Adjacent lobe invasion of T2 tumor in non-small cell lung cancer has T3 disease-like survival fissure invasion: T2 or T3?
Controversy still exists regarding the staging of non-small cell lung cancer (NSCLC) with adjacent lobe invasion (T-ALI) according to the TNM system in terms of T factor and the appropriate surgical resection method. We performed an analysis to compare the prognosis of T-ALI with T2 and T3 disease and to see the effect of our surgical method for these tumors. Two hundred consecutive patients between January 2012 and November 2020, with anatomical lobectomy for T2 or T3 tumor (Group-1) and non-anatomical lobectomy resection (lobectomy plus wedge resection [LWR]) (Group-2) for T-ALI (T2-ALI and T3-ALI) due to primary NSCLC, who did not have lymph node metastases were analyzed retrospectively. All surgeries were performed by two experienced surgeons who adopted the same surgical technique. Those who underwent additional segmentectomy and bilobectomy due to fissure invasion were excluded from the study. Overall survival rates of all patients were determined and factors affecting survival were evaluated by performing univariate and multivariate analyses. Of the patients with a mean age of 62.2 ± 7.8 years, 175 (87.5%) were male and 25 (12.5%) were female. There were 137 (68.5%) patients in Group 1 and 63 (31.5%) patients in Group 2. The mean tumor size in Group 1 (4.4 ± 1.4 cm) was significantly smaller than that in Group 2 (4.9 ± 1.4 cm) (p = 0.014). When T distribution within the groups was considered, the rate of pathological T3 in Group 1 (33.6%) was significantly lower than that in Group 2 (55.6%) (p = 0.005). While the 5-year overall survival rate was 70.1% in Group 1, it was 50.6% in Group 2 (p = 0.022). When tumors were grouped as T2, T2-ALI, T3, and T3-ALI according to T factor, the 5-year overall survival rates were 71.4% and 67.8% in T2 and T3 tumors, respectively, and 49.2% and 51.5% in T2-ALI and T3-ALI tumors, respectively. In the multivariate analysis of these four groups, the overall survival rates for T2-ALI and T3-ALI were significantly lower than those of T2 tumors (p = 0.046 and p = 0.025, respectively). In the analysis made between the T2 tumor group and the new T3 group (T2-ALI, T3, T3-ALI), which was formed by upgrading T2-ALI tumors to the T3 group, T2 tumors were found to have a significantly better survival rate (p = 0.019). The disease-free survival of pT2 patients and new T3 group patients was statistically significant, 63.7% and 45.7%, respectively (p = 0.050). Our results suggest that LWR for T-ALI can be performed with acceptable oncologic outcomes when compared to anatomical lobectomy. T2-ALI has a worse overall survival than T2 tumor and offers a similar prognosis to T3. Given this situation, it is more appropriate to classify T2-ALI as T3. Further studies based on larger series are needed to confirm these preliminary data.


Proteolytic activity of Candida albicans and other yeasts.
Clinical isolates of C. albicans (75 strains) and other yeasts (20 strains) were evaluated for their ability to produce a carboxyl acid proteinase in an effort to assess its potential role as a virulence factor. Yeasts were categorized as to the infectious process present in the patient: (1) isolates from patients with invasive disease, (2) isolates from patients with possible invasive disease, (3) isolates from superficially infected patients and (4) isolates from noninfected, colonized patients. Yeasts were grown for 7 days in medium containing bovine serum albumin (BSA) as the sole nitrogen source. The amount of extracellular proteinase was measured at pH 3.2, using BSA as substrate. The majority (97%) of C. albicans isolates produced a detectable proteinase. Some non-C. albicans isolates produced proteinase; however, the amount of activity was generally less than for C. albicans. No correlation was found between the amount of proteolytic activity and the degree of invasiveness of the strains.


Highly magnetizable superparamagnetic colloidal aggregates with narrowed size distribution from ferrofluid emulsion.
The formation of spherical superparamagnetic colloidal aggregates of magnetite nanoparticles by emulsification of a ferrofluid and subsequent solvent evaporation has been systematically studied. The colloidal aggregates occur as a dense sphere with magnetite nanoparticles randomly packed and preserved particle-particle separation due to chemisorbed oleic acid. The voids between nanoparticles are filled with solvent and free oleic acid. The latter was found to influence the formation of colloidal aggregates and their surface properties. The choice of surfactant, whether low molecular weight or polymeric, was shown to lead to the colloidal aggregates having tailored interfacial behavior. Magnetization measurements at ambient temperature revealed that the magnetite colloidal aggregates preserve the superparamagnetic properties of the starting nanoparticle units and show high saturation magnetization values up to 57 emu/g. The size distribution of magnetite nanoparticle colloidal aggregates produced by such an approach was found to be a function of emulsion droplet breakup-coalescence and stabilization kinetics and therefore is influenced by the emulsification process conditions and concentrations of the emulsion compounds.


Stress research: its present status and issues for future developments.
In this article the contribution of nine approaches to stress research is discussed. These approaches are: (1) the biological approach; (2) the (classic) psychosomatic approach; (3) the life event approach; (4) interactionistic or transactional approaches; (5) life style and behavior; (6) group differences; (7) sociocultural (macro-)factors; (8) work and organizational psychology; and (9) intervention and prevention. It is concluded that, more and more, exchanges take place between different approaches and that the willingness to collaborate increases. Not only do we observe collaboration between different disciplines, there also are examples of an integration of laboratory research and field research. In addition, interest of animal workers for human research and vice versa seems to increase. Although it is realized that stress research has its own inherent characteristic problems (e.g. ethics), the authors feel that the future still can bring important progress.


Primary bilateral small lymphocytic lymphoma of ocular adnexal origin: Imprint cytology suggests the intraoperative diagnosis.
Ocular adnexal lymphomas (OAL) involve the peri-global soft tissues like orbit, eyelid, conjunctiva, lacrimal gland. We describe a rare case of primary bilateral OAL, histomorphologically small lymphocytic lymphoma, B cell phenotype of lacrimal gland origin. Rapid intraoperative diagnosis can be suggested on imprint cytology; subsequent histology and immunohistochemistry are helpful for confirmation and further line of management. Since no preformed lymphoid structures are expected within the orbit or lacrimal gland, any lymphoid mass here should be critically evaluated as a lymphoproliferative lesion.


Comparative evaluation of a new frugal binocular indirect ophthalmoscope.
We compare the optical quality and design characteristic a new low cost solar powered binocular indirect ophthalmoscope (BIO), Holo, to Keeler BIO. Twenty-four participants each examined 10 simulation eyes using both the Holo and the Keeler BIO with a 30-diopter condensing lens. Number of Lea symbols printed on the retina of simulation eyes seen and time taken to identify them was recorded. Stereoacuity of 12 participants was tested while using the BIOs. Using 7-point Likert scale, participants gave feedback on design characteristic of both BIOs. There was no statistical difference in number of Lea symbols correctly identified (15.63/20 for Holo vs. 15/20 for Keeler BIO, p = 0.366, paired t test) or time taken to correctly identify each symbol (Holo 0.39 s faster; 95% confidence interval -2.24 to 3.03 s, p = 0.763) using each device. 12 out of 12 participants achieved stereoacuity of 60 arcsec using the Holo while with the Keeler BIO 11 achieved 60 arcsec and one 90 arcsec. There was no statistically significant difference in the scores for clarity of view, quality of illumination, field of view, binocularity, eye strain and robustness between the two devices. The Holo, scored higher for ease of use (6.5 vs. 6, p = 0.00488, Wilcoxon signed-rank test), comfort of wear (6 vs. 5, p = 0.000337) and portability (7 vs. 6, p = 0.000148). The Holo has the potential to be a clinically useful yet affordable diagnostic tool suitable for the first time of equipping eye care workers in low resource settings with a BIO at volume.


Optimizing the patient for surgical treatment of the wound.
Plastic surgeons are consulted often to close wounds that fail or are difficult to heal. Optimizing the patient's medical condition before surgical closure of a wound can mean the difference between a successful outcome and an undesirable one. It is imperative that plastic surgeons have an extensive knowledge of the modifiable risk factors affecting the wound-healing process and their subsequent complications. This knowledge allows the surgeon to tailor the treatment options and intervene when appropriate to optimize outcomes for successful surgical closure of a wound. Whether the impairments to wound healing and closure are local or systemic, they must be addressed appropriately.


Role of passive immunotherapies in managing infectious outbreaks.
The historical and current role of passive immunization in managing outbreaks of infectious diseases reviewed.


Helical motion analysis of the knee--II. Kinematics of uninjured and injured knees during walking and pivoting.
The knee kinematics of eight individuals with uninjured knees and of seven individuals with ruptured anterior cruciate ligaments have been investigated during walking and pivoting. The kinematics were measured using a six degree of freedom goniometer and quantitated using helical motion analysis. The helical motion variables reveal clearly that the knee is definitely neither a hinge nor a planar joint and its dynamic behavior changes over the stride. Ligamentous loss results in more adduction and external rotation during certain periods of the stride. Also, the range of translation of the tibia in the medial/lateral direction is reduced, and its average translation is more medial.


