Influence of CD94 and NKG2A variants on susceptibility to rheumatoid arthritis and efficacy of anti-TNF treatment.
The present study aimed to investigate relationships between the CD94 and NKG2A gene polymorphisms and the risk of rheumatoid arthritis (RA) development as well as their association with the response to anti-TNF therapy. A total of 284 patients with RA receiving anti-TNF therapy and 124 healthy subjects were enrolled to the study. Genotypings for CD94 (rs2302489) and NKG2A (rs7301582, rs2734440, rs2734414) polymorphisms were performed using a polymerase chain reaction (PCR) amplification employing LightSNiP assays (TIB-MolBiol, Berlin, Germany). Clinical response was evaluated at 12th and 24th week after initiation of the therapy according to the EULAR response criteria. The frequency of the CD94 AA genotype was significantly decreased in RA patients compared to controls (OR=0.44; P=0.016). The CD94 AA homozygotes were also more common among patients negative to anti-cyclic citrullinated peptide (anti-CCP) antibodies (OR=11.28; P=0.001) as compared to anti-CCP-positive patients and the presence of the CD94 allele A was associated with lack of anti-CCP antibodies (OR=5.00; P=0.0005). The CD94 rs2302489 TT genotype was over-represented in patients exhibiting worse EULAR response at 12th week (OR=3.33; P=0.017). Furthermore, the lack of response after 12 weeks was more frequent among patients carrying the NKG2A rs7301582C allele (OR=3.68; P=0.019) or the CC genotype (OR=3.58; P=0.035) in comparison to allele T or CT/TT genotypes, respectively. These results indicate that CD94 and NKG2A polymorphisms may contribute to genetic susceptibility to RA or affect the response to anti-TNF therapy in patients of Caucasian origin.


Splenic injury after colonoscopy: case report and review of literature.
Splenic injury as a result of colonoscopy is rare but may be underreported and cases may remain undetected. Review of the literature and analysis of 93 cases, including a new case report. Neither a history of abdominal surgery nor performance of a biopsy seems related to an increased incidence of splenic injury. However, a number of colonoscopy-related factors, such as difficulty intubating, looping of the instrument, and traction on the splenocolic ligament, lead to capsular avulsions and lacerations of the spleen. In addition, excess external pressure on the left hypochondrium can simulate blunt trauma, and other maneuvers can increase traction at the splenic flexure. In the majority of cases, symptoms develop within 24 hours of the colonoscopy. Computed tomography scan provides the most sensitive and specific method of diagnosis. The number of colonoscopies continues to increase with the aging population, increasing the potential number of associated splenic injuries. The physician needs to have a high index of suspicion when a patient presents after colonoscopy with abdominal pain associated with hemodynamic instability. Abdominal pain within 24 hours is the most reliable indicator and requires further workup and monitoring. Persistent hemodynamic instability mandates operative management.


Adsorption of alkaloids on ordered mesoporous carbon.
An ordered mesoporous carbon (OMC) adsorbent was synthesized, characterized, and evaluated for effective separation and purification of alkaloid compounds from aqueous solutions. The OMC adsorbent has a large BET specific surface area (1532.2m(2)/g), large pore volume (2.13cm(3)/g), and narrow pore diameter distribution with a median pore diameter of 4.21nm. Berberine hydrochloride, colchicine, and matrine were selected as the model compounds for evaluating the adsorption properties of the OMC adsorbent for alkaloid purification. Batch adsorption experiments of pure components in water were carried out to measure both adsorption equilibria and kinetics, and column breakthrough and desorption experiments were performed to validate the separation and regeneration efficacy of the OMC adsorbent. The adsorption equilibrium capacities of berberine hydrochloride, colchicine, and matrine on the OMC adsorbent at 0.100mg/L and 298K are 450, 600, and 480mg/g, respectively, which are more than double the adsorption capacities of these compounds on two commonly used commercial resins (HPD300 and HPD100B) at similar conditions. Adsorption equilibrium of all three alkaloids could be obtained within 120min at 298K. The dynamic adsorption capacities determined from the breakthrough experiments are within 12% of the estimated equilibrium capacities from the Langmuir isotherms; and 74.3-92.8% of the adsorbed amounts could be recovered by desorbing with a 70% alcohol solution. The adsorption isotherms are analyzed with both Langmuir and Freundlich models, the adsorption kinetic data with the pseudo-first-order and pseudo-second-order models, and the breakthrough curves with four breakthrough models. The large adsorption capacity, fast adsorption rate, and easy regeneration make the ordered mesoporous carbon a promising adsorbent for adsorption and purification of alkaloid compounds from the extracts of herbal plants.


Tension-free thoracoscopic repair of congenital diaphragmatic hernia combined with a percutaneous extracorporeal closure technique: how to do it.
Thoracoscopic repair (TR) of congenital diaphragmatic hernia (CDH) is associated with a higher recurrence rate than the conventional open method. We evaluated the effectiveness of our strategy for quality improvement, named "tension-free TR of CDH". The subjects of this retrospective analysis were 11 consecutive patients with CDH who underwent TR at our hospital between 2017 and 2021. Tension-free TR of CDH included the proactive use of an oversized patch for dome-shaped reconstruction and gapless suturing. We developed a percutaneous extracorporeal closure technique for secure suturing using a commercially available needle. Patch repair was performed in 8 (73%) patients and none required conversion to open surgery because of technical difficulties. Recurrence developed in one patient (9%), who underwent successful reoperation via TR. All patients had an uneventful postoperative course. Tension-free TR combined with extracorporeal closure could reduce the difficulty of suturing and the risk of recurrence of CDH.


Severity and probability of harm of medication errors intercepted by an emergency department pharmacist.
OBJECTIVES The objective of this study was to evaluate the severity and probability of harm of medication errors (MEs) intercepted by an emergency department pharmacist. The phases of the medication-use process where MEs were most likely to be intercepted were determined. METHODS The emergency department was staffed with a full-time pharmacist during the 7-month study period. The MEs that were intercepted by the pharmacist were recorded in a database. Each ME in the database was independently scored for severity and probability of harm by two pharmacists and one physician investigator who were not involved in the data collection process. KEY FINDINGS There were 237 ME interceptions by the pharmacist during the study period. The final classification of MEs by severity was as follows: minor (n = 42; 18%), significant (n = 160; 67%) and serious (n = 35; 15%). The final classification of MEs by probability of harm was as follows: none (n = 13; 6%), very low (n = 96; 41%), low (n = 84; 35%), medium (n = 41; 17%) and high (n = 3; 1%). Inter-rater reliability for classification was as follows: error severity (agreement = 75.5%, kappa = 0.35) and probability of harm (agreement = 76.8%, kappa = 0.42). The MEs were most likely to be intercepted during the prescribing phase of the medication-use process (n = 236; 90.1%). CONCLUSIONS A high proportion of MEs intercepted by the emergency department pharmacist are considered to be significant or serious. However, a smaller percentage of these errors are likely to result in patient harm.


Mutants of Staphylococcus aureus deficient in recombinational repair. Improved isolation by selecting for mutants exhibiting concurrent sensitivity to ultraviolet radiation and N-methyl-N'-nitro-N-nitrosoguanidine.
Recombination-deficient (rec) mutants of Staphylococcus aureus strains 152 and Ps29 were sought by initially screening mutagenized cultures for mutants exhibiting increased sensitivity to both ultraviolet (UV) radiation and N-methyl-N'-nitro-N-nitrosoguanidine (NG). Mutants thus isolated were analyzed for recombinational ability by transduction, and further characterized in terms of sensitivity to UV, NG, ability to repair UV-irradiated bacteriophage, and spontaneous and UV-induced DNA degradation. Mutagenesis of strain 152 yielded three isolates, one of which was rec, the second potentially lex, and the third possessing an undetermined repair deficiency. Mutagenesis of strain Ps29 resulted in the isolation of one mutant, which exhibited a rec genotype. In searching for rec mutants of S. aureus, the value of initially screening mutagenized cultures for mutants exhibiting concurrent sensitivity to UV and NG, as opposed to screening for UV sensitivity alone, is discussed.


Pathologic discordance of differentiation between endoscopic biopsy and postoperative specimen in mucosal gastric adenocarcinomas.
Tumor differentiation is a major determinant of endoscopic resection in mucosal gastric cancers, and the treatment decision is usually based on a preoperative endoscopic biopsy. However, in a proportion of patients, the pathologic assessment of differentiation differs between the endoscopic biopsy and postgastrectomy specimen. This discrepancy is important in that it may lead to an additional radical gastrectomy after endoscopic resection or unnecessary operation for patients who could have been treated with endoscopic resection. This study aimed to investigate the frequency of such cases and to identify risk factors for discordance in patients with mucosal gastric adenocarcinoma. The clinicopathologic characteristics of 1,326 patients who underwent curative gastrectomy for mucosal gastric cancer at Asan Medical Center from 2007 to 2011 were retrospectively reviewed. The overall discordance was 21.5 % (285 cases), and clinically significant discordant rate was 11.9 % (157 cases). Ninety-nine tumors (7.5 %) with differentiated histology on preoperative biopsy were found to be undifferentiated on postoperative pathology. Additionally, 58 patients (4.4 %) with undifferentiated histology on preoperative biopsy exhibited differentiated histology postoperatively. Multivariate analysis revealed that age, sex, tumor location, size, and gross pattern were associated with overall pathologic discordance. In patients with clinically significant discordance, only tumor location (cardia) and size ([2 cm) were independent factors for discordance. Considering a high discordance rate of differentiation between biopsy samples and resected specimens in mucosal cancer in cardia, performing endoscopic resection for confirmative diagnosis of differentiation before total gastrectomy can be a good option.


Radiation carcinogenesis in humans: is it necessary to revise exposure dose limits based on recent estimates of lifetime risks?
Radiation protection dose limits for populations and workers have been recommended on the basis of linear, no threshold dose response and constant absolute risk (AR) models. In 1980, the Committee on the Biological Effects of Ionizing Radiations (BEIR) showed that lifetime cancer risk is three times greater if the relative risk (RR) model is used instead of the AR model. Recently, several arguments have been advanced to promote the RR model to the detriment of the AR model. As a result, one may raise the question whether exposure dose limits should be reduced. This work shows that, together with the RR model, the linear-quadratic dose-response model has also been set forth as a competitor to the linear model. If the linear dose response and AR models are to be replaced by the linear-quadratic dose response and RR models, then lifetime risk predictions remain unchanged and a revision of exposure dose limits might be not necessary.


