Contact X-ray Brachytherapy as an Adjunct to a Watch and Wait Approach is an Affordable Alternative to Standard Surgical Management of Rectal Cancer for Patients with a Partial Clinical Response to Chemoradiotherapy.
Emerging evidence suggests that contact X-ray brachytherapy (CXB) may increase the clinical complete response rate and durability when administered after standard chemoradiotherapy in patients with rectal cancer. The addition of CXB in partial responders is therefore probably cost-effective. The affordability of widening access to CXB in the UK, however, has not been evaluated. Decision analytical modelling with Monte Carlo simulation was used to evaluate long-term costs for the management of patients with rectal cancers who were given a CXB boost when a clinical complete response was not initially achieved following chemoradiotherapy in order to facilitate a watch and wait approach. A third-party payer (National Health Service) perspective was adopted, probabilistic sensitivity analysis was carried out and a scenario analysis was performed to investigate the effect of the number of referral centres and number of patients treated with CXB. We estimate that 818 (95% confidence interval 628-1021) patients per year are eligible for CXB as an adjunct to a watch and wait approach in England and Wales. As this management is less costly than surgical management for each individual patient, the more patients treated, the more affordable the technology. Even if as few as 125 patients are treated nationally in 15 centres, the cost of implementing this technology would be less than £4 million. If the average number of patients treated in each centre is 30, this technology would be cost saving within 5 years. The cost of CXB is not prohibitive according to the National Institute for Health and Care Excellence threshold for implementation of new technology and may even be cost saving within 5 years compared with standard surgical management, depending on the uptake of the technology and the number of referral centres.


Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T-wave parameters.
The T wave of the electrocardiogram (ECG) reflects ventricular repolarization. Repolarization heterogeneity is associated with reentrant arrhythmias. Several T-wave markers (including QT interval) have been associated with ventricular arrhythmias, but studies linking such markers to underlying local repolarization time (RT) inhomogeneities are lacking. We aimed to investigate the relation of several T-wave markers to controlled drug-induced regional RT gradients in intact pig hearts. Repolarization time gradients were created by regional infusion of dofetilide and pinacidil in four atrially paced porcine Langendorff-perfused hearts placed inside a torso tank. From the 12-lead ECG on the torso tank, the mean, maximum, and dispersion (max-min) of QTtime , JTtime , Tpeak-end , Twidth , TQratio , dV/dtmax , Tarea , Tamp , and T-upslope duration were determined, as well as upslope end difference between leads V1 and V6 . Temporal T-wave parameters Tpeak-end , Twidth, and TQratio show a significant and high correlation with RT gradient, best reflected by mean value. Tarea (mean, max and dispersion) and dV/dtmax dispersion show only a moderate significant correlation. T-upslope duration shows a significant correlation in particular for mean values. Mean, maximum, or dispersion of QTtime and V1 -V6 upslope end difference were not significantly correlated with RT gradient. Composite 12-lead ECG T-wave parameters Tpeak-end , Twidth , TQratio , upslope duration, and Tarea show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QTtime do not reflect local RT heterogeneity. The composite T-wave metrics may thus provide better insights in arrhythmia susceptibility than traditional QTtime metrics.


The size distribution of poly(A) in newly synthesized and old Balbiani ring RNA.
The size distribution of newly synthesized and old poly(A) sequences on transcripts of the giant tissue specific puffs, Balbiani rings in salivary glands of Chironomus tentans has been determined. After labeling with [3H]adenosine, poly(A) containing Balbiani ring RNA(75S RNA) was selectively collected by means of a recently developed technique. This combines electrophoretic fractionation and affinity chromatography in one run by insertion of poly(U) immobilized in glass fiber filters in an agarose gel slab. The majority of short-term labeled poly(A) chains released from poly(A) containing 75S RNA molecules is distributed within a narrow size range migrating as one peak with a mean value of 103 +/- 2 nucleotides, which is probably the initial length of poly(A). The labeling pattern of ribonuclease resistant poly(A) stretches after chase with unlabeled adenosine displays a relatively broad and heterogeneous size spectrum from at least 20 to more than 100 nucleotides. The main peak of labeled adenylate core in newly formed poly(A) containing RNA of non-Balbiani ring origin is dispersed within a broader size range than that of Balbiani ring RNA and possesses an average value of 94 +/- 2 nucleotides. During chase conditions, the relative frequency of occurrence of poly(A) chains of 75S RNA in the size range of 100 nucleotides exhibits a significant decrease in parallel with a rather uniform gain in the size classes between 20--50 nucleotides. However, the results are inconsistent with the existence of an age-dependent shortening of poly(A) chains in the balbiani ring RNA. A significant portion of 75S RNA molecules remain associated with poly(A) segments which are essentially of original size even after 21 hr in the presence of unlabeled adenosine. This finding provides support for the possibility that the initiation of the poly(A) shortening in 75S RNA is a stochastic process.


The structure of capsular polysaccharide of the Pneumococcus type II.
The pneumococcus type II capsular polysaccharide (SII) is composed of singly-branched hexasaccharide repeating units, for which three alternative structures have been proposed. The correct structure has now been determined by consecutive eliminations of the sugar residues in the side chain. The terminal D-glucuronic acid group was eliminated by treating the fully methylated and esterified SIIpolysaccharide first with base, and then with weak acid. The hydroxyl group at C-6 in the penultimate D-glucose residue released by this elimination was transformed into the 6-deoxy-6-tosyl derivative, and the residue thereafter eliminated by treatment with base. As the side-chains were eliminated by these reactions, it is considered that they contain only two sugar residues, which thus excludes two of the three alternative structures. Structure 1 was further confirmed by subjecting SII to a Smith degradation, which yielded the tetrasaccharide L-Rhap-(1 yields 3)-L-Rhap-(1 yields 3)-L-Rhap-(1 yields 2-erythritol, characterised by methylation analysis.


Gliptins normalize posttraumatic hippocampal neurogenesis and restore cognitive function after controlled cortical impact on sensorimotor cortex.
Traumatic brain injury (TBI) often leads to long-term neurocognitive dysfunctions. Adult neurogenesis in the hippocampal dentate gyrus (DG) serves critical functions in cognition but can be disrupted by brain injury and insult in serval forms. In the present study, we explore the cellular and molecular targets of DPP-4 inhibitors (or gliptins) as related to hippocampal function and TBI cognitive sequelae. Two structurally different gliptins, sitagliptin and vildagliptin, were examined using a controlled cortical impact (CCI) model of moderate TBI in mice. Sensorimotor CCI, although distal from the hippocampus, impaired hippocampal-dependent cognition without obvious hippocampal tissue destruction. Neurogenic cell proliferation in the DG was increased accompanied by large numbers of reactive astrocyte. Increased numbers of immature granule cells with abnormal dendritic outgrowth were ectopically localized in the outer granule cell layer (GCL) and hilus. Long-term potentiation of dentate immature granule cells was also impaired. Both sitagliptin and vildagliptin attenuated the CCI-induced ectopic migration of doublecortin-positive immature neurons into the outer GCL and hilus, restored the normal dendritic branching pattern of the immature neurons and prevented astrocyte reactivation. Both gliptins prevented loss of normal synaptic integration in the DG after sensorimotor CCI and improved cognitive behavior. Sensorimotor cortical injury thus results in an abnormal neurogenesis pattern and astrocyte reactivation in the distal hippocampus which appears to contribute to the development of cognitive dysfunction after TBI. DPP-4 inhibitors prevent astrocyte reactivation, normalize the posttraumatic hippocampal neurogenesis and help to maintain normal electrophysiology in the DG with positive behavioral effect in a mouse model.


HLA-G expression and regulation during Pseudomonas aeruginosa infection in cystic fibrosis patients.
Deregulated immune response fails to control biofilm-forming bacteria, as Pseudomonas aeruginosa, in the lungs of cystic fibrosis (CF) patients. HLA-G is an immune-modulatory molecule involved in respiratory diseases and infections. HLA-G mRNA and protein were analyzed in plasma and exhaled breath condensate from CF patients undergoing intravenous antibiotic treatment, CF cell line and murine model. Therapy normalizes HLA-G plasmatic in CF patients suggesting a systemic anti-inflammatory role while in CF airway system, higher expression of HLA-G is associated with P. aeruginosa infection. CF cell line and murine model expressed higher HLA-G molecules in the presence of P. aeruginosa. Plasmatic and lung HLA-G expression suggest a role in reducing systemic inflammation and supporting P. aeruginosa infection.


Long-term outcome of thoracoscopic ablation and radiofrequency catheter ablation for persistent atrial fibrillation as a de novo procedure.
Limited data are available regarding the efficacy of thoracoscopic ablation as the first procedure for persistent atrial fibrillation (AF). We sought to compare the long-term efficacy of thoracoscopic ablation vs. radiofrequency (RF) catheter ablation as the first procedure for persistent AF. Between February 2011 and December 2020, 575 patients who underwent ablation for persistent AF were studied. Among them, thoracoscopic ablation was performed in 281 patients, RF catheter ablation in 228, and hybrid ablation in 66. Rhythm, clinical, and safety outcomes during 7-year follow-up were compared. The patients who underwent thoracoscopic ablation were older, had a higher prevalence of stroke, and had a larger left atrial volume than those who underwent RF catheter ablation. In the propensity score-matched population (n = 306), incidences of atrial tachyarrhythmia recurrence were 51.4% in the thoracoscopic ablation group and 62.5% in the RF catheter ablation group [adjusted hazard ratio (HR) 0.869, 95% confidence interval (CI) 0.618-1.223, P = 0.420]. Stroke and total procedural adverse events were not significantly different between thoracoscopic and RF catheter ablation (2.7 vs. 2.5%, P = 0.603, and 7.1 vs. 4.8%, P = 0.374, respectively). The hybrid ablation group showed similar rhythm outcomes compared with both the thoracoscopic and the RF catheter ablation groups. At the redo procedure, pulmonary vein gaps were more frequently observed in the RF catheter ablation group (32.6%) than in the thoracoscopic ablation group (7.9%) and in the hybrid ablation group (8.8%) (P < 0.001). As a first procedure in persistent AF, thoracoscopic ablation and RF catheter ablation showed comparable efficacy, clinical, and safety outcomes during long-term follow-up.


