Trends in mortality of hospitalised COVID-19 patients: A single centre observational cohort study from Spain.
We aimed to describe changes in characteristics and treatment strategies of hospitalised patients with COVID-19 and detail the mortality trend over time. Observational cohort study of all consecutive patients admitted ≥ 48 h to Hospital Clinic of Barcelona for COVID-19 (1 March-30 September 2020). A total of 1645 consecutive patients with COVID-19 were assessed over a 7-month period. Overall mortality (≤30 days) was 9.7% (159 patients), 7.7% in patients hospitalised in regular wards and 16.7 % in patients requiring ICU admission. Overall mortality decreased from 11.6% in the first month to 1.4% in the last month, reflecting a progressive, significant downward trend (p for trend <0.001). Patients' age changed over time, peaking in June. Most changes in the use of antivirals and anti-inflammatory treatments were documented. Age (OR 1.1, CI 1.1-1.12), chronic heart disease, (OR 1.7, CI 1.1-2.9), D-dimer>700 ng/mL (OR 2.3, CI 1.3-4.1), ferritin>489 ng/mL (OR 1.9; CI 1.5-3.2), C-RP>7 mg/dL (OR 2.6; CI 1.5-4.6), and shorter duration from symptom onset to hospital admission (OR 1.11; CI 1.04-1.17) were factors associated with 30-day mortality at hospital admission. Conversely, hospital admission in the last months (OR 0.80; CI 0.65-0.98) was significantly associated with lower mortality. In-hospital mortality has decreased in patients with COVID-19 over the last, few months, even though main patient characteristics remain similar. Several changes made when managing patients may explain this decreasing trend. Our study provides current data on mortality of patients hospitalised with COVID-19 that might be useful in establishing quality of standard of care. EIT Health, European Union´s Horizon 2020 Research and Innovation Programme), EDRD. PPA [CM18/00132], NGP [FI19/00133], and CGV [FIS PI18/01061], have received grants from Ministerio de Sanidad y Consumo, ISCIII.


Risk of type 2 diabetes mellitus in polycystic ovary syndrome is associated with obesity: a meta-analysis of observational studies.
The exact risk of type 2 diabetes mellitus (T2DM) in women with polycystic ovary syndrome (PCOS) is unknown. It is also unclear if obesity independently increases T2DM risk in this population. The aim of this study was to systematically review and synthesize the best available evidence regarding the association between PCOS and T2DM, stratified according to obesity status. A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases up to October 31, 2020. Data are expressed as relative risk (RR) with 95% confidence interval (CI). The I2 index was employed for heterogeneity. The eligibility criteria were fulfilled by 23 studies (319,780 participants; 60,336 PCOS and 8847 type 2 diabetes cases). Women with PCOS demonstrated a higher risk of T2DM than those without PCOS (RR 3.45, 95% CI, 2.95-4.05, p < 0.001; I2 81.6%). This risk remained significant both in studies matched or unmatched for participants' age. With regard to body mass index (BMI), the RR for developing T2DM in obese and non-obese PCOS women compared with their non-PCOS counterparts was 3.24 (95% CI 2.25-4.65; p < 0.001; I2 30.9%) and 1.62 (95% CI 0.14-18.50; p = 0.70; I2 89.9%), respectively. The RR for developing T2DM was 3.85 (95% CI 1.99-7.43; p < 0.001; I2 46.2%) in obese compared with non-obese women with PCOS. This was also the case for overweight compared with lean women with PCOS. Women with PCOS present an increased risk of T2DM compared with non-PCOS women only if they are obese/overweight.


Decay of the water reed Phragmites communis caused by the white-rot fungus Phlebia tremellosa and the influence of some environmental factors.
The strain Phlebia tremellosa SBUG 1630 isolated from a thatched roof in Northern Germany is capable of colonizing and degrading effectively the water reed Phragmites communis. Within 96 h after inoculation, mycelia covered both the outer and the inner surface of reed shoot fragments as observed by scanning electron microscopy. Interestingly, top culm sections and culm edges were particularly susceptible towards fungal degradation. The weight loss of culms reached 20-73% depending on the environmental conditions applied during the incubation of 70 days. Reed degradation was stable at pH 4 to pH 8 and optimal between 25 and 30 °C. Short-term incubation at elevated temperatures (37 to 55 °C) affected the fungal reed degradation to only a minor extent, whereas > 18 h at 55 °C completely inhibited fungal growth and reed degradation. Supplementation with 43 mM NH4Cl enhanced the reed degradation up to 9%. In contrast, the addition of diammonium tartrate increased the weight loss of the samples considerably up to 16% at 344 mM. Furthermore, reed degradation by P. tremellosa was increased by supplementing the test medium with Mn (99 to 1584 μM), Cu (150 to 300 μM), and less significantly phosphate (4 mM), Zn (37 to 74 μM), and Ag (76 μM) after 70 days. In addition, activities of the ligninolytic enzymes laccase (max. 27.4 nmol ml-1 min-1) and lignin peroxidase (max. 22.8 nmol ml-1 min-1) were rather low in nitrogen-limited medium, whereas considerably higher levels of manganese peroxidase (max. 635.9 nmol ml-1 min-1) were observed.


Acid-Mediated Intermolecular [3 + 2] Cycloaddition toward Pyrrolo[2,1-a]isoquinolines: Total Synthesis of the Lamellarin Core and Lamellarin G Trimethyl Ether.
A novel one-pot reaction has been developed for the efficient synthesis of pyrrolo[2,1-a]isoquinolines and 1-dearyllamellarin core from (E)-(2-nitrovinyl)benzenes and azomethine ylides generated in situ. This strategy provides a concise total synthesis of the lamellarin core and lamellarin G trimethyl ether using electrophilic substitution and palladium-catalyzed Suzuki-Miyaura cross-coupling reactions.


Discovering a new anatomy: exploration of oral mucosa with ultra-high frequency ultrasound.
Ultra-high frequency ultrasound (UHFUS) is a recently developed diagnostic technique involving the use of ultrasound frequencies up to 70 MHz, allowing to obtain 30 µm resolution of targets located within 1 cm from the surface. Oral mucosa can be affected by diverse pathological conditions, which are currently investigated by means of clinical examination. In this scenario, intraoral UHFUS can provide additional information and support clinical assessment of oral mucosa. In this preliminary study, typical features of normal oral mucosa are described, in order to set a benchmark for the future identification of oral soft tissue alterations. Twenty healthy subjects (10 males and 10 females, mean age 30 years) were enrolled and underwent intraoral UHFUS examination. In all the subjects, tongue, buccal mucosa, gingiva, lip mucosa, and palate were scanned, and images acquired. Intraoral UHFUS scan included Brightness-mode and Doppler mode acquisitions performed with a standardized protocol. UHFUS images were postprocessed and analyzed using a dedicated software. UHFUS-based biomarkers (epithelial thickness, echogenicity, and vascularization) were employed for image description. Normal oral anatomy of the different sites analyzed was described. For all the sites, UHFUS biomarkers were characterized, and information on typical aspect of oral mucosa was retrieved. In this explorative study, we suggest a potential role for intraoral UHFUS in the study of oral mucosa, giving insights into the possibility to improve the assessment, diagnosis, and management of the conditions involving oral mucosa. UHFUS seems a promising tool, which could potentially support clinical examination in daily oral medicine practice.


Effect of age on the functional outcome of total abdominal colectomy for colonic inertia.
Colonic inertia (CI) usually presents in women in the third decade of life; however, elderly patients are at times diagnosed with the disease. Total abdominal colectomy (TAC) is considered the preferred surgical treatment for patients with well established CI refractory to conservative and medical management. Surgeons are reluctant to proceed with colectomy in aged patients because of anticipated high morbidity and poor functional outcome. We retrospectively reviewed the outcome in 14 patients over the age of 65 years (range 65-80) (Group I) who underwent TAC for CI between 1988 and 1996. The functional and clinical outcome was compared with that of 41 patients under the age of 65 (range 21-61) (Group II) operated upon during the same time period. Functional outcome was assessed by postal and telephone questionnaires at least 12 months following surgery. There was no major postoperative morbidity in either group. Three (21%) patients in Group I developed small bowel obstruction postoperatively and, of them, 2 required surgical treatment. In Group II the rate of obstruction was 7% (3 patients), with one patient requiring surgery. One patient in Group I subsequently underwent completion proctectomy and creation of an end ileostomy due to continued panenteric hypomotility. Three patients in Group I died during follow-up from causes unrelated to surgery. The mean frequency of spontaneous bowel movements following surgery was 3.8 (range 1-10)/day in Group I and 2.9 (range 1-8)/day in Group II (P=NS). 'Excellent' outcome was reported by 7 patients (64%) in Group I and 39 patients (95%) in Group II (P=0.01). TAC can be performed in elderly patients with established CI with acceptable functional results and no increase in morbidity, resulting in lifestyle improvement. Complete physiological evaluation with increased emphasis on small bowel and gastric motility studies is required in this patient population.


Intercellular voltage gradient between oocyte and nurse cell in a polychaete.
In the polychaete Ophryotrocha labronica the oocyte is supported during vitellogenesis by a single nurse cell, which is cytoplasmically contiguous with the oocyte through an intercellular bridge. Our electrical measurements demonstrate a marked potential difference (22-32 mV) between the oocyte and the nurse cell in mid-vitellogenesis, suggesting an electrophoretically caused migration of nurse cell constituents into the oocyte. Possibly this potential gradient helps to create a developmental prepattern in the oocyte, a role postulated for similar gradients within the oocyte-nurse cell complex of the Cecropia moth.


Assessment of gelatinase expression and activity in articular cartilage.
Two methods for the assessment of the expression of gelatinases A and B, MMP-2 and MMP-9, in articular cartilage are described. Immunohistochemical analysis of tissue sections provides information about the precise localization of the enzymes within the tissue, pinpointing the cells that synthesize the proteinases, and zymography of cell/ tissue conditioned culture media allows a semi-quantitative assessment of the gelatinases and their activation status.


Diagnosis strategy of adipocytic soft-tissue tumors in adults: a consensus from European experts.
Fat-containing tumors are very commonly found in daily practice with benign lipoma accounting for the majority of superficial tumors. Overlap in imaging findings between benign and intermediate or malignant fat-containing tumor is common. Guidelines recommend a core needle biopsy (CNB) for all deep tumors, and superficial tumors over 3 cm. However, specific strategy for diagnosis and referral to a sarcoma center should be applied on adipocytic tumors. The aim of this consensus statement is to provide a specific algorithm for adipocytic tumors, to discriminate patients who do require a CNB for preoperative diagnosis from those who can simply undergo active surveillance or a simple excision.