Postoperative radiotherapy for laryngeal cancer. The prognostic role of programmed death-ligand 1: An immune microenvironment-based cluster analysis.
The prognostic role of programmed death-ligand 1 (PD-L1) expression and the tumor's immune microenvironment has yet to be investigated in the specific setting of adjuvant postoperative radiotherapy (PORT) for laryngeal carcinoma (LSCC). The main aim of this exploratory study was to investigate, also by cluster analysis, whether PD-L1 expression (in terms of combined positive score [CPS]), tumor-infiltrating lymphocytes (TIL), and tertiary lymphoid structures (TLS) correlated prognostically with response to PORT in a cohort of consecutive LSCC patients. PD-L1, TIL and TLS were assessed in 24 consecutive patients with LSCC who underwent PORT. Cluster analysis was used to classify cases on the strength of these parameters. A CPS ≥ 1 was associated with a significantly lower recurrence rate (p = 0.033), and longer disease-free survival (DFS) (p = 0.012) than a CPS < 1. Two clusters of prognostic relevance emerged from our analysis. Cluster 1 was characterized by a mean CPS of 23.0 ± 37.9, a mean TIL count of 68.0 ± 16.4, and the presence of TLS in all cases. Cluster 2 featured a mean CPS of 3.1 ± 7.3, a mean TIL count of 23.9 ± 16.5, and no cases with TLS. Cluster 1 showed a trend towards a lower recurrence rate (p = 0.071) and longer DFS (p = 0.054) than cluster 2. Judging from this preliminary investigation, assessing PD-L1 and immune microenvironment markers seems a promising approach for identifying patients at higher risk of LSCC recurrence after PORT, who might reasonably benefit from adjuvant postoperative chemo-RT, or immunotherapy.


Electrophysical characteristics of Azospirillum brasilense Sp245 during interaction with antibodies to various cell surface epitopes.
This work was undertaken to examine the electrooptical characteristics of cells of Azospirillum brasilense Sp245 during their interaction with antibodies developed to various cell surface epitopes. We used the dependences of the cell suspension optical density changes induced by electroorientation on the orienting field frequency (740, 1000, 1450, 2000, and 2800kHz). Cell interactions with homologous strain-specific antibodies to the A. brasilense Sp245 O antigen and with homologous antibodies to whole bacterial cells brought about considerable changes in the electrooptical properties of the bacterial suspension. When genus-specific antibodies to the flagellin of the Azospirillum sheathed flagellum and antibodies to the serologically distinct O antigen of A. brasilense Sp7 were included in the A. brasilense Sp245 suspension, the changes caused in the electrooptical signal were slight and had values close to those for the above changes. These findings agree well with the immunochemical characteristics of the Azospirillum O antigens and with the data on the topographical distribution of the Azospirillum major cell surface antigens. The obtained results can serve as a basis for the development of a rapid test for the intraspecies detection of microorganisms.


Kojic acid production by Aspergillus flavus using gelatinized and hydrolyzed sago starch as carbon sources.
Direct conversion of gelatinized sago starch into kojic acid by Aspergillus flavus strain having amylolytic enzymes was carried out at two different scales of submerged batch fermentation in a 250-mL shake flask and in a 50-L stirred-tank fermentor. For comparison, fermentations were also carried out using glucose and glucose hydrolyzate from enzymic hydrolysis of sago starch as carbon sources. During kojic acid fermentation of starch, starch was first hydrolyzed to glucose by the action of alpha-amylase and glucoamylase during active growth phase. The glucose remaining during the production phase (non-growing phase) was then converted to kojic acid. Kojic acid production (23.5 g/L) using 100 g/L sago starch in a shake flask was comparable to fermentation of glucose (31.5 g/L) and glucose hydrolyzate (27.9 g/L) but in the 50-L fermentor was greatly reduced due to non-optimal aeration conditions. Kojic acid production using glucose was higher in the 50-L fermentor than in the shake flask.


Epidemiology of hip and knee pain in a community based sample of Italian persons aged 65 and older.
To describe prevalence, characteristics and correlates of hip pain (HP) and knee pain (KP) in an Italian community based cohort aged 65 and older (65+). Baseline survey (1998-2000), population-based study in the Chianti area (Tuscany, Italy); 1299 persons aged 65+ were selected from the city registry of Greve in Chianti and Bagno a Ripoli (multistage sampling method); 1006 participants (564 women and 442 men, age 75.2+/-7.1) provided information for this analysis. Persons reporting HP/KP in the past 4 weeks were recorded and their Western Ontario and McMaster University Osteoarthritis Index pain score (WPS-range 0-20) calculated. Potential correlates of HP/KP, including clinical, lifestyle and psycho-social features and physical measures, were tested in age- and gender-adjusted regression analyses and then entered a multivariate regression model. HP was reported by 11.9% participants, while 22.4% reported KP and 7.2% both conditions. Climbing/descending stairs and walking were the activities eliciting more severe pain in either condition. Average WPSs were 5.6+/-3.5 for HP and 5.4+/-10.4 for KP. Both HP and KP were related to back pain, reduced hip abduction, reduced muscle power and increased trunk flexibility. HP was also related to KP and poor self-rated health (SRH), while KP to HP, foot pain, high body mass index, reduced knee passive flexion and knee extension torque, low education. In a community sample of an Italian persons aged 65+, the prevalence of KP almost doubled that of HP. While both conditions were related to pain in other joints and specific joint impairment, only HP was related to poor SRH, and only KP to mechanical overload.


Information recovery in molecular biology: causal modelling of regulated promoter switching experiments.
The recovery of information from indirect measurements takes different forms depending on the sophistication with which the process being researched can be modelled mathematically. The forms range from (1) the historical and classical inverse problems regularization situation where explicit models which guaranteed existence and uniqueness have been formulated, through (2) situations where model formulation is performed implicitly as a calibration-and-prediction ansatz, to (3) the exploratory (biology) situation where the underlying mechanism is unknown and constraining information about its dynamics is being sought through appropriate experimentation. Each represents a different aspect of the solution of inverse problems. It is the nature of the exploratory form that is discussed in this paper. The focus is the causal modelling of regulated promoter switching experiments performed to understand the dynamics of the genetic control of various biological developmental processes such as vernalization in plants; in particular, regulated promoter switching experiments used to examine the relationship between FLC transcription activity and the associated histone H3 lysine 27 trimethylation at a vernalization-responsive gene in plants. Using a causal representation with Kohlrausch function fading memory, it is shown how such modelling can be used to quantitatively assess the closeness of the linking of one biological process with another, and, in particular, to conclude that the dynamics of FLC transcription and associated H3K27me3 activity are closely linked biologically.


Mechanistic insight of platelet apoptosis leading to non-surgical bleeding among heart failure patients supported by continuous-flow left ventricular assist devices.
Non-surgical bleeding (NSB) is the most common clinical complication in heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). In this study, oxidative stress and alteration of signal pathways leading to platelet apoptosis were investigated. Thirty-one HF patients supported by CF-LVADs were divided into bleeder (n = 12) and non-bleeder (n = 19) groups. Multiple blood samples were collected at pre-implant (baseline) and weekly up to 1-month post-implant. A single blood sample was collected from healthy subjects (reference). Production of reactive oxygen species (ROS) in platelets, total antioxidant capacity (TAC), oxidized low-density lipoproteins (oxLDL), expression of Bcl-2 and Bcl-xL, Bax and release of cytochrome c (Cyt.c), platelet mitochondrial membrane potential (Δψ m), activation of caspases, gelsolin cleavage and platelet apoptosis were examined. Significantly elevated ROS, oxLDL and depleted TAC were evident in the bleeder group compared to non-bleeder group (p < 0.05). Platelet pro-survival proteins (Bcl-2, Bcl-xL) were significantly reduced in the bleeder group in comparison to the non-bleeder group (p < 0.05). Translocation of Bax into platelet mitochondria membrane and subsequent release of Cyt.c were more prevalent in the bleeder group. Platelet mitochondrial damage, activation of caspases, gelsolin cleavage, and ultimate platelet apoptosis in the bleeder group were observed. Oxidative stress and activation of both intrinsic and extrinsic pathways of platelet apoptosis may be linked to NSB in CF-LVAD patients. Additionally, biomarkers of oxidative stress, examination of pro-survivals and pro-apoptotic proteins in platelets, mitochondrial damage, caspase activation, and platelet apoptosis may be used to help identify HF patients at high risk of NSB post-implant.


Consistency of vertebral motion and individual characteristics in gait sequences.
Vertebral motion reveals complex patterns, which are not yet understood in detail. This applies to vertebral kinematics in general but also to specific motion tasks like gait. For gait analysis, most of existing publications focus on averaging characteristics of recorded motion signals. Instead, this paper aims at analyzing intra- and inter-individual variation specifically and elaborating motion parameters, which are consistent during gait cycles of particular persons. For this purpose, a study design was utilized, which collected motion data from 11 asymptomatic test persons walking at different speed levels (2, 3, and 4 km/h). Acquisition of data was performed using surface topography. The motion signals were preprocessed in order to separate average vertebral orientations (neutral profiles) from basic gait cycles. Subsequently, a k-means clustering technique was applied to figure out, whether a discrimination of test persons was possible based on the preprocessed motion signals. The paper shows that each test sequence could be assigned to the particular test person without additional prior information. In particular, the neutral profiles appeared to be highly consistent intra-individually (across the gait cycles as well as speed levels), but substantially different between test persons. A full discrimination of test persons was achieved using the neutral profiles with respect to flexion/extension data. Based on this, these signals can be considered as individual characteristics for the particular test persons.


Potential use of optical coherence tomography in oral potentially malignant disorders: in-vivo case series study.
Evidence confirms that the use of Optical Coherence Tomography (OCT) in oral medicine can be a reliable aid for the diagnosis and management of Oral Potentially Malignant Disorders (OPMDs). Several authors described the ability of this system to detect the structural changes of the epithelia involved by the OPMDs. The purpose of this case series is to provide a suggestion for interpretation of OCT images from different OPMDs, compared to OCT images of healthy tissues. A sample of 11 OPMDs patients was recruited and analyzed with OCT. The images obtained were then compared with an OCT repertoire image. In this work the reflectance degree was considered, together with the analysis of the increased/decreased thicknesses of the various layers. Keratin Layer (KL), Epithelial Layer (EP), Lamina Propria (LP), Basal Membrane (BM) assessment, for each lesion, was performed. OCT measurements of KL, EP and LP layers, together with BM assessing, should aid the physicians to recognize and describe different oral lesions, relating them to the corresponding oral pathology. More studies like this, on larger samples, are needed to validate the results and provide, in the future, a kind of manual that could guide clinicians to correctly interpret the OCT images in relation to the causing pathologies. The present trial has been registered with ISRCTN (#17,893,224).


Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins.
This article reviews findings up to the end of 1997 about the inducible transcription factors (ITFs) c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif268); and the constitutive transcription factors (CTFs) CREB, CREM, ATF-2 and SRF as they pertain to gene expression in the mammalian nervous system. In the first part we consider basic facts about the expression and activity of these transcription factors: the organization of the encoding genes and their promoters, the second messenger cascades converging on their regulatory promoter sites, the control of their transcription, the binding to dimeric partners and to specific DNA sequences, their trans-activation potential, and their posttranslational modifications. In the second part we describe the expression and possible roles of these transcription factors in neural tissue: in the quiescent brain, during pre- and postnatal development, following sensory stimulation, nerve transection (axotomy), neurodegeneration and apoptosis, hypoxia-ischemia, generalized and limbic seizures, long-term potentiation and learning, drug dependence and withdrawal, and following stimulation by neurotransmitters, hormones and neurotrophins. We also describe their expression and possible roles in glial cells. Finally, we discuss the relevance of their expression for nervous system functioning under normal and patho-physiological conditions.


Increasing selectivity of interlimb coordination during spontaneous movements in 2- to 4-month-old infants.
In the field of motor development, a question exists whether spontaneous activity in early infancy serves as a precursor to later-emerging goal-directed behaviors. To answer this question, it is necessary to investigate in detail the properties of spontaneous movements in individual infants. In the current study, we longitudinally examined the spontaneous movements of the end points of the limbs in 6 infants aged 2-4 months. Examinations were carried out every week by using a motion analysis system, and the number of recordings performed for each infant varied from 6 to 9 times. Our major finding was that there was an age-related increase in the velocity and position correlation between arms and between legs, whereas there was no significant change in the velocity, duration, and amplitude of movements of individual limbs. That is, the pattern of spontaneous movements changes from a general activity involving all the limbs to an activity involving more selective interlimb coordination from 2 to 4 months of age. These findings suggest that the dissociated movements of a selective combination of arms or legs during spontaneous movements may be a precursor to functionally dissociated movements during goal-directed behaviors.


Effects of oral equiblocking doses of a cardioselective and noncardioselective beta-adrenergic blocking agent on left ventricular function in the normal conscious dog.
The effects of propranolol, a noncardioselective beta-adrenergic blocking agent, and practolol, a cardioselective agent, on left ventricular function were compared in an awake dog model at an equiblocking dose range. Both agents produced modest depression of inotropic state at rest, and during volume and phenylephrine loading. No significant differences between the two agents were detected.


Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance.
Diabetes mellitus (DM) can increase the risk of Alzheimer's disease (AD) in patients. However, no effective approaches are available to prevent its progression and development. Recently, autophagy dysfunction was identified to be involved in the pathogenesis of neurodegenerative diseases. This study was designed to investigate the effect of metformin on hyperphosphorylated tau proteins in diabetic encephalopathy (DE) by regulating autophagy clearance. db/db mice were randomly divided into four groups, db/+ mice were used as control group. Twelve-week old male db/db mice received consecutive intraperitoneal injection of 200 mg/kg/d metformin or (and) 10 mg/kg/d chloroquine for eight weeks. Morris water maze (MWM) tests were performed to test cognitive functions before the mice were euthanized. Metformin attenuated cognitive impairment in db/db mice, reduced hyperphosphorylated tau proteins, restored the impaired autophagy in diabetic mice, all of which were reversed by inhibiting of autophagy activity. In high glucose-cultured HT22 cells, metformin increased autophagy in a dose-dependent manner. Besides, metformin enhanced autophagy activity in an AMPK dependent manner. These data show that metformin may reduce tauopathy and improve cognitive impairment in db/db mice by modulating autophagy through the AMPK dependent pathway. These findings highlight metformin as a new therapeutic strategy for the treatment of DE.


Depression of local cell-mediated immunity and histological characteristics of disseminated AIDS-related Mycobacterium avium infection after the initiation of antiretroviral therapy.
The aim of the present study was to examine the immunohistological characteristics of disseminated Mycobacterium avium infection after the initiation of antiretroviral therapy (ART) for acquired immunodeficiency syndrome (AIDS). We histologically investigated five autopsied AIDS patients with systemic M. avium infection. The inflammatory cell composition in the affected tissues was assessed using immunohistochemistry. The celiac lymph nodes and intestinal canal were the most commonly involved organs in the AIDS cases. The most common histological feature was unstructured aggregation of histiocytes. Immunohistochemistry revealed depression of CD4(+), CD8(+) and CD57(+) cells in the gut lamina propria and mesenteric lymph nodes. These findings suggest that local cell-mediated immunity is depressed in affected tissues and that the primary histological feature is poor organization of granulomas in mycobacterial lesions, despite the administration of adequate ART.


Isolation of a promoter region of a secreted metalloprotease gene from Microsporum canis.
MEP3 of Microsporum canis encodes a 43.5 kDa extracellular keratinolytic metalloprotease, which is thought to be one of the virulence-related factors in dermatophytosis. In order to analyze the system underlying the regulation of MEP3 gene expression, the 5'-upstream region was isolated by inverse PCR. The nucleotide sequence of a DNA fragment of about 2.1 kb containing the coding region contains putative transcription factor binding sites and transcriptional initiation points. Further analyses of the regulatory sequence may be useful for understanding the molecular basis of the coordinated expression of the various genes involved in dermatophytosis.


Tubal pregnancy in a case of unicornuate uterus with contralateral streak ovary and renal agenesis: A case report.
A 24-year-old woman presented to the emergency department with symptoms consistent with an ectopic pregnancy. Ultrasonographic evaluation reported no evidence of intrauterine pregnancy, a heterogenous mass in the left adnexa, and normal-appearing bilateral ovaries. The right kidney was imaged, though the left kidney was not visualized. Beta-HCG was reported below the discriminatory zone. Two days later, her ultrasound remained unchanged, and beta-HCG had not risen appropriately. Diagnostic laparoscopy revealed a dilated right fallopian tube with products of conception exuding from the fimbriated end. Laparoscopically, the patient's pelvic anatomy was found to be abnormal. There was no left fallopian tube and the uterus appeared unicornuate with absent left horn. A left streak ovary was present superior to the pelvic brim in the pericolic gutter, though the right ovary appeared normal and in the appropriate position. At follow-up, hysterosalpingography showed a right-sided unicornuate uterus without septation, a small tubular endometrial cavity, and a patent right fallopian tube. Defects of unification of the Mullerian ducts, such as unicornuate uterus, do not reduce the ability to achieve pregnancy, but do increase the risk of adverse outcomes and fetal malpresentation.


Safety and effectiveness assessment of endovascular recanalization for non-acute middle cerebral artery occlusion.
Endovascular treatment for patients with symptomatic nonacute middle cerebral artery occlusion remains clinically challenging, and proof of a beneficial effect on functional outcome is lacking. We aim to evaluate the effectiveness and safety of endovascular recanalization for patients with symptomatic nonacute middle cerebral artery occlusion. Ninety-eight patients with symptomatic atherosclerotic nonacute middle cerebral artery occlusion were divided into drug treatment groups (42) and endovascular treatment groups (56). The rate of recanalization, peri-procedural complications, and follow-up results were evaluated. Among the 56 patients who received endovascular treatment, 53 (94.6%) achieved successful recanalization. The rate of peri-procedural complications was 7.1% (4/56), and the death rate was 1.8% (1/56). Any stroke within 90 days was 7.1% (4/56). Among the 42 patients in drug treatment group, any stroke within 90 days was 19.0% (8/42), death rate was 0. Among patients with symptomatic nonacute middle cerebral artery occlusion with a short length of occlusion and a moderate-to-good collateral circulation, endovascular treatment seems to be safe. And endovascular treatment could reduce the recurrence rate of stroke.


Agents of cancer immunosurveillance: HSPs and dsDNA.
Tumor immunosurveillance requires tumor cell-derived molecules to initiate responses through corresponding receptors on antigen presenting cells (APCs) and a specific effector response designed to eliminate the emerging tumor cells. This is supported by evidence from immunodeficient individuals and experimental animals. Recent discoveries suggest that adjuvanticity of tumor-derived heat shock proteins (HSPs) and double-stranded DNA (dsDNA) are necessary for tumor-specific immunity. There is also the obligatory early transfer of tumor antigens to APCs. We argue that tumor-derived HSPs deliver sufficient chaperoned antigen for cross-priming within the quantitative limits set by nascent tumors. In contrast to late-stage tumors, we are only just beginning to understand the unique interactions of the immune system with precancerous/nascent neoplastic cells, which is important for improved cancer prevention measures.


Neoepitopes as biomarkers of cartilage catabolism.
Progressive degradation of articular cartilage is a central feature of arthritis and a major determinant of long term joint dysfunction. There are no treatments able to halt the progression of cartilage destruction presently available, and monitoring the benefit of potential therapies is hampered by our inability to measure the "health" of articular cartilage. Serial radiographic assessment of joint space narrowing, the current gold standard, requires measurements over a prolonged time (1-5 years) and is prone to technical difficulties. Other strategies for evaluating cartilage degradation are needed to enable both short and long term monitoring of disease progression and response to therapy. One avenue that holds promise is the use of biomarkers that accurately reflect the degradative state of the articular cartilage. Antibodies that recognise terminal amino acid sequences generated by proteolysis at specific sites in the core protein of both aggrecan and type II collagen (neoepitope antibodies) have become available in recent years. These antibodies have been invaluable for identifying the proteinases responsible for cartilage breakdown both in vitro and in vivo. The presence of neoepitope sequences generated by specific metalloenzyme cleavage of aggrecan and type II collagen correlates well with the progression of cartilage degeneration, both in vitro and in mouse models of arthritis. Preliminary results with quantitative assays of type II collagen neoepitopes suggest that they may be useful markers of joint disease in humans. Long term studies correlating neoepitope concentration with clinical and radiographic disease are now required to validate the utility of neoepitopes as surrogate markers of cartilage degeneration and joint disease.


