite broad eligibility for GDMT in patients with HFrEF and ICD/CRT, significant gaps in prescription and titration exist. Our results highlight the need to embed quality assurance initiatives in cardiac device clinics to improve HFrEF care.


Validated LC-MS/MS method for the determination of 3-hydroxflavone and its glucuronide in blood and bioequivalent buffers: application to pharmacokinetic, absorption, and metabolism studies.
The purpose of this study is to develop an UPLC-MS/MS method to quantify 3-hydroxyflavone (3-HF) and its metabolite, 3-hydroxyflavone-glucuronide (3-HFG) from biological samples. A Waters BEH C8 column was used with acetonitrile/0.1% formic acid in water as mobile phases. The mass analysis was performed in an API 5500 Qtrap mass spectrometer via multiple reaction monitoring (MRM) with positive scan mood. The one-step protein precipitation by acetonitrile was used to extract the analytes from blood. The results showed that the linear response range was 0.61-2500.00 nM for 3-HF and 0.31-2500.00 nM for 3-HFG. The intra-day variance is less than 16.5% and accuracy is in 77.7-90.6% for 3-HF and variance less than 15.9%, accuracy in 85.1-114.7% for 3-HFG. The inter-day variance is less than 20.2%, accuracy is in 110.6-114.2% for 3-HF and variance less than 15.6%, accuracy in 83.0-89.4% for 3-HFG. The analysis was done within 4.0 min. Only 10 μl of blood is needed due to the high sensitivity of this method. The validated method was successfully used to pharmacokinetic study in A/J mouse, transport study in the Caco-2 cell culture model, and glucuronidation study using mice liver and intestine microsomes. The applications revealed that this method can be used for 3-HF and 3-HFG analysis in blood as well as in bioequivalent buffers such HBSS and KPI.