The diagnostic validity of hip provocation maneuvers to detect intra-articular hip pathology.
To determine which hip provocation maneuvers best predict the presence of an intra-articular hip pathology. Prospective diagnostic study. Musculoskeletal clinic at a university-based multispecialty group practice. Fifty subjects referred for intra-articular hip injection under fluoroscopic guidance. Subjects were examined with 4 pain provocation maneuvers before and after anesthetic intra-articular hip injection administered under fluoroscopic guidance. Presence of intra-articular hip pain generator was confirmed by > or =80% improvement on visual analog scale after intra-articular hip injection. The most sensitive tests were flexion abduction external rotation (FABER) test and internal rotation over pressure (IROP) maneuver. For the FABER test, sensitivity was 0.82 (95% CI 0.57-0.96); sensitivity for the IROP maneuver was 0.91 (95% CI 0.68-0.99). The most specific test was the Stinchfield maneuver, with specificity at 0.32 (95% CI 0.14-0.55). FABER and IROP had the highest positive predictive value, with 0.46 (95% CI 0.28-0.65) and 0.47 (95% CI 0.29-0.64), respectively. IROP had the highest negative predictive value at 0.71 (95% CI 0.25-0.98). IROP and FABER may be worthwhile components of the clinical evaluation of hip pain to determine intra-articular hip pathology. These tests are nonspecific and therefore not necessarily negative in the absence of intra-articular hip pathology. These hip provocation maneuvers are a useful part of an evaluation that includes history, further examination findings, and other diagnostic studies.


Dual-mobility total hip arthroplasty in patients younger than 55 years old: a systematic review.
Total hip arthroplasty (THA) is regarded as one of the most successful and cost-effective orthopedic procedures. However, THA is a surgical procedure with potential intraoperative and postoperative risks. Dislocation is one of the common postoperative complications and remains one of the main indications for THA revision. The purpose of this systematic review was to evaluate the role and the outcomes of dual-mobility implant to prevent dislocation in patients younger than < 55 years in primary THA. In this systematic review, we included observational, prospective, and retrospective studies that evaluated the outcome and the complications of the dual-mobility cup in < 55-year-old patients. After applying exclusion criteria (femoral neck fractures or THA revision, case series, reviews, and meta-analyses), ten articles were included in the study. The overall number of participants in all the studies was 1530. The mean age of the participants was 50 years. The mean follow-up was 11.7 years. A total of 46 patients (2.7%) reported intraprosthetic dislocations, in which the polyethylene liner dissociates from the femoral head, while 4.8% of revision was due to aseptic loosening. The mean revision rate at twelve years was 11%. The mean value of Harris Hip Score increased from 50.9 pre-operatively to 91.6 after surgery. Dual mobility is a valid option for young patients with extended survivorship and low rates of instability and dislocation after primary THA.


Cardiac output regulation in the moving actuator total artificial heart without a compliance chamber.
A new cardiac output regulation method for the moving actuator total artificial heart (TAH) has been developed without using an extra compliance chamber or any transducer. The left and right ventricular sacs are alternately pumped by the pendulous moving actuator, with the left sac attached to the actuator and a free right ventricle. Preload sensitive cardiac output response is achieved by adjusting heart rate just below the level needed to generate atrial collapse, while maintaining full-fill and full-ejection conditions. The motor current waveform analysis detects mild atrial suction related to the amount of venous return. In addition, the structural characteristic of the pendulous moving actuator allows for manipulation of the left and right ventricular output difference by adjusting the asymmetry of stroke angle to either the left or right. In mock circulatory system tests, cardiac output increased from 5 to 9 L/min, with left atrial pressure (LAP) maintained at approximately 5 mmHg higher than right atrial pressure (RAP) over a physiologic range of preload (0-12 mmHg of RAP) and afterload [80-120 mmHg of aortic pressure (AoP)].


Double-chambered left ventricle: An unusual finding in a middle-aged woman.
Double-chambered left ventricle (DCLV) is a rare congenital abnormality and is characterized by the subdivision of the left ventricle into two separate chambers by an abnormal septum or muscle band. This rare congenital entity is usually diagnosed in the neonatal or pediatric age. Nevertheless, it can be asymptomatic and incidentally found in the adulthood. A comprehensive multimodality imaging approach is crucial for the correct final diagnosis.


Effects of imidacloprid on the oxidative stress, detoxification and gut microbiota of Chinese mitten crab, Eriocheir sinensis.
Imidacloprid (IMI) is used in integrated aquaculture systems for pest control and the toxicity of IMI to non-target aquatic animals such as fish and microcrustaceans has been recognised. However, knowledge about the toxic effect of IMI on commercial crabs is still scarce. In the present study, effects of IMI on the acute toxicity, antioxidative status, detoxification systems and gut microbiota in Chinese mitten crab, Erocheir sinensis were investigated. In the present study, the 96-h LC50 of IMI for E. sinensis was 24.97 mg/L. Under sublethal exposure, superoxide dismutase (SOD) activities increased under low concentration (LC, 5 μg/L) and median concentration (MC, 50 μg/L) exposure, but decreased in high concentration group (HC, 500 μg/L). Activities of catalyse (CAT) decreased in a dose-dependent manner. Detoxification-related enzymes aminopyrine N-demethylase (APND) and erythromycin N-demethylase (ERND) increased in all treatments whereas glutathione-S-transferase (GST) decreased dose-dependently. The relative mRNA expression of the cytochrome P4502 (cyp2) gene was induced significantly in LC and HC groups while no significant change was observed in cytochrome P4503 (cyp3) gene. The expression of gst was also significantly decreased in HC group. Up-regulation of heat shock protein hsp70 and 90 was observed in MC and HC groups whereas hsp60 up-regulated only in LC group. In addition, significant changes of composition of microbial communities at both phylum and genus levels were found in this test. In particular, beneficial bacteria were found to decrease and pathogens increased after exposure to IMI. These results indicate that high concentration of IMI could induce oxidative stress and suppress the detoxification system mainly by down-regulation of gst mRNA expression, inhibition of enzyme activities and dysbiosis of gut microbiota.


Recent advancements in synthesis and drug delivery utilization of polysaccharides-based nanocomposites: The important role of nanoparticles and layered double hydroxides.
Drug delivery systems are explained as methods to deliver a specific drug to desired organs, tissues, and cells for drug release to diseases treatment. Recently, considerable development has been interested in stimuli-responsive nano-systems, which respond to the essential pathological and physicochemical issues in diseased sites. During the last decades, researchers in the world presented, investigated, and implemented novel different nanomaterials with a focus on developing drug delivery. Polysaccharides including chitosan, alginate, hyaluronic acid, gums, and cellulose, as natural bio-materials, are suitable candidates for designing and formulations of these nano-systems because of the outstanding merits such as bio-compatibility, bio-degradability, non-toxicity, and gelling characteristics. On the other side, nanoparticles including metals (Au, Ag), metal oxides (Fe3O4, ZnO, CuO), or non-metal oxides (SiO2) and also, layered double hydroxides nanostructures have appealed significant consideration in the fields of biomedical therapeutics and cancer therapy owing to the bio-compatibility, great surface area, good chemical and mechanical features, and also proper magnetic characteristics. This comprehensive review provides an overview of current advancements in drug delivery strategies, and manufacturing methods using chitosan, alginate, hyaluronic acid, gums, and also, metals, metal oxides, non-metal oxides, and LDHs for delivery system uses.


Universal Primers for Rapid Detection of Six Pospiviroids in Solanaceae Plants Using One-Step Reverse-Transcription PCR and Reverse-Transcription Loop-Mediated Isothermal Amplification.
A number of viruses and viroids infect solanaceous plants causing severe yield losses. Several seed-borne viroids are listed as quarantine pathogens in many countries. Among them, columnea latent viroid, pepper chat fruit viroid, potato spindle tuber viroid, tomato apical stunt viroid, tomato chlorotic dwarf viroid, and tomato planta macho viroid are of major concerns. The objective of this study was to design and test universal primers that could be used to detect six viroids in solanaceous plants using one-step reverse transcription PCR (RT-PCR) and reverse transcription loop-mediated isothermal amplification (RT-LAMP). Results revealed that a pair of degenerate primers could be used in a one-step RT-PCR to amplify six pospiviroids from Solanaceae seeds and plants. Moreover, five primers were designed and used in RT-LAMP to amplify six pospiviroids. The minimal concentration of viroid RNA required for a successful detection varied, ranging from 1 fg to 10 ng, depending on the species of viroid and detection method. In general, RT-LAMP was more sensitive than RT-PCR, but both assays were rapid and highly sensitive tools to detect six pospiviroids. Detection methods in use for these viroids require at least two different sets of primers. The assays developed in this research could facilitate the ability to screen a large number of solanaceous plants and seeds intended for import and export.


Protein folding transition states probed by loop extension.
We propose a new way to characterize protein folding transition states by (1) insertion of one or more residues into an unstructured protein loop, (2) measurement of the effect on protein folding kinetics and thermodynamics, and (3) analysis of the results in terms of a rate-equilibrium free energy relationship, alpha(Loop). alpha(Loop) reports on the fraction of molecules that form the perturbed loop in the transition state. Interpretation of the changes in equilibrium free energy using standard polymer theory can help detect residual structure in the unfolded state. We illustrate our approach with data for the model proteins CI2 and the alpha spectrin SH3 domain.


Accessory mitral valve tissue in combination with subaortic membrane and significant impairment of left ventricular function.
A 6-year-old girl was found to have a combination of accessory mitral valve tissue and subaortic membrane. The association caused left ventricular outflow tract obstruction leading to severe left ventricular dysfunction. Surgical relief of the obstruction resulted in immediate improvement of ventricular function.