Dose-response relationship between tobacco and lung cancer: new findings.
The purpose of this work is to model the relationship between smoking-related variables and the risk of lung cancer by using parametric and non-parametric models. A hospital-based case-control study was conducted to ascertain the influence of smoking on risk of lung cancer. We used parametric logistic regression with a series of categorized independent variables and non-parametric logistic regression models. Such models allow for variables to be treated as continuous, since they avoid arbitrariness in the selection of cut-offs and furnish information on the dose-risk relationship. The results point to the possible existence of a saturation effect for a lifetime tobacco consumption of around 25 000-30 000 packets. Duration of habit and years of abstinence show a linear relationship marked by opposite, though similar, slopes, which would seem to indicate that for every year of smoking, risk rises by an amount (8.00%, 95% confidence interval (CI) 5.94-10.06) equal to the decline in risk for every year of abstinence (6.98%, 95% CI 2.53-11.84). Lastly, a lower age of smoking initiation appears to have an influence, although non-significant, on the appearance of the disease. The risk of lung cancer due to duration of the habit would seem to be proportional to years of abstinence, and there could be a saturation effect with respect to lifetime tobacco consumption.


Metabolic health and cardiometabolic risk clusters: implications for prediction, prevention, and treatment.
Among 20 leading global risk factors for years of life lost in 2040, reference forecasts point to three metabolic risks-high blood pressure, high BMI, and high fasting plasma glucose-as being the top risk variables. Building upon these and other risk factors, the concept of metabolic health is attracting much attention in the scientific community. It focuses on the aggregation of important risk factors, which allows the identification of subphenotypes, such as people with metabolically unhealthy normal weight or metabolically healthy obesity, who strongly differ in their risk of cardiometabolic diseases. Since 2018, studies that used anthropometrics, metabolic characteristics, and genetics in the setting of cluster analyses proposed novel metabolic subphenotypes among patients at high risk (eg, those with diabetes). The crucial point now is whether these subphenotyping strategies are superior to established cardiometabolic risk stratification methods regarding the prediction, prevention, and treatment of cardiometabolic diseases. In this Review, we carefully address this point and conclude, firstly, regarding cardiometabolic risk stratification, in the general population both the concept of metabolic health and the cluster approaches are not superior to established risk prediction models. However, both subphenotyping approaches might be informative to improve the prediction of cardiometabolic risk in subgroups of individuals, such as those in different BMI categories or people with diabetes. Secondly, the applicability of the concepts by treating physicians and communication of the cardiometabolic risk with patients is easiest using the concept of metabolic health. Finally, the approaches to identify cardiometabolic risk clusters in particular have provided some evidence that they could be used to allocate individuals to specific pathophysiological risk groups, but whether this allocation is helpful for prevention and treatment still needs to be determined.


Lack of micronuclei induction by fumonisin B(1) mycotoxin in BALB/c mice.
The genotoxic potential of fumonisin B(1) (FB(1)) in vivo in BALB/c mice (male and female) was assessed by induction of micronuclei (MN) formation in bone marrow polychromatic erythrocytes. The ratio of polychromatic erythrocytes to normochromatic erythrocytes (PCE/NCE) was also determined. Mice were injected intraperitoneally (i.p.) with FB(1) at a low dose (0.1 mg kg(-1) body mass), middle dose (1.0 mg kg(-1) body mass) and high dose (10 mg kg(-1) body mass) as single and multiple doses in normal saline to test the genotoxicity. Mitomycin C, a known clastogen, was used as positive control. The frequency of MN and the PCE/NCE value in animals treated with FB(1) at low, middle, and high doses in single dose studies, and the frequency of MN in multiple dose studies, were statistically non-significant from that of the controls injected with saline only. The multiple dose studies at all doses revealed that the PCE/NCE value was found to be reduced upon exposure to FB(1) as compared to the controls. In animals injected with multiple low doses of FB(1), the PCE/NCE value was found to be 0.66 in males and 0.82 in the females; at multiple middle doses the value was 0.30 in males and 0.41 in the females and was statistically significant (p < 0.001); however, at multiple high doses, the ratio was found to be 0.36 in both males and females. The present study confirms that FB(1) is non-genotoxic in nature while the reduced ratio of PCE/NCE suggests the cytotoxic nature of FB(1).


Comparison of the diuretic effect and absorption of a single dose of furosemide and free and the fixed combinations of furosemide and triamterene in healthy male adults.
The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F + T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men. A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC480) F2.58 micrograms.h.ml-1; F + T 2.46 micrograms.h.ml-1; FT 1.97 micrograms.h.ml-1. There was a significant reduction in the AUC480 of plasma triamterene (F + T 204.9 micrograms.h.l-1; FT 130.2 micrograms.h.l-1). Sodium excretion after F + T and FT was more pronounced than after F (F + T 302 mmol; FT 311 mmol; F259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F + T as well as after FT (F 121 mmol; F + T 104 mmol; FT 107 mmol). It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.


[Praemii loco: the Halle promotion of Georg Forster (1754-1794) and his Halle circle of contacts].
The 200th anniversary of Georg Forster's (1754-1794) graduation in Halle gives rise to refer to the modalities and practices of academic and especially medical graduations in the 18th century. As to Georg Forster a graduation "praemii loco" is concerned in recognition of the excellent achievements in natural sciences of the scientist who took part in the second circumnavigation of the globe by Cook.


Reproductive Medicine in Guinea Pigs, Chinchillas and Degus.
Guinea pigs, chinchillas, and degus are hystricomorph rodents originating from South America. They are commonly presented as exotic pets in veterinary practice. Reviewing the anatomy and physiology of their reproductive tract helps to offer better client education about preventive medicine and helps to act faster in emergency situations. Choosing the right anesthetic protocol helps to prevent complications. This article should aid as a guideline on the most common reproductive problems of these 3 species and help in making decisions regarding the best treatment options.


Hand-assisted laparoscopic live donor nephrectomy.
Hand-assisted laparoscopic donor nephrectomy (HLDN) may have advantages over laparoscopic donor nephrectomy, such as shorter learning curve, operation and warm ischaemia times. The aim of this study was to evaluate the feasibility and safety of HLDN. Between January 2000 and October 2002, 50 consecutive HLDN procedures were performed through a low transverse abdominal incision, 23 right sided and 27 left sided. The median age of the donors was 44 years. No HLDN required conversion to an open procedure. The median operating time for HLDN was 153 min. The median warm ischaemia time was 3 (range 1.0-4.5) min and the median blood loss was 50 (range 20-500) ml in both left- and right-sided procedures. Eight patients suffered ten minor complications during their admission. The duration of hospital stay was 5 days for donors. Three recipients developed graft failure owing to acute rejection, renal vein thrombosis and ischaemic necrosis. Both left- and right-sided HLDN procedures were feasible and safe through a low transverse abdominal incision.


In vitro modulation of L-arginine transport in trophoblast cells by glucose.
The uptake of the semi-essential amino acid, L-arginine, into trophoblast cells was measured with the aim of determining the effect of different glucose concentrations on L-arginine influx kinetics. This study used a novel superfused microcarrier culture system of BeWo cells (an established choriocarcinoma cell line with many characteristics of normal human trophoblast) and a rapid, paired-tracer dilution technique to measure unidirectional influx into the cells. At 10 mmol L-1 D-glucose, L-arginine unidirectional influx across the microvillous border of the cells was saturable with a Km of 1.14 +/- 0.14 mmol L-1 and a Vmax of 121. 36 +/- 5.89 nmol mg-1 protein min-1. When cells were preincubated for 24 h in the presence of 30 mmol L-1 D-glucose, there was a significant increase in the Vmax for L-arginine of nearly 30%. Similarly, preincubation in the presence of 1 mmol L-1 D-glucose and 12.5 mIU mL-1 human insulin reduced the Km for L-arginine influx by over 55%. These data suggest that the modulation of placental transport of L-arginine by glucose and insulin could contribute to the fetal macrosomia observed in diabetic mothers.


Sudden sensorineural hearing loss in a post-COVID-19 patient.
A detailed history and diagnostic evaluation for recent or past COVID-19 infection is vital in patients presenting with Sudden Sensorineural Hearing Loss (SSNHL) since SSNHL could be a sequelae of COVID-19 and timely diagnosis and intervention could significantly improve hearing and quality of life.


Etiology of overactive bladder: a diet and lifestyle model for diabetes and obesity in older women.
To evaluate a coherent, evidence-based hypothesis that specific modifiable lifestyle factors implicated in the development of diabetes and associated obesity are related to the onset of OAB. A hypothetical causative model for OAB involving modifiable lifestyle factors implicated in the development of diabetes and obesity was constructed, based on a systematic literature review. Secondary analysis of data was undertaken in a prospective cohort of women aged 40 and over, living in Leicestershire, UK. Subjects included 3,411 women free from OAB at baseline and 277 incident cases of OAB. Reported diet, lifestyle, morbid, and social factors were measured at baseline and incident cases at 1-year follow-up. Graphical chain modeling was used to estimate the associations between variables and identify likely pathways involved. All hypothesized lifestyle factors (physical activity, high glycemic index, and high energy intake) plus diabetes and obesity were retained within the graph as potential contributors. However, low physical activity was the only direct risk factor linked prospectively to the onset of OAB (RR 2.47; 95% CI 1.82, 3.36), in addition to older age. Poor lifestyle factors causally linked to diabetes and obesity may contribute to the onset of OAB; low physical activity appears to be an important modifiable causal factor for OAB operating directly as well as indirectly via pathways involving obesity or diabetes. Further research is needed to demonstrate a causal link between lifestyle and OAB.


trans-Diamminebis(1,2-di-cyano-ethene-1,2-di-thiol-ato)platinum(IV).
The title compound, [Pt(C4N2S2)2(NH3)2], represents an octa-hedral platinum(IV) complex with two trans-ammine and two mnt (mnt = 1,2-di-cyano-ethene-1,2-di-thiol-ato) ligands. The Pt-N and Pt-S distances are consistent with those in other platinum(IV) complexes. As a result of a slight canting of the coordination of the mnt ligand to the platinum(IV) atom, the nitrile nitro-gen atoms are positioned suitably to hydrogen-bond with adjacent ammines.


Metatranscriptomic Sequencing of Winter and Spring Planktonic Communities from Lake Erie, a Laurentian Great Lake.
Previous reports suggest planktonic and under-ice winter microbial communities in Lake Erie are dominated by diatoms. Here, we report the assembled metatranscriptomes of 79 Lake Erie surface water microbial communities spanning both the winter (28 samples) and spring (51 samples) months over spatial, temporal, and climatic gradients in 2019 through 2020.