Analysis of in vivo mutation data can inform cancer risk assessment.
Under the new U.S. Environmental Protection Agency (EPA) Cancer Risk Assessment Guidelines [U.S. EPA, 2005. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001B, March 2005], the quantitative model chosen for cancer risk assessment is based on the mode-of-action (MOA) of the chemical under consideration. In particular, the risk assessment model depends on whether or not the chemical causes tumors through a direct DNA-reactive mechanism. It is assumed that direct DNA-reactive carcinogens initiate carcinogenesis by inducing mutations and have low-dose linear dose-response curves, whereas carcinogens that operate through a nonmutagenic MOA may have nonlinear dose-responses. We are currently evaluating whether the analysis of in vivo gene mutation data can inform the risk assessment process by better defining the MOA for cancer and thus influencing the choice of the low-dose extrapolation model. This assessment includes both a temporal analysis of mutation induction and a dose-response concordance analysis of mutation with tumor incidence. Our analysis of published data on riddelliine in rats and dichloroacetic acid in mice indicates that our approach has merit. We propose an experimental design and graphical analysis that allow for assessing time-to-mutation and dose-response concordance, thereby optimizing the potential for in vivo mutation data to inform the choice of the quantitative model used in cancer risk assessment.


Tomographic image and visual recovery of acute macula-off rhegmatogenous retinal detachment.
To observe the macula of acute rhegmatogenous retinal detachment involving the macula with optical coherence tomography (OCT) after scleral buckling and to study the relation between pre- and postoperative visual acuity and the OCT image. Prospective study of 15 eyes of 15 patients with macula-off rhegmatogenous retinal detachment. We selected cases with preoperative visual acuity worse than 0.5 to analyze the improvement in postoperative visual acuity. The time period between macula-off retinal detachment and surgery was less than 1 week. Indirect ophthalmoscopy indicated that all retinal detachments were reattached at 2 weeks postoperatively. Accumulation of subretinal fluid at the fovea was observed in nine (60%) cases with OCT. In four of these nine eyes, the accumulation of subretinal fluid persisted up to 6 months after the operation. The presence of residual subretinal fluid did not influence visual recovery during the 6 months' postsurgical follow-up. OCT revealed postoperative residual subretinal fluid at the macula in some acute macula-off retinal detachment cases. Residual subretinal fluid did not influence the recovery of visual acuity for at least 6 months after surgery.


Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.
TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis-acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the "peaceful" coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3-based cancer therapeutics.


Detrimental effects of high levels of antioxidant vitamins C and E on placental function: considerations for the vitamins in preeclampsia (VIP) trial.
Supplementation with antioxidant vitamins has been proposed to reduce the risk of preeclampsia and perinatal complications. In a recent study, it has been shown that this supplementation to above physiological doses does not reduce the risk of preeclampsia, but increases the rate of low birthweight babies, suggesting a detrimental effect on placental function, given the lower birthweight. The aim of the present study was to investigate the effects of high levels of antioxidants vitamins C and E on placental cells in vitro. Isolated fresh human cytotrophoblasts were exposed to high concentrations of vitamins C and E for 48 h. Then the secretion of human chorionic gonadotropin (hCG) and the production of tumor necrosis factor-alpha (TNF-alpha) were assessed. High levels of vitamins C and E, separately or combined, decrease the secretion of hCG by cytotrophoblasts and increase their production of TNF-alpha. Exposure of cytotrophoblasts to high levels of antioxidant vitamins C and E may affect placental function, as reflected by decreased secretion of hCG; and placental immunity, as reflected by increased production of TNF-alpha. Such alterations are known to lead to endothelial dysfunction and adverse pregnancy outcomes, such as fetal growth restriction (FGR).


Serenics fluprazine (DU 27716) and eltoprazine (DU 28853) enhance neophobic and emotional behaviour in mice.
Two tests designed to elicit responses to novelty and to aversive stimuli were used to study the effects of the serenics fluprazine and eltoprazine on the behaviour of male Swiss mice: a free exploratory test (fluprazine; 2.5, 5 and 10 mg/kg; eltoprazine: 2.5, 5, 10 and 15 mg/kg) and a two-box choice procedure (fluprazine: 1.25, 2.5, 5 and 7.5 mg/kg; eltoprazine: 2.5, 5, 7.5 and 10 mg/kg). Both drugs increased the neophobic reaction, as well as the avoidance of a brightly illuminated box. These effects closely resemble those of psychostimulant drugs such as methamphetamine and caffeine. It is hypothesized that the behavioural changes induced by these drugs may be due to a nonspecific increase of the emotional reactivity of animals.


Intravoxel incoherent motion (IVIM) MR imaging of colorectal liver metastases: are we only looking at tumor necrosis?
To determine if intra-voxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters, including free molecular-based (D) and perfusion-related (D*, f) diffusion parameters, correlate with the degree of tumor necrosis and viable tumor in colo-rectal cancer (CRC) metastasis. Fifteen patients referred for resection of liver metastases from CRC were retrospectively included in this Institutional Review Board approved study. An IVIM-DWI sequence was performed on a 1.5 Tesla MR imaging system, with 10 b factors (0, 10, 20, 30, 50, 80, 100, 200, 400 and 800 s/mm(2) ). Mean D, D*, f and apparent diffusion coefficient (ADC) values were determined in metastases with a longest diameter above 10 mm. Correlations between the diffusion parameters and the degree of liver tumor necrosis and viable tissue were determined (Spearman). Correlation between diffusion parameters and histopathological findings was performed in 35 hepatic metastases with a diameter of more than 10 mm (mean size of 17.9 mm; range, 1-68 mm). Both D (r = 0.36; P = 0.035) and ADC (r = 0.4; P = 0.02) correlated with the degree of tumor necrosis but not with viable tumor. ADC variation observed in CRC metastases following systemic chemotherapy reflects a specific increase in free-molecular diffusion (D), in itself correlated to the degree of metastasis necrosis.


Interplay of long non-coding RNAs and HIF-1α: A new dimension to understanding hypoxia-regulated tumor growth and metastasis.
Hypoxia is a feature of the solid tumor microenvironment that is associated with poor clinical outcomes in multiple tumor types. Hypoxia-induced factor-1 alpha (HIF-1α) is a master regulator of hypoxic adaption, has been demonstrated to modulate hypoxic gene expression profiling and signaling transduction networks, and is thus a potential therapeutic target. Despite hypoxic response signaling having being extensively studied, the involvement of long non-coding RNAs (lncRNAs) in the hypoxic response has become a new focus of attention. Emerging evidence has documented complex interactions between HIF-1α and lncRNAs, which contribute to the acquisition of multiple hallmarks of cancer. In this review, we focus on recent advances in the study of hypoxia and HIF-1α-regulated lncRNAs, and summarize the molecular mechanisms and functional outcomes of the interplay between lncRNAs and HIF-1α, which may provide important insights into cancer diagnosis and prognosis, enabling better control of cancer.


Reactivation of Chagas disease with central nervous system involvement in HIV-infected patients in Argentina, 1992-2007.
The objective of this study was to evaluate clinical and microbiological characteristics of Chagas disease (ChD) with central nervous system (CNS) involvement in AIDS patients. This was a retrospective study of clinical and laboratory findings of HIV-infected patients with a confirmed diagnosis of ChD involving the CNS during the period 1992-2007 at the "Francisco J. Muñiz" Infectious Diseases Hospital, Buenos Aires, Argentina. Of a total of 15 patients, 14 were male and the median age was 33 years (range 25-54 years). Seven out of nine had lived in a Chagas endemic area and 7/10 were intravenous drug users (IDUs). The disease was reactivated during corticosteroid therapy in three patients. Clinical manifestations were: headache (11/15), focal neurological deficits (9/15), fever (9/15), meningismus (7/15), seizures (7/15), altered mental status (5/15), and cardiac involvement (3/10). The median CD4 T-cell count at the time of reactivation was 64cells/microl (range 1-240). Twelve of 14 had positive serology for Trypanosoma cruzi; the two negative were IDUs. Cerebrospinal fluid (CSF) findings (median (range)): cell count 5/mm(3) (2-90), protein level 0.68g/l (0.1-1.84), and glucose level 0.45g/l (0.13-0.73). CSF direct examination for T. cruzi was positive in 11/13. Neuroimaging findings showed a single hypodense lesion in 7/14 and normal images in 2/14. Twelve patients were treated with benznidazole. The global mortality was 79% (11/14). ChD reactivation should be considered as a differential diagnosis of meningoencephalitis in HIV patients with low CD4 T-cell counts, previous residency in an endemic area, and/or IDUs. Whenever possible, lumbar puncture should be performed because of the high accuracy for early diagnosis.


Creation of new physicochemical methods for blood analysis on the base of fluorescent probes.
This review deals with the development of new methods for studies of blood cells and plasma, based on the use of special dye molecules, the so-called fluorescent probes. These probes can also be used for clinical diagnosis. Probes and new methods on the basis of these probes were created for measurements of plasma and serum lipoproteins, serum albumin binding centers, blood leukocyte intracellular lipoproteins, allergens.


Nitrous oxide reduction-coupled alkene-alkene coupling catalysed by metalloporphyrins.
Porphyrin complexes of iron, manganese and cobalt catalysed reductive dimerization of alkenes with NaBH4 under N2O. The reaction system using Fe(III) porphyrin generated an Fe(I) porphyrin intermediate that reduced N2O to regenerate Fe(III) porphyrin.


[Peculiarities in the development of the superior semicircular canal].
Our objective was to study the ontogeny of the superior semicircular canal in order to describe its peculiarities. We analyzed 76 series of human embryos aged between 32 days (6mm) and newborns. The samples were cut serially and stained using Martin's trichrome technique. In semicircular canal development there were a number of peculiarities, such as: a defined chronological sequence of osteogenesis with a variable rate of ossification; the fact that each nucleus of ossification was involved in the formation of one of its covers (the upper in the superficial and the lower in the deep); the appearance of transitory dehiscence; and canal closure by means of bone with laminar pattern, with a minimum thickness of 0.1mm. The peculiarities in canal development could explain the origin of pathological dehiscence in the canal, whether congenital or acquired.