Cost-Effectiveness Analysis of Evolocumab for the Treatment of Dyslipidemia in the Kingdom of Saudi Arabia.
Proprotein convertase subtilisin/kexin type 9 inhibitors, such as evolocumab, are cholesterol-lowering drugs effective in lowering lipid levels in high-risk patients with primary hypercholesterolemia or mixed dyslipidemia. This study assessed the cost effectiveness of evolocumab in combination with lipid-lowering therapies (LLTs) compared with LLTs alone, from a public healthcare perspective in the Kingdom of Saudi Arabia (KSA). A Markov cohort state transition model was used, incorporating efficacy estimates from the FOURIER clinical trial and baseline cardiovascular event rates observed in clinical practice. Other model inputs were extracted from the literature and Saudi sources. In patients with clinically evident atherosclerotic cardiovascular disease and baseline low-density lipoprotein cholesterol ≥ 70 or ≥ 100 mg/dL, adding evolocumab to a maximally tolerated statin, with or without ezetimibe, was associated with incremental cost-effectiveness ratios (ICERs) of Saudi Arabian riyal (SAR) 109,274 ($US60,708) per quality-adjusted life-year (QALY) gained and SAR75,163 ($US41,757) per QALY gained, respectively. The ICER was SAR22,391 ($US12,440) per QALY gained in patients with heterozygous familial hypercholesterolemia. Sensitivity analysis results were robust to changes in model parameters and fell below the willingness-to-pay threshold of up to three times gross domestic product per capita in 2019 (SAR264,813 [$US147,118]). Evolocumab can be considered a cost-effective treatment option for patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia in the KSA.


Contrasting effects of organic and inorganic toxicants on freshwater periphyton.
This study analyses the factors influencing the response of periphyton communities to toxicants in order to test the validity of the short-term physiological method. The effects of two model compounds, atrazine and zinc, on the photosynthesis of periphyton from different lotic systems were analyzed using short-term toxicity tests. Periphyton communities from seven sites belonging to a relatively small area were used to explore the ecological parameters affecting toxicity in flowing waters. Furthermore, time course studies of zinc toxicity on intact and suspended periphyton were carried out in order to evaluate the significance of periphyton structure (thickness) on toxicity. Atrazine toxicity varied slightly (0.42-2.42 microM) in tests with photosynthesis as an endpoint. Only environmental light was detected to lead to systematic changes in sensitivity of field collected communities. In contrast, the range of EC(10) values for zinc was very broad (7->1000 microM), and mainly related to algal biomass, while also water chemistry (alkalinity) was important. The results of time-course experiments indicated that the penetration of zinc into thick biofilms was limited. The model compounds tested in the present study may exemplify two different situations. In the case of atrazine, the effect on periphyton is easy to predict from the physiological tests used here. On the other hand, zinc toxicity assessed using photosynthesis of periphyton is much affected by many biological and chemical variables. It is concluded that toxicity tests of metals and other organic and inorganic compounds should be based on longer times of exposure.


Two-domain hemoglobin from the blood clam, Barbatia lima. The cDNA-derived amino acid sequence.
The blood clam, Barbatia lima, from Kochi, Japan, expresses a tetrameric (alpha 2 beta 2) and a polymeric hemoglobin in erythrocytes. The latter hemoglobin is composed of unusual 34-kDa hemoglobin with a two-domain structure, and its molecular mass (about 430 kDa) is exceptionally large for an intracellular hemoglobin. The 3' and 5' parts of the cDNA of B. lima two-domain globin have been amplified separately by polymerase chain reaction and the complete nucleotide sequence of 1147 bp was determined. The open reading frame is 930 nucleotides in length and encodes a protein with 309 amino acid residues, of which 73 amino acids were identified directly by protein sequencing. The mature protein begins with the acetylated Ser, and thus the N-terminus Met is cleaved. The molecular mass for the protein was calculated to the 35,244 Da. The cDNA-derived amino acid sequence of B. lima two-domain globin shows 89% homology with that of two-domain globin from B. reeveana, a North American species. The sequence homology between the two domains is 75%, suggesting that the two-domain globin resulted from the gene duplication of an ancestral 17-kDa globin.


[In vitro study of the effect of a lactoperoxidase-peroxidase-thiocyanate system with iodine on the cariogenicinity of streptococcus mutans].
This study aimed to investigate the effect of a lactoperoxidase-peroxidase-thiocyanate (LPO-H2O-SCN-) system with different concentrations of iodine (I-) on Streptococcus mutans (S. mutans), particularly on various parameters, including growth, adhesion, glucosyltransferase (GTF) enzyme activity, and insoluble exopolysaccharide synthesis. S. mutans ATCC 25175 was used as experimental species. Clonal formation unit (CFU) were counted to investigate the inhibitory effect on bacterial growth. The inhibition rate of bacterial adherence was calculated to analyze the effect on adhesion. Anthrone method was used to determine the content of insoluble exopolysaccharides and the amount of reducing saccharides. GTF activity and enzyme activity were then determined. The inhibitory ability of the LPO-H2O2-SCN- system with I- on the cariogenicinity of S. mutans was strengthened as I- concentration was increased. At I- concentration > or = 100 micromol x L(-1) the antibacterial effects were significantly increased compared with those of the control group (P < 0.05). At I- concentration > or = 1,000 micromol x L(-1), the antibacterial effects were significantly improved compared with those of the group with SCN-only (P < 0.05). At I- concentration > or = 100 micromol x L(-1), the inhibition rate of bacterial adherence was > 50%; insoluble exopolysaccharide synthesis and GTF enzyme activity were reduced (P < 0.05). The antibacterial effects of the LPO-H2O2-I- system were enhanced by adding I- to overcome the antagonistic effect of physiological SCN- concentration. LPO-H2O2-SCN- system with different concentrations of I- showed statistically significant inhibitory effects on growth, adhesion, insoluble exopolysaccharide synthesis, and GTF enzyme activity.


Medical reporting in the lay press.
Medical articles appearing in The Age during the first half of 1978 were reviewed. Thirty-three per cent were warnings or reports of adverse reactions, and 27% were reports of "new discoveries". A sample of these two groups of news items was evaluated by panels of doctors and laymen, and also assessed in the light of current literature. Results suggest that medical news items which fall into these categories may be misleading, often contain unsubstantiated claims, and present routine practice as news.


Non-Pharmaceutical Interventions as Controls to mitigate the spread of epidemics: An analysis using a spatiotemporal PDE model and COVID-19 data.
We investigate the spatiotemporal dynamics and control of an epidemic using a partial differential equation (PDE) based Susceptible-Latent-Infected-Recovered (SLIR) model. We first validate the model using empirical COVID-19 data corresponding to a period of 45 days from the state of Ohio, United States. Upon optimizing the model parameters in the learning phase of the analysis using actual infection data from a period of the first 30 days, we then find that the model output closely tracks the actual data for the next 15 days. Next, we introduce a control input into the model to represent the Non-Pharmaceutical Intervention of social distancing. Implementing the control using two distinct schemes, we find that in both cases the control input is able to significantly mitigate the infection spread. In addition to opening a novel pathway towards the characterization, analysis and implementation of Non-Pharmaceutical Interventions across multiple geographical scales using Control frameworks, our results highlight the importance of first-principles based PDE models in understanding the spatiotemporal dynamics of epidemics triggered by novel pathogens.


Spine-GFlow: A hybrid learning framework for robust multi-tissue segmentation in lumbar MRI without manual annotation.
Most learning-based magnetic resonance image (MRI) segmentation methods rely on the manual annotation to provide supervision, which is extremely tedious, especially when multiple anatomical structures are required. In this work, we aim to develop a hybrid framework named Spine-GFlow that combines the image features learned by a CNN model and anatomical priors for multi-tissue segmentation in a sagittal lumbar MRI. Our framework does not require any manual annotation and is robust against image feature variation caused by different image settings and/or underlying pathology. Our contributions include: 1) a rule-based method that automatically generates the weak annotation (initial seed area), 2) a novel proposal generation method that integrates the multi-scale image features and anatomical prior, 3) a comprehensive loss for CNN training that optimizes the pixel classification and feature distribution simultaneously. Our Spine-GFlow has been validated on 2 independent datasets: HKDDC (containing images obtained from 3 different machines) and IVDM3Seg. The segmentation results of vertebral bodies (VB), intervertebral discs (IVD), and spinal canal (SC) are evaluated quantitatively using intersection over union (IoU) and the Dice coefficient. Results show that our method, without requiring manual annotation, has achieved a segmentation performance comparable to a model trained with full supervision (mean Dice 0.914 vs 0.916).


Acute Liver Failure.
Acute liver failure (ALF) is an uncommon medical emergency whose rapid progression and high mortality demand early diagnosis and expert management, including immediate transfer of any potential case to facilities for intensive care and orthotopic liver transplantation (OLT). All patients with ALF must be screened aggressively for acetaminophen toxicity (history, serum levels, "hyperacute" presentation with renal failure), for other drugs, and viral hepatitis; rare causes of ALF should also be considered. After an acetaminophen overdose, N-acetylcysteine must be given as early as possible, preferably in the emergency room, but any patient with ALF should promptly receive N-acetylcysteine if there is suspicion of acetaminophen toxicity irrespective of the time of ingestion. Supportive care for all patients with ALF includes adequate enteral nutrition, aggressive screening and treatment of infection, prophylactic broad-spectrum antibiotics, and antifungal agents. Sedation with propofol is given for severe agitation or mechanical ventilation. With advanced coma grades, intensive care is needed with hemodynamic monitoring, ventilatory support, continuous renal replacement for renal failure, and intracranial pressure monitoring. Intracranial hypertension is treated with mannitol and/or acute short-term hyperventilation, but if the patient is refractory to treatment, mild-moderate hypothermia is achieved by a cooling blanket that is continued throughout OLT. Barbiturate coma is only used in refractory cases as the last treatment modality. Seizures are aggressively treated with phenytoin, with additional diazepam as needed. Candidacy and activation for OLT should be completed as early as possible in the course of ALF, especially in "hyperacute" cases such as acetaminophen toxicity. The final decision to proceed with OLT is made when a donor organ becomes available. King's College Hospital criteria for OLT are still the best prognostic assessment for fatal outcome in ALF, but the criteria fail to identify some patients who will die.