Added value of diffusion-weighted images and dynamic contrast enhancement in multiparametric magnetic resonance imaging for the detection of clinically significant prostate cancer in the PICTURE trial.
To determine the additional diagnostic value of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced imaging (DCE) in men requiring a repeat biopsy within the PICTURE study. PICTURE was a paired-cohort confirmatory study in which 249 men who required further risk stratification after a previous non-magnetic resonance imaging (MRI)-guided transrectal ultrasonography-guided biopsy underwent a 3-Tesla (3T) multiparametic (mp)MRI consisting of T2-weighted imaging (T2W), DWI and DCE, followed by transperineal template prostate mapping biopsy. Each mpMRI was reported using a LIKERT score in a sequential blinded manner to generate scores for T2W, T2W+DWI and T2W+DWI+DCE. Area under the receiver-operating characteristic curve (AUROC) analysis was performed to compare the diagnostic accuracy of each combination. The threshold for a positive mpMRI was set at a LIKERT score ≥3. Clinically significant prostate cancer was analysed across a range of definitions including UCL/Ahmed definition 1 (primary definition), UCL/Ahmed definition 2, any Gleason ≥3 + 4 and any Gleason ≥4 + 3. Of 249 men, sequential MRI reporting was available for 246. There was a higher rate of equivocal lesions (44.6%) using T2W alone compared to the addition of DWI (23.9%) and DCE (19.8%). Using the primary definition of clinically significant disease, there was no significant difference in the overall accuracy between T2W, with an AUROC of 0.74 (95% confidence interval [CI] 0.68-0.80), T2W+DWI at 0.76 (95% CI 0.71-0.82), and T2W+DWI+DCE, with an AUROC of 0.77 (95% CI 0.71-0.82; P = 0.55). The AUROC values remained comparable using other definitions of clinically significant disease including UCL/Ahmed definition 2 (P = 0.79), Gleason ≥3 + 4 (P = 0.53) and Gleason ≥4 + 3 (P = 0.53). Using 3T MRI, a high level of diagnostic accuracy can be achieved using T2W as a single parameter in men with a prior biopsy; however, such a strategy can lead to a higher rate of equivocal lesions.


De novo biosynthesis of linalool from glucose in engineered Escherichia coli.
Linalool is an important terpenoids of floral scents and has wide applications. In the past, several groups reported on a strategy to establish biosynthesis of linalool in yeast based on co-expression of Saccharomyces cerevisiae farnesyl diphosphate synthase ERG20 and Actinidia arguta linalool synthase LIS. However, ERG20 has both geranyl diphosphate synthase and farnesyl diphosphate synthase activities, which can lead to metabolic flow to farnesyl diphosphate. In this study, a heterologous linalool biosynthesis pathway was constructed in Escherichia coli and showed that using Abies grandis geranyl diphosphate synthase GPPS2 instead of ERG20 can effectively improve linalool biosynthesis. Subsequently, we further improved the biosynthesis of linalool by overexpression of isopentenyl diphosphate isomerase Idi.


(E)-1-(4-ethoxyphenyl)-3-(4-nitrophenyl)-prop-2-en-1-one suppresses LPS-induced inflammatory response through inhibition of NF-κB signaling pathway.
Flavonoids are a class of compounds that exist in nature with the structure of 2-phenyl-chromone. In Chinese traditional medicine, herbal drugs containing flavonoids are widely used for the treatment of inflammation, cardiovascular disease, tumor and so on. In this study, we investigated the anti-inflammatory effect and related mechanisms of a novel synthetic flavonoid, (E)-1-(4-ethoxyphenyl)-3-(4-nitrophenyl)-prop-2-en-1-one (ETH) in lipopolysaccharide (LPS) stimulated macrophages. Our results showed that ETH inhibited LPS-induced TNF-α and IL-6 release in a dose-dependent manner, and decreased TNF-α, IL-1β, IL-6 and iNOS mRNA production. LPS-induced expression of cyclooxygenase-2 (COX-2) was also significantly attenuated by ETH. Pretreatment with ETH reduced the I-κBα phosphorylation, p65 nuclear translocation as well as NF-κB-dependent transcriptional activity. In addition, ETH exhibited a significant protection against LPS-induced inflammatory mortality in mice. Taken together, these findings suggest that ETH can inhibit LPS-induced inflammation via suppressing NF-κB signaling pathway, indicating that ETH may be a potential anti-inflammatory agent.


ChatGPT: Friend or Foe?-Utility in Trauma Triage.
Artificial intelligence (AI) has been growing rapidly in the health and production industry. The most recent AI program that has caught everyone's eye is, Chat Generative Pre-trained Transformer (ChatGPT). It is a program based on Open AI and was released in November 2022 to the public. It is a chatbot that helps with analyzing and learning data from the net, based on human literature and data. Jacob J. ChatGPT: Friend or Foe?-Utility in Trauma Triage. Indian J Crit Care Med 2023;27(8):563-566.


Evaluation of a new generation of plastic culture bottles with an automated microbial detection system for nine common contaminating organisms found in PLT components.
A microbial detection system (BacT/ALERT 3D, bioMérieux [formerly Organon Teknika]) has previously been validated with a variety of bacterial contaminants in PLTs. The recovery of nine organisms seeded into PLTs with new plastic culture bottles was studied in comparison to the current glass bottles. The use of plastic instead of glass would be expected to reduce the risk of injury. Isolates of Bacillus cereus, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens, Streptococcus viridans, and Propionibacterium acnes were inoculated into Day 2 (>24 hr <48 hr) apheresis PLT units to 10 and 100 CFUs per mL. Replicate samples (4 mL) were inoculated into both current- and new-generation standard aerobic and anaerobic bottles. All organisms (with the exception of P. acnes) were detected in a mean time of 9.3 to 18.9 hours (10 CFUs/mL) or 8.7 to 18.2 hours (100 CFUs/mL). In aggregate (with the exception of P. acnes), the plastic and glass aerobic bottles had a mean difference in detection of 1.2 hours (p < 0.0001), and the plastic and glass anaerobic bottles had a mean difference of 3.3 hours (p < 0.0001). In all cases, the mean detection time was superior or clinically comparable (within 0.1 hr) with the new plastic bottles. P. acnes (an anaerobic organism) was detected with the new and current anaerobic bottles in a mean of 72.8 and 90.4 hours (10 CFUs/mL) or 64.0 and 80.8 hours (100 CFUs/mL), respectively. The narrower bottle neck and smaller inoculation septum present with the new-generation plastic bottles were inoculated with comparable ease to that of the glass bottles. These data demonstrate that the new plastic bottles are clinically comparable or superior to the current glass standard aerobic and anaerobic culture bottles.


Complications of blepharoplasty.
Various involutional eyelid changes, such as fine rhytids, dynamic laugh lines in the lateral canthal area, secondary malar bags, and dermal pigmentation are not effectively treated by a blepharoplasty. Preoperative discussions are important to ensure that adequate expectations are held. Too often, a patient is informed that fine rhytids and dermal pigmentation can be successfully treated with lid surgery alone. The importance of the preoperative interview in determining patient expectations cannot be minimized. Preoperative ophthalmic and periocular examination is essential to identify any pre-existing pathology. Even though the surgical approach is adapted to the individual needs of each patient, the most meticulous of surgeons is predetermined to encounter his or her share of complications. There is a fine line between a "complication" and a common, but unwanted, sequela of surgery. Patients, overwhelmingly, do have some widening of their palpebral fissures, even following conservative surgery. Unfortunately, this occasionally creates ocular irritation or gross discomfort in allergic or borderline dry eyed patients. Lower eyelid bowing is so common even in the face of minimal skin resection that we do not consider it a "complication" if it does not produce a functional problem. It is humbling for all surgeons to review their blepharoplasty problems and helpful to recognize that, statistically, we are all due to face these events eventually.


Expression and prognostic value of transcription factor PROX1 in colorectal cancer.
PROX1 is a specific target of the β-catenin/TCF pathway in the intestinal epithelium. It acts as a regulator of progression from a benign to a highly dysplastic phenotype in colorectal tumours. However, the clinical significance of PROX1 expression is not known. We studied the prognostic value of immunohistochemical expression of PROX1 in a series of 517 patients with colorectal cancer (CRC). The majority of the tumour samples expressed PROX1 (91%, 471 out of 517). High PROX1 expression was associated with a poor grade of tumour differentiation (P<0.0001). In the subgroup of patients with colon cancer, high PROX1 expression was associated with unfavourable colorectal cancer-specific survival (CCSS) as compared with low PROX1 expression (CCSS 47% vs 62%; P=0.045; RR 1.47). The association between high PROX1 and poor outcome was further strengthened in female colon cancer patients (CCSS 38% vs 63%; P=0.007; RR 2.02). Nonetheless, in multivariate survival analysis PROX1 expression was not retained as an independent prognostic factor. High PROX1 expression is associated with a poor grade of tumour differentiation, and, in colon cancer patients, also with less favourable patient outcome. Our results strengthen the previous preclinical observations that PROX1 has a role in tumour progression in CRC.