Craniospinal radiation in the treatment of biopsy-proven intracranial germinomas: twenty-five years' experience in a single center.
The optimal treatment for intracranial germinomas remains controversial. We report on our 25-year experience using craniospinal irradiation (CSI) for this disease. Between September 1976 and May 2001, 39 patients with biopsy-proven intracranial germinomas seen at the Children's Hospital of Philadelphia/Hospital of the University of Pennsylvania received CSI. Thirteen of 36 patients (36%) had evidence of spinal dissemination. Median doses to the whole brain, primary site, and spine were 36 Gy (range, 18-44.2 Gy), 50.4 Gy (range, 44-55.8 Gy), and 30.6 Gy (range, 18-40 Gy), respectively. With a median follow-up of 7.1 years (range: 1.5-20.2 years), there have been no documented relapses. This includes 5 patients without spinal dissemination who received 18-19.8 Gy to the craniospinal axis; for these patients, the median length of follow-up was 5.5 years (range, 1.3-6.8 years). One patient, who had no evidence of disease 12.9 years after CSI, died of unknown causes 4 months later. Our treatment of intracranial germinomas with CSI has yielded outstanding results with no known relapses during a long follow-up period. These results must be considered when evaluating other approaches, such as chemotherapy only or local field irradiation.


Triple-color fluorescence co-localization of PD-L1-overexpressing cancer exosomes.
Programed cell death ligand 1 (PD-L1) is a protein biomarker overexpressed on exosomes derived from tumor cells. It plays an important role in tumor diagnosis, screening, evaluation of therapeutic efficacy, and prognosis. In this study, a facile method is presented to detect PD-L1-overexpressing cancer exosomes with high specificity and sensitivity. First, gold nanospheres (GNSs) were attached to the bottom of an eight-well chambered slide by electrostatic adsorption, forming the detection substrate. Then, Cy5-labeled CD63 aptamers (i.e., the capture probes) were modified on the GNSs by Au-S bond. After adding samples containing target exosomes which were stained by membrane dyes DiI in advance, FAM-labeled PD-L1 aptamers (i.e., the immunoprobes) were added to recognize PD-L1 on the target exosomes. By triple-color fluorescence co-localization (TFC) of the Cy5, DiI, and FAM channels, highly sensitive and reliable detection of the PD-L1-overexpressing exosomes was achieved in the concentration range 7.78 × 101 to 7.78 × 104 particles/mL with a detection limit down to 6 particles/mL. The advantages of the proposed detection method include the following; first, the detection substrate is easy to prepare and convenient to clean. Second, the TFC strategy can completely exclude nonspecific reaction sites and thus significantly improves the accuracy. Such a facile and reliable detection method holds a great potential in exosome-based cancer theranostics. In this paper, we proposed a triple-color fluorescence co-localization (TFC) strategy to significantly improve the reliability of exosome detection and the detection substrate is easy to prepare and convenient to clean. In addition, the LOD is down to 6 particles/mL, which is quite low compared with other detection methods.


A simplified approach for anaesthetic management of diagnostic procedures in children with anterior mediastinal mass.
Children with an anterior mediastinal mass (AMM) need general anaesthesia (GA) or deep sedation for diagnostic procedures more often than adult patients. Anaesthetic management to prevent such complications includes maintenance of spontaneous ventilation (SV) and prebiopsy corticosteroids/radiotherapy. We reviewed the medical records of children with AMM who were brought to the operating theatre for diagnostic procedures (prior to chemotherapy) between 2001 and 2013. Our aim was to describe the clinical features, radiological findings and anaesthetic management, as well as determine any association with complications. 25 patients (age range 10 months-14 years) were identified during the study period. Corticosteroid therapy was started before the biopsy for one patient. All 25 patients had GA/sedation. A senior paediatric anaesthesiologist was involved in all procedures. Among 13 high-risk patients, SV was maintained in 11 (84.6%) patients, ketamine was used as the main anaesthetic in 8 (61.5%) patients, 6 (46.2%) patients were in a sitting position and no airway adjunct was used for 7 (53.8%) patients. There were 3 (12.0%) minor complications. Based on our results, we propose a simplified workflow, wherein airway compression of any degree is considered high risk. For patients with high-risk features, multidisciplinary input should be sought to decide whether the child would be fit for a procedure under GA/sedation or considered unfit for any procedure. Recommendations include the use of less invasive methods, involving experienced anaesthesiologists to plan the anaesthetic technique and maintaining SV.


Environmental effects on variation and covariation in reproductive traits of Western Bluebirds.
Environmental conditions can influence the expression and correlations of phenotypic traits. I studied phenotypic plasticity in reproductive traits of Western Bluebirds breeding in northern Arizona. Data collected over 4 years on two contrasting habitats identified significant spatial and temporal variation in bluebird reproduction. Clutch size was similar over different environmental conditions whereas timing of clutch initiation, percent fledging success, and frequency of second nest attempts were flexible. Correlations between traits varied widely-often changing sign-among samples from different years or habitats. Correlations of traits with reproductive success were also dependent on environmental conditions. Variation in traits reflected behavioral responses by nesting adults to differences in time for breeding and feeding conditions. Density of trees differed between habitats and had opposing effects on these environmental variables; breeding seasons were generally longer, but feeding rates to nestlings were lower on the more open habitat. Late Spring snows delayed reproduction and increased the importance of limited time for breeding; feeding conditions were more influential following a dry Spring. This and other studies illustrate that data on phenotypic plasticity are important when evaluating the ecological and evolutionary forces underlying life histories.


A malignant omental extra-gastrointestinal stromal tumor on a young man: a case report and review of the literature.
Gastrointestinal stromal tumors (GIST) are uncommon intra-abdominal tumors. These tumors tend to present with higher frequency in the stomach and small bowel. In fewer than 5% of cases, they originate primarily from the mesentery, omentum, or peritoneum. Furthermore, these extra-gastrointestinal tumors (EGIST) tend to be more common in patients greater than 50 years of age. Rarely do EGIST tumors present in those younger than 40 years of age. We report a case of a large EGIST in a 27-year-old male. An abdominal pelvic computerized tomography imaging demonstrated an intra-abdominal mass of 22 cm, without invasion of adjacent viscera or liver lesions. This mass was resected en bloc with its fused omentum and an adherent portion of sigmoid colon. Pathology results demonstrated a malignant gastrointestinal stromal tumor with positive CD117 (c-kit) staining, and negative margins of resection, and no continuity of tumor with the sigmoid colon. Due to the malignant and aggressive nature of this patient's tumor, he was started on STI-571 as adjuvant chemotherapy. Stromal tumors of an extra-gastrointestinal origin are rare. Of the reported omental and mesenteric EGISTs in four published series, a total of 99 tumors were studied. Of the 99 patients in these series only 8 were under 40 years of age, none were younger than 30 years old; and only 5 were younger than 35 years old. Our patient's age is at the lower end of the age spectrum for the reported EGISTs. Young patients who present with an extra-gastrointestinal stromal tumor (EGIST), who have complete resection with negative margins, have a good prognosis. There is little data to support the role of STI-571 in adjuvant or neoadjuvant therapy after curative resection. Given the lack of data, the use of STI-571 must be individualized.


Tumor cell phagocytosis. Its occurrence in a patient with medulloblastoma.
Phagocytosis was observed in tumor cells from a metastatic medulloblastoma to the bone marrow. Erythrocytes and leukocytes were seen in the cytoplasm of the tumor cells. Another abnormal finding was self-phagocytosis, in which tumor cells engulfed one another. The mechanism of tumor phagocytosis is not yet clearly understood. Only a few cases of erythrophagocytosis by epithelial tumor cells have been reported in the literature. To our knowledge, this is the first reported case of a medulloblastoma with hematophagocytosis.


The regulation role and diagnostic value of fibrinogen-like protein 1 revealed by pan-cancer analysis.
Although the role of fibrinogen-like protein 1 (FGL1) in tumorigenesis is well known, a pan-cancer analysis of FGL1 lacks. We used bioinformatics techniques to analyze cancer data from publicly available datasets from The Cancer Genome Atlas, UALCAN, TIMER, Gene Expression Profiling Interactive Analysis, cBioPortal, Search Tool for the Retrieval of Interacting Genes, and DAVID. FGL1 expression was significantly regulated in various common tumors than in normal tissues; it was increased in lung adenocarcinoma and decreased in colon adenocarcinoma. Cox regression analysis demonstrated that the upregulation of FGL1 expression was correlated with poor overall survival (OS) and disease-free survival (DFS) in stomach adenocarcinoma, brain low-grade glioma, cervical squamous cell carcinoma, and endocervical adenocarcinoma. Decreased FGL1 methylation levels were observed in majority of tumor types. FGL1 expression was significantly associated with the levels of immune cell subtypes and immune checkpoint genes. Deep deletion was the most common genetic mutation in FGL1 that led to frame-shift mutations, which was closely associated with poor progression-free interval, disease-specific survival, and OS in patients with FGL1 mutations. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that FGL1-related genes participate in diverse pathways. Ubiquitin-mediated proteolysis is significantly correlated to the function of FGL1, which was identified for the first time in the present study. This pan-cancer study provides a deep understanding of the functions of FGL1 in progression of many tumors and demonstrates that FGL1 may be a potential biomarker for the diagnosis, prognosis, and immune infiltration in cancer.


Dentin perfusion effects on the shear bond strengths of bonding agents to dentin.
The effect of pulpal pressure on the shear bond strength of Scotchbond and Gluma was evaluated in the presence and absence of smear layers. There was no statistically significant difference in bond strength for either Scotchbond or Gluma on dentin with a smear layer in the presence or absence of 32 cm of hydrostatic pulpal pressure. When no pulpal pressure was present and the smear layer was removed, the bond strength of Scotchbond fell while that of Gluma nearly doubled. When 32 cm of pulp pressure was applied, the bond strength of Scotchbond/Silux fell 86% and that of Gluma fell 75% in 24 hours.