Patient Perceptions of Their Own Data in mHealth Technology-Enabled N-of-1 Trials for Chronic Pain: Qualitative Study.
N-of-1 (individual comparison) trials are a promising approach for comparing the effectiveness of 2 or more treatments for individual patients; yet, few studies have qualitatively examined how patients use and make sense of their own patient-generated health data (PGHD) in the context of N-of-1 trials. The objective of our study was to explore chronic pain patients' perceptions about the PGHD they compiled while comparing 2 chronic pain treatments and tracking their symptoms using a smartphone N-of-1 app in collaboration with their clinicians. Semistructured interviews were recorded with 33 patients, a consecutive subset of the intervention group in a primary study testing the feasibility and effectiveness of the Trialist N-of-1 app. Interviews were transcribed verbatim, and a descriptive thematic analysis was completed. Patients were enthusiastic about recording and accessing their own data. They valued sharing data with clinicians but also used their data independently. N-of-1 trials remain a promising approach to evidence-based decision making. Patients appear to value their roles as trial participants but place as much or more importance on the independent use of trial data as on comparative effectiveness results. Future efforts to design patient-centered N-of-1 trials might consider adaptable designs that maximize patient flexibility and autonomy while preserving a collaborative role with clinicians and researchers.


Appraising community driven health research with Aboriginal and Torres Strait Islander communities: a scoping review using the Aboriginal and Torres Strait Islander Quality Appraisal Tool.
Most research involving Aboriginal and Torres Strait Islander peoples has been conducted by non-Indigenous people and has not been a positive experience for many Aboriginal and Torres Strait Islander communities. This scoping review maps approaches to health research involving Aboriginal and Torres Strait Islander peoples and communities in Australia from the last two decades. A literature search found 198 papers, of which 34 studies met the inclusion criteria. The Aboriginal and Torres Strait Islander Quality Appraisal Tool was then used to map the quality of the reported community driven research. The Quality Appraisal Tool privileges, Aboriginal and Torres Strait Islander people's epistemologies and ethical research governance. The findings reported on strengths and identified areas for improvement in reporting community driven research.


The replication protein of pHW126 auto-controls its expression.
pHW126 belongs to a small group of rolling circle plasmids. So far, the region mediating autonomous replication has been identified and it was shown that the rep gene is required for replication. However, the regulation of rep expression remained elusive. Here evidence is presented that expression of the replication gene rep is auto-regulated. Sequence analysis revealed a conserved stretch in the rep promoter consisting of three imperfect direct repeats (DR2.1, DR2.2 and DR2.3). Assays for promoter activity showed that these direct repeats act as an enhancer of transcriptional activity. Interestingly, the activating effect was reduced in the presence of Rep protein. Electrophoretic mobility shift assays demonstrated that the Rep protein can directly bind to direct repeats DR2.1 and DR2.3 while DR2.2 is not bound but places DR2.1 and DR2.3 in an appropriate distance. These results show that the synthesis of Rep protein is auto-regulated. In the absence of Rep protein the promoter is, due to the presence of the direct repeats acting as a transcriptional enhancer, highly active. Binding of Rep to the direct repeats reduces the transcription rate significantly. Since this regulation mechanism is independent of a specialised regulator protein it is presumably a very economic strategy.


Subdeltoid Rice Bodies in a Patient with Rheumatoid Arthritis on Disease Modifying Antirheumatic Drug Therapy: A Case Report.
A 58-year-old man with rheumatoid arthritis (RA) on disease modifying antirheumatic drug therapy presented with chronic right shoulder pain. Magnetic resonance imaging was concerning for rice body disease which was confirmed through histology after intraoperative deltoid bursa resection. Rice bodies can develop regardless of RA symptom severity or the degree of RA medical therapy administered. Therefore, physicians should not disregard rice bodies as a possible cause of symptoms in individuals on appropriate RA medical therapy or who are demonstrating adequate RA symptom and flair control.


Enhanced electrogenerated chemiluminescence of tris(2,2'-bipyridyl)ruthenium(II) system by l-cysteine-capped CdTe quantum dots and its application for the determination of nitrofuran antibiotics.
This paper reports a new approach to enhance the electrogenerated chemiluminescence (ECL) of the tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)3(2+)) system using resonance energy transfer with l-cysteine-capped cadmium telluride quantum dots (CdTe-QDs) in aqueous solution. The oxidative peak signal of Ru(bpy)3(2+) occurred at a voltage of 1.10V when the potential was cycled between 0.4 and 1.6V using cyclic voltammetry with a carbon screen-printed electrode (SPE) in a 0.11M phosphate buffer at pH 7.50. The l-cysteine-capped CdTe-QDs were synthesized and added into the solution of Ru(bpy)3(2+) to magnify the ECL signal. The ECL emission signal was investigated and the extreme enhancement of the ECL intensity was achieved due to the energy transfer by the l-cysteine-capped CdTe-QDs. It was found that the induced ECL from the Ru(bpy)3(2+) CdTe-QDs system was inhibited by the presence of selected nitrofurans. This quenching effect of nitrofuran antibiotics on the anodic ECL of Ru(bpy)3(2+) CdTe-QDs was found to be selective and concentration dependent and was observed to have a linear relationship over the concentration range 10-100×10(-6)M. The detection limits were found to be 0.40, 0.73 and 0.60µM for furaltadone (FTD), furazolidone (FZD) and nitrofurantoin (NFT). In addition, the proposed ECL method was successfully applied to detect the total residuals of selected nitrofuran residues in animal feed samples with satisfactory results.


Phenotypic and functional analysis of B lymphopoiesis in interleukin-7-transgenic mice: expansion of pro/pre-B cell number and persistence of B lymphocyte development in lymph nodes and spleen.
Transgenic mice in which mouse interleukin (IL)-7 cDNA is expressed under the control of the mouse major histocompatibility complex (MHC) class II (E alpha) promoter develop a lymphoproliferative disease characterized by the early polyclonal expansion of T cells followed in many cases by the development of lymphomas of immature B cells. Here, we have analyzed B cell development in these transgenic mice. Phenotypic analysis using monoclonal antibodies to B220, IgM, IgD, c-kit, IL-7 receptor, MHC class II, AA4.1, CD19, CD23, CD25, CD40 and CD43 shows that B lymphopoiesis in the bone marrow is dramatically altered and the number of pro/pre-B and immature B cells is significantly increased. Interestingly, pro/pre-B and immature B cells persist in the spleens of adult transgenic mice and are also present in lymph nodes and blood. Cell cycle analysis of lymph node cells shows that subpopulations of developing B cells retain the cell cycle profiles of their bone marrow counterparts. Limiting dilution analysis shows that the number of clonable pre-B cells is significantly increased and that at limiting dilution, growth of transgenic pre-B cells is still dependent on exogenous IL-7. Using semiquantitative polymerase chain reaction (PCR) and in situ hybridization, the level of IL-7 transcripts in the spleen was found to decrease between 2 and 4 weeks in control mice with levels in transgenics mice being approximately 50 times greater. These transgenic mice represent an interesting model with which to study the effects of IL-7 overexpression in the bone marrow and raise interesting questions regarding the regulation of B lymphopoiesis in normal mice.


Serodetection of Ehrlichia canis infection in dogs from Ludhiana district of Punjab, India.
Dot-ELISA (enzyme-linked immunosorbent assay) Immunocomb(®) assay was conducted to detect the presence of antibodies against Ehrlichia canis in blood samples of 60 privately owned dogs suspected to be infected with E. canis from the Small Animal Clinics, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, Punjab (India). Antibodies reactive to E. canis were detected in plasma in 48 samples out of 60 samples by Immunocomb(®) Dot-ELISA. Out of these 39.58% samples were low positive (Titre 1:20-1:40), 31.25% were medium positive (Titre 1:80-1:640) and 29.16% were high positive (Titre >1,280), for the infection. When examined by microscopy, only two samples revealed typical E. canis morulae. Haemato-cellular examination revealed thrombocytopenia along with anaemia and leucopenia. Results suggest that E. canis infection circulates in dogs in India in low non-detectable numbers by microscopy and is transmitted by the brown dog tick Rhipicephalus sanguineus.


Spectrochemical analysis of liquid biopsy harnessed to multivariate analysis towards breast cancer screening.
Mortality due to breast cancer could be reduced via screening programs where preliminary clinical tests employed in an asymptomatic well-population with the objective of identifying cancer biomarkers could allow earlier referral of women with altered results for deeper clinical analysis and treatment. The introduction of well-population screening using new and less-invasive technologies as a strategy for earlier detection of breast cancer is thus highly desirable. Herein, spectrochemical analyses harnessed to multivariate classification techniques are used as a bio-analytical tool for a Breast Cancer Screening Program using liquid biopsy in the form of blood plasma samples collected from 476 patients recruited over a 2-year period. This methodology is based on acquiring and analysing the spectrochemical fingerprint of plasma samples by attenuated total reflection Fourier-transform infrared spectroscopy; derived spectra reflect intrinsic biochemical composition, generating information on nucleic acids, carbohydrates, lipids and proteins. Excellent results in terms of sensitivity (94%) and specificity (91%) were obtained using this method in comparison with traditional mammography (88-93% and 85-94%, respectively). Additional advantages such as better disease prognosis thus allowing a more effective treatment, lower associated morbidity, fewer false-positive and false-negative results, lower-cost, and higher analytical frequency make this method attractive for translation to the clinical setting.


Targeted next-generation sequencing reveals that a compound heterozygous mutation in phosphodiesterase 6a gene leads to retinitis pigmentosa in a Chinese family.
Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 70 causative genes identified to date. However, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing mutations are yet to be identified. The purpose of this study is to identify the causative mutations of a Chinese RP family. Targeted next-generation sequencing (NGS) for a total of 163 genes which involved in inherited retinal disorders were used to screen the possible causative mutations. Sanger sequencing was used to verify the mutations. As results, we identified two heterozygous mutations: a splicing site mutation c.1407 + 1G>C and a nonsense mutation c. 1957C>T (p.R653X) in phosphodiesterase 6A (PDE6A) gene in the RP patient. These two mutations are inherited from his father and mother, respectively. Furthermore, these mutations are unique in our in-house database and are rare in human genome databases, implicating that these two mutations are pathological. By using targeted NGS method, we identified a compound heterozygous mutation in PDE6A gene that is associated with RP in a Chinese family.