Perceiving the numerosity of rapidly occurring auditory events in metrical and nonmetrical contexts.
Experiment 1 determined the fastest tempo at which participants could tap in synchrony with every nth tone (n = 2 to 9) in an isochronous sequence. Tapping was difficult with every 5th or 7th tone but easy with every 2nd, 4th, or 8th tone, suggesting that evenly divisible groups of n tones are automatically subdivided into equal groups of 2 or 3-a form of auditory subitizing that generates metrical hierarchies commonly found in Western music. Experiments 2 and 3 sought evidence of subitizing and subdivision in timed explicit enumeration of short, rapidly presented tone sequences (n = 2 to 10). Enumeration accuracy decreased monotonically with n. Response time increased monotonically up to n = 5 or 6, but less between 2 and 3 than between 3 and 4. Thus, a single group of 2 or 3 tones perhaps can be subitized, but subdivision of larger groups into subgroups of 2 or 3 tones seems to be specific to a repetitive, metrical context.


Sertoli cell-only phenotype and scRNA-seq define PRAMEF12 as a factor essential for spermatogenesis in mice.
Spermatogonial stem cells (SSCs) have the dual capacity to self-renew and differentiate into progenitor spermatogonia that develop into mature spermatozoa. Here, we document that preferentially expressed antigen of melanoma family member 12 (PRAMEF12) plays a key role in maintenance of the spermatogenic lineage. In male mice, genetic ablation of Pramef12 arrests spermatogenesis and results in sterility which can be rescued by transgenic expression of Pramef12. Pramef12 deficiency globally decreases expression of spermatogenic-related genes, and single-cell transcriptional analysis of post-natal male germline cells identifies four spermatogonial states. In the absence of Pramef12 expression, there are fewer spermatogonial stem cells which exhibit lower expression of SSC maintenance-related genes and are defective in their ability to differentiate. The disruption of the first wave of spermatogenesis in juvenile mice results in agametic seminiferous tubules. These observations mimic a Sertoli cell-only syndrome in humans and may have translational implications for reproductive medicine.


Control of foreign Ag-specific Ab responses by Treg and Tfr.
Regulatory T cells (Tregs) expressing the transcription factor Foxp3 play a critical role in the control of immune homeostasis including the regulation of humoral immunity. Recently, it has become clear that a specialized subset of Tregs, T-follicular regulatory cells (Tfr), have a particular role in the control of T-follicular helper (Tfh) cell-driven germinal center (GC) responses. Following similar differentiation signals as received by Tfh, Tfr gain expression of characteristic chemokine receptors and transcription factors such as CXCR5 and BCL6 allowing them to travel to the B-cell follicle and deliver in situ suppression. It seems clear that Tfr are critical for the prevention of autoimmune antibody induction. However, their role in the control of foreign antigen-specific antibody responses appears more complex with various reports demonstrating either increased or decreased antigen-specific antibody responses following inhibition of Tfr function. Due to their recent discovery, our understanding of Tfr formation and function still has many gaps. In this review, we discuss our current knowledge of both Tregs and Tfr in the context of humoral immunity and how these cells might be manipulated in order to better control vaccine responses.


Weaker signals induce more precise temporal-integration.
It is well known that our perceptual system integrates local information to generate global percepts. Although events in the real world occur over time, it is still unclear how we integrate temporally dispersed information. Here, I systematically explore the relation between the intensity of local signals and the resultant of temporal-integration. Presented sequentially with two directions of variably coherent random dot patterns (40 degrees apart), participants were instructed to report a perceived motion direction by using a mouse driven cursor. As the strength of the motion signal was varied, the behavioral results and qualitative analyses indicate existence of two aspects of temporal-integration, subthreshold integration and suprathreshold integration. In subthreshold integration (when the local signals are subthreshold), stronger signals enhance integration. On the other hand, in suprathreshold integration (when the signals are above threshold), stronger signals decrease integration. As a result, relatively weaker, subthreshold or near threshold signals produce more precise temporal-integration than suprathreshold signals.


Estimation of haemodynamic changes in varicocele testis and results after microsurgical sub-inguinal varicocelectomy.
Varicocele is among the most frequently encountered, surgically correctable causes of male infertility. Since varicocele is a primary abnormality of testicular vessels, a thorough understanding of haemodynamic changes in the microcirculation of varicocele testis is needed. To estimate changes in the microcirculation of varicocele testis and correlate them with symptomatic and semen parameters changes before and after varicocelectomy. This prospective, observational study includes 47 patients of age group 18-40 years who underwent microsurgical varicocelectomy during June 2016 to April 2018 at a tertiary medical institute. Testicular haemodynamic was evaluated using a colour spectral doppler study (PSV-Peak systolic velocity/ESV-End diastolic velocity/RI-Resistive index/PI-Pulsatility index). Semen analysis parameters and testicular blood flow were compared with pre-operative values. RI in the capsular artery of varicocele affected testis, which was 0.61 ± 0.11 (mean ± SD), significantly reduced to 0.56 ± 0.09 (mean ± SD) in post-operative follow-up, indicating improved perfusion. Pre-operative sperm density was noted to be 15.94 ± 7.88 (mean ± SD), which improved to 28.41 ± 10.99, Progressive sperm motility from 33.81 ± 10.88 to 38.32 ± 9.21 and morphology from 36.13 ± 10.68 to 41.43 ± 9.29 on 6-month follow-ups (p < 0.05). Varicocele testis is associated with altered testicular haemodynamic, which insults spermatogenesis. Microsurgical varicocelectomy with testicular artery and lymphatic preservation leads to correction of this altered haemodynamic state and improves the testicular microcirculation.


Reading comprehension strategies used by deaf middle-school students.
13 reading strategies of deaf adolescent boys and girls attending residential middle schools were compared. Boys reported the lower-level strategy of reading aloud more often than girls. Both reported top strategies of asking someone to explain (dependent) and rereading and looking at the pictures (independent).


A multicentre Canadian survey of caregiver perspectives on COVID vaccine-related pain and stress for their family.
Caregiver hesitancy for their children to receive the COVID-19 vaccine remains due to concerns regarding safety and efficacy, but also due to fear of vaccine administration-related pain and distress. Study objectives were to determine caregivers' perceptions regarding both their personal and child's COVID-19 vaccine administration-related stress and fear and relate this to their likelihood to allow their child to receive COVID-19 vaccinations. This study was a secondary data analysis of a multicentre, cross-sectional survey of caregivers presenting to four Canadian pediatric emergency departments. Caregivers were surveyed between December 2020 and March 2021 and completed a digital survey on their own smartphones. 331 caregivers responded to the survey (mean age 39.9 years [SD 7.71]); 74.2% (245/331) were mothers. Children's mean age was 8.8 years [SD 5.4]; 49.8% (165/331) were female. 64.1% (209/326) of caregivers were willing to vaccinate their child against COVID-19, while 35.9% (117/326) were not. Greater perceived COVID-19 vaccine administration-related pain (0.88 [0.80; 0.95], p = .003) and stress (0.82 [0.76; 0.89], p = <.001) for their child as well as greater perceived personal stress with their own COVID-19 vaccine administration (0.81 [0.75; 0.88], p = <.001) were associated with caregivers being less likely to vaccinate their child. During the time period between COVID-19 pandemic waves 2 and 3, and after the vaccine had been federally approved for adults, one-third of Canadian caregivers surveyed reported being unwilling to vaccinate their child against COVID-19 in the future. Managing children's and caregivers' vaccine administration-related fear and stress may improve vaccine uptake for children.


Site-selective installation of BASHY fluorescent dyes to Annexin V for targeted detection of apoptotic cells.
Fluorophores are indispensable for imaging biological processes. We report the design and synthesis of azide-tagged boronic acid salicylidenehydrazone (BASHY) dyes and their use for site-selective labelling of Annexin V. The Annexin V-BASHY conjugate maintained function and fluorescence as demonstrated by the targeted detection of apoptotic cells.


Infection and early atherosclerosis: does the evidence support causation?
Although clinical manifestations of atherosclerotic coronary heart disease occur in adult life, the initial stages of its development commence in childhood. Therefore, elucidating the pathogenesis of early atherosclerosis and identifying the network of risk factors have become fundamental priorities for both cardiovascular healthcare providers and scientists. There is mounting evidence from both human studies and animal experiments that infectious pathogens could be implicated in atherosclerosis development. The vulnerability of the arterial wall to the adverse effects of infection is probably augmented when additional risk factors and/or certain proatherogenic genetic profiles are also present. The precise mechanisms whereby infection, alone or in synergy with conventional cardiovascular risk factors, could contribute to atherosclerosis are not fully understood. Injury to the vascular endothelium, which could be elicited by infection through inflammatory, metabolic, autoimmune, and pathogen-related mechanisms, might be a central link between infection and early atherosclerosis.