Effects of Lipids on in Vitro Release and Cellular Uptake of β-Carotene in Nanoemulsion-Based Delivery Systems.
β-Carotene (BC) nanoemulsions were successfully prepared by microfluidization. BC micellarization was significantly affected by bile salts and pancreatin concentration. Positive and linear correlation was observed between BC release and bile salts concentration. Pancreatin facilitated BC's release in simulated digestion. Compared to the control (bulk oil) (4.6%), nanoemulsion delivery systems significantly improved the micellarization of BC (70.9%). The amount of BC partitioned into micelles was positively proportional to the length of carrier oils. Unsaturated fatty acid (UFA)-rich oils were better than saturated fatty acid (SFA)-rich oils in transferring BC (p < 0.05). No significant difference was observed between monounsaturated fatty acid (MUFA)-rich oils and polyunsaturated fatty acid (PUFA)-rich oils (p > 0.05). A positive and linear relationship between the degree of lipolysis and the release of BC in vitro digestion was observed. Bile salts showed cytotoxicity to Caco-2 cells below 20 times dilution. BC uptake by Caco-2 cells was not affected by fatty acid (FA) compositions in micelles, but BC uptake was proportional to its concentration in the diluted micelle fraction. The results obtained are beneficial to encapsulate and deliver BC or other bioactive lipophilic carotenoids in a wide range of commercial products.


"Upstream markers" provide for early identification of patients at high risk for myocardial necrosis and adverse outcomes.
For patients presenting with acute coronary syndrome (ACS) to the emergency department, early identification of those that are at high risk for subsequent myocardial necrosis or adverse outcomes would allow earlier or more aggressive treatment. We determined if a panel of biomarkers can be used to identify high risk patients. A cohort (84 females/132 males) from our 1996 ACS study population that had EDTA specimens stored (-70 degrees C) was selected and the earliest available specimen was analyzed for 11 biomarkers (IL-6, IL-8, MCP-1, VEGF, L-selectin, P-selectin, E-selectin, ICAM-1, VCAM-1, NT-proBNP, cTnT). These data were linked to the existing cTnI and health outcome databases for this population. ROC curve analysis for myocardial necrosis (i.e., peak cTnI >0.04 microg/l) identified 3 candidate biomarkers. These 3 biomarkers were applied together to generate a panel test (2 of the 3 biomarkers increased for a positive result) and assessed for its ability to identify patients at risk for myocardial necrosis and the combined endpoint of death, myocardial infarction (MI) and heart failure (HF). The panel test (IL-6, NT-proBNP, E-selectin) alone detected 60% (95% CI: 49-69; false positive rate: 26%) of subjects that would be classified with myocardial necrosis. Kaplan-Meier and Cox proportional analyses indicated that patients positive by the biomarker panel (including those with cTnI < or =0.04 microg/l) had significantly worse outcomes (death/MI/HF) as compared to those negative by both cTnI and the panel test. A biomarker panel analyzed early after pain onset can identify individuals at risk for both myocardial necrosis and the combined endpoint of death/MI/HF. Additional prospective studies are required to assess this panel for both early MI detection and to further refine which health outcomes (death, MI, HF) are associated with positive panel results.


A monoclonal antibody against catalytic subunits of acetylcholinesterase in the electric organ of an electric ray, Narke japonica.
A hybridoma cell line secreting a monoclonal antibody against catalytic subunits of acetylcholinesterase in the electric organ of Narke japonica has been obtained by using a mouse immunized with the nerve terminal membranes prepared from the electric organ of Narke japonica. This monoclonal antibody (Nj-501) reacted with asymmetric, low salt-soluble and detergent-soluble forms of acetylcholinesterase of the electric organ of Narke japonica. Immunoblot analysis showed that the catalytic subunits of the asymmetric, low salt-soluble and detergent-soluble forms of acetylcholinesterase were polypeptides of molecular weight (Mr) 70K, 70K / 66K and 66K, respectively. Nj-501 markedly inhibited the activity of all these forms of acetylcholinesterase.


Short-term effects of various ozone metrics on cardiopulmonary function in chronic obstructive pulmonary disease patients: Results from a panel study in Beijing, China.
Short-term exposure to ambient air pollution has been associated with lower pulmonary function and higher blood pressure (BP). However, controversy remains regarding the relationship between ambient multiple daily ozone (O3) metrics and cardiopulmonary health outcomes, especially in the developing countries. To investigate and compare the short-term effects of various O3 metrics on pulmonary function, fractional exhaled nitric oxide (FeNO) and BP in a panel study of COPD patients. We measured pulmonary function, FeNO and BP repeatedly in a total of 43 patients with COPD for 215 home visits. Daily hourly ambient O3 concentrations were obtained from central-monitoring stations close to subject residences. We calculated various O3 metrics [daily 1-h maximum (O3-1 h max), maximum 8-h average (O3-8 h max) and 24-h average (O3-24 h avg)] based on the hourly data. Daily indoor O3 concentrations were estimated based on estimated indoor/outdoor O3 ratios. Linear mixed-effects models were used to estimate associations of various O3 metrics with cardiopulmonary function variables. An interquartile range (IQR) increase in ambient O3-8 h max (80.5 μg/m3, 5-d) was associated with a 5.9% (95%CI: -11.0%, -0.7%) reduction in forced expiratory volume in 1 s (FEV1) and a 6.2% (95%CI: -10.9%, -1.5%) reduction in peak expiratory flow (PEF). However, there were no significant negative associations between ambient O3-1 h max, O3-24 h avg and FEV1, PEF. An IQR increase in ambient O3-1 h max (85.3 μg/m3, 6-d) was associated with a 6.7 mmHg (95%CI: 0.7, 12.7) increase in systolic BP. The estimated indoor O3 were still significantly associated with reduction of FEV1 and PEF. No significant associations were found between various O3 metrics and FeNO. Our results provide clues for the adverse cardiopulmonary effects associated with various O3 metrics in COPD patients and highlight that O3-8 h max was more closely associated with respiratory health variables.


Invasive opportunistic mycoses: clinical trials review, 2007-2008.
Invasive fungal infections are important causes of morbidity and mortality in severely ill patients. The past decade has seen considerable expansion in the development of new antifungal compounds, and clinical trials continue to define their role in our antifungal armamentarium. This brief article summarizes the most pivotal clinical trials in the settings of treatment and prophylaxis of invasive opportunistic mycoses published between 2007 and 2008.


Gamma-ray imaging with a Si/CsI(Tl) Compton detector.
We present results from Compton imaging of gamma-ray sources using an instrument constructed from thin silicon scattering detectors and CsI(Tl) absorbing detectors. We have successfully imaged single and double point sources for several common radioactive isotopes ((137)Cs, (60)Co, (22)Na, (54)Mn). The measured angular resolution is 11.6( composite function) FWHM at 662keV. In parallel with the hardware effort, a GEANT4-based simulation code was developed. Comparisons between real and simulated data are discussed.


TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers.
We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-alpha knocked out (TNF-alphaRKO) fail to develop fibroproliferative lesions after asbestos exposure. There is good evidence that TNF-alpha plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we present here new data obtained by in situ hybridization showing that expression of the genes coding for transforming growth factor alpha (TGF-alpha) and platelet-derived growth factor A-chain (PDGF-A) is reduced in the TNF-alphaRKO mice compared with control animals. In accordance with this observation, data on bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-alphaRKO mice show no increases over unexposed control animals. In contrast, wild-type control mice exposed to asbestos exhibit 15- to 20-fold increases in BrdU uptake and consequently develop fibrogenic lesions. Even though the levels of TNF-alpha gene expression and protein production were increased in the asbestos-exposed TNF-alphaRKO mice, the lack of receptor signaling protected the mice from developing fibroproliferative lesions. We agree with the view that TNF-alpha is essential for the development of interstitial pulmonary fibrosis and postulate that TNF-alpha mediates its effects through activation of other growth factors such as PDGF and TGF-alpha that control cell growth and matrix production.


Identification of aryl dihydrouracil derivatives as palm initiation site inhibitors of HCV NS5B polymerase.
Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase.


Reconstruction of hepatic organoid by rat small hepatocytes and hepatic nonparenchymal cells.
Hepatic cells isolated from an adult rat liver, consisting of small hepatocytes (SHs), mature hepatocytes (MHs), liver epithelial cells (LECs), Kupffer cells, sinusoidal endothelial cells, and stellate cells, were cultured in a medium supplemented with 10% fetal bovine serum, 10 mmol/L nicotinamide, 1 mmol/L ascorbic acid 2-phosphate, 10 ng/mL epidermal growth factor, and 1% dimethyl sulfoxide. The SHs rapidly proliferated and formed a colony. About 10% of cytokeratin 8 (CK8)-positive cells formed SH colonies. All SHs at day 10 immunocytochemically showed positivity for albumin, transferrin, CK8, and CK18, which are markers for hepatocytes. In contrast, alpha-fetoprotein (AFP)-, CK14-, OC2-, and glutathione S-transferase placental type (GST-P)-positive cells, which are thought to be markers for hepatic immature cells, were rarely observed. At day 20 some cells in the colonies were positive for AFP, CK7, CK19, and GST-P. LECs and stellate cells proliferated and surrounded the colonies. About 2 weeks after plating, piled up cells were often observed on the SH colonies. In those colonies LECs and stellate cells invaded under the colonies. The invasion of the cells and gradual deposits of extracellular matrix (ECM) such as type I collagen, type IV collagen, and laminin induced alteration of the shape of the SHs from relatively flat to cuboidal or rectangular. With the cellular structural changes, the expression of albumin, connexin 32 (Cx32), and tryptophan 2,3-dioxygenase (TO) messenger RNAs increased. In addition, overlapping nonparenchymal cells (NPCs) on the piled up cells induced the formation of duct- or cyst-like structures consisting of MHs. In the present experiment we showed that SHs could differentiate to MHs by interacting with NPCs and ECM. Thus, SHs may be "committed progenitor cells" that can further differentiate into MHs.


Study on cytotoxicity and structure-activity relationship of HL-7702 cell exposed to naphthoquinones.
The acute cytotoxicities of six naphthoquinone compounds, including Atovaquone, Buparvaquone, Menadione, 2-acetoxy-1,4-naphthoquinone and 2-ethoxy-1,4-naphthoquinone, to HL-7702 cells were determined. The results showed that the toxicities of these naphthoquinones were characterized by a steep response pattern except for 2-hydroxy-1,4-naphthoquinone. Meanwhile, the cellular injuries were unrecoverable. Several molecular descriptors, such as the octanol-water partition coefficients (LogP), diameter (Dia) and topological index (TIndx), played an important role in the toxicity of naphthoquinones to HL-7702 cell. Our results provide a foundation for further investigation using 3D-QSAR and HQSAR to evaluate the aquatic ecological risk and the possible mechanisms of toxicity of naphthoquinones.