Care of the HIV-exposed child--to breast feed or not?
Breast milk is the best form of nutrition for infants. However, it places infants born to HIV infected women at risk of acquiring HIV infection. Total avoidance of breastfeeding is the only way of completely avoiding HIV transmission through breast milk. However, this strategy has not proved to be viable in resource constrained nations. A high infection related mortality and morbidity, and a high prevalence of malnutrition have been observed in HIV exposed infants on replacement feeding. Exclusive breastfeeding for the first six months followed by rapid weaning has also not proved to be a good strategy, with a surge in infection related morbidity and malnutrition reported after weaning. Current evidence indicates that continued use of ARV prophylaxis to mother/infant starting during pregnancy and continued to cover the entire duration of breastfeeding offers the infant best chance of HIV free survival, combining the benefits of breast milk with safety induced by ARV prophylaxis.


Children exposed to valproate in utero--population based evaluation of risks and confounding factors for long-term neurocognitive development.
To evaluate neurological and cognitive functioning of school-aged (> or =6 years) children exposed to valproate monotherapy in utero in a population based, evaluator-blinded, controlled study. Studied children (N=39, aged 6.6-13.4 years) and their mothers were identified through a population based pregnancy registry. Mothers with carbamazepine monotherapy and mothers with epilepsy but without antiepileptic drug (AED) treatment during pregnancy and their age and gender matched children served as controls. Hospital records were reviewed and neurological examination (Touwens test), intelligent quotients (IQ) of mothers (WAIS), and children (WISC-III) and neuropsychological assessment of children (NEPSY) were performed evaluator-blinded. The prevalence of low intelligence (FIQ<80) was 19% (4/21) and the prevalence of exceptionally low intelligence (FIQ<70) 10% (2/21) in valproate (VPA) monotherapy exposed children. Children exposed to carbamazepine (CBZ) and children of women with epilepsy but without AED exposure during pregnancy had all at least low average intelligence. The mothers using valproate scored significantly lower (p<0.05) in FIQ, VIQ and PIQ tests and had also significantly lower (p=0.035) educational level. Altogether 21% (8/39) of the children had minor neurological dysfunctions. In a population based setting inheritance and cumulating environmental factors may partly explain the increased prevalence of neurocognitive symptoms in children exposed to valproate in utero although concern about the possible long-term effects of intrauterine valproate exposure does exist.


A structural study of PrCrO3 under extreme conditions: a comparison with the effects of doping.
The nuclear and magnetic structure of [Formula: see text] has been investigated using neutron and X-ray powder diffraction as a function of pressure and temperature. The orthorhombic symmetry (space group [Formula: see text]) remains stable up to the highest temperature (1500 K) and pressure (approx. [Formula: see text]) considered. There is a crossover in the magnitude of the a- and b-lattice parameters at approximately 1135 K, caused by competing effects of octahedral tilting and distortion. The material is antiferromagnetic ([Formula: see text] K) with [Formula: see text] symmetry, with a maximum moment of [Formula: see text] on the [Formula: see text] sites aligned along the direction of the [Formula: see text]-axis. The application of pressure shows an abnormal softening in the unit-cell volume, which is suggestive of a continuous approach to a second-order phase transition. Raman spectroscopy measurements at ambient temperature were collected as a function of pressure up to approximately [Formula: see text] GPa, with discontinuous mode behaviour further suggesting the existence of a transition above 7 GPa. The measured structural changes in [Formula: see text] are compared extensively in the wider context of other lanthanide orthochromites, and the comparative effects of A- and B-site substitution on the polyhedral tilts and distortion are discussed. This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 1)'.


Keratouveitis and conjunctivitis caused by Euphorbia ingens: A case review.
Euphorbia ingens is a ubiquitous plant who has a milky sap. It can accidentally harm human´s eye by its caustic nature, causing conjunctivitis, keratitis, uveitis, anterior staphyloma and corneal scarring in untreated patients. We present the case of a patient whose eye came into contact with the milky sap. He suffered conjunctivitis, corneal epithelial defect and uveitis. After intensive treatment, his eye made a complete recovery. We recommend gloves and protecting glasses before handling these types of plants.


"Follow to *actually* heal binge eating": A mixed methods textual content analysis of #BEDrecovery on TikTok.
Binge eating disorder (BED) has been relatively overlooked in research on eating disorders and social media. Existing literature suggests that time spent on social media may be associated with increased binge eating. However, more granular details of social media experiences such as the consumption of pro-recovery content have not received sufficient scholarly attention. The present study begins to address this gap through analysis of 1074 captions from public posts on TikTok, a video-based social media platform, tagged with #BEDrecovery between July 2021-2022. We generated six themes by examining word frequencies in the data and engaging in reflexive categorization of commonly used words within the context of different posts. These themes were: (1) diets and eating approaches, (2) help and support, (3) mental health, (4) diet culture critique, (5) body monitoring, and (6) fitness. To understand which videos in the BED recovery community had the broadest reach, we also examined how themes were associated with user engagement - concretely, the number plays (times the post was watched) and shares (times users shared a link to the post with other TikTok users). Notably, we found that the number of shares was significantly lower in posts that included diet culture critique than in those that did not. By contrast plays and shares were higher in posts with body monitoring than in those without. Our findings suggest that highly engaged with #BEDrecovery TikTok content may include the promotion of diet culture and potentially create an unproductive environment for individuals seeking BED recovery support.


Effect of anti-inflammatory compounds on edema formation and myeloperoxidase activity in the arachidonic acid-induced ear model in the mouse.
The arachidonic acid (AA)-induced ear edema model in the mouse has been demonstrated as an effective in vivo experimental tool to screen compounds showing anti-inflammatory activity. Since neutrophil influx is a component of the inflammatory reaction, we have modified this assay by quantitating myeloperoxidase (MPO) levels which reflect neutrophil accumulation in the edematous biopsies of the mouse ear. Our work has shown that orally administered 5-lipoxygenase inhibitors, dual inhibitors (CO/LO), and steroids dose-dependently inhibit both edema formation and MPO activity, whereas oral activity is not seen with NSAID's. There is a good correlation between the inhibition of edema formation and of MPO activity by these compounds. Thus, measurement of MPO, in addition to the AA-induced edema in the mouse ear, can provide another parameter to profile potential anti-inflammatory compounds.


Excision of a sclerosing polycystic adenosis of the deep parotid gland.
A 15-year-old male presented to the hospital with a 2-month history of a right parotid mass. Magnetic resonance imaging revealed an encapsulated 3.7 cm mass. Fine-needle aspiration suggested a monomorphic adenoma (prior to utilization of the Milan Classification system). Total parotidectomy was performed with dissection and preservation of the facial nerve. Surgical pathology identified the lesion as sclerosing polycystic adenosis (SPA) after examining the histopathological and immunohistochemistry findings. SPA is a rare lesion which leads to inflammatory changes in the salivary gland. The most common site impacted is the parotid gland but also can affect other major or minor salivary glands. The fibrocystic changes are morphologically like the histological developments of sclerosing adenosis of breast tissue. Those changes consist of fibrosis, apocrine metaplasia, and different degrees of proliferation of ducts, acini, and myoepithelial cells. The pathogenesis of SPA is unknown but recent studies suggest that it could be a neoplasm. Treatment with surgical excision is effective and its' recurrence is rare. This case report details the cytomorphology, histology, and immunohistochemical profile of SPA.


[Drug treatment of chronic myeloid leukemia: a cost effectiveness analysis of first- and second-line treatment ].
To determine the average cost-effectiveness ratio of treatment of patients with chronic myeloid leukaemia (CML): with first-line interferon alpha-2a (IFN) or with second-line imatinib following IFN failure. Cost-effectiveness analysis. A general cost-effectiveness analysis was performed using a model. This model consists of two phases: an induction phase of eight months, in which newly-diagnosed patients are treated with either IFN or imatinib, and a chronic treatment phase wherein patients are treated according the result of the induction phase. The model calculated the costs and effects of the treatment. Input for this model was derived from literature and expert opinion. Costs were based on real cost prices and tariffs. Treatment with imatinib resulted in 6.67 quality-adjusted life years (QALYs) and treatment with IFN resulted in 4.98 QALYs. Average costs of treatment with 5 million IU/day of IFN were [symbol: see text] 76,969 and [symbol: see text] 53,257 with 3 million IU/day. For imatinib at 400 mg/day the costs were [symbol: see text] 140,765 per patient. Costs per QALY were [symbol: see text] 15,445, [symbol: see text] 10,687 and [symbol: see text] 21,082, respectively. The addition of imatinib to the treatment options in CML resulted in increased quality-adjusted survival, but also higher costs of treatment.


Assessment of private economic benefits and positive environmental externalities of tea plantation in China.
Tea plantations are rapidly expanding in China and other countries in the tropical and subtropical zones, driven by relatively high private economic benefit. However, the impact of tea plantations on the regional environment, including ecosystem services and disservices are unclear. In this study, we developed an assessment framework for determining the private economic benefits and environmental externalities (the algebraic sum of the regulating services and disservices) of tea plantations in China. Our results showed that tea plantations provided private economic benefits of 5,652 yuan ha(-1) year(-1) (7.6 yuan = 1 USD in 2007) for tea farmers, plus positive environmental externalities of 6,054 yuan ha(-1) year(-1) for the society. The environmental externalities were calculated as the sum of the value of four regulating services, including carbon sequestration (392 yuan ha(-1) year(-1)); soil retention (72 yuan ha(-1) year(-1)); soil fertility protection (3,189 yuan ha(-1) year(-1)) and water conservation (2,685 yuan ha(-1) year(-1)), and three disservices, including CO2 emission (-39 yuan ha(-1) year(-1)), N2O emission (-137 yuan ha(-1) year(-1)) and nonpoint source pollution (-108 yuan ha(-1) year(-1)). Before the private optimal level, the positive environmental externalities can be maintained by private economic benefits; if a social optimal level is required, subsidies from government are necessary.