Understanding haemophilic arthropathy: an exploration of current open issues.
Haemophilic arthropathy is joint damage evolving from recurrent joint bleeds that occur in patients suffering from the clotting disorder haemophilia. Insight into the pathogenetic mechanism of this blood-induced arthropathy yields possible treatment targets and modalities useful to reduce this invalidating co-morbidity of haemophilia. Joint bleeding leads to initially independent adverse changes in both the synovial tissue and the articular cartilage. These subsequently influence each other: the synovial inflammatory changes enhancing cartilage damage and vice versa. Consequently, effective treatment strategies will have to affect both pathways.


Examining Cultural and Linguistic Sensitivity of Pathways Early Autism Intervention with Hispanic Families.
This research aimed to evaluate evidence of Pathways parent-mediated early autism intervention as a culturally and linguistically sensitive intervention (CLSI) for Hispanic families with autistic children. We used Bernal et al.'s ecologically valid (EV) framework to evaluate current practice and Hispanic parents' perceptions of Pathways 1 ½ years after completing the intervention. Both quantitative and qualitative methods were used. Nineteen parents were contacted, of which 11 completed a semi-structured interview about their experience with Pathways. On average, the group that completed the interview was less educated, had more monolingual Spanish speakers, and rated their general experience with the intervention slightly more positively than those who did not agree to complete the interview. A review of Pathways's current practices through the lens of the EV framework suggested that Pathways was a CLSI for Hispanic participants in the domains of context, methods, language, and persons. Parental interviews echoed these strengths. However, Pathways did less well balancing evidence-based intervention strategies for autistic children with the heritage value of respeto. Pathways demonstrated strengths regarding cultural and linguistic sensitivity for Hispanic families with young autistic children. Future work with our community stakeholder group will integrate heritage and majority culture perspectives to strengthen Pathways as a CLSI.


Generation and phenotypic characterization of Aspergillus nidulans methylisocitrate lyase deletion mutants: methylisocitrate inhibits growth and conidiation.
Propionate is a very abundant carbon source in soil, and many microorganisms are able to use this as the sole carbon source. Nevertheless, propionate not only serves as a carbon source for filamentous fungi but also acts as a preservative when added to glucose containing media. To solve this contradiction between carbon source and preservative effect, propionate metabolism of Aspergillus nidulans was studied and revealed the methylcitrate cycle as the responsible pathway. Methylisocitrate lyase is one of the key enzymes of that cycle. It catalyzes the cleavage of methylisocitrate into succinate and pyruvate and completes the alpha-oxidation of propionate. Previously, methylisocitrate lyase was shown to be highly specific for the substrate (2R,3S)-2-methylisocitrate. Here, the identification of the genomic sequence of the corresponding gene and the generation of deletion mutants is reported. Deletion mutants did not grow on propionate as sole carbon and energy source and were severely inhibited during growth on alternative carbon sources, when propionate was present. The strongest inhibitory effect was observed, when glycerol was the main carbon source, followed by glucose and acetate. In addition, asexual conidiation was strongly impaired in the presence of propionate. These effects might be caused by competitive inhibition of the NADP-dependent isocitrate dehydrogenase, because the K(i) of (2R,3S)-2-methylisocitrate, the product of the methylcitrate cycle, on NADP-dependent isocitrate dehydrogenase was determined as 1.55 microM. Other isomers had no effect on enzymatic activity. Therefore, methylisocitrate was identified as a potential toxic compound for cellular metabolism.


On the relations between action planning, object identification, and motor representations of observed actions and objects.
Recent evidence suggests that viewing a static prime object (a hand grasp), can activate action representations that affect the subsequent identification of graspable target objects. The present study explored whether stronger effects on target object identification would occur when the prime object (a hand grasp) was made more action-rich and dynamic. Of additional interest was whether this type of action prime would affect the generation of motor activity normally elicited by the target object. Three experiments demonstrated that grasp observation improved the identification of grasp-congruent target objects relative to grasp-incongruent target objects. We argue from this data that identifying a graspable object includes the processing of its action-related attributes. In addition, grasp observation was shown to influence the motor activity elicited by the target object, demonstrating interplay between action-based and object-based motor coding.


[Diagnosis and care of Wilson disease with neurological revelation].
Wilson disease is an autosomal recessive disease that produces a copper accumulation in many organs, initially in the liver, progressing to liver cirrhosis, and in the brain, with different neurologic symptoms. Diagnosis is based on clinical, biochemical, and genetic tests. Different treatments based on chelating agents may help reduce the disease's spontaneous morbidity and mortality. We describe three patients who presented Wilson disease before 18 years of age, with initial neurologic symptoms between 1998 and 2010. After comparison with literature reports, their clinical symptoms, progression, and care allowed us to propose a treatment algorithm. Neurologic symptoms are present in 35% of the patients with Wilson disease such as dystonia, extrapyramidal syndrome, dysarthria, dysphagia, and psychiatric symptoms. The time to diagnosis remains too long and may account for the increased severity of the illness encountered and problems treating these patients. The first treatment choice must be triethylenetetramine, which causes fewer side effects of initial worsening of symptoms compared to D-penicillamine. Zinc therapy is the first treatment for asymptomatic patients or those on maintenance treatment. Finally, liver transplantation is a potential treatment even if the patient presents severe neurological disability because it may improve clinical symptoms. However, further research is warranted on this matter.


Excruciating Low Back Pain After Strenuous Exertion: Beware of Lumbar Paraspinal Compartment Syndrome.
Low back pain is extremely common and usually a minor self-limiting condition. Rarely, however, it is a harbinger of serious medical illness. Paraspinal compartment syndrome is a rare condition, but its timely recognition is important to allow adequate treatment. A 16-year-old boy presented to the Emergency Department (ED) with severe low back pain, necessitating intravenous opioids. Laboratory results showed severe rhabdomyolysis. Magnetic resonance imaging of the lumbar spine showed diffuse edema and swelling in the paraspinal muscles. Aggressive fluid therapy was started but despite narcotic analgesia the pain persisted and creatine kinase (CK) levels increased. Compartment pressures of the erector spinae were found to be increased. The decision was made to proceed with bilateral paraspinal fasciotomies. Postoperatively, the patient noted immediate pain relief with rapid decrease of CK level. The patient is pain free and resumed running and swimming 3 months after admission in the ED. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although paraspinal compartment syndrome is a rare condition, its recognition is of paramount importance to allow adequate surgical treatment, preventing muscle necrosis. Although back pain most often has a benign course, a careful history and physical examination in patients presenting with low back pain allows determination of "red flags." Mandatory further diagnostic tests can identify underlying serious illness.


Cell position regulates endodermal differentiation in embryonal carcinoma cell aggregates.
It has been suggested that cell position regulates endodermal differentiation in mouse embryo inner cell masses and in aggregates of embryonal carcinoma (EC) cells. This hypothesis states that cells at the interface between the cell mass and blastocoel fluid or culture medium differentiate into endoderm, whereas internally located cells follow alternative developmental pathways. To test the cell position hypothesis, pluripotent PSA-1 cells were aggregated with hypoxanthine phosphoribosyltransferase-deficient, parietal-like, endodermal cells. The resulting aggregates consisted of cores of PSA-1 cells surrounded by endodermal cells. Autoradiography was used to distinguish between endodermal cells that were the products of EC cell differentiation and the exogenous endoderm. Alkaline phosphatase staining was used to distinguish EC cells from endodermal cells. As predicted by the cell position hypothesis, the PSA-1 EC cells, all of which were internally located, did not differentiate into endodermal cells. Nonspecific inhibition of differentiation did not account for the lack of PSA-1-derived endoderm since the PSA-1 cells in such aggregates did differentiate into columnar ectodermal-like cells. Similar experiments were also conducted with F9 cells. In this case, aggregation cultures contained retinoic acid to induce F9 cells to differentiate into visceral endoderm. In cultures containing F9 cells surrounded by parietal-like endodermal cells, no F9-derived endoderm was detected either autoradiographically or by assaying for alpha-fetoprotein production, a visceral endoderm marker. Thus, retinoic acid-induced endodermal differentiation was also regulated by cell position. Collectively, the above results provide strong evidence for the hypothesis that cell position regulates endodermal differentiation in aggregates of EC cells.


The effect of essential fatty acid and specific vitamin supplements on vascular sensitivity in the mid-trimester of human pregnancy.
Vascular sensitivity to angiotensin II was determined in the mid-trimester of pregnancy in women after taking a diet with supplemented essential fatty acids and vitamins. The essential fatty acids linoleic and dihommogammalinolenic acid were administered as evening primrose oil capsules (Efamol) for one week prior to the study. Vascular sensitivity was then determined in response to 4, 8 and 16 ng kg-1 min-1 angiotensin II. Vitamin supplements (Efavit) were given with the Efamol capsules. Seven women have been studied, and their vascular sensitivity compared with controls on normal diet. The vascular sensitivity was significantly reduced in all the patients on essential fatty acid supplements, and all values fell below the mean of the control group.