Anterior capsulotomy with an ultrashort-pulse laser.
To assess the precision of laser anterior capsulotomy compared with that of manual continuous curvilinear capsulorhexis (CCC). Asociación Para Evitar La Ceguera en México IAP, Hospital Dr. Luis Sánchez Bulnes, Mexico City, Mexico. Nonrandomized single-center clinical trial. In patients presenting for cataract surgery, the LensAR Laser System was used to create a laser anterior capsulotomy of the surgeon's desired size. Capsule buttons were retrieved and measured and then compared with buttons retrieved from eyes having a manually torn CCC. Deviation from the intended diameter and the regularity of shape were assessed. When removing the capsule buttons at the start of surgery, the surgeon rated the ease of removal on a scale of 1 to 10 (1 = required manual capsulorhexis around the whole diameter; 10 = button free floating or required no manual detachment from remaining capsule during removal). The mean deviation from the intended diameter was 0.16 mm ± 0.17 (SD) for laser anterior capsulotomy and 0.42 ± 0.54 mm for CCC (P=.03). The mean absolute deviation from the intended diameter was 0.20 ± 0.12 mm and 0.49 ± 0.47 mm, respectively (P=.003). The mean of the average squared residuals was 0.01 ± 0.03 and 0.02 ± 0.04, respectively (P=.09). The median rating of the ease of removal was 9 (range 5 to 10). Laser anterior capsulotomy created a more precise capsule opening than CCC, and the buttons created by the laser procedure were easy to remove at the beginning of cataract surgery.


D-dimer as a predictor of progressive hemorrhagic injury in patients with traumatic brain injury: analysis of 194 cases.
This study sought to describe and evaluate any relationship between D-dimer values and progressive hemorrhagic injury (PHI) after traumatic brain injury (TBI). In patients with TBI, plasma D-dimer was measured while a computed tomography (CT) scan was conducted as soon as the patient was admitted to the emergency department. A series of other clinical and laboratory parameters were also measured and recorded. A logistic multiple regression analysis was used to identify risk factors for PHI. A cohort of 194 patients with TBI was evaluated in this clinical study. Eighty-one (41.8%) patients suffered PHI as determined by a second CT scan. The plasma D-dimer level was higher in patients who demonstrated PHI compared with those who did not (P < 0.001. Using a receiver-operator characteristic curve to predict the possibility by measuring the D-dimer level, a value of 5.00 mg/L was considered the cutoff point, with a sensitivity of 72.8% and a specificity of 78.8%. Eight-four patients had D-dimer levels higher than the cut point value (5.0 mg/L); PHI was seen in 71.4% of these patients and in 19.1% of the other patients (P < 0.01). Factors with P < 0.2 on bivariate analysis were included in a stepwise logistic regression analysis to identify independent risk factors for TBI coagulopathy. Logistic regression analysis showed that the D-dimer value was a predictor of PHI, and the odds ratio (OR) was 1.341 with per milligram per liter (P = 0.020). The stepwise logistic regression also identified that time from injury to the first CT shorter than 2 h (OR = 2.118, P = 0.047), PLT counts lesser than 100 x 109/L (OR = 7.853, P = 0.018), and Fg lower than 2.0 g/L (OR = 3.001, P = 0.012) were risk factors for the development of PHI. When D-dimer values were dichotomized at 5 mg/L, time from injury to the first CT scan was no longer a risk factor statistically while the OR value of D-dimer to the occurrence of PHI elevated to 11.850(P < 0.001). The level of plasma D-dimer after TBI can be a useful prognostic factor for PHI and should be considered in the clinical management of patients in combination with neuroimaging and other data.


A randomised control trial to determine if use of the iResus© application on a smart phone improves the performance of an advanced life support provider in a simulated medical emergency.
This study sought to determine whether using the Resuscitation Council UK's iResus© application on a smart phone improves the performance of doctors trained in advanced life support in a simulated emergency. Thirty-one doctors (advanced life support-trained within the previous 48 months) were recruited. All received identical training using the smart phone and the iResus application. The participants were randomly assigned to a control group (no smart phone) and a test group (access to iResus on smart phone). Both groups were tested using a validated extended cardiac arrest simulation test (CASTest) scoring system. The primary outcome measure was the overall cardiac arrest simulation test score; these were significantly higher in the smart phone group (median (IQR [range]) 84.5 (75.5-92.5 [64-96])) compared with the control group (72 (62-87 [52-95]); p=0.02). Use of the iResus application significantly improves the performance of an advanced life support-certified doctor during a simulated medical emergency. Further studies are needed to determine if iResus can improve care in the clinical setting.


Puerarin ameliorates depression-like behaviors of with chronic unpredictable mild stress mice by remodeling their gut microbiota.
Puerarin is an isoflavone derivative isolated from the traditional Chinese medicine Pueraria Lobelia, which has proven to relieve depression-like behavior. However, its underlying antidepressant mechanisms have been poorly characterized. Herein, we explored whether Puerarin's antidepressant effect is associated with changes in the gut microbiota (GM). The model of depression in mice featuring chronic unpredictable mild stress (CUMS) was eastablished, and its antidepressant effect was estimated by sugar water preference and forced swimming test. Genomic DNA extracted from fecal samples was employed to sequence the 16S rRNA gene for gut microbiota identification. Puerarin (100 mg/kg) treatment was found to alleviate the CUMS-induced depression-like behaviors. Furthermore, chronic stress led to pathological microbial flora, which was principally marked by the increased abundance of pathogenic bacteria (Proteobacteria, Flexispira, Desulfovibrio) and the decreased abundance of beneficial bacteria (Firmicutes, Bacillales, Lactobacillus). Intriguingly, puerarin treatment reversed these changes. The specific role and anti-depression mechanism of characteristic gut microflora were not confirmed. Puerarin can remedy stress-induced disruptions of normal gut microflora. It is suggested that the antidepressant mechanism of puerarin may closely interact with restoring beneficial microflora.


Novel Maneuver for Endobronchial Fogarty Embolectomy Catheter Placement for Lung Isolation in Infants: An Experience of Four Cases.
One-lung anesthesia in infant is always a challenge to the pediatric anesthesiologist. Thoracoscopic diaphragmatic eventration repair requires high quality of lung isolation for proper surgical access. We are reporting a new technique of lung isolation by Fogarty embolectomy catheter alongside the endotracheal tube in four infants.


P53 transformation-related protein accumulates in the nucleus of transformed fibroblasts in association with the chromatin and is found in the cytoplasm of non-transformed fibroblasts.
The subcellular localization of the p53 molecule was studied in transformed and non-transformed fibroblasts. A newly established transformed cell line obtained by treating primary embryonic mouse cells in vitro with the chemical carcinogen methylcholanthrene was compared with the embryonic parent fibroblasts. The transformed cells lost the spindle shape characteristic of the parent fibroblasts, acquired an accelerated growth rate, developed into tumors when injected into syngeneic mice and expressed high levels of p53 synthesis estimated by immunoprecipitation of [35S]methionine-labeled cell extracts. The cellular localization of the p53 molecule was studied by immunofluorescent staining of fixed cells with monoclonal antibodies and by immunoprecipitation of [35S]-methionine-labeled p53 from various subcellular fractions. p53 was mainly found in the nucleus of the transformed fibroblast, while in the parent non-transformed primary embryonic cells, p53 was detected in the cytoplasm in a Triton X-100 soluble fraction, and associated with the cytoskeleton. The modulated distribution of p53 was also confirmed by analyzing a wide range of independently established transformed and non-transformed fibroblastic cell lines growing in vitro. The switch from the cytoplasmic localization of p53 in the non-transformed fibroblasts to a chromatin-associated accumulation in the transformed cells suggests a possible mechanism by which this protein may function in the transformed fibroblasts.


Squamabietenols A-F, undescribed abietane-O-abietane dimeric diterpenoids from the ornamental conifer Juniperus squamata and their ATP-citrate lyase inhibitory activities.
Six undescribed naturally occurring abietane-O-abietane dimers (squamabietenols A-F) together with one 3,4-seco-totarane-type, a pimarane-type, and 17 related known mono-/dimeric diterpenoids were isolated and characterized from the needles and twigs of the ornamental conifer Juniperus squamata. The undescribed structures and their absolute configurations were established by extensive spectroscopic methods, GIAO NMR calculations with DP4+ probability analyses, and ECD calculations. Squamabietenols A and B showed significant inhibitory effects against ATP-citrate lyase (ACL, a novel drug target for hyperlipidemia and other metabolic disorders), with IC50 values of 8.82 and 4.49 μM, respectively. A molecular docking study corroborated the findings by highlighting the interactions between the bioactive compounds and the ACL enzyme (binding affinities: -7.1 to -9.0 kcal/mol). The unique abietane-O-abietane dimeric diterpenoids are quite rare in the vegetable kingdom, and they are of chemotaxonomic significance for the Cupressaceae family.


Early behavioral and physiological markers of social anxiety in infants with fragile X syndrome.
Social anxiety is highly prevalent in neurotypical children and children with fragile X syndrome (FXS). FXS is a genetic syndrome that is characterized by intellectual disability and an increased risk for autism spectrum disorder. If social anxiety is left untreated, negative outcomes are highly prevalent later in life. However, early detection of social anxiety is challenging as symptoms are often subtle or absent very early in life. Given the prevalence and impairment associated with childhood social anxiety, efforts have accelerated to identify risk markers of anxiety. A cluster of early features of anxiety have been identified including elevated behavioral inhibition, attentional biases, and physiological dysregulation that index early emerging markers of social anxiety. Infants with FXS provide a unique opportunity to study the earlier predictors of social anxiety. The current study utilized a multi-method approach to investigate early markers of social anxiety in 12-month-old infants with FXS. Participants included 32 infants with FXS and 41 low-risk controls, all approximately 12 months old. Parent-reported social behavioral inhibition was recorded from the Infant Behavior Questionnaire (IBQ-R). Direct observations of behavioral inhibition and attention were measured during a stranger approach task with respiratory sinus arrhythmia collected simultaneously. Parent-reported social behavioral inhibition was not significantly different between groups. In contrast, direct observations suggested that infants with FXS displayed elevated behavioral inhibition, increased attention towards the stranger, and a blunted respiratory sinus arrhythmia response. Findings suggest that infants with FXS show both behavioral and physiological markers of social anxiety at 12 months old using a biobehavioral approach with multiple sources of input. Results highlight the importance of a multi-method approach to understanding the complex early emergent characteristics of anxiety in infants with FXS.