Do patients treated with Invisalign have less swelling after orthognathic surgery than those with fixed orthodontic appliances?
Patients treated with perioperative Invisalign for orthognathic surgery may experience less postoperative swelling than those with fixed appliances because of a lack of mucosal irritation from bonded brackets and wires. The aims of this study were to (1) compare facial swelling after orthognathic surgery in subjects with Invisalign to those with fixed appliances using 3-dimensional (3D) subtraction imaging and (2) determine if the type of operation influences differences in swelling. This is a retrospective case-control study. To be included in the case group (Invisalign), patients had to have had: (1) LeFort I and/or bilateral sagittal split osteotomies, with or without genioplasty, (2) perioperative orthodontic treatment using Invisalign, and (3) 3D photographs at postoperative timepoints 1 week (T1), 3-4 weeks (T2), and 5-7 weeks. A sex and operation-matched control group with fixed appliances (standard) was also included. The primary outcome variable was the volume of facial swelling, measured by subtraction imposition of the T1 and T2 3D images using reference images (5-7 weeks). Twenty-two subjects (36% female; mean age 20.7 ± 3.15 years) were included: Invisalign (n = 11) and standard (n = 11). For each group, 7 subjects had 1 operation (LeFort I or bilateral sagittal split osteotomies), and 4 had bimaxillary surgery ± genioplasty. At T1, the Invisalign group had significantly less swelling than the standard group (17.52 ± 10.79 cm3 vs 37.53 ± 14.62 cm3; P <0.001). By T2, the differences were no longer significant (6.62 ± 5.19 cm3 for Invisalign; 5.85 ± 4.39 cm3 for standard, P = 0.728). Subjects with Invisalign had significantly less facial swelling in the first postoperative week than those with fixed appliances.


The prevalence of hypertension and its relationship with obesity: results from a national blood pressure survey in Eritrea.
The prevalence of cardiovascular diseases has been shown to be on the increase in Africa based on hospital-based information and limited national surveys. A recent report on analysis of data from Health Information Management Systems (HIMS) highlighted an increasing burden of noncommunicable diseases (NCDs) in Eritrea, with the incidence of hypertension doubling in a space of 6 years. HMIS data are only a proxy of national prevalence rates, necessitating the conduct of national surveys. The WHO STEPwise approach to surveillance of NCDs was used for the national NCD risk factor survey in 2004. This report focuses on blood pressure (BP) and obesity (body mass index (BMI) > 30 kg/m2) as NCD risk factors in Eritrea. A total of 2352 people in age groups 15 to 64 years participated in the survey. The prevalence of hypertension defined as BP > 140/90 mmHg was 15.9% in the general population, with 16.4% in urban and 14.5% in rural areas, 17% of whom were males while 15% were females. BMI was positively associated with systolic (SBP), diastolic and mean arterial pressure. Although the prevalence of obesity (3.3%) was higher in females, the effect of BMI on BP was higher in males than in females (regression coefficient 0.64 and 0.38, respectively, P < or = 0.05), especially in those >45 years. BMI did not have a significant effect on BP in lean people (BMI < 19) and in those with high BMI, but was positively correlated to SBP in those with normal BMI (P < or = 0.02). BMI and age appear to play a synergistic role in creating a strong association with BP.


Myxoid calcified hamartoma and natal teeth: a case report.
We report the case of a 4-month-old Caucasian male baby who presented an uncommon mass in the anterior mandibular ridge. The patient was born with two natal mandibular incisors, which exfoliated some weeks after birth, followed by a growth of nodular lesion in the same region. Based on the clinical and histopathological features, the diagnosis was of myxoid calcified hamartoma. Immunohistochemical and scanning electron microscopic analysis of the lesion were performed. Hamartomas in the mandibular ridges associated with natal teeth are rare, but they must be considered in the differential diagnosis of common lesions, such as congenital granular cell epulis.


Definition and characteristics of acute exacerbation in adult patients with chronic rhinosinusitis: a systematic review.
Acute exacerbations (AE) in chronic rhinosinusitis (CRS) have been increasingly recognized as an important clinical issue. The purpose of this study is to summarize the current definitions and evaluation parameters of AE and then identify and quantify the clinical and immunopathologic characteristics of AE in CRS. A systematic review of the literature was performed on PubMed, Scopus, and Cochrane databases from January 1990 through August 2020 to identify studies relating to AE in CRS. Exclusion criteria included non-English and non-human studies, and case reports. The definitions of AE in CRS among all the studies were based on a description of short-term worsening sinonasal symptoms. Patient-reported sinus infection and exacerbation related medical treatment during the preceding 3 months to 1 year were used to evaluate the frequency of AE in CRS. The average decline in 22-item Sino-Nasal Outcome Test (SNOT-22) score during an exacerbation was 7.83 points relative to baseline. Comorbid asthma, SNOT-22 scores ≥24, allergic rhinitis, eosinophil count ≥150/μL and autoimmune disease were positively associated with an exacerbation-prone CRS phenotype. AE in chronic rhinosinusitis with nasal polyps (CRSwNP) was associated with increased expression of mucus cytokines including myeloperoxidase (percentage increase [PI] = 101%), IL-5 (PI = 125%), and IL-6 (PI = 162%) and could be predicted by the increasing mucus cystatin and periostin. The definition of AE in CRS is largely driven by patient-reported symptoms and is associated with several risk factors. Quantitative changes in mucus cytokines associated with AE in CRSwNP and may be used to predict events. The development of a consistent definition of AE in CRS is critical to help define disease control and treatment efficacy.


DDX4 (DEAD box polypeptide 4) colocalizes with cancer stem cell marker CD133 in ovarian cancers.
DDX4 (DEAD box polypeptide 4), characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), is an RNA helicase which is implicated in various cellular processes involving the alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. DDX4 is known to be a germ cell-specific protein and is used as a sorting marker of germline stem cells for the production of oocytes. A recent report about DDX4 in ovarian cancer showed that DDX4 is overexpressed in epithelial ovarian cancer and disrupts a DNA damage-induced G2 checkpoint. We investigated the relationship between DDX4 and ovarian cancer stem cells by analyzing the expression patterns of DDX4 and the cancer stem cell marker CD133 in ovarian cancers via tissue microarray. Both DDX4 and CD133 were significantly increased in ovarian cancer compared to benign tumors, and showed similar patterns of expression. In addition, DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. Furthermore, almost all CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4, suggesting a strong possibility that DDX4 plays an important role in cancer stem cells, and/or can be used as an ovarian cancer stem cell marker.


Number of ways of joining SH groups to form multi-peptide chain proteins.
The expression for the total number of isomeric structures formed upon oxidation of SH groups has previously been correctly obtained for single chain proteins only. Expressions have now been obtained for molecules consisting of 2 and 4 peptide chains of the types A2 and A2B2. The latter type is particularly important as exemplified by the immunoglobulins and the insulin receptor. For the oxidation of insulin A chain with 4 SH groups, the total number of isomeric A2 structures is 59--this is different to all the values previously reported. Lack of consideration of symmetry problems probably accounts for the erroneous results obtained by earlier workers for the number of ways of randomly joining two identical chains. The total number of isomeric structures formed from the oxidation of two light and two heavy chains with 5 and 11 SH groups respectively of the human immunoglobulin GI has been found to be 4.8 X 10(16).


Follow-up observation of patients with obstructive sleep apnea treated by maxillomandibular advancement.
This study aimed to evaluate the follow-up observation of patients with obstructive sleep apnea treated with maxillomandibular advancement (MMA) procedure with or without genial tubercle advancement (GTA). A total of 25 patients (mean age 37.1 ± 17.3 years) were included in the study. Cone-beam computed tomography scans were taken before treatment; after presurgical orthodontic treatment; immediately after MMA procedure; and follow-up visit. All Digital Imaging and Communications in Medicine files were analyzed using the Dolphin 3D Imaging software program (Dolphin Imaging and Management Solutions, Chatsworth, Calif) to determine the total airway volume (TAV), airway area (AA), and minimal cross-sectional area (MCA). Dolphin 3D voxel-based superimposition was used to determine the amount of skeletal advancement with MMA and changes after surgery. Significant increase in TAV, AA, and MCA was found with MMA treatment (40.6%, 28.8%, and 56.4%, respectively, P <0.0001). Smaller but significant decrease in TAV, AA, and MCA was found during a follow-up visit (20.0%, 9.7%, and 26.8%, respectively, P <0.0001) giving a net increase of TAV, AA and MCA (35.8%, 27.1%, and 45.9%, respectively). No significant differences were found in any of the airway measurements with or without the GTA procedure. The average forward movements of the maxilla, mandible, and chin were 6.6 mm, 8.2 mm, and 11.4 mm, respectively. A relapse of less than 1 mm was found in each of the variables during the follow-up period. No correlation was found between the magnitudes of skeletal advancement and the change in oropharyngeal airway space (OPAS). Significant increase in OPAS can be expected with MMA surgery with or without GTA procedure in patients diagnosed with obstructive sleep apnea. A partial loss in OPAS was found during the follow-up visit. The surgical movements were found to be stable, with less than 1 mm of relapse during the follow-up period, which was not clinically significant.


Prevention of deep vein thrombosis with low molecular-weight heparin in patients undergoing total hip replacement. A randomized trial. The German Hip Arthroplasty Trial (GHAT) Group.
In a double-blind, randomized multicentre trial, the efficacy and safety of two regimens for the prevention of postoperative venous thrombo-embolism, low-molecular-weight heparin (LMWH) CY 216 and unfractionated heparin (UH), were compared in 341 patients undergoing elective total hip replacement. A group of 169 patients received one subcutaneous injection of 48 mg (approximately 10,000 anti-Xa IC units) LMWH and two placebo injections per day and 172 patients received a fixed dose of 5000 IU UH t.i.d. Deep vein thrombosis was assessed by bilateral phlebography on day 14 +/- 1 after surgery. Phlebography was successfully performed in 136 patients in the LMWH group and 137 patients in the UH group. Deep vein thrombosis occurred in 45 of 137 patients (33.1%) treated with LMWH CY 216 and in 47 of 136 patients (34.3%) who received UH. Pulmonary embolism occurred in 2 of 167 evaluable patients (1.2%) in the LMWH group and in 6 of 168 patients (3.6%) in the UH group. In addition, the incidence of proximal deep vein thrombosis was evaluated and was found to be 10.3% (14/137 patients) in the LMWH group and 19% (26/136 patients) in the UH group (P = 0.044, two-sided). The safety of the treatments, as assessed by the incidence of major haemorrhage, intra- and postoperative blood loss, transfusion requirements, haemoglobin drop and frequency of wound haematomata, was similar in the two groups. It is concluded that prophylaxis of postoperative thrombo-embolism in hip surgery with one subcutaneous injection (48 mg) of LMWH CY 216 is as effective and as safe as prevention with fixed low-dose heparin (5000 IU t.i.d.). A tendency to reduced rates of pulmonary embolism (3.6% vs. 1.2%) and proximal deep vein thrombosis (19% vs. 10.3%) was observed in favour of LMWH CY 216.