Recollection and familiarity in amnestic mild cognitive impairment: a global decline in recognition memory.
Despite memory failures being a central feature of amnestic mild cognitive impairment (a-MCI), there is limited research into the nature of the memory impairment associated with this condition. A further understanding could lead to refinement of criteria needed to qualify for this designation and aid in prediction of who will progress to development of clinical Alzheimer's disease. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. The present study sought to evaluate recognition memory in a-MCI in the framework of the dual process model. Patients with a-MCI and age- and education-matched controls were tested on three memory paradigms. Two paradigms were modifications of the process-dissociation procedure in which recollection required either memory of word-pair associations (associative) or the font color of words at study (featural). A final paradigm utilized the task-dissociation methodology comparing performance for item and visual spatial source memory. All three tasks revealed that familiarity was impaired to at least the same extent as recollection. As familiarity is thought to be spared in normal aging, its measurement may provide a relatively specific marker for the early pathological changes of Alzheimer's disease.


Effects of a new analog of thyrotropin-releasing hormone, N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate (YM-14673) on spinal reflex potentials and flexor reflexes in spinalized rats.
Experiments were performed on spinalized rats, transected at the Cl level. The intravenous administration of TRH and its analog YM-14673 (N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate) produced marked increases in the amplitude of mono- and polysynaptic reflex potentials and those of the withdrawal flexor reflexes. The effects of YM-14673 were stronger and longer-lasting than those of TRH. The stimulant action of TRH and YM-14673 on the flexor reflexes was not antagonized by prazosin, chlorpromazine, haloperidol or cyproheptadine, suggesting no involvement of the release of catecholamines or serotonin in the stimulant effects of TRH and its analog. Therefore, YM-14673 may be beneficial for the treatment of several spinal motor neuron diseases.


Separation of poly-3-hydroxyvalerate-co-3-hydroxybutyrate through gradient polymer elution chromatography.
Polyhydroxyalkanoates are biodegradable polyesters produced by bacteria that can have a wide distribution in molecular weight, composition of monomers, and functionalities. This large distribution often leads to unpredictable physical properties making commercial applications challenging. To improve polymer homogeneity and obtain samples with a clear set of physical characteristics, poly-3-hydroxyvalerate-co-3-hydroxybutyrate copolymers were fractionated using gradient polymer elution chromatography (GPEC) as opposed to extensively used bulk fractionation. Separation was achieved using a reversed-phase column with chloroform and ethanol as the solvent and non-solvent, respectively. A separation was also conducted on a normal-phase column to compare elution patterns between columns of varied polarity. The fractions were analyzed using Size Exclusion Chromatography (SEC) and NMR to determine the percentage of 3-hydroxyvalerate in the copolymer as well as its molecular weight. It was found that as the percentage of "good" solvent was increased in the mobile phase, the polymers eluted with decreasing percentage of 3-hydroxyvalerate and increasing molecular weight which indicates the importance of precipitation/redissolution in the separation. The elution pattern of the polymer remained unchanged when using both a normal- and reversed-phase column which also illustrates the dominance of precipitation/redissolution in GPEC of polyhydroxyalkanoates. As such, GPEC is shown to be an excellent choice to provide polyhydroxyalkanoate samples with a narrower distribution in composition than the original bulk copolymer sample.


Antioxidant enzymatic activities and resistance to oxidative stress in primary and subcultured rat astroglial cells.
The survival of neural tissues depends in part on the balance between the formation of free radicals due to oxidative metabolism and the transformation of the free radicals to non-toxic compounds. Serial subculture of rat glial cells as described here resulted in a decrease of the specific activities of several antioxidant enzymes and a glial specific marker for astrocytes. Thus, there was an increased susceptibility to oxidative stress in cultures by the third passage. These subcultured glial cell cultures may represent a useful model for the study of free radical induced neural damage that may be relevant to CNS trauma and aging.


Non-specific cytotoxicity of spleen cells in mice bearing transplanted chemically induced fibrosarcomas.
Spleen cells collected from mice bearing transplanted chemically induced syngeneic fibrosarcomas non-specifically inhibited DNA synthesis of sarcoma and lymphoma target cells in vitro. Splenocytes from mice hyper-immunized against a syngeneic sarcoma specifically inhibited DNA synthesis of the tumour used for immunization. The impairment of tumour-cell DNA synthesis was associated in vitro with cytostasis, and lysis of the target cells was not seen. Since treatment with anti-theta serum and complement did not impair cytostatic action of the spleen cells, and since thymus-deprived animals showed similar activity to normal mice, T lymphocytes were not involved in non-specific cytostasis. Removal of phagocytic adherent cells by carbonyl iron markedly inhibited the cytostatic activity of the spleen cells, suggesting a role in this reaction for cells of the monocyte-macrophage series. The presence of an actively growing sarcoma was a prerequisite for the expression of non-specific cytostasis, since surgical excision resulted in complete disappearance of this activity of spleen cells.


Solvation of cobalt(II) and trifluoromethanesulfonate ions in N,N-dimethylformamide-methanol mixed solvent studied by means of FT-IR spectroscopy.
FT-IR spectra of Co(CF(3)SO(3))(2)-N,N-dimethylformamide (DMF)-methanol (MeOH) solutions have been measured over the whole range of solvent composition. The data together with the obtained previously spectra of DMF-MeOH mixtures have been analyzed using the difference spectra method in the region of CO and OH stretching bands. The number of DMF and MeOH molecules in the first solvation sphere of Co(II) ion versus solvent composition has been determined. The second solvation sphere has been revealed and characterized quantitatively. Solvation of trifluoromethanesulfonate (triflate) ion as well as ion association in DMF solution have been also studied.


Is Growth Hormone Insufficiency the Missing Link Between Obesity, Male Gender, Age, and COVID-19 Severity?
Evidence has emerged regarding an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with worse prognosis in elderly male patients with obesity, and blunted growth hormone (GH) secretion represents a feature of this population subgroup. Here, a comprehensive review of the possible links between GH-insulinlike growth factor 1 axis impairment and coronavirus disease 2019 (COVID-19) severity is offered. First, unequivocal evidence suggests that immune system dysregulation represents a key element in determining SARS-CoV-2 severity, as well as the association with adult-onset GH deficiency (GHD); notably, if GH is physiologically involved in the development and maintenance of the immune system, its pharmacological replacement in GHD patients seems to positively influence their inflammatory status. In addition, the impaired fibrinolysis associated with GHD may represent a further link between GH-insulin-like growth factor 1 axis impairment and COVID-19 severity, as it has been associated with both conditions. In conclusion, several sources of evidence have supported a relationship between GHD and COVID-19, and they also shed light upon potential beneficial effects of recombinant GH treatment on COVID-19 patients.


Effects of Ro 15-4513 on the motor impairment and hypnotic effects of ethanol and pentobarbital.
The selectivity of Ro 15-4513 in reversing the actions of sedative-hypnotic drugs was examined. The motor impairment induced by i.p. administration of 1.8 g/kg of ethanol was partially reversed by doses of Ro 15-4513 ranging from 2-8 mg/kg. Antagonism of the similar effect induced by 20 mg/kg of pentobarbital was observed only at the 8 mg/kg dose of Ro 15-4513. Treatment with 4 mg/kg of Ro 15-4513 shifted the dose-effect curve for motor impairment by ethanol to the right but did not affect the corresponding curve for pentobarbital. Ro 15-4513 also increased the onset latency and shortened the duration of sleep time induced by ethanol but not by pentobarbital. Blood ethanol and pentobarbital levels measured at 32 min after drug administration were not affected by Ro 15-4513. The selectivity of Ro 15-4513 and the mechanism(s) underlying its proconvulsant effect in reversing the actions of ethanol are discussed.


The Effects of Decreasing Dietary Crude Protein on the Growth Performance, Feed Efficiency and Meat Quality of Finishing Charolais Bulls.
This study aimed to evaluate the effect of decreasing dietary crude protein (CP) on the performance of finishing Charolais bulls in the Italian rearing system. Animals were fed two diets, differing only in the CP level (low protein (LP), 13.5% CP versus control (CON), 15.0% CP). Dry matter (DM) intake (DMI) and animals' weights were recorded to obtain average daily gain (ADG) and feed conversion rate (FCR). Feed and fecal samples were collected to evaluate digestibility of diet components. Daily cost of the ration (DRC), feed cost per kg of daily weight gain (CDG) and daily gross margin (DGM) were calculated to analyze the possible benefits of decreasing the protein level. Meat quality analyses were also conducted. Higher DMI (10.6 versus 10 kg/d; p < 0.05) and ADG (1.47 versus 1.36 kg/d; p < 0.05) were observed for CON. No differences in FCR or digestibility were found. Even if the DRC was lower (p < 0.05) for the LP diet (2.26 versus 1.97 €; CON versus LP), no difference was reported for CDG and DGM. Meat lightness and redness were significantly lower and higher in the LP, respectively. To conclude, the CP requirement in these rearing conditions appeared to be higher than 13.5%.