Aspergillus osteomyelitis. Report of a case and review of the literature.
Aspergillus is a ubiquitous saprophytic fungus seldom pathogenic for normal hosts. Aspergillus osteomyelitis occurs infrequently and is typically limited to patients with predisposing factors, including leukocyte dysfunction, malignancy with neutropenia, steroid or antibiotic therapy, pulmonary aspergillosis, and surgical manipulation. The spine is most frequently affected, and the clinical presentation is nonspecific (50% afebrile). Diagnosis requires demonstration of characteristic, acutely branching, broad, septate hyphae in biopsy material, and culture of Aspergillus. Therapy includes debridement of necrotic bone and loculated purulence combined with amphotericin B and possibly 5-fluorocytosine or rifampin.


Effect of HELP-LDL-apheresis on serum concentrations of human lipoprotein(a): kinetic analysis of the post-treatment return to baseline levels.
In addition to LDL, Lp(a) can be quantitatively eliminated from plasma in an extracorporeal LDL-apheresis procedure based on precipitation with heparin at pH 5.12. The rates of return of post-apheresis Lp(a) and LDL-cholesterol concentrations to baseline levels were investigated in six individuals with familial hypercholesterolaemia (one homozygote, five heterozygote) and one normolipaemic individual. The first-order disappearance constants (kappa) were derived for LDL and Lp(a) according to Apstein et al. The kappa values for LDL in the homozygous FH and the normolipaemic individual were 0.082 and 0.43 respectively while the heterozygous FH patients had kappa values intermediate between the two (median 0.231; range 0.116-0.261). The first-order disappearance constants of Lp(a) did not correlate with those of LDL. The homozygous FH and normolipaemic individuals had Lp(a) kappa values of 0.158 and 0.199 respectively; the corresponding values in the heterozygous FH patients were: median 0.142; range 0.045-0.179.


Supersonic impact resilience of nanoarchitected carbon.
Architected materials with nanoscale features have enabled extreme combinations of properties by exploiting the ultralightweight structural design space together with size-induced mechanical enhancement at small scales. Apart from linear waves in metamaterials, this principle has been restricted to quasi-static properties or to low-speed phenomena, leaving nanoarchitected materials under extreme dynamic conditions largely unexplored. Here, using supersonic microparticle impact experiments, we demonstrate extreme impact energy dissipation in three-dimensional nanoarchitected carbon materials that exhibit mass-normalized energy dissipation superior to that of traditional impact-resistant materials such as steel, aluminium, polymethyl methacrylate and Kevlar. In-situ ultrahigh-speed imaging and post-mortem confocal microscopy reveal consistent mechanisms such as compaction cratering and microparticle capture that enable this superior response. By analogy to planetary impact, we introduce predictive tools for crater formation in these materials using dimensional analysis. These results substantially uncover the dynamic regime over which nanoarchitecture enables the design of ultralightweight, impact-resistant materials that could open the way to design principles for lightweight armour, protective coatings and blast-resistant shields for sensitive electronics.


Adipocyte Proteins and Storage of Endogenous Fatty Acids in Visceral and Subcutaneous Adipose Tissue in Severe Obesity.
This study tested whether substrate concentrations or fatty acid storage proteins predict storage of endogenous lipids in visceral adipose tissue (VAT) and upper body subcutaneous adipose tissue (UBSQ) fat. The day prior to surgery, 25 patients undergoing bariatric procedures received an infusion of autologous [1-14 C]triolein-labeled very low-density lipoprotein (VLDL) particles, and during surgery, they received a continuous [U-13 C]palmitate infusion/bolus [9,10-3 H]palmitate tracer. VAT and UBSQ fat were collected to measure VLDL-triglyceride (TG) storage, direct free fatty acid (FFA) storage rates, CD36 content, lipoprotein lipase (LPL), acyl-CoA synthetase, diacylglycerol acetyl-transferase, and glycerol-3-phosphate acyltransferase activities. Storage of VLDL-TG and FFA-palmitate in UBSQ and VAT was not different. Plasma palmitate concentrations correlated with palmitate storage rates in UBSQ and VAT (r = 0.46, P = 0.02 and r = 0.46, P = 0.02, respectively). In VAT, VLDL-TG storage was correlated with VLDL concentrations (r = 0.53, P < 0.009) and LPL (r = 0.42, P < 0.05). In UBSQ, VLDL-TG storage was correlated with LPL (r = 0.42, P < 0.05). CD36, acyl-CoA synthetase, glycerol-3-phosphate acyltransferase, and diacylglycerol acetyl-transferase were not correlated with VLDL-TG or palmitate storage. Adipose storage of VLDL-TG is predicted by VLDL-TG concentrations and LPL; FFA concentrations predict direct adipose tissue FFA storage rates.


MRI presentation of hepatocellular carcinoma in non-alcoholic steatohepatitis (NASH).
To describe the magnetic resonance imaging (MRI) features of hepatocellular carcinoma (HCC) in patients with non-alcoholic steatohepatitis (NASH). MRI examinations of 21 patients with HCC and NASH were analyzed by two observers. There were 18 men and 3 women with a mean age of 67.9 ± 10.2 (SD) years (range: 36-85 years). Images were qualitatively and quantitatively analyzed with respect to imaging presentation. HCC presented as a single tumor in 13/21 patients (62%), with a mean longest diameter of 26.9 ± 20.2 (SD) mm (range: 12-88 mm); 17/30 HCC (57%) had a largest diameter <20 mm. A signal drop between in- and out-of-phase T1-weighted MR images was observed in 16/30 HCC nodules (53%). All HCC nodules (30/30; 100%) showed hyperenhancement on arterial phase images and 12/30 HCC nodules (40%) did not show a wash-out on portal or delayed phase images. Encapsulation was observed in 18/30 HCC nodules (60%). MRI findings consistent with liver cirrhosis were present in 16/21 patients (76%). Our results show that 57% of HCC in NASH can present as a lesion smaller than 20 mm and 40% do not display wash-out. These results suggest that classical imaging criteria developed for noninvasive diagnosis of HCC should be applied with caution to HCC in patients with NASH.


GEAR: A database of Genomic Elements Associated with drug Resistance.
Drug resistance is becoming a serious problem that leads to the failure of standard treatments, which is generally developed because of genetic mutations of certain molecules. Here, we present GEAR (A database of Genomic Elements Associated with drug Resistance) that aims to provide comprehensive information about genomic elements (including genes, single-nucleotide polymorphisms and microRNAs) that are responsible for drug resistance. Right now, GEAR contains 1631 associations between 201 human drugs and 758 genes, 106 associations between 29 human drugs and 66 miRNAs, and 44 associations between 17 human drugs and 22 SNPs. These relationships are firstly extracted from primary literature with text mining and then manually curated. The drug resistome deposited in GEAR provides insights into the genetic factors underlying drug resistance. In addition, new indications and potential drug combinations can be identified based on the resistome. The GEAR database can be freely accessed through http://gear.comp-sysbio.org.


Adherent neoplastic cells grown at confluence downregulate HLA class I expression and enhance their susceptibility to lysis mediated by natural killer cells.
The number of HLA class I molecules and the susceptibility to lysis mediated by natural killer (NK) cells were evaluated on cell targets obtained from confluent and sparsely plated cultures of both normal and tumor cell lines. Sparsely plated proliferating cells expressed high amounts of HLA class I molecules and were more resistant to NK cell-mediated lysis than confluent cells, which expressed low amounts of HLA class I antigens. This characteristic could be involved in the control of cancer progression and could also explain the wide variability of assays of lymphocyte-mediated cytotoxic activity.


Individuals with knee osteoarthritis demonstrate increased passive stiffness of the hip flexor muscles.
People with knee osteoarthritis stand and walk with increased trunk flexion. This altered postural alignment increases hamstring activation, elevating mechanical knee loads during walking. Increased hip flexor stiffness may lead to increased trunk flexion. Therefore, this study compared hip flexor stiffness between healthy individuals and individuals with knee osteoarthritis. This study also sought to understand the biomechanical effect of a simple instruction to reduce trunk flexion by 5° during walking. Twenty individuals with confirmed knee osteoarthritis and 20 healthy individuals participated. The Thomas test was used to quantity passive stiffness of the hip flexor muscles and three-dimensional motion analysis used to quantify trunk flexion during normal walking. Using a controlled biofeedback protocol, each participant was then instructed to decrease trunk flexion by 5°. Passive stiffness was greater in the group with knee osteoarthritis (effect size = 1.04). For both groups, there was relatively strong correlation between passive stiffness and trunk flexion in walking (r = 0.61-0.72). The instruction to decrease trunk flexion produced only small, non-significant, reductions in hamstring activation during early stance. This is the first study to demonstrate that individuals with knee osteoarthritis exhibit increased passive stiffness of the hip muscles. This increased stiffness appears to be linked to increased trunk flexion and may therefore underlie the increased hamstring activation which is associated with this disease. As simple postural instruction does not appear to reduce hamstring activity, interventions may be required which can improve postural alignment by reducing passive stiffness of the hip muscles.


Automation of enzyme-linked immunosorbent assay (ELISA).
A prototype of automatized enzyme-linked immunosorbent assay (ELISA) in tubes is described, using a commercially available basic material, easily modified. Nine hundred samples could be completely studied in a day by only one person. The different steps of the automatized ELISA were systematically studied to obtain the best performance. Its application is described in toxoplasmosis serodiagnosis.


Presynaptic GABAB receptor inhibition sex dependently enhances fear extinction and attenuates fear renewal.
Anxiety and trauma-related disorders are highly prevalent worldwide, and are associated with altered associative fear learning. Despite the effectiveness of exposure therapy, which aims to reduce associative fear responses, relapse rates remain high. This is due, in part, to the context specificity of exposure therapy, which is a form of extinction. Many studies show that fear relapses when mice are tested outside the extinction context, and this is known as fear renewal. Using Pavlovian fear conditioning and extinction, we can study the mechanisms underlying extinction and renewal. The aim of the current experiment was to identify the role of presynaptic GABAB receptors in these two processes. Previous work from our lab showed that genetic deletion or pharmacological inhibition of GABAB(1a) receptors that provide presynaptic inhibition on glutamatergic terminals reduces context specificity and leads to generalization. We therefore hypothesized that inactivation of these presynaptic GABAB receptors could be used to reduce the context specificity associated with fear extinction training and suppress renewal when mice are tested outside of the extinction context. Using CGP 36216, an antagonist specific for presynaptic GABAB receptors, we blocked presynaptic GABAB receptors using intracerebroventricular injections during various time points of extinction learning in male and female mice. Results showed that blocking these receptors pre- and post-extinction training led to enhanced extinction learning in male mice only. We also found that post-extinction infusions of CGP reduced renewal rates in male mice when they were tested outside of the extinction context. In an attempt to localize the function of presynaptic GABAB receptors within regions of the extinction circuit, we infused CGP locally within the basolateral amygdala or dorsal hippocampus. We failed to reduce renewal when CGP was infused directly within these regions, suggesting that presynaptic inhibition within these regions per se may not be necessary for driving context specificity during extinction learning. Together, these results show an important sex-dependent role of presynaptic GABAB receptors in extinction and renewal processes and identify a novel receptor target that may be used to design pharmacotherapies to enhance the effectiveness of exposure therapy.