Bis(μ-cobaltoceniumseleno-late-1:2κ2 Se:Se)bis[bis-(cobaltoceniumseleno-late-κSe)mercury(II)] tetra-kis-(hexa-fluorido-phosphate) aceto-nitrile disolvate.
The title compound, [Co6Hg2(C5H5)6(C5H4Se)6](PF6)4·2CH3CN or [Hg2(CcSe)6][PF6]4·2CH3CN (Cc = C10H9Co), was obtained as bright-orange needle-shaped crystals. It is a salt containing a tetra-cationic dimercury species with six cobaltoceniumseleno-late ligands, four hexa-fluorido-phosphate counter-ions and two aceto-nitrile solvent mol-ecules. The cation (point group ) has a bi-tetra-hedral {Hg2Se6} core with two bridging Se atoms and four terminal Se atoms.


Is attenuation of tRNA charging responsible for the inhibition of protein labelling accompanying depolarisation of the cerebral cortical cells?
Topical application of concentrated solutions of KCl resulted in reduction of charging of tRNA 7 min after s.c. injection of L-(U-14C) leucine. Neither radioactivity nor pool size of the total amino acids changed during this period.


Pharmacokinetics of tacrolimus in living donor liver transplant and deceased donor liver transplant recipients.
Hepatic dysfunction is an important determinant of the clearance of tacrolimus; however, the impact of reduced hepatic mass in living donor liver transplant (LDLT) patients on the drug exposure and clearance of tacrolimus is not known. AIM.: The aim of the present study is to compare the dosage, concentration and pharmacokinetics parameters of tacrolimus between LDLT and deceased donor liver transplant (DDLT) recipients. Daily doses used and trough concentrations measured were compared in 12 LDLT and 12 DDLT patients. Multiple blood samples were taken over one dosing interval after oral tacrolimus administration, and pharmacokinetics differences were compared. The mean tacrolimus dosage in first 14 postoperative days was (0.06 mg/kg/day) for LDLT and (0.09 mg/kg/day) for DDLT (P=0.0001). Despite the lower doses used, mean trough concentration was significantly greater in LDLT as compared with DDLT (8.8+/-2.5 ng/mL vs. 6.79+/-1.5 ng/mL, respectively, P=0.013). On the day of the pharmacokinetic study, minimum Concentration (Cmin), 12-hr postdose concentration (Clast), and average concentration (Cavg) were significantly greater in LDLT as compared with DDLT (LDLT: 6.6+/-2.4 ng/mL, 7.2+/-1.8 ng/mL, 8.9+/-3.0 ng/mL; DDLT: 4.3+/-1.0 ng/mL, 4.9+/-1.6 ng/mL, 5.9+/-1.4 ng/mL, P=0.02, 0.04, and 0.02, respectively). Dose normalized AUC was 37.7% greater and clearance, 47.5% lower in LDLT as compared with DDLT. Although not statistically significant, the dose normalized AUC was 37.7% greater and clearance 47.5% lower in LDLT as compared with DDLT. An initial tacrolimus dose reduction of about 30-40% may be prudent in LDLT compared with DDLT recipients.


scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells.
The high-order three-dimensional (3D) organization of regulatory genomic elements provides a topological basis for gene regulation, but it remains unclear how multiple regulatory elements across the mammalian genome interact within an individual cell. To address this, herein, we developed scNanoHi-C, which applies Nanopore long-read sequencing to explore genome-wide proximal high-order chromatin contacts within individual cells. We show that scNanoHi-C can reliably and effectively profile 3D chromatin structures and distinguish structure subtypes among individual cells. This method could also be used to detect genomic variations, including copy-number variations and structural variations, as well as to scaffold the de novo assembly of single-cell genomes. Notably, our results suggest that extensive high-order chromatin structures exist in active chromatin regions across the genome, and multiway interactions between enhancers and their target promoters were systematically identified within individual cells. Altogether, scNanoHi-C offers new opportunities to investigate high-order 3D genome structures at the single-cell level.


Study of feces of neotropical otters (Lontra longicaudis) in the Ayuquila-Armería basin, Mexico as biomonitors of the spatiotemporal distribution of pesticides.
The pesticides used have contributed to increasing food production; it has also caused them to be found in most ecosystems and have negative effects on biota. The neotropical otter (Lontra longicaudis) is vulnerable to pesticide accumulation and is characterized by being elusive, so it is necessary to address the use of indirect techniques that evaluate its populations' state in an efficient, logistically simple, and non-invasive way. This study aimed to determine the concentration of 20 pesticides in neotropical otter feces in the Ayuquila-Armería basin and to describe the spatiotemporal variation of these pesticides. The presence of 11 pesticides was determined. Imazalil, picloram, and malathion the pesticides with the highest concentrations; emamectin, λ-cyhalothrin, methomyl, and picloram were present in all samples. Emamectin was the only pesticide that presented significant differences concerning the temporality of the samplings, presenting higher concentrations in the wet season. Molinate concentrations showed significant differences concerning the location of the sampling sections in the basin; the lower part of the basin presented higher concentrations. The distribution of the populations of L. longicaudis in the Ayuquila-Armería basin does not respond to the degree of contamination by pesticides in surface waters or to the proximity to agricultural activities, and this in places with evident chemical and organic contamination and human presence. The use of otter feces for pesticide monitoring is an accepted non-invasive method to assess the degree of exposure and can be used to determine sites with pollution problems.


Structural and dynamical aspects of skin studied by multiphoton excitation fluorescence microscopy-based methods.
This mini-review reports on applications of particular multiphoton excitation microscopy-based methodologies employed in our laboratory to study skin. These approaches allow in-depth optical sectioning of the tissue, providing spatially resolved information on specific fluorescence probes' parameters. Specifically, by applying these methods, spatially resolved maps of water dipolar relaxation (generalized polarization function using the 6-lauroyl-2-(N,N-dimethylamino)naphthale probe), activity of protons (fluorescence lifetime imaging using a proton sensitive fluorescence probe--2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein) and diffusion coefficients of distinct fluorescence probes (raster imaging correlation spectroscopy) can be obtained from different regions of the tissue. Comparative studies of different tissue strata, but also between equivalent regions of normal and abnormal excised skin, including applications of fluctuation correlation spectroscopy on transdermal penetration of liposomes are presented and discussed. The data from the different studies reported reveal the intrinsic heterogeneity of skin and also prove these strategies to be powerful noninvasive tools to explore structural and dynamical aspects of the tissue.


Distinct serine residues in CBP and p300 are necessary for their activation by phenylephrine.
The ability of CREB binding protein (CBP) and p300 co-activators to stimulate transcription has previously been shown to be enhanced by treatment of cardiac cells with the hypertrophic agent phenylephrine (PE). This effect is dependent on activation of the mitogen activated protein kinase pathway (p42/44 MAPK). Here, we demonstrate the first identification of potential phosphorylation sites targeted by PE within the proteins CBP and p300. We show that serine 2015 of CBP and serine 89 of p300 are necessary for PE to stimulate the transcriptional activity of these proteins. Furthermore, we have shown that PE is capable of mediating phosphorylation of endogenous p300 at serine 89. This phosphorylation mediated regulation of CBP and p300 suggests a potential signal transduction pathway for the induction of cardiac cell hypertrophy by PE.


Successful diagnosis and management of biliary cast syndrome in a liver transplant patient using single operator cholangioscopy.
Biliary cast syndrome is an unusual complication of orthotopic liver transplantation with serious clinical implications. Surgical management has been the mainstay of treatment. Endoscopic techniques are recently described in the successful removal of biliary casts. Peroral single operator cholangioscopy is useful for direct visualization of bile ducts, tissue sampling and therapeutic applications. We report here a post liver transplant patient who underwent successful complete endoscopic removal of biliary cast using single operator cholangioscopy in a single sitting. Single operator cholangioscopy provides a safe means of diagnosing and treating patients with biliary cast syndrome.


Facial nerve paralysis related to HIV disease. Case report and dental considerations.
Neurologic manifestations of human immunodeficiency virus disease have been well documented and include peripheral neuropathy of the facial nerve. HIV-related peripheral facial nerve paralysis may be of predictive value in endemic populations, and it may be associated with acute HIV infection. It may herald the onset of seroconversion, and it is more common in the later stages of HIV disease. Treatment is palliative in nature and, although self-limiting, the condition may be of an extended duration and result in increased patient morbidity. The nutritional impact of HIV-related peripheral facial nerve paralysis on the patient and associated exacerbation of oral manifestations of HIV disease resulting from the presence of oral dryness are addressed. Early dental intervention is essential to reduce patient morbidity.


High prevalence of myocardial monoclonal antimyosin antibody uptake in patients with chronic idiopathic dilated cardiomyopathy.
Monoclonal antimyosin antibody studies were undertaken to assess the presence of myocardial uptake in patients with chronic idiopathic dilated cardiomyopathy. Three groups were studied: 17 patients with chronic (greater than 12 months) idiopathic dilated cardiomyopathy, 12 patients with a large, poorly contracting left ventricle not due to dilated cardiomyopathy (control patients) and 8 normal individuals. The patients in the cardiomyopathy and control groups showed a similar degree of clinical and functional impairment. Imaging was undertaken 48 h after antimyosin injection. The heart/lung ratio of antimyosin uptake was used to assess the results. The mean ratio in the cardiomyopathy group was 1.83 +/- 0.36 (range 1.40 to 2.80), a value significantly higher than that obtained in the control patients without cardiomyopathy (mean 1.46 +/- 0.04, range 1.38 to 1.50) or normal subjects (mean 1.46 +/- 0.13, range 1.31 to 1.6) (p less than 0.01). No difference in the ratio was noted between the normal subjects and control patients. Abnormal antimyosin uptake was seen in 12 (70%) of the 17 patients with cardiomyopathy and in only 1 (8%) of the 12 control patients. Positive monoclonal antimyosin antibody studies are highly prevalent in chronic idiopathic dilated cardiomyopathy.