Video-assisted thoracic surgery for esophagus for treating locally recurrent gastric cancer at the anastomotic site.
To report a case of video-assisted thoracic surgery for esophagus (VATS-E) for the treatment of locally recurrent gastric cancer at the anastomotic site. A 59-year-old man underwent total gastrectomy for gastric cancer. Histopathologically, it was mucinous adenocarcinoma [pT1(sm), pN1, sM0, PM(-), DM(-), stage IB]. Local recurrence was detected and he received chemotherapy and radiotherapy; histopathologically, it was identified as mucinous adenocarcinoma [pT1(sm), pN0, sM0, stage IA]. As the local recurrence was uncontrollable, he underwent VATS-E. At the 1-year follow-up, he was recurrence-free. The VATS-E minimally invasive surgery was a very useful technique for anastomotic recurrence after total gastrectomy in our patient.


Anesthetic management in atrial fibrillation ablation procedure: Adding non-invasive ventilation to deep sedation.
Anesthetic management of patients undergoing pulmonary vein isolation for atrial fibrillation has specific requirements. The feasibility of non-invasive ventilation (NIV) added to deep sedation procedure was evaluated. Seventy-two patients who underwent ablation procedure were retrospectively revised, performed with (57%) or without (43%) application of NIV (Respironic(®) latex-free total face mask connected to Garbin ventilator-Linde Inc.) during deep sedation (Midazolam 0.01-0.02 mg/kg, fentanyl 2.5-5 μg/kg and propofol: bolus dose 1-1.5 mg/kg, maintenance 2-4 mg/kg/h). In the two groups (NIV vs deep sedation), differences were detected in intraprocedural (pH 7.37 ± 0.05 vs 7.32 ± 0.05, p = 0.001; PaO2 117.10 ± 27.25 vs 148.17 ± 45.29, p = 0.004; PaCO2 43.37 ± 6.91 vs 49.33 ± 7.34, p = 0.002) and in percentage variation with respect to basal values (pH -0.52 ± 0.83 vs -1.44 ± 0.87, p = 0.002; PaCO2 7.21 ± 15.55 vs 34.91 ± 25.76, p = 0.001) of arterial blood gas parameters. Two episodes of respiratory complications, treated with application of NIV, were reported in deep sedation procedure. Endotracheal intubation was not necessary in any case. Adverse events related to electrophysiological procedures and recurrence of atrial fibrillation were recorded, respectively, in 36% and 29% of cases. NIV proved to be feasible in this context and maintained better respiratory homeostasis and better arterial blood gas balance when added to deep sedation.


An increase of CD8+ T cell infiltration following recurrence is a good prognosticator in HNSCC.
Programmed death-ligand 1 (PD-L1) expression and CD8-positive tumor-infiltrating lymphocyte (CD8+ TIL) infiltration are essential biomarkers for immune checkpoint inhibitor therapy. The objective of this study was to compare the expression of those biomarkers between initial and recurrent HNSCCs using paired analysis. Prognostic significance of those immunological changes was also investigated. Forty-two consecutive patients with locally recurrent HNSCCs were included. Immunohistochemical staining of CD8 and PD-L1 was done for both initial and recurrent tumor specimens. The IHC findings were verified with mRNA expression profiling. Also, the prognostic impact was analyzed based on overall survival (OS). Recurrent-to-initial (R/I) ratios of CD8+ TILs and PD-L1 were widely variable. CD8+ TIL density and PD-L1 expression decreased in 59.5% and 69% of patients, respectively (R/I ratio < 1). The R/I ratio of CD8A mRNA was significantly higher in patients with a CD8 R/I ratio > 1 (1.7 ± 1.5 vs. 0.6 ± 0.6, p = 0.042). CD8 R/I ratio (> 1) was a good prognosticator for OS (HR 0.293, 95% CI 0.091-0.945, p = 0.040). CD8+ TIL infiltration and PD-L1 expression changed variably following local recurrence of HNSCC. The increase of CD8+ TILs at recurrence was an excellent independent prognosticator.


Effect of food on hepatic blood flow: implications in the "food effect" phenomenon.
It has been suggested that alteration in the apparent oral bioavailability of propranolol taken with food may be due to a transient increase in QH. To investigate this hypothesis more closely, the time course of effect of a high-protein meal on QH was examined with the model compound ICG. Forty minutes postprandial, the mean increase in estimated QH was 69% above the control. QH was still elevated a mean of 36% at 100 min but by 280 min had decreased to a value that did not differ from control. Computer simulations were performed to predict the magnitude of change in the apparent oral bioavailability of propranolol that would be expected based on the observed QH changes. These simulations suggest that simple changes in QH alone cannot account for the increase in apparent oral bioavailability when propranolol is taken with food.


Analytical quality-by-design approach for development and validation of HPLC method for the simultaneous estimation of omarigliptin, metformin, and ezetimibe: application to human plasma and dosage forms.
A simple, selective, and sensitive RP-HPLC method was proposed for the simultaneous determination of two co-administered antidiabetic drugs (omarigliptin and metformin) with an anti-hyperlipidemic drug (ezetimibe) in a medicinally-recommended ratio of 2.5:50:1, respectively. The proposed procedure was optimized by adopting a quality-by-design approach. The influence of different factors on chromatographic responses was optimized by applying the two-level full factorial design (25). The optimum chromatographic separation was achieved using Hypersil BDS C18 column at 45 °C, and the mobile phase pumped isocratically composed of methanol: potassium dihydrogen phosphate buffer (6.6 mM; pH 7, 67:33% v/v) at a flow rate of 0.814 mL/min using 235 nm as a detection wavelength. The developed method was capable of separating this novel mixture in less than 8 min. The calibration plots of omarigliptin, metformin, and ezetimibe showed acceptable linearity over the ranges of 0.2-2.0, 0.5-25.0, and 0.1-2.0 µg/mL with quantitation limits of 0.06, 0.50, and 0.06 µg/mL, respectively. The proposed method was successfully applied to determine the studied drugs in their commercial tablets with high % recoveries (96.8-102.92%) and low % RSD values (less than 2%). The applicability of the method was extended to the in-vitro assay of the drugs in spiked human plasma samples with high % recoveries (94.3-105.7%). The suggested method was validated in accordance with ICH guidelines.


The association between epidural labor analgesia and maternal fever.
The association between epidural labor analgesia and maternal fever is complex and controversial. Observational, retrospective, before-and-after, and randomized controlled trials all support the association, with the most current evidence supporting the mechanistic involvement of noninfectious inflammation. Considering the clinically significant neonatal consequences that have been previously demonstrated, and the possibility of more common subclinical fetal brain injury that animal models imply, the avoidance of maternal fever during labor is imperative. With the current popularity of epidural analgesia in labor, it is important that clinicians delineate how epidurals cause maternal fever and how to block the noninfectious inflammatory response that seems to warm a subset of women laboring with epidurals.


LncRNA MIAT promotes the proliferation, migration, and invasion of melanoma cells through recruiting TCF12 and activating NFAT5.
The present study aimed to explore the biological functions and mechanism of long non-coding RNA myocardial infarction-associated transcript (MIAT) in melanoma progression. MIAT expression in melanoma tissue samples and cells was detected by quantitative real-time PCR. After gain-of-function and loss-of-function models were constructed, cell counting kit-8, EdU, and Transwell assays were employed to detect the proliferation, migration, and invasion of melanoma cells. catRAPID database was employed and RNA pull-down assay and RNA immunoprecipitation assay were utilized to verify, the binding relationship between MIAT and transcription factor 12 (TCF12). The binding of TCF12 to the promoter region of the gene of nuclear factor of activated T cells 5 (NFAT5) was verified by chromatin immunoprecipitation-quantitative PCR assay and dual-luciferase reporter gene assay. The regulatory effects of MIAT and TCF12 on NFAT5 expression were detected via Western blot. The results showed that MIAT expression was increased in melanoma tissues and cells, and was significantly associated with the AJCC stage and the differentiation of melanoma tissues. MIAT overexpression markedly facilitated melanoma cells' multiplication, migration, and invasion, while MIAT knockdown inhibited the multiplication, migration, and invasion. MIAT showed direct interaction with TCF12. MIAT promoted the binding of TCF12 to NFAT5 promoter region, thereby promoting NFAT5 transcription. In conclusion, MIAT promotes melanoma progression through recruiting TCF12 and its interaction with NFAT5.