Cortical map reorganization without cholinergic modulation.
Acetylcholine has been shown to modulate many forms of cortical plasticity. New evidence indicates that reorganization of adult primary auditory cortex is still possible after removal of cholinergic inputs. This finding suggests that acetylcholine may act less as a gate and more as a gain control on cortical plasticity.


[Responses of somatotropin to stimuli after brief administration of estradiol in short children].
Ethinyl estradiol has been administered orally, 100 micrograms per day during three days, to enhance the growth hormone (GH) response to usual pharmacological stimuli. 102 prepubertal short patients aged 2 to 17 years with height between 2 to 6 SD below the mean, were studied. Human growth hormone (hGH) treatment was given only to those patients whose GH response was still below 10 ng/ml after estradiol. Under hGH treatment, their growth rate increased twofold, as much in patients with partial GH deficiency as in those with complete GH deficiency. It is concluded that the lack of GH response after estradiol priming contributes to the assessment of the indication for treatment with hGH. However, since it has not been possible to give this treatment to very short children whose GH response became normal after priming, this study does not allow to preclude the effect of hGH in such conditions. Thus estradiol priming must not be included among the practical criteria leading to therapeutic decision in doubtful cases.


Trends in pancreatic surgery experience in general surgery residency in the US, 1990-2021.
We hypothesized a decline in resident pancreatic operative experience. The study assesses trends in that experience since 1990. Accreditation Council for Graduate Medical Education (ACGME) national case log data of general surgery residency graduates from 1990 to 2021 were reviewed. Collected and analyzed were the mean and median total number of pancreatic operations per resident, the mean number of specific case types performed, and the annual number of residency graduates. For selected procedures, the mean number of cases by resident role (Surgeon-Chief and Surgeon-Junior) was also analyzed. Both the mean and median total number of resident pancreatic operations has declined since 2009 as have the mean number of several specific pancreatic case types, including resections. The annual number of residency graduates has significantly increased since 1990, and particularly since 2009. Resident volume in pancreatic operations has significantly declined over the last decade.


Captivity-Induced Depression in Animals.
Concern over the welfare of captive animals is growing. Captivity is often associated with frequent exposure to stressors, which may be the source of persistent negative affective states. We argue that captivity may lead to depressive-like states and call for more research on this topic.


Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum.
To evaluate the epidemiology, possible etiologic factors, complications encountered, and treatment administered to a group of patients with ocular involvement in the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum who were seen at two large tertiary referral centers over a 34-year period. Hospital records from 1960 to 1994 at the Massachusetts General Hospital and Shriners Hospital for Crippled Children were reviewed for patients with erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Only patients fulfilling specific clinical diagnostic criteria and those who received a diagnosis by a dermatologist were included in the review. A total of 366 patients with erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis were identified. Drugs were the most commonly identified etiologic factor in all three conditions: sulfonamides were the most frequently identified agents. Eighty-nine patients (24%) had ocular manifestations at the time of their acute hospital stay. Ocular involvement was seen in 9% of patients with erythema multiforme, in 69% with Stevens-Johnson syndrome, and in 50% with toxic epidermal necrolysis. The ocular problems were more severe in patients with both Stevens-Johnson syndrome and toxic epidermal necrolysis. There was no significant difference between the number of patients who were treated with systemic steroids and those who were not (P = 0.42). The erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum remains an important cause of severe visual loss in a significant number of patients. Systemic steroids used during the acute phase of the disease appear to have no effect on the development of ocular manifestations. Studies on the acute immunopathogenic mechanisms occurring in these disease are warranted if more effective therapies are to be found.


Agreement of Spectral-Domain OCT with Fluorescein Leakage in Neovascular Age-Related Macular Degeneration: Post Hoc Analysis of the HARBOR Study.
To evaluate the agreement between detection of activity of choroidal neovascularization (CNV) in neovascular age-related macular degeneration (AMD) by fundus fluorescein angiography (FFA) and spectral-domain (SD) OCT in the HARBOR study. Most retina specialists rely on OCT to guide treatment decisions in neovascular AMD. However, OCT may not always detect exudative activity. Traditionally, FFA was frequently performed in clinical practice, but its use has diminished due to reliance on OCT. Retrospective post hoc analysis of prospective clinical trial (HARBOR; ClinicalTrials.gov identifier, NCT00891735). Patients with neovascular AMD in the HARBOR Trial. Baseline to month 24 data from all randomized study eyes in HARBOR with both FFA and SD OCT data were analyzed for (1) evidence of CNV activity on SD OCT (presence of subretinal fluid, intraretinal fluid, and/or cystoid spaces); (2) evidence of CNV activity on FFA identified by the presence of leakage, and (3) cross-tabulation of CNV activity identified by FFA and SD OCT by office visit. The percent agreement between FFA and SD OCT in detecting CNV activity and sensitivity and specificity of SD OCT to detect fluorescein leakage in neovascular AMD using FFA as the reference standard. At baseline, 1094 patients (99.9%) had agreement between SD OCT and FFA in detecting CNV activity. By month 24, of the 779 total active cases, the agreement was only 36% (277 cases). By month 24, most cases (n = 452 [58%]) had evidence of CNV activity on SD OCT only, whereas 6% of cases (n = 50) had CNV activity identified by FFA only. At screening and months 3, 6, 12, and 24, 92% to 100% of cases identified by FFA only were occult CNV lesions. Using FFA as the reference standard, the sensitivity and specificity of SD OCT in detecting CNV activity was 91% (95% confidence interval [CI], 84%-99%) and 13% (95% CI, 4%-22%). Spectral-domain OCT alone can be relied upon for detecting CNV activity while monitoring eyes with neovascular AMD. However, FFA may still be of value in those with occult lesions that appear quiescent on SD OCT, as this type of lesion may show leakage on FFA.


Intraductal tubular adenomas (pyloric gland-type) of the pancreas: clinicopathologic features are similar to gastric-type intraductal papillary mucinous neoplasms and different from intraductal tubulopapillary neoplasms.
Intraductal tubular adenoma of the pancreas, pyloric gland type (ITA), is an infrequent intraductal benign lesion located in the main duct and large branch duct of the pancreas. The purpose of this report is to introduce seven new cases and to compare their clinicopathologic features and KRAS mutations to gastric-type intraductal papillary mucinous neoplasms (IPMNs) and intraductal tubulopapillary neoplasms (ITPNs). Clinical findings, morphologic features, immunophenotypes and KRAS alterations were investigated in 7 patients with intraductal tubular adenomas, 16 patients with gastric-type intraductal papillary mucinous neoplasms and 6 patients with intraductal tubulopapillary neoplasms. There were more female patients in the ITA and gastric-type IPMN groups, whereas the opposite pattern was observed in the ITPN group. ITAs and gastric-type IPMNs were lined by columnar cells, similar to pyloric glands, with large extracellular deposits of mucin. ITPNs were polypoid and papillary mass located in the pancreatic ducts, which did not show large deposits of mucin. All ITAs and gastric-type IPMNs expressed MUC5AC strongly and diffusely, and 3/6 ITPNs expressed MUC5AC focally and weakly. KRAS mutations were identified in 4 ITAs (4/7, 57%), 9 IPMNs (9/16, 56%) and 2 ITPNs (2/6, 33%). The intraductal tubular adenoma should not be considered a precursor lesion of intraductal tubulopapillary neoplasms. No adequate data established ITA should separate as a specific entity from IPMNs. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_172.


Acupuncture for experimental cerebral ischemia/reperfusion injury: a systematic review of methodology and reporting quality.
Preclinical research is essential to the advancement of science but susceptible to insufficient reporting and methodological shortcomings, which compromise internal validity. We aimed to systematically assess the methodological and reporting quality of studies conducted on acupuncture for experimental cerebral ischemia/reperfusion injury (CIRI). A comprehensive search in six databases was performed for animal research concerning acupuncture for CIRI. Two authors independently selected articles, extracted data, and assessed the methodological and reporting quality of identified articles using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool, and Animal Research: Reporting In Vivo Experiments (ARRIVE) guideline, respectively. A total of 24 studies were identified. Only 1 article (4%) achieved a decent overall rating in using SYRCLE (percentage of items with "low risk" ⩾50%). Of the 22 items on the SYRCLE tool, only 8 items (37%) were rated as "low risk" of bias in more than 50% of the included studies. Of the 39 items of ARRIVE, 20 (51%) items were rated as "low risk" in more than 50% of the included studies. The methodological and reporting quality of included studies was generally low, which demands further improvement. These findings should inform the development of evidence-based guidelines for future preclinical research assessing the effect of acupuncture on CIRI.


Context-based sensing of orthosomycin antibiotics by the translating ribosome.
Orthosomycin antibiotics inhibit protein synthesis by binding to the large ribosomal subunit in the tRNA accommodation corridor, which is traversed by incoming aminoacyl-tRNAs. Structural and biochemical studies suggested that orthosomycins block accommodation of any aminoacyl-tRNAs in the ribosomal A-site. However, the mode of action of orthosomycins in vivo remained unknown. Here, by carrying out genome-wide analysis of antibiotic action in bacterial cells, we discovered that orthosomycins primarily inhibit the ribosomes engaged in translation of specific amino acid sequences. Our results reveal that the predominant sites of orthosomycin-induced translation arrest are defined by the nature of the incoming aminoacyl-tRNA and likely by the identity of the two C-terminal amino acid residues of the nascent protein. We show that nature exploits this antibiotic-sensing mechanism for directing programmed ribosome stalling within the regulatory open reading frame, which may control expression of an orthosomycin-resistance gene in a variety of bacterial species.