An unusual hormone pattern in a virilized woman affected by Sertoli-Leydig cell tumor. Report of a case.
A 24-year-old woman was admitted to hospital because of hirsutism, virilism and amenorrhea, which had appeared 6 months earlier. Endocrinological evaluation showed a slightly elevated serum level of testosterone (1.2 +/- 0.05 ng/ml), normal plasma levels of dehydroepiandrosteronesulfate (DHEA-S) (2,070 +/- 6 ng/ml), androstenedione (1.8 +/- 0.5 ng/ml) and sex hormone-binding globulin (SHBG)(42 +/- 3 nM/L); there was normal urinary 17-ketosteroid (17-KS) excretion (11.7 mg/24 h), low urinary estrogen (E) excretion (3 +/- 0.4 micrograms/24 h), suppressed basal gonadotropin concentrations (LH 0.9 microUI/ml; FSH 3.2 microUI/ml) and an exaggerated response to the LH-RH test. At laparotomy, a monolateral ovarian tumor was found, which was proved histologically to be a Sertoli-Leydig cell tumor. After tumor ablation, a regular menstrual cycle followed and progressive reduction of virilism was noted. This was followed within 4 months by complete normalization of LH, FSH, estrogen and progesterone serum levels. The responsiveness to LH-RH also became normalized. Two years after this operation, the patient had a normal pregnancy. This case of virilization in a woman affected by a benign Sertoli-Leydig cell tumor was primarily characterized by an unusual response of the hypothalamopituitary axis against an endocrinological background of notable alteration of the androgen/estrogen ratio, where the androgens were slightly increased and the estrogens greatly reduced.


Sequence of guinea pig myelin basic protein.
This paper proposes a tentative amino acid sequence of guinea pig myelin basic protein obtained by comparison of peptide fragments of the guinea pig and bovine proteins. Analyses of the tryptic peptides confirmed the known sequence differences in the NH2-terminal half of the molecule and showed that in the COOH-terminal half of the guinea pig protein Ser131 was missing, Ala136 - His137 was deleted, Leu140 was replaced by Phe, and an extra Ala was inserted somewhere within sequence 142-151 (tryptic peptide T23 ). Sequence determination of guinea pig tryptic peptides corresponding to residues 130-134 ( T20 ), 135-138 ( T21 ), and 142-151 ( T23 ) of the bovine protein confirmed the above sequence changes and placed the extra Ala between Gly142 and His143 . The sequence of the region corresponding to bovine residues 130-143 is thus Ala-Asp-Tyr-Lys-Ser-Lys-Gly-Phe-Lys-Gly-Ala-His. No species differences were observed in the amino acid compositions of the remaining tryptic peptides obtained from the COOH-terminal half of the molecule. Based upon these results, the guinea pig basic protein contains 167 amino acid residues and has a molecular weight of 18,256.


Novel mutations in the ATP2C1 gene in two patients with Hailey-Hailey disease.
Benign familial chronic pemphigus (Hailey-Hailey disease, HHD) is a rare hereditary condition characterized by development of blisters at sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene, which encodes the human secretory pathway calcium ATPase 1 (hSPCA1), have been identified as possible causative mutations. Studying Hungarian patients with HHD, we found two novel, distinct, heterozygous mutations. In a 65-year-old man with a 41-year history of severe recurrent symptoms, a single nucleotide insertion, 1085insA, was detected. In a patient whose symptoms were induced by environmental contact allergens, we found a nonsense mutation, Q506X, in exon 17. Our study further illustrates the diversity of mutational events in the pathogenesis of HHD.


Sentinel Lymph Node Mapping With Near-Infrared Fluorescent Imaging Using Indocyanine Green: A New Tool for Laparoscopic Platform in Patients With Endometrial and Cervical Cancer.
Indocyanine green (ICG) represents a feasible alternative to the more traditional methods of sentinel lymph node (SLN) mapping, and interest in this promising tracer is growing. This report outlines our experience with ICG in a minimally invasive laparoscopic approach in women with endometrial cancer and cervical cancer using the Storz SPIES ICG near-infrared fluorescence imaging technology. A total of 49 patients with clinical stage I endometrial cancer (n = 40) or stage I cervical cancer (n = 9) were retrospectively reviewed. All patients had undergone simple or radical laparoscopic hysterectomy with pelvic and/or aortic lymphadenectomy and SLN mapping by means of an intracervical injection of ICG dye at the 3 o'clock and 9 o'clock locations after the induction of general anesthesia. The detection rate of ICG was 100% (49 of 49). The rate of bilateral SLN detection was 86% (42 of 49). Positive lymph nodes were found in 6 patients (12%), with at least 1 positive SLN. The sensitivity and negative predictive value of SLN detection were 100%. All procedures were successfully completed without conversion to open laparotomy, and no intraoperative or postoperative complications occurred. In our preliminary experience, ICG showed a high overall detection rate, and bilateral mapping appears to be a feasible alternative to the more traditional methods of SLN mapping in patients with endometrial cancer and cervical cancer. Laparoscopic SLN mapping with ICG appears to be safe, easy, and reproducible, with a positive impact on patient management.


Combined fine needle percutaneous transhepatic cholangiography and hypotonic duodenography in obstructive jaundice.
The information obtained at percutaneous transhepatic cholangiography in patients with obstructive jaundice is not always conclusive about the nature of the obstructing lesion. Hypotonic duodenography performed immediately after transhepatic cholangiography may assist in such cases by demonstrating the presence or absence of duodenal involvement. This ensures that the appropriate surgical procedure can be planned before operation. Our experience using the combined techniques in nine patients is reported.


Sooner, later, or never: Changing fertility intentions due to Covid-19 in China's Covid-19 epicentre.
Using survey data collected from Hubei province, China's Covid-19 epicentre, in August 2020, this study examines how fertility intentions of Chinese citizens changed during the Covid-19 pandemic. We consider not only whether people changed their fertility plans due to Covid-19 but also distinguish three types of change: bringing forward ('sooner'), postponing ('later'), and abandoning ('never') planned fertility. Over half of those who planned to have a child intended to change their fertility plans due to Covid-19. Younger individuals, those of non-Han ethnicities, urban residents, those with one child already, and those with ever-infected family members were more likely to change their fertility plans. While the effects of some characteristics seem to be short term, other characteristics such as age and number of children show more consequential influences. Older individuals and those planning their second child were particularly prone to abandoning their childbearing plans due to Covid-19. The pandemic may thus complicate China's latest efforts to boost its low fertility.


Efficient production of acetoin in Saccharomyces cerevisiae by disruption of 2,3-butanediol dehydrogenase and expression of NADH oxidase.
Acetoin is widely used in food and cosmetic industry as taste and fragrance enhancer. For acetoin production in this study, Saccharomyces cerevisiae JHY605 was used as a host strain, where the production of ethanol and glycerol was largely eliminated by deleting five alcohol dehydrogenase genes (ADH1, ADH2, ADH3, ADH4, and ADH5) and two glycerol 3-phosphate dehydrogenase genes (GPD1 and GPD2). To improve acetoin production, acetoin biosynthetic genes from Bacillus subtilis encoding α-acetolactate synthase (AlsS) and α-acetolactate decarboxylase (AlsD) were overexpressed, and BDH1 encoding butanediol dehydrogenase, which converts acetoin to 2,3-butanediol, was deleted. Furthermore, by NAD(+) regeneration through overexpression of water-forming NADH oxidase (NoxE) from Lactococcus lactis, the cofactor imbalance generated during the acetoin production from glucose was successfully relieved. As a result, in fed-batch fermentation, the engineered strain JHY617-SDN produced 100.1 g/L acetoin with a yield of 0.44 g/g glucose.


Long-term in vitro turtle preparation for the study of spinal organization.
A method by which muscles, nerves, and a section of spinal cord from a turtle can be stably maintained in vitro for many days has been developed. Tests of the viability of central and neuromuscular synapses, and the histochemical properties of muscle fibers have indicated that the preparation is viable and shows little decrement in function over a period of 3-5 days. The system allows continuous access to the muscles, nerves, and the spinal cord, as well as a controlled external environment.


Polymeric glabrescione B nanocapsules for passive targeting of Hedgehog-dependent tumor therapy in vitro.
With the purpose of delivering high doses of glabrescione B (GlaB) to solid tumors after systemic administration, long-circulating GlaB-loaded oil-cored polymeric nanocapsules (NC-GlaB) were formulated. Synthesis of GlaB and its encapsulation in nanocapsules (NCs) was performed. Empty and GlaB-loaded NCs were assessed for their physico-chemical properties, in vitro cytotoxicity and in vivo biodistribution. GlaB was efficiently loaded into NCs (∽90%), which were small (∽160 nm), homogeneous and stable upon storage. Further, GlaB and NC-GlaB demonstrated specific activities against the cancer stem cells. Preliminary studies in tumor-bearing mice supported the ability of NC to accumulate in pancreatic tumors. This study provides early evidence that NC-GlaB has the potential to be utilized in a preclinical setting and justifies the need to perform therapeutic experiments in mice.


A structural perspective on the dynamics of kinesin motors.
Despite significant fluctuation under thermal noise, biological machines in cells perform their tasks with exquisite precision. Using molecular simulation of a coarse-grained model and theoretical arguments, we envisaged how kinesin, a prototype of biological machines, generates force and regulates its dynamics to sustain persistent motor action. A structure-based model, which can be versatile in adapting its structure to external stresses while maintaining its native fold, was employed to account for several features of kinesin dynamics along the biochemical cycle. This analysis complements our current understandings of kinesin dynamics and connections to experiments. We propose a thermodynamic cycle for kinesin that emphasizes the mechanical and regulatory role of the neck linker and clarify issues related to the motor directionality, and the difference between the external stalling force and the internal tension responsible for the head-head coordination. The comparison between the thermodynamic cycle of kinesin and macroscopic heat engines highlights the importance of structural change as the source of work production in biomolecular machines.