Virtual Reality for Anxiety Reduction in Women Undergoing Colposcopy: A Randomized Controlled Trial.
To test whether headset-delivered virtual reality (VR) content affects satisfaction and/or anxiety in women with cervical squamous intraepithelial lesions undergoing colposcopy and colposcopically guided cervical biopsy. In this single-center, randomized trial, the authors measured overall satisfaction (100-mm visual analog scale) and situation-specific anxiety (STAI-S) in 247 women with suspected cervical squamous intraepithelial lesions wearing either no VR headset (arm 1, control) or a VR headset before (arm 2) or before and during colposcopy (arm 3). Secondary endpoints were pain, discomfort, and anxiety during colposcopy, heart rate, and 72-hour follow-up parameters: overall satisfaction, bleeding severity, bleeding duration, pain, and use of analgesics. Analysis was by intention to treat. Median values for overall satisfaction were 100 (interquartile range, 90-100) in controls (n = 83), 100 (95-100) in arm 2 (n = 82), and 100 (95-100) in arm 3 (n = 82), respectively ( p = .92). The median Δ of situational anxiety (baseline vs after colposcopy) was -8 (-13 to -3), -8 (-16.5 to -4), and -10 (-20.5 to -4.5), respectively ( p = .09). The secondary endpoints pain during colposcopy (20 [10-50] vs 20 [10-40] vs 30 [10-50]; p = .65), discomfort during colposcopy (30 [10-50] vs 30 [10-50] vs 20 [10-50]; p = .46), and anxiety during colposcopy (20 [0-50] vs 10 [0-40] vs 10 [0-30]; p = .44), were not different between arms. Follow-up data showed no improvement in the 2 VR arms compared with controls (overall satisfaction, p = .37; bleeding severity, p = .09; pain level, p = .89; duration of pain; p = .23; and use of analgesics; p = .39). Per-protocol analysis did not change the results. A VR headset showing a 360-degree surround vision film has no effect on satisfaction or anxiety in women undergoing colposcopy.


Neurotechnology to reduce recidivism: Ethical and legal challenges.
Crime comes with enormous costs, not only financial but also in terms of loss of mental and physical health and, in some cases, even loss of life. Recidivism is responsible for a considerable percentage of the crimes, and therefore, society deems reducing recidivism a priority. To reduce recidivism, several types of interventions can be used, such as education and employment-focused rehabilitation programs which are intended to improve psychological and social factors. Another way to prevent reoffending is to influence the offender's brain functions. For example, medication can be offered to treat delusions or to diminish sexual drive. In the near future, innovative neurotechnologies are expected to improve prediction and prevention of reoffending. Potential positive effects of such neurotechniques include a safer society and earlier release of prisoners who are no longer "at high risk" to relapse into criminal behavior. Meanwhile, employing these neurotechniques in the criminal justice system raises fundamental concerns, for example, about autonomy, privacy and mental integrity. This chapter aims to identify some of the ethical and legal challenges of using neurotechnologies to reduce recidivism.


Frequency dependent study of the correlation functions in EPR spectroscopy--The Cole-Davidson approach. II. 2,N-(4-n-Butyl benzilidene) 4-amino 2,2,6,6-tetramethyl piperidine 1-oxide in toluene.
EPR linewidth measurements of 2,N-(4-n-butyl benzilidene) 4-amino 2,2,6,6-tetramethyl piperidine 1-oxide (BBTMPO) in toluene at 1 GHz (L-Band), 4 GHz (S-Band), 9 GHz (X-Band) and 34 GHz (Q-Band) microwave frequencies indicate the presence of a distribution of relaxation times. The empirical response parameter introduced by Cole-Davidson for the analysis of dielectric relaxation in liquids has been used for the analysis of EPR relaxation data in the L-Band and S-Band frequency regions. The Cole-Davidson parameter can assume values in the range 0 < β ≤ 1. When β = 1, one obtains the Debye-type spectral density. The calculated linewidth data at 1 GHz and 4 GHz agree with a Cole-Davidson parameter of 0.7 for the spherocone shaped BBMTPO solute. β < 1 at the L- and S-bands suggests the presence of an asymmetrical distribution of relaxation times associated with different modes of relaxation mechanisms or internal molecular motions. This study shows EPR experiments at low microwave frequencies are more sensitive to the shape of the correlation function. Differences between this study and an earlier study [6] on perdeuterated 2,2,6,6-tetramethly-4-piperidone N oxide (PD-Tempone) in toluene are attributed to the size of and absence of deuteration in the BBTMPO probe.


Occurrence and dietary intake of dioxins, furans (PCDD/Fs), PCBs, and flame retardants (PBDEs and HBCDDs) in baby food and infant formula.
This study determines the levels of 49 persistent organic pollutants which were grouped into polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and hexabromocyclododecanes (HBCDDs), in infant formula and varieties of baby food. The analyzed samples (n = 80) came from stores all over Poland. The presence of PCDD/F, PCDD/F/PCB and non dioxin-like (ndl)-PCB congeners above the maximum levels stipulated in Commission Regulation (EU) No 1259/2011 was not detected in any sample. The determined average content of PCDD/Fs/dl-PCBs in the tested baby foods was in the range of 4-10 % of the maximum level, and content of ndl-PCBs was in the range of 2-6 % of the maximum level. Despite these low levels of dioxins, furans, and PCBs, a risk analysis assuming weekly consumption of the recommended food intake showed exceedances of the tolerable weekly intake (TWI). The content of flame retardants was low in all examined categories of food for children and infant formula. The lower-bound concentration of the sum of HBCDD isomers (LB ∑HBCDDs) ranged from below the limit of quantification (LOQ) to 0.0313 ng/g w.w. and the concentration of ∑PBDEs was in a 0.001-1.014 ng/g w.w. range. Neither infant formula nor baby food contributed considerably to infant exposure to HBCDDs or PBDEs. Our research indicates that the safe exposure thresholds for dioxins and PCBs in foods for infants and young children may be too high and perhaps it may be necessary to amend the legislation setting acceptable limits for baby food. It seems reasonable to introduce a recommendation on the frequency of food consumption for children and the control of raw materials for food production, in particular fish and cow milk, should be a permanent control point in the food safety assurance system.


Acetylcholine and potassium elicit different patterns of exocytosis in chromaffin cells when the intracellular calcium handling is disturbed.
During fast superfusion of bovine chromaffin cells with normal Krebs-HEPES solution containing 2 mM Ca2+, pulses of 100 microM ACh or 100 mM K+ of increasing duration (1-5 s) caused similar exocytosis of about 3-4 microC catecholamine. Depletion of endoplasmic reticulum (ER) Ca2+ by pretreatment with 1 microM thapsigargin, 10 mM caffeine and 10 microM ryanodine more than halved the responses to ACh but did not affect the responses to K+ responses. In these ER Ca2+-depleted cells the protonophore carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) (20 microM given during the 5 s preceding each pulse) augmented the responses to ACh responses fourfold for all pulse durations applied (1-5 s) whereas responses to K+ were potentiated twofold with 1 to 2 s pulses but were not affected with longer pulse durations. ACh pulses applied to fura-2-loaded cells evoked increases of bulk cytosolic [Ca2+] ([Ca2+](c)) that were substantially smaller than those elicited by K+ pulses. Confocal microscopy of fluo-3-loaded cells showed that ACh pulses elicited discrete and more localized [Ca2+](c) elevations, whereas K+ pulses produced higher [Ca2+](c) transients that spread out quickly throughout the cytosol. These results suggest that mitochondria sense the increase of local [Ca2+](c) elicited by ACh (that evokes firing of action potentials) much better than that induced by K+ (that produces sustained cell depolarisation). This implies that mitochondria are more sensitive to the local [Ca2+](c) changes resulting from the physiological triggering of action potentials by ACh.


Propantheline as a diagnostic tool--a serious complication.
Propantheline bromide is a synthetic quaternary ammonium compound widely used in urologic patients to block the action of acetylcholine at the postganglionic nerve endings of the bladder's parasympathetic innervation. It is used clinically in a wide range of doses in ambulatory outpatients as well as hospitalized patients. To document its effects on the bladder, test doses are given with a cystometrogram documenting the dynamic changes. Herein we report a case of serious cardiac toxicity from a diagnostic test dose.


5-lipoxygenase pathway is essential for the control of granuloma extension induced by Schistosoma mansoni eggs in lung.
According to WHO, it is estimated that approximately 2 billion people are infected with intestinal helminths worldwide and the number of people who are cured of these diseases is relatively low, resulting in a large percentage of chronically infected individuals. Schistosomiasis is one of the most important parasitic diseases present in developing countries configuring it as a serious public health problem, directly related to poverty and social disadvantage. Once the parasite infection is established, Schistosoma mansoni eggs fall into the bloodstream and are trapped in the liver microcirculation where a strong granulomatous response and fibrosis formation occurs. In the experimental model, granulomas develop in the mouse lung after intravenous injection of purified eggs. Here we aim to understand how leukotrienes are involved in the granuloma formation. Leukotrienes are lipid mediators derived from arachidonic acid metabolites via 5-lipoxygenase (5LO) enzyme. They are potent proinflammatory agents and induce recruitment, cell activation, regulation of microbicidal activity of polymorphonuclear and mononuclear cells. In this study, 5LO deficient mice (5LO(-/-)) were inoculated with S. mansoni eggs for evaluation of immunopathological parameters involved in the induction of type 2 granulomas. We showed that in the absence of leukotrienes, the size of granulomas were decreased comparing to the wild type mice and the inflammatory compromised areas had a lower extension. In 5LO(-/-) mice granulomas presented extensive areas of fibrosis, detected by α-SMA expression along the lesions, indicating remodeling in attempt to reestablish the normal tissue. Also, comparing to WT mice we detected decrease of IL-4 and IL-13 and increase of TGF-β in the lung of 5LO(-/-), but these mice failed to produce protective IFN-γ and IL-12. These results evidenced 5-Lipoxygenase as an important pathway during lung injury due to Schistosoma-eggs injection.