Laparoscopy should be strongly considered for women with unexplained infertility.
Women with unexplained infertility frequently become pregnant after diagnostic laparoscopy. In this study the effect of laparoscopic surgery on such women was evaluated by the pregnancy rate after laparoscopic surgery. A total of 47 unexplained infertile women underwent laparoscopic evaluation during the period August 2002 to January 2005 in our center. The percentage of positive laparoscopic findings and the pregnancy rate after laparoscopy were calculated. The patients were divided into 5 subgroups according to maternal age, pregnancy rates were calculated for each group, and compared with the outcome of assisted reproductive technology (ART) treatment for the same age groups. In 87.2% of the women, laparoscopy revealed abnormal findings; endometriosis lesions, peritubal adhesions and tubal obstructions were found in 21, 17 and 3 cases, respectively. After laparoscopy 23 achieved pregnancy (pregnancy rate: 48.9%). The pregnancy rates of the groups at the age of 25 years old or less, 26-30, 31-35, 36-40 and over 41 years old were 100%, 75.0%, 45.5%, 27.2% and 0%, respectively. In the case of the 26-30 years old group, the pregnancy rate after laparoscopy was significantly higher than that in the ART treatment group (33.3%, P < 0.05). Laparoscopy should be strongly considered for examining women with unexplained infertility.


Hot dense silica glass with ultrahigh elastic moduli.
Silicate and oxide glasses are often chemically doped with a variety of cations to tune for desirable properties in technological applications, but their performances are often limited by relatively lower mechanical and elastic properties. Finding a new route to synthesize silica-based glasses with high elastic and mechanical properties needs to be explored. Here, we report a dense SiO2-glass with ultra-high elastic moduli using sound velocity measurements by Brillouin scattering up to 72 GPa at 300 K. High-temperature measurements were performed up to 63 GPa at 750 K and 59 GPa at 1000 K. Compared to compression at 300 K, elevated temperature helps compressed SiO2-glass effectively overcome the kinetic barrier to undergo permanent densification with enhanced coordination number and connectivity. This hot compressed SiO2-glass exhibits a substantially high bulk modulus of 361-429 GPa which is at least 2-3 times greater than the metallic, oxide, and silicate glasses at ambient conditions. Its Poisson's ratio, an indicator for the packing efficiency, is comparable to the metallic glasses. Even after temperature quench and decompression to ambient conditions, the SiO2-glass retains some of its unique properties at compression and possesses a Poisson's ratio of 0.248(11). In addition to chemical alternatives in glass syntheses, coupled compression and heating treatments can be an effective means to enhance mechanical and elastic properties in high-performance glasses.


Tenosynovial giant cell tumor in the foot and ankle.
Tenosynovial giant cell tumor (TSGCT) originates from the synovial cells of the tendon sheath and is the most common soft tissue tumor of the foot and ankle. Due to the lack of clinical data about TSGCT in the foot and ankle, this study was performed with the aim of investigating the clinical characteristics, and surgical outcomes that might predict the likelihood of recurrence. Clinical data, obtained from the pathology records and the clinic files, along with the tumor subtype, local recurrence, and patient functional status among 26 cases of TSGCT were evaluated with the mean 73 months follow-up period. There were 26 patients including 16 males and 10 females with a mean age of 40 years, who underwent surgery. There were 15 localised TSGCT and 11 diffuse TSGCT. The diffuse TSGCT was more likely to be in the hindfoot dorsum (54,5%, 6/11). The localised TSGCT was mostly located in the forefoot (80%, 12/15). The recurrence rate in the diffuse TSGCT was 27,3% (3/11). In the localised TSGCT, recurrence was seen in 6,6% of patients (1/15). The mean AOFAS score was 79. Diffuse TSGCT is more likely to occur in the hindfoot and localised TSGCT is more common in the forefoot. Excision with clear margins is an effective treatment for TSGCT, with good oncological and clinical outcomes. But the orthopaedic surgeons should consider the equilibrium between surgical margins and the functional status of the patient.


Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway.
Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway. Among the 14 colon cancer cell lines tested, their sensitivity to JQ1, a BET inhibitor, was not correlated with c-MYC expression. Three of four BRAFV600E-mutant cell lines were sensitive. Addition of JQ1 to vemurafenib, a specific mutant BRAF inhibitor, suppressed cell growth by arresting cell cycle progression and inducing apoptosis in the BRAFV600E-mutant cells. Mechanistically, the feedback activation of MAPK signaling pathway by vemurafenib was repressed by JQ1. Further, the addition of JQ1 to a BRAF inhibitor enhanced the in vivo anti-tumor effect. Thus, this study indicates the therapeutic potential of targeting of super-enhancers and mutant BRAF in patients with BRAFV600E-mutant colorectal cancer.


Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with urinary bladder cancer risk.
Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case-control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case-control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02-1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12-1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case-control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case-control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups.


Autonomous Purkinje cell activation instructs bidirectional motor learning through evoked dendritic calcium signaling.
The signals in cerebellar Purkinje cells sufficient to instruct motor learning have not been systematically determined. Therefore, we applied optogenetics in mice to autonomously excite Purkinje cells and measured the effect of this activity on plasticity induction and adaptive behavior. Ex vivo, excitation of channelrhodopsin-2-expressing Purkinje cells elicits dendritic Ca2+ transients with high-intensity stimuli initiating dendritic spiking that additionally contributes to the Ca2+ response. Channelrhodopsin-2-evoked Ca2+ transients potentiate co-active parallel fiber synapses; depression occurs when Ca2+ responses were enhanced by dendritic spiking. In vivo, optogenetic Purkinje cell activation drives an adaptive decrease in vestibulo-ocular reflex gain when vestibular stimuli are paired with relatively small-magnitude Purkinje cell Ca2+ responses. In contrast, pairing with large-magnitude Ca2+ responses increases vestibulo-ocular reflex gain. Optogenetically induced plasticity and motor adaptation are dependent on endocannabinoid signaling, indicating engagement of this pathway downstream of Purkinje cell Ca2+ elevation. Our results establish a causal relationship among Purkinje cell Ca2+ signal size, opposite-polarity plasticity induction, and bidirectional motor learning.


CRISPR and Antisense RNA Technology: Exploiting Nature's Tool to Restrain Virulence in Tenacious Pathogens.
Pathogenic bacteria constitute a significant threat to mankind and at the same time represent a huge reservoir of abeyant therapeutics to prevent and treat various diseases. The concept of virulence determinants has been a compelling tool in driving research in the field of bacterial pathogenesis and infectious diseases. In this review, we highlight a few virulence elements forged by the pathogens from the viewpoint of the damage-response scaffold, vandalizing the susceptible host. Seeking an alternative to target the virulence determinants heads a road map toward the exemplary molecular approach. Hence, here we explore some of the exceptional applications of the clustered regulatory interspaced short palindromic repeat (CRISPR)- based therapy and antisense RNA (asRNA) approach, which could be exploited to selectively dismantle adamant components of the pathogen's virulence machinery. To the best of our knowledge, this is the first review paper involving both CRISPR and antisense RNA technology, as an alternative strategy to evade virulence mechanisms in bacterial pathogens.


Comparative evaluation of alteration in taste perception among Gutkha chewers with and without OSMF and healthy subjects: A prospective case-control study.
The major afflictions such as odynophagia (painful swallowing) and trismus that occur in patients with oral submucous fibrosis (OSMF) are well documented, but the impairment of gustatory functions has not received much consideration in the past. The present study was planned with a similar intent to assess and compare the alteration in taste perception among gutkha chewers with and without OSMF and healthy subjects. The present study was designed as a prospective case-control study comprising 90 individuals within an age range of 15-50 years who were divided into three groups with Group A consisting of 30 patients who were gutkha chewers with OSMF, Group B consisting of 30 individuals who were gutkha chewers but without OSMF and Group C consisting of 30 healthy subjects who were included as normal controls. The taste intensity response scores for the four basic tastes were recorded and the results obtained were, then, subjected to statistical analysis. The data were analyzed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). Comparison of the said parameters was done using Chi-square test, analysis of variance and Tukey's post-hoc test. P < 0.05 was considered statistically significant. The findings of the present study suggested that all taste sensations were affected more in Group A patients than the Group B and Group C individuals. The results obtained in the present study were found to be encouraging as it was demonstrated that taste perception varied significantly among the patients with OSMF as against those having habit of betel nut/gutkha chewing but those who did not develop OSMF and the normal healthy controls and this data, though, initial, might be used on a scientific basis to improve the quality of life in the affected patients as well as to prevent the further progression of the disease process.


Transcriptional response of abscisic acid (ABA) metabolism and transport to cold and heat stress applied at the reproductive stage of development in Arabidopsis thaliana.
The phytohormone abscisic acid (ABA) plays an important role in developmental processes in addition to mediating plant adaptation to stress. In the current study, transcriptional response of 17 genes involved in ABA metabolism and transport has been examined in vegetative and reproductive organs exposed to cold and heat stress. Temperature stress activated numerous genes involved in ABA biosynthesis, catabolism and transport; however, several ABA biosynthesis genes (ABA1, ABA2, ABA4, AAO3, NCED3) were differentially expressed (up- or down-regulated) in an organ-specific manner. Key genes (CYP707As) involved in ABA catabolism responded differentially to temperature stress. Cold stress strongly activated ABA catabolism in all organs examined, whereas heat stress triggered more subtle activation and repression of select CYP707A genes. Genes involved in conjugation (UGT71B6), hydrolysis (AtBG1), and transport (ABCG25, ABCG40) of ABA or ABA glucose ester responded to temperature stress and displayed unique organ-specific expression patterns. Comparing the transcriptional response of vegetative and reproductive organs revealed ABA homeostasis is differentially regulated at the whole plant level. Taken together our findings indicate organs in close physical proximity undergo vastly different transcriptional programs in response to abiotic stress and developmental cues.


Neuroimaging patterns in paediatric onset hereditary spastic paraplegias.
Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs with a notable phenotypic variation and an autosomal recessive (AR), autosomal dominant (AD), and X-linked inheritance pattern. The recent clinical use of next generation sequencing methods has facilitated the diagnostic approach to HSPs, but the diagnosis remains quite challenging considering its wide clinical and genetic heterogeneity. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool in helping to exclude mimicking disorders and to guide genetic testing. The aim of this study is to investigate the presence of possible patterns of morphostructural MRI findings that may provide relevant clues for a specific genetic HSP subtype. In our cohort, for example, white matter abnormalities were the most common finding followed by the thinning of the corpus callosum, which, interestingly, presented different thinning characteristics depending on the HSP subtype.