COVID-19 seasonality in temperate countries.
While the beneficial effect of vaccination, restrictive measures, and social distancing in reducing mortality due to SARS-CoV-2 is intuitive and taken for granted, seasonality (predictable fluctuation or pattern that recurs or repeats over a one-year period) is still poorly understood and insufficiently taken into consideration. We aimed to examine SARS-CoV-2 seasonality in countries with temperate climate. We identified countries with temperate climate and extracted average country temperature data from the National Center for Environmental information and from the Climate Change Knowledge Portal. We obtained mortality and vaccination rates from an open access database. We used the stringency index derived from the Oxford COVID-19 Government Response Tracker to quantify restriction policies. We used Spearman's and rank-correlation non-parametric test coefficients to investigate the association between COVID-19 mortality and temperature values. We employed multivariate regression models to analyze how containment measures, vaccinations, and monthly temperatures affected COVID-19 mortality rates. The time series for daily deaths per million inhabitants and average monthly temperatures of European countries and US states with a temperate climate had a negative correlation (p < 0.0001 for all countries, 0.40 < R < 0.86). When running multivariate regression models with country fixed effects, we noted that mortality rates were significantly lower when temperature were higher. Interestingly, when adding an interaction term between monthly temperatures and vaccination rates, we found that as monthly temperatures dropped, the effect of the vaccination campaign on mortality was larger than at higher temperatures. Deaths attributed to SARS-CoV-2 decreased during the summer period in temperate countries. We found that the effect of vaccination rates on mortality was stronger when temperatures were lower. Stakeholders should consider seasonality in managing SARS-CoV-2 and future pandemics to minimize mortality, limit the pressure on hospitals and intensive care units while maintaining economic and social activities.


Serum levels of circulating miRNA-21, miRNA-10b and miRNA-200c in triple-negative breast cancer patients.
Breast cancer can be classified into five subtypes based on variations in the status of three hormonal receptors that are responsible for the cancer's heterogeneity: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). These classifications influence the choice of therapies (either neoadjuvant or adjuvant), and the range of prognoses, from good (luminal A subtype) to poor (triple-negative cancers). The aim of the study was to compare the serum concentration of selected miRNAs (miRNA-21, miRNA-10b, and miRNA-200c) between in two groups of breast cancer patients with differing ER, PR, and HER2 statuses. The study was performed on two groups of patients. One group (TNBC) consisted of patients with triple-negative cancer, and the other group (ER(+)/PR(+)) was comprised of patients with positive ER and PR receptors. The mean level of miRNA-200c was significantly higher in the ER(+)/PR(+) group than in the TNBC group (p < 0.05). No statistically significant difference was found between the two groups with regard to the mean levels of miRNA-21 or miRNA-10b. The level of miRNA-200c was lower in triple-negative patients when compared with the levels in the study's ER/PR positive group.


Blunted superior temporal gyrus activity to negative emotional expression after mindfulness-based cognitive therapy for late-life depression.
Facial emotion recognition plays an important role in social functioning. Patients with late-life depression (LLD) often have abnormal facial emotion recognition. Mindfulness-based cognitive therapy (MBCT) is beneficial in treating depression. This study examined whether MBCT can act as an effective augmentation of antidepressants and improve facial emotion recognition in patients with LLD and its underlying neural mechanism. Patients with LLD were randomized into two groups (n = 30 per group). The MBCT group received an eight-week MBCT in conjunction with stable medication treatment. The other group was treated as usual (TAU group) with stable medication treatment. The positive affect (PA) scale, negative affect (NA) scale, and facial emotion recognition task with an fMRI scan were performed before and after the trial. After eight weeks of treatment, the repeated ANOVA showed that the PA score in the MBCT group significantly increased [F (1,54) = 13.31, p = 0.001], but did not change significantly [F (1,54) = 0.58, p = 0.449] in the TAU group. The NA scores decreased significantly in both the MBCT group [F (1,54) = 19.01, p < 0.001] and the TAU group [F (1,54) = 16.16, p < 0.001]. Patients showed an increase in recognition accuracy and speed of angry and sad faces after 8 weeks of MBCT. No improvement was detected in the TAU group after treatment. A significant interaction effect was found in the change of activation of the left superior temporal gyrus (L-STG) to negative emotional expression between time and groups. Furthermore, a decrease in activation of L-STG to negative emotional expression was positively correlated with the increase in PA score. The MBCT is beneficial for improving affect status and facial emotion recognition in patients with LLD, and the L-STG is involved in this process.


Heparin-Binding Protein as a Prognostic Biomarker of Sepsis and Disease Severity at the Emergency Department.
Rapid and early detection of patients at risk to develop sepsis remains demanding. Heparin-binding protein (HBP) has previously demonstrated good prognostic properties in detecting organ dysfunction among patients with suspected infections. This study aimed to evaluate the plasma levels of HBP as a prognostic biomarker for infection-induced organ dysfunction among patients seeking medical attention at the emergency department. Prospective, international multicenter, convenience sample study. Four general emergency departments at academic centers in Sweden, Switzerland, and Canada. All emergency encounters among adults where one of the following criteria were fulfilled: respiratory rate >25 breaths per minute; heart rate >120 beats per minute; altered mental status; systolic blood pressure <100 mm Hg; oxygen saturation <90% without oxygen; oxygen saturation <93% with oxygen; reported oxygen saturation <90%. None. A total of 524 emergency department patients were prospectively enrolled, of these 236 (45%) were eventually adjudicated to have a noninfectious disease. Three hundred forty-seven patients (66%) had or developed organ dysfunction within 72 h, 54 patients (10%) were admitted to an intensive care unit, and 23 patients (4%) died within 72 h. For the primary outcome, detection of infected-related organ dysfunction within 72 h, the area under the receiver operating curve (AUC) for HBP was 0.73 (95% CI 0.68-0.78) among all patients and 0.82 (95% CI 0.76-0.87) among patients confidently adjudicated to either infection or no infection. Against the secondary outcome, infection leading to admittance to the ICU, death or a persistent high SOFA-score due to an infection (SOFA-score ≥5 at 12-24 h) HBP had an AUC of 0.87 (95% CI 0.79-0.95) among all patients and 0.88 (95% CI 0.77-0.99) among patients confidently adjudicated to either infection or noninfection. Among patients at the emergency department, HBP demonstrated good prognostic and discriminatory properties in detecting the most severely ill patients with infection.


[Body and memory--physical diseases and cognitive disorders].
Physiological and pathologic changes of various body functions have a great influence on the cognitive performance of a human being in the course of aging. Knowledge-based neuropsychological abilities do not change much during the physiological aging process. However, the decreasing capacity of the working and sensory memory lead to lesser attention and learning performance in the elderly, compared to younger population groups. Pathological mental function changes correlate with the existence of certain physical diseases, the most important of which show an increasing incidence with old age. Degenerative diseases especially Alzheimer's disease and other demential syndromes as well as vascular diseases of the central nervous system, tumors, inflammation, epilepsy, traumatic as well as metabolic and toxic damages to the central nervous system can affect cognitive and physical function to a high degree. Prevention in old age plays a key role. The therapeutic approach to the cognitive disorder is selected according to the disease stage and should be multiprofessional, including the best applicable medical and nonmedical treatment and support for the patient and his family.


Prevalence and Influencing Factors of Metabolic Syndrome among Adults in China from 2015 to 2017.
The prevalence and influencing factors of metabolic syndrome (MetS) in Chinese residents aged 20 or older were investigated. The data were collected from China Nutrition and Health Surveillance (2015-2017), which used a stratified, multistage, random sampling method. A total of 130,018 residents aged 20 years or older from 31 provinces were included in this study. The National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) criteria were used to define MetS. The standardised prevalence of high waist circumference, high blood pressure and low high-density lipoprotein cholesterol were 40.8%, 49.4% and 41.1%, respectively. The following factors were associated with a higher prevalence of MetS: female [odds ratio (OR) = 1.773, 95% CI = 1.709-1.840]; older age (OR = 1.037, 95% CI = 1.036-1.039); living in north China (OR = 1.087, 95% CI = 1.058-1.117); high body mass index (OR = 1.402, 95% CI = 1.395-1.408); higher income [OR (95% CI): 1.044 (1.007-1.083), 1.083 (1.044-1.124) and 1.123 (1.078-1.170) for moderate, high, and very high income, respectively]; family history of hypertension (OR = 1.237, 95% CI = 1.203-1.273); family history of diabetes (OR = 1.491, 95% CI = 1.426-1.558) and current smoking status (OR = 1.143, 95% CI = 1.098-1.191). Living in the countryside (OR = 0.960, 95% CI = 0.932-0.988), moderate alcohol consumption (OR = 0.917, 95% CI = 0.889-0.946) and being physically active (OR = 0.887, 95% CI = 0.862-0.913) were associated with a lower prevalence of MetS. The prevalence of MetS among residents aged 20 years or older in China is increasing, especially among women, people aged 45 years or older and urban residents. Preventive efforts, such as quitting smoking and engaging in physical activity, are recommended to reduce the risk of MetS.


Alcoholism and the Bender-Gestalt Test.
Research with the Bender-Gestalt Test and alcoholism has focused on possible organic deficits in alcoholics and elucidation of hypothesized alcoholic personality characteristics. The evidence for both is equivocal.


Photopolymerizable dental composite resins with lower shrinkage stress and improved hydrolytic and hygroscopic behavior with a urethane monomer used as an additive.
This work reports the synthesis of a monomer 2-((2-(3-(prop-1-en-2-yl)phenyl)propan-2-yl)carbamoyl)oxy)ethyl methacrylate (MVTPM) and the evaluation of its performance as an additive in the formulation of Bis-GMA/TEGDMA based composite resins. Experimental composite resins formulated with the MVTPM monomer were compared with a control reference. Double bond conversion, polymerization kinetics, shrinkage and associated stress, sorption, and aqueous solubility, cell viability, as well as mechanical properties were evaluated according to international measurements standards. The experimental composite resins show comparable mechanical properties with the control reference and improvements in other properties, such as better hydrolytic and hygroscopic behavior and lower shrinkage stress, are reported. This makes MVTPM monomer potentially useful in the formulation of dental composite resins.


Pulmonary sarcoidosis: new genetic clues and ongoing treatment controversies.
The wide-ranging, multisystemic manifestations of sarcoidosis can make diagnosis and management difficult. Corticosteroid treatment is effective, but the optimal time to start, the dose, and the duration of treatment are controversial. We are just beginning to understand the genetic basis of sarcoidosis.