Pain Examination and Diagnosis.
Pain is a clinical challenge to health care providers who care for hand disorders. Pathologic pain that prevents recovery leads to dissatisfaction for both patients and providers. Despite pain being common, the root cause is often difficult to diagnose. This article reviews the examination and diagnostic tools that are helpful in identifying pathologic and neuropathic pain. This article provides tools to speed recognition of these processes to allow earlier intervention and better patient outcomes.


Clinicopathological features and BRCA1 and BRCA2 mutation status in a prospective cohort of young women with breast cancer.
Breast cancer in young women is more likely to have higher risk features and be associated with germline BRCA1/BRCA2 mutations. We present the clinicopathologic features of breast cancers in a prospective cohort of young women, and associations between surrogate molecular subtype and BRCA1/BRCA2 mutation status. Histopathological features, biomarker status, tumour stage and BRCA status were collected. Invasive tumours were categorised as luminal A-like (ER + and/or PR + , HER2-, grade 1/2), luminal B-like (ER + and/or PR + , HER2 + , or ER + and/or PR + , HER2-, and grade 3), HER2-enriched (ER/PR-, HER2 + ) or triple-negative. In all, 57.3% (654/1143) of invasive tumours were high grade. In total, 32.9% were luminal A-like, 42.4% luminal B-like, 8.3% HER2-enriched, and 16.4% triple-negative. Among different age groups, there were no differences in molecular phenotype, stage, grade or histopathology. 11% (131) of tumours were from BRCA mutation carriers; 64.1% BRCA1 (63.1% triple-negative), and 35.9% BRCA2 (55.3% luminal B-like). The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.


Pasteurella multocida osteomyelitis caused by cat bite.
A previously healthy 15-year-old girl was bitten by a cat in her left thumb. Despite initial treatment with penicillin she developed osteomyelitis after a period of four months. Pasteurella multocida was cultured from the necrotic bone. The infection showed low activity and was successfully treated with surgery combined with penicillin.


The effect of abdominal stabilization contractions on posteroanterior spinal stiffness.
Intrasubject controls with randomized intervention order. To quantify the immediate change in posteroanterior (PA) spinal stiffness produced by different combinations of trunk muscle contraction. The abdominal hollow and the abdominal brace are 2 different combinations of trunk muscle contractions that are commonly prescribed to increase spinal stability. Unfortunately, the immediate effect of these different contractions on spinal stiffness (one indicator of spinal stability) has not yet been quantified directly. Twenty-eight asymptomatic subjects were taught abdominal hollow and brace contractions then performed them in a randomized order framed by periods of rest. Surface electromyography and B-mode ultrasound confirmed that all contractions were performed appropriately. During each test condition (hollow, brace, and rest), a noninvasive indentation technique was used to quantify PA spinal stiffness. A repeated measures analysis of variance was used to assess the significance of changes in the PA spinal stiffness between test conditions. Both the abdominal hollow and abdominal brace contractions increased PA spinal stiffness significantly when compared with the rest condition (P < 0.001). When the abdominal hollow and brace contractions were compared with each other, the abdominal brace contraction produced significantly greater PA spinal stiffness (P < 0.05). In asymptomatic subjects, the abdominal brace contraction provided an immediate PA stiffening effect that was significantly greater in magnitude when compared with conditions of rest and abdominal hollowing. These findings may allow clinicians to better match commonly prescribed contraction-based interventions with specific patient needs. Future work is required to assess the long-term effect of repeated abdominal brace and hollow contractions on PA spinal stiffness and low back pain.


Spontaneous platelet aggregation: observations on potential mechanisms.
We identified SPA in three young apparently healthy women. SPA was associated with release of TXA2 and was only partially inhibited by ADP-inhibitor apyrase and alpha 2-adrenoceptor blocker yohimbine. In vitro incubation of aspirin (90 micrograms/ml) or selective TXA2 synthetase inhibitor OKY-046 (0.1 uM) with platelet rich plasma (PRP) did not abolish SPA, although platelet generation of TXA2 was markedly inhibited. In contrast, oral administration of large amounts of aspirin in one subject or in vitro incubation of PRP with TXA2 -endoperoxide receptor blocker SQ 29,548 (20-100 nM) significantly inhibited SPA. These studies suggest that SPA is associated with TXA2 release. Since TXA2 -endoperoxide receptor blocker completely abolishes the secondary wave, agents like this may be of therapeutic value in individuals with SPA and evidence of tissue ischemia.


Steady pressure-flow relationship in a cast of the upper and central human airways.
Pressure drops across the upper (larynx) and central airways of a human lung cast were measured at steady state inspiratory and expiratory flows. Air, He-O2 and SF6-O2 gas mixtures were used at tracheal Reynolds' numbers ranging from 145 to 30,000. The pressure-flow characteristics of the model were analysed using standard pressure-flow diagrams and Moody plots. We found that the asymmetry between inspiratory and expiratory resistances, observed in the central airways (larynx excluded), was markedly reduced in the presence of the larynx. However, static pressure differences were greater across the entire model of the upper and central airways than across the model of the five generations of the tracheo-bronchial tree (without larynx) at the same flow-rates. In addition, our results showed that the presence of the larynx tended to reduce the zone of fully developed laminar flow in the Moody diagram with the higher density gas, while extending the zone of turbulent flow even for the low density gas at low Reynold's numbers.


Effects of commonly consumed vegetables on hepatic xenobiotic-metabolizing enzymes in the mouse.
To investigate the effects of consuming a variety of common vegetables on the activities of xenobiotic-metabolizing enzymes in the mouse liver, male C57BL/6 mice were fed purified diets supplemented isocalorically with 20% freeze-dried powdered kidney bean, soya bean, alfalfa, cauliflower, mustard greens, carrot, kale, Brussels sprouts, beet, egg plant or onion or with 40% sweet potato. Hepatic ethoxycoumarin O-deethylase (ECD) activity was increased significantly (P less than or equal to 0.05) over the controls in the mice fed diets containing kidney bean (1.5-fold), alfalfa (1.6-fold), cauliflower (2.2-fold), mustard greens (1.2-fold), carrots (1.2-fold) and kale (1.3-fold). No significant increases in ECD activity were seen in the other groups. Aryl hydrocarbon hydroxylase (AHH) activity was assayed in the cauliflower and Brussels sprouts groups and was found to be unaffected by these diets. Glutathione S-transferase (GST) and epoxide hydratase (EH) activities were increased (P less than or equal to 0.05) by soya bean (1.2- and 1.6-fold respectively), Brussels sprouts (2.0- and 1.6-fold), cauliflower (1.2- and 1.6-fold), alfalfa (1.3- and 2.0-fold) and onion (1.8- and 2.3-fold). No significant increases in GST or EH activities were seen in the other groups. Of the twelve vegetables investigated, only three (sweet potato, beet and egg plant) had no statistically significant effects on any of the xenobiotic-metabolizing parameters tested. However, the beet diet caused an apparent inhibition of ECD activity (74% of control) and the sweet potato diet caused an apparent increase (1.3-fold) in GST activity, although statistical significance could not be established at P less than or equal to 0.05.


Emotional responses of piglets under long-term exposure to negative and positive auditory stimuli.
The stress caused by sound is inevitable. The stress caused by noise and the positive effects of music can affect the endocrine of animals and their welfare. In this study, a total of 72 hybrid piglets (Large White × Duroc × Min pig) were randomly divided into 3 groups, including music (Mozart K.448, 60-70 dB), noise (recorded mechanical noise, 80-85 dB), and control (natural background sound, <40 dB) groups. S-IgA (secretory immunoglobulin A), IL-6 (interleukin-6), IL-8 (interleukin-8), and positive emotion-related behaviors were used as indicators to discuss whether noise induced stress and inflammation in piglets or whether music could have positive effects. Six hours of auditory exposure were given daily (10:00-16:00), which lasted for 56 days. Behavioral responses of the piglets were observed, and the concentrations of salivary S-IgA and serum IL-6 and IL-8 were measured. The results showed that the concentration of S-IgA increased in the noise and control groups on the 57th day (P < 0.05); S-IgA concentration in the music group was unchanged after long-term music exposure. The concentrations of IL-6 and IL-8 showed that long-term noise exposure might lead to stress and inflammation in piglets. Tail-wagging and play behaviors of the piglets in the music group were significantly greater than those in the noise and control groups, which implied that long-term music exposure improved the emotional state of the piglets in a restricted and barren environment.


Adult c-kit(pos) cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair.
The epidemic of heart failure has stimulated interest in understanding cardiac regeneration. Evidence has been reported supporting regeneration via transplantation of multiple cell types, as well as replication of postmitotic cardiomyocytes. In addition, the adult myocardium harbors endogenous c-kit(pos) cardiac stem cells (eCSCs), whose relevance for regeneration is controversial. Here, using different rodent models of diffuse myocardial damage causing acute heart failure, we show that eCSCs restore cardiac function by regenerating lost cardiomyocytes. Ablation of the eCSC abolishes regeneration and