Genetic covariance among measures of information processing speed, working memory, and IQ.
The genetic relationship between lower (information processing speed), intermediate (working memory), and higher levels (complex cognitive processes as indexed by IQ) of mental ability was studied in a classical twin design comprising 166 monozygotic and 190 dizygotic twin pairs. Processing speed was measured by a choice reaction time (RT) task (2-, 4-, and 8-choice), working memory by a visual-spatial delayed response task, and IQ by the Multidimensional Aptitude Battery. Multivariate analysis, adjusted for test-retest reliability, showed the presence of a genetic factor influencing all variables and a genetic factor influencing 4- and 8-choice RTs, working memory, and IQ. There were also genetic factors specific to 8-choice RT, working memory, and IQ. The results confirmed a strong relationship between choice RT and IQ (phenotypic correlations: -0.31 to -0.53 in females, -0.32 to -0.56 in males; genotypic correlations: -0.45 to -0.70) and a weaker but significant association between working memory and IQ (phenotypic: 0.26 in females, 0.13 in males; genotypic: 0.34). A significant part of the genetic variance (43%) in IQ was not related to either choice RT or delayed response performance, and may represent higher order cognitive processes.


[PTa bladder tumours: prognostic factors of recurrence and progression].
The aim of this work has been to study the prognostic factors of recurrence and progression of stage pTa bladder tumours. The case files of 193 patients, consecutively undergoing transurethral resection for primary pTa bladder tumour between 1980 and 2003, were retrospectively reviewed. Recurrence, progression and specific survival rates were studied. Prognostic factors associated with this type of tumour were then investigated. After a mean follow-up of 58 months, the recurrence rate was 56.5% and the rate of progression to stage T1 was 9.3%. The 10-year specific survival was 95.8%, but the 10-year recurrence-free survival rate was only 22.5%. Two risk factors for recurrence were identified on univariate analysis: haematuria at the time of diagnosis (p=0.009) and tumour size (p=0.01). Two factors were associated with a risk of progression: tumour size (p=0.03) and relapse during the first year after initial resection (p=0.003). None of these factors were independent prognostic factors on multivariate analysis. pTa bladder tumours present a high risk of recurrence. However, with attentive follow-up, the risk of progression is low and their 10-year specific survival rate is greater than 95 %. Tumour size at the initial diagnosis and early relapse increase the risk of progression to more aggressive disease.


Review of historic article: Huxley 1957 Muscle Structure and theories of contraction. Progress in Biophysics and biophysical chemistry, 7, 255-318.
The article by Andrew Huxley in this journal in 1957, "Muscle Structure and theories of Contraction" is much more than a standard review of a field. It is itself a major theoretical modelling achievement: the first mathematical model of the contractile process in skeletal muscle. That model was based on careful microscopic analysis of the striation patterns in skeletal muscles. Cited 4456 times, it holds the record for this journal.


ADULT TAPEWORM (PLATYHELMINTHES: CESTODA) PARASITES OF NORTH AMERICAN HERPETOFAUNA: CHECKLIST OF SPECIES AND IDENTIFICATION KEY TO FAMILIES AND GENERA.
An updated checklist of adult tapeworms (Platyhelminthes: Cestoda) that parasitize wild North American amphibians and reptiles is presented: A total of 58 species grouped in 15 genera, 5 families, and 3 orders, are registered; these infect a total of 90 species of reptiles and 88 species of amphibians in the region. An illustrated identification key for the families and genera listed is proposed.


[Development of a Series of Neutralizing Nanobodies against SARS-CoV-2 Spike Protein].
Countering the spread of new respiratory infections and reducing the damage they cause to society requires efficient strategies for rapidly developing of targeted therapeutics, such as monoclonal antibodies. Nanobodies, defined as variable fragments of heavy-chain camelid antibodies, have a set of characteristics that make them particularly convenient for this purpose. The speed at which the SARS-CoV-2 pandemic spread confirmed that the key factor in the development of therapeutics is obtaining highly effective blocking agents as soon as possible, as well as the diversity of epitopes to which these agents bind. We have optimized the selection process of blocking nanobodies from the genetic material of camelids and obtained a panel of nanobody structures with affinity to Spike protein in the lower nanomolar and picomolar ranges and with high binding specificity. The subset of nanobodies that demonstrate the ability to block the interaction between the Spike protein and the cellular ACE2 receptor was selected in experiments in vitro and in vivo. It has been established that the epitopes bound by the nanobodies are located in the RBD domain of the Spike protein and have little overlap. The diversity of binding regions may allow a mixture of nanobodies to retain potential therapeutic efficacy towards new Spike protein variants. Furthermore, the structural features of nanobodies, particularly their compact size and high stability, indicate the possibility of their utilization in the form of aerosols.


Integrated proteogenomic characterization of medullary thyroid carcinoma.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy derived from parafollicular cells (C cells) of the thyroid. Here we presented a comprehensive multi-omics landscape of 102 MTCs through whole-exome sequencing, RNA sequencing, DNA methylation array, proteomic and phosphoproteomic profiling. Integrated analyses identified BRAF and NF1 as novel driver genes in addition to the well-characterized RET and RAS proto-oncogenes. Proteome-based stratification of MTCs revealed three molecularly heterogeneous subtypes named as: (1) Metabolic, (2) Basal and (3) Mesenchymal, which are distinct in genetic drivers, epigenetic modification profiles, clinicopathologic factors and clinical outcomes. Furthermore, we explored putative therapeutic targets of each proteomic subtype, and found that two tenascin family members TNC/TNXB might serve as potential prognostic biomarkers for MTC. Collectively, our study expands the knowledge of MTC biology and therapeutic vulnerabilities, which may serve as an important resource for future investigation on this malignancy.


Zwischen Traum und Trauma - Aufbau und Betrieb einer Kohortenstation für Patient_innen mit COVID-19 in einem Akutspital - Eine Fallstudie.
Between dream and distress - Setting up and running a cohort ward for COVID-19 Patients at an acute hospital - A case study Abstract. Background: In the context of the pandemic, hospitals must be able to care for COVID-19 patients within a very short timeframe. Description of the setting up of a cohort ward for patients with COVID-19 on a surgical ward including the development of the nursing team. The intrinsic retrospective case study describes the situation, identifies special phenomena in a reflective manner and links them to existing knowledge. Data were anecdotal, routine data were collected in the context of nursing practice development. Setting up the cohort ward in a Swiss hospital consisted of structural and technical planning, infection control measures, the establishment of interprofessional structures, and internal communication. During the four-week operation, 71 patients were treated. The use of practice development methodology initiated a cultural change. The reflection describes a field of tension between "dream and distress": As a dream, the lived experience of optimal care, with well-functioning processes, sufficient material, sufficient personnel and a very good interprofessional cooperation was evaluated. Distress in the form of high infection rates as well as psychological and physical stress did not occur. After the cohort ward was closed, there was a risk working back in normal operations based on existing economical and organizational conditions, with the knowledge that a different cooperation and organization is possible. Positive experiences from the "crisis mode" should be used to further develop essential operations during normal times.


Higher Rates of Tuberculosis Among Class B1 Filipino Immigrants to Hawaii Compared to Nationwide, 2010-2014.
Immigrants to the United States from countries with a high burden of tuberculosis (TB) who have abnormal chest radiographs but negative sputum cultures during pre-immigration screening (TB Class B1) have a high risk of being diagnosed with TB disease within 1 year of arrival. Using 2010-2014 national surveillance data, we compared proportions of Class B1 Filipino immigrants who received a diagnosis of TB disease within 1 year of arrival to Hawaii to proportions in other U.S. states (not including Hawaii) using chi-squared tests. In Hawaii, 40/1190 (3.4%) of Class B1 Filipino immigrants to Hawaii received a diagnosis of TB disease within 1 year of arrival compared with 220/16,035 (1.4%) nationwide (P < .01). During 2010-2014, the percentage of recent Class B1 Filipino immigrants in Hawaii with TB disease diagnosed within 1 year of arrival was over twice that as nationwide.


Cutting Edge: IL-25 Targets Dendritic Cells To Attract IL-9-Producing T Cells in Acute Allergic Lung Inflammation.
Asthma is a common inflammatory disease of airways that is often associated with type 2 responses triggered by allergens, such as house dust mites (HDMs). IL-25 is a key mucosal cytokine that may be produced by stressed epithelial cells; it rapidly activates type 2 innate lymphoid cells to produce IL-13 and IL-5. When administered directly into lungs, IL-25 induces acute inflammation. However, the mechanisms underlying IL-25-initiated inflammation and the roles of this cytokine in the context of HDM-induced allergic inflammation are not fully understood. We show in this article that lung-resident conventional dendritic cells were direct targets of IL-25. IL-25-stimulated dendritic cells rapidly induced mediators, such as the chemokine CCL17, which, in turn, attracted IL-9-producing T cells. Importantly, these mechanisms also operated during HDM-induced allergic lung inflammation.


Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes.
We investigated the effect of single-nucleotide polymorphisms in sterol regulatory element-binding factors-1a and -2 (SREBF-1a and SREBF-2) and SREBF cleavage-activating protein (SCAP) genes on lipid-lowering response to simvastatin. In all, 146 hypercholesterolemic patients of European descent were prospectively treated with simvastatin 20 mg/day for over 6 months. Of these 99 subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. The mean percentage decrease in plasma total cholesterol (TC) was greater in subject carriers of SCAP 2386G allele compared with those homozygous for 2386A allele (-29.6+/-13.4 vs -22.1+/-13.8%, P=0.007). About 61% of the 2386G carriers were above-average responders for TC levels (DeltaTC -27.8%), whereas only 29% of 2386A homozygous reached this reduction (P=0.009). Our data suggest that the SCAP 2386A>G gene polymorphism was a significant predictor of TC and triglyceride responses to simvastatin treatment.


Is parental emotional reliability predictive of toddlers' learning and helping?
This study set out to examine how toddlers' word learning, imitation, and instrumental helping would be affected by the emotional reliability of a familiar model. Therefore, forty-two 24-month-olds were observed in interactions with their primary caregiver, who was evaluated on the quality of his or her sensitive behavior, such as responsiveness and emotional availability. Parents were first instructed how to administer different tasks to their child that included: teaching a novel word, demonstrating an "irrational" means of putting a dog inside a toy house through the chimney instead of the door, and appearing in need of help. The parent-child dyad was then observed during a 10-min period and the parent's level of responsiveness and availability was subsequently coded from this interaction. Finally, children were examined as to whether they learned a novel word, imitated, and helped their caregiver. It was observed that toddlers learned novel words better from an emotionally reliable primary caregiver. In addition, higher parental responsiveness and availability predicted better imitation in older children and higher levels of helping in girls. Taken together, these findings are the first to suggest that the emotional reliability of a familiar model, such as a parent's sensitive nature and consistent responsiveness, influences young children's willingness to learn and help.