The value of the pragmatic-explanatory continuum indicator summary wheel in an ongoing study: the bullous pemphigoid steroids and tetracyclines study.
The Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) tool is intended to be used in the design phase of trials to help investigative teams design trials in-line with their purpose. Our team applied this tool to an ongoing trial (BLISTER) to determine whether the initial suggestion among some team members that the trial could be described as largely pragmatic was the consensus. Each of the six members of the BLISTER trial team was sent a blank PRECIS wheel to independently complete. The results obtained were averaged and plotted on a single PRECIS wheel to illustrate the degree of pragmatism of the trial. The trial team found that the design of the trial was closest to the pragmatic end of the pragmatic-explanatory continuum. The strongest consensus was found on the 'flexibility of the comparison intervention' and 'practitioner adherence' domains (SD = 13). The trial team appeared to disagree most on the 'eligibility criteria' (SD = 35) and 'participant compliance' (SD = 31) domains, although the large standard deviations were a result of a single outlier in the two domains. The PRECIS tool can be used to retrospectively determine the pragmatism of a trial provided enough expertise and information on the trial is available. Illustrating the design of a trial on the PRECIS wheel can help research users more easily identify studies of interest. We hope our recommendations for applying this useful tool will encourage others to consider using it when designing, conducting and reporting studies. Current Controlled Trials http://www.controlled-trials.com/ISRCTN13704604.


Decreased teratogen susceptibility in mouse fetuses obtained from delayed mating.
We examined whether the susceptibility of fetuses to a teratogen differs between fetuses from delayed mating and those from normal mating. Mitomycin-C (MMC; 2.5 mg/kg or 5.0 mg/kg) was administered to pregnant mice intraperitoneally on day 10 of gestation after either normal or delayed mating (6 h). The incidence of MMC-induced malformations in fetuses from delayed mating was significantly lower than in those from the normal mating group when the treatment time was adjusted to be at the same critical period according to the "catch-up" phenomenon of developmental progression in the delayed mating group.


Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice.
Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4(+) T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (βGlu69), and HLA-DPB1*02:01 is the most prevalent βGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here we characterized the T-cell receptor (TCR) repertoire of Be-responsive CD4(+) T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice. The majority of Be-specific T-cell hybridomas expressed TCR Vβ6, and a subset of these hybridomas expressed identical or nearly identical β-chains that were paired with different α-chains. We delineated mimotopes that bind to HLA-DP2 and form a complex recognized by Be-specific CD4(+) T cells in the absence of Be. These Be-independent peptides possess an arginine at p5 and a tryptophan at p7 that surround the Be-binding site within the HLA-DP2 acidic pocket and likely induce charge and conformational changes that mimic those induced by the Be(2+) cation. Collectively, these data highlight the interplay between peptides and Be in the generation of an adaptive immune response in metal-induced hypersensitivity.


Monocyte/macrophage derived cells in normal and transplanted human kidneys.
The existence of HLA-DR/Ia-like antigen (Ia)-bearing cells of the mononuclear phagocyte system, macrophages (Mac), and/or interdigitating cells (IDC), in the normal kidney is controversial. If present, such cells may be important in renal transplant rejection. We performed enzyme histochemistry using alpha-naphthyl acetate/butyrate esterases (alpha NAE, alpha NBE), 5'-nucleotidase (5'N), acid phosphatase (AcP), alkaline phosphatase (AlkP), and ATPase (ATP) as well as immunoperoxidase staining for Ia and lectin binding (Ulex europaeus I; UEA) on plastic-embedded tissue sections of normal kidneys and rejected renal allografts. Plastic embedding provides clear visualization of histologic detail and allows specific identification of immunoperoxidase-stained cells. Mac and IDC (shown to be Ia+, alpha NAE+, AcP+, ATP+ in other sites) could not be demonstrated in normal renal interstitium. IDC and Mac were not generally identified in normal mesangium, although they could not be altogether distinguished from Ia+ endothelial cells. Focal mesangial staining for alpha NAE but not alpha NBE was present. Rejected kidneys showed increased numbers of alpha NAE+ cells in glomeruli. These cells were frequently Ia negative and often appeared to be blood monocytes present in capillary lumens. Peritubular capillaries and glomerular endothelium stained strongly for UEA, 5'N, and Ia. Our results suggest that previous reports of the presence of IDC in renal tissue on the basis of staining for Ia on frozen tissue may be due to staining of compressed or obliquely sectioned vascular structures that were not adequately visualized.


Wound disinfection with ultraviolet radiation.
Bacteria were counted concurrently in the air and wounds during the first 20 min of total joint arthroplasty procedures in two theatres: a conventional plenum ventilated theatre with ultraviolet C (UVC) tubes installed and a filtered vertical laminar flow theatre. Four theatre environments were tested: conventional theatre and clothing; conventional theatre with UVC protective clothing, with UVC set to produce 100 or 300 microW cm-2 s-1 irradiation; and filtered vertical laminar flow air with staff wearing cuffed cotton/polyester clothing. When used, the UVC was activated 10 min after starting an operation to assess the effect of UVC clothing alone, and of UVC radiation on bacteria already present in the wound. Compared with conventional theatres, UVC clothing reduced air counts by 38%, UVC at 100 microW cm-2 s-1 by 81%, at 300 microW cm-2 s-1 by 91%, and laminar flow by 92%. Wounds counts fell correspondingly by 66% with UVC clothing, 87% with UVC at 100 microW cm-2 s-1 and 92% both with UVC at 300 microW cm-2 s-1 and laminar flow. In conventional and laminar flow theatres air and wound counts correlated closely but in UVC theatres wound counts were lower than levels expected from prevailing air counts suggesting that UVC kills bacteria in wounds as well as in air.


Hearing Preservation With a New Atraumatic Lateral Wall Electrode.
Many individuals have some residual hearing which should be preserved with cochlear implantation. To achieve this goal electrode arrays must fulfil certain design requirements. A new thin lateral wall electrode array (HiFocus SlimJ) was systematically designed on the basis of μCT studies of human cochlea anatomy. The primary objective of this study was to report on initial retrospective hearing preservation results from a cohort of subjects consecutively implanted with this electrode. Secondary objectives were to report on insertion depth and speech perception results for this new array. Twenty subjects with considerable residual hearing in low frequencies were consecutively implanted with the SlimJ electrode array. The electrode was inserted slowly through the round window and the insertion process was controlled by intracochlear electrocochleography measuring cochlear microphonics through the cochlear implant.Postoperative cone beam computed tomography was conducted and precise scalar location and angular insertion depth was estimated following image fusion with the preoperative images. Low frequency hearing at 1 month postsurgery was preserved within 30 dB HL in 85% of subjects and within 15 dB HL in 50% of subjects. Mean angular insertion depth was 393 degrees (SD 62 degrees) with a range from 294 to 520 degrees. All electrode contacts in all subjects were identified within scala tympani. The SlimJ electrode array is easy to handle for atraumatic insertion through the round window, adjusted insertion depth controlled by electrocochleography measurements, and reliable fixation at the posterior tympanotomy. Hearing preservation rates are encouraging on the short term. We aim to further report on larger data sets and long-term outcomes.


The Diagnostic Ability of Follow-Up Imaging Biomarkers after Treatment of Glioblastoma in the Temozolomide Era: Implications from Proton MR Spectroscopy and Apparent Diffusion Coefficient Mapping.
To prospectively determine institutional cut-off values of apparent diffusion coefficients (ADCs) and concentration of tissue metabolites measured by MR spectroscopy (MRS) for early differentiation between glioblastoma (GBM) relapse and treatment-related changes after standard treatment. Twenty-four GBM patients who received gross total resection and standard adjuvant therapy underwent MRI examination focusing on the enhancing region suspected of tumor recurrence. ADC maps, concentrations of N-acetylaspartate, choline, creatine, lipids, and lactate, and metabolite ratios were determined. Final diagnosis as determined by biopsy or follow-up imaging was correlated to the results of advanced MRI findings. Eighteen (75%) and 6 (25%) patients developed tumor recurrence and pseudoprogression, respectively. Mean time to radiographic progression from the end of chemoradiotherapy was 5.8 ± 5.6 months. Significant differences in ADC and MRS data were observed between those with progression and pseudoprogression. Recurrence was characterized by N-acetylaspartate ≤ 1.5 mM, choline/N-acetylaspartate ≥ 1.4 (sensitivity 100%, specificity 91.7%), N-acetylaspartate/creatine ≤ 0.7, and ADC ≤ 1300 × 10(-6) mm(2)/s (sensitivity 100%, specificity 100%). Institutional validation of cut-off values obtained from advanced MRI methods is warranted not only for diagnosis of GBM recurrence, but also as enrollment criteria in salvage clinical trials and for reporting of outcomes of initial treatment.


Modeling the dynamics of mountain pine beetle aggregation in a lodgepole pine stand.
At least once a year the mountain pine beetle searches for lodgepole pines that provide a suitable habitat for a new brood. After attacking females feed, they produce an attractant pheromone that causes beetles to aggregate and, during outbreaks, to usually mass attack the "focus" tree. Near the completion of mass attack, incoming beetles are repelled and initiate attacks on adjacent "recipient" trees. An understanding of this "switching" process is useful for prescribing measures that minimize beetle damage.A mathematical model was developed to (1) describe beetle aggregation, (2) predict the relation of tree susceptibility and switching to changes in beetle density, (3) provide a structure for current knowledge, and (4) pose questions for further research. The model indicates that a high population density ensures mass aggregation and consequently successful tree colonization and switching. The model also indicates that the number of beetles attracted per attacking beetle differs from tree to tree, possibly depending on resin quality and production and/or the local flying density of beetles. Field and model results indicate that tree size appears to affect the repellence of beetles, suggesting that the attack density or the visual attractiveness of large trees is a factor. Further research could be directed at our assumptions on host resistance, repellence, pheromone emission rates, threshold concentrations, navigation, and pheromone dispersion.


Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant.
In clinical practice, patients with acromegaly may be switched from therapy with long-acting somatostatin analogs to pegvisomant. The effect of changing therapies on glucose homeostasis and safety has not been reported. The objectives of this study were to monitor changes in IGF-I levels, glycemic control, and safety, particularly liver function and tumor size. This was a multicenter, open-label, 32-wk trial study. The study was performed at outpatient clinics. Fifty-three patients with acromegaly previously treated with octreotide long-acting release (LAR) participated in this study. Pegvisomant (10 mg/d) was initiated 4 wk after the last dose of octreotide LAR and was adjusted based on serum IGF-I concentrations at wk 12, 20, and 28. The main outcome measures were changes in IGF-I, glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, and safety during the first 12 wk after conversion. At the end of pegvisomant treatment, IGF-I was normalized in 78% of patients. At wk 32, median fasting glucose concentration and HbA1c were reduced (-1.4 mmol/liter and -0.4%, respectively; both P < or = 0.0001) in the study population. Improvements in glycemic control occurred in patients with normal IGF-I concentrations at wk 4 [n = 15; fasting glucose, -1.7 mmol/liter (P < or = 0.0001); HbA1c -0.2% (P = 0.03)]. Decreases in fasting glucose and HbA1c levels were observed in patients with and without diabetes. HbA1c was reduced by more than 1.0% in patients with diabetes. Median pituitary tumor volume did not change, although tumor volume increased in two patients with macroadenomas. Conversion from octreotide LAR to pegvisomant was safe and well tolerated. Improved glycemic control indicates that pegvisomant should be considered in patients with acromegaly and diabetes.


All-Polysaccharide, Self-Healing Injectable Hydrogels Based on Chitosan and Oxidized Hydroxypropyl Polysaccharides.
Polysaccharide-based hydrogels are attractive materials for biomedical applications for reasons that include their polyfunctionality, generally benign nature, and biodegradability. However, the use of polysaccharide-based hydrogels may be limited by toxicity arising from small-molecule crosslinkers, or may involve undesired chemical modification [Hennink, W. E.; et al. Adv. Drug Delivery Rev. 2012, 64, 223-236]. Here, we report a green, simple, efficient strategy for the preparation of polysaccharide-based, in situ forming hydrogels. The Edgar group reports in the accompanying manuscript that chemoselective oxidation of oligo(hydroxypropyl)-substituted polysaccharides introduces ketone groups at the termini of the side chains [Nichols, B. L. B.; et al]. Amine-containing moieties can condense with ketones to form imines. The imine linkage is dynamic in the presence of water, providing the potential for self-healing [Wei, Z.; et al. Adv. Funct. Mater. 2015, 25, 1352-1359], injectability [Wei, Z.; et al. Adv. Funct. Mater. 2015, 25, 1352-1359], and pH responsiveness [Yao, K.; et al. J. Appl. Polym. Sci. 1993, 48, 343-354]. In this work, we designed and prepared two different types of hydrogels, oxidized hydroxypropyl cellulose/chitosan (Ox-HPC-Chitosan) and oxidized hydroxypropyl dextran/chitosan (Ox-HPD-Chitosan), each cross-linked by imine bonds. The mechanical properties of these hydrogels were characterized by rheometry, revealing that hydrogel storage modulus could be tuned from 300 Pa to 13 kPa simply by controlling the degree of substitution (DS) of ketone groups. Rheological characterization also illustrated the rapid self-healing property of these all-polysaccharide hydrogels. Moreover, these hydrogels exhibited high swelling rates and facile injectability. Therefore, this work reveals a potential strategy for the construction of hydrogels that require no small-molecule crosslinkers and are therefore highly attractive for biomedical, agricultural, controlled release, and other applications.


A high-resolution model for soft tissue deformation based on point primitives.
In order to achieve a high degree of visual realism in surgery simulation, we propose a new model, which is based on point primitives and continuous elastic mechanics theory, for soft tissue deformation, tearing and/or cutting. The model can be described as a two-step local high-resolution strategy. First, appropriate volumetric data are sampled and assigned with proper physical properties. Second, sparsely sampled points in non-deformed regions and densely-sampled points in the deformed zone are selected and evaluated. By using a meshless deformation model based on point primitives for all volumetric data, the affine transform matrix of collision points can be computed. The new positions of neighboring points in the collided surface can be then calculated, and more details in the local deformed zone can be obtained for rendering. Technical details about the derivations of the proposed model as well as its implementation are given. The visual effects and computation cost of the proposed model are evaluated and compared with conventional primitives-based methods. Experimental results show that the proposed model provides users (trainees) with improved visual feedback while the computational cost is at the same magnitude of other similar methods. The proposed method is especially suitable for the simulation of soft tissue deformation and tearing because no grid information needs to be maintained. It can simulate soft tissue deformation in a high degree of authenticity with real-time performance. It could be considered implemented in the development of a mixed reality application of neurosurgery simulators in the future.


A distributed computing system for magnetic resonance imaging: Java-based processing and binding of XML.
Recently we have developed a Java-based heterogeneous distributed computing system for the field of magnetic resonance imaging (MRI). It is a software system for embedding the various image reconstruction algorithms that we have created for handling MRI data sets with sparse sampling distributions. Since these data sets may result from multi-dimensional MRI measurements our system has to control the storage and manipulation of large amounts of data. In this paper we describe how we have employed the extensible markup language (XML) to realize this data handling in a highly structured way. To that end we have used Java packages, recently released by Sun Microsystems, to process XML documents and to compile pieces of XML code into Java classes. We have effectuated a flexible storage and manipulation approach for all kinds of data within the MRI system, such as data describing and containing multi-dimensional MRI measurements, data configuring image reconstruction methods and data representing and visualizing the various services of the system. We have found that the object-oriented approach, possible with the Java programming environment, combined with the XML technology is a convenient way of describing and handling various data streams in heterogeneous distributed computing systems.


Comparison of mathematical frameworks for modeling erythropoiesis in the context of malaria infection.
Malaria is an infectious disease present all around the globe and responsible for half a million deaths per year. A within-host model of this infection requires a framework capable of properly approximating not only the blood stage of the infection but also the erythropoietic process that is in charge of overcoming the malaria induced anemia. Within this context, we compare ordinary differential equations (ODEs) with and without age classes, delayed differential equations (DDEs), and discrete recursive equations (DREs) with age classes. Results show that ODEs without age classes are fair approximations that do not provide a crisp temporal representation of the processes involved, and inclusion of age classes only mitigates the problem to some degree. DDEs perform well with respect to generating the essentially fixed delay between cell production and cell removal due to age, but the inclusion of any other processes, such as sudden blood loss, becomes cumbersome. The framework that was found to perform best in representing the dynamics of red blood cells during malaria infection is a DRE with age classes. In this model structure, the amount of time a cell remains alive is easily controlled, and the addition of age dependent or independent processes is straightforward. All events that populations of cells face during their lifespan, like growth or adaptation in differentiation or maturation rate, are properly represented in this framework.


mAb MDR1-modified chitosan nanoparticles overcome acquired EGFR-TKI resistance through two potential therapeutic targets modulation of MDR1 and autophagy.
Tyrosine kinase inhibitors (TKIs) that act against the epithelial growth factor receptor (EGFR) were once widely used in chemotherapy for many human cancers. However, acquired chemoresistance occurred in almost all patients, limiting the clinical application of EGFR-TKI. Thus far, no effective methods existing can resolve this problem. Designing a therapeutic treatment with a specific multi-target profile has been regarded as a possible strategy to overcome acquired EGFR-TKI resistance. MDR1 antibody-modified chitosan nanoparticles loading gefitinib and autophagy inhibitor chloroquine were prepared by ionic crosslinking and electrostatic attracting method. MTT assay, flow cytometry analysis and western blot assay were all performed to confirm the effect of different formulations of gefitinib on the proliferation of SMMC-7721/gefitinib cells. The preparations demonstrated their multi-target potential to achieve both tumor-targeting selectivity and the desired antitumor effects by blocking cell-surface MDR1 and inhibiting autophagy. mAb MDR1-modified CS NPs, when combined with the co-delivery of gefitinib and chloroquine, showed targeting and therapeutic potential on enhancing the delivery of anticancer drugs and inducing significant cell apoptosis against acquired EGFR-TKI resistance through the modulation of autophagy and while blocking the activity of the MDR1 receptor. A new approach to design an excellent nanoparticle drug-delivery system can overcome acquired EGFR-TKI resistance against various multiple antitumor targets.


Global scanning of antihistamines in the environment: Analysis of occurrence and hazards in aquatic systems.
Concentration of the global population is increasingly occurring in megacities and other developing regions, where access to medicines is increasing more rapidly than waste management systems are implemented. Because freshwater and coastal systems are influenced by wastewater effluent discharges of differential quality, exposures in aquatic systems must be considered. Here, we performed a global scanning assessment of antihistamines (AHs), a common class of medicines, in surface waters and effluents. Antihistamines were identified, literature occurrence and ecotoxicology data on AHs collated, therapeutic hazard values (THVs) calculated, and environmental exposure distributions (EEDs) of AHs compared to ecotoxicity thresholds and drug specific THVs to estimate hazards in surface waters and effluents. Literature searches of 62 different AHs in environmental matrices identified 111 unique occurrence publications of 24 specific AHs, largely from Asia-Pacific, Europe, and North America. However, the majority of surface water (63%) and effluent (85%) observations were from Europe and North America, which highlights relatively limited information from many regions, including developing countries and rapidly urbanizing areas in Africa, Latin America and Asia. Less than 10% of all observations were for estuarine or marine systems, though the majority of human populations reside close to coastal habitats. EED 5th and 95th centiles for all AHs were 2 and 212ng/L in surface water, 5 and 1308ng/L in effluent and 6 and 4287ng/L in influent, respectively. Unfortunately, global hazards and risks of AHs to non-target species remain poorly understood. However, loratadine observations in surface waters exceeded a THV without an uncertainty factor 40% of the time, indicating future research is needed to understand aquatic toxicology, hazards and risks associated with this AH. This unique global scanning study further illustrates the utility of global assessments of pharmaceuticals and other contaminants to identify chemicals requiring toxicology study and regions where environmental monitoring, assessment and management efforts appear limited and necessary.


Nod2 protects mice from inflammation and obesity-dependent liver cancer.
Nod2 is a pattern recognition receptor that modulates host innate immune responses and protects from inflammation, steatosis, and obesity. Obesity and inflammation are risk factors for hepatocellular carcinoma, however, the role of Nod2 in obesity-dependent hepatic tumorigenesis is not known. Here we tested the hypothesis that Nod2 protects from high fat diet (HFD)-dependent hepatic cancer. We used an obesity-dependent hepatic tumor model. WT and Nod2-/- mice were treated with the carcinogen dimethylbenz[a]anthracene (DMBA) and maintained on HFD. Nod2-/- mice treated with DMBA and maintained on HFD gain significantly more weight and develop more liver tumors than similarly treated WT mice. Livers of Nod2-/- tumorigenic mice had increased expression of genes involved in cell proliferation, immune responses, and cholesterol biosynthesis, increased infiltration of neutrophils, inflammatory monocytes, and T cells, and increased activation of STAT3 and ERK during the later stages of tumorigenesis. Bioinformatic analyses of genes with differential expression predicted an increase in cancer, immune, and cholesterol biosynthesis pathways. In summary, we have identified a novel role for Nod2 and demonstrate that Nod2 protects from HFD-dependent liver malignancy and this protection is accompanied by decreased cell proliferation, inflammation, steroid biosynthesis, neutrophils and macrophages infiltration, and STAT3 and MAPK signaling in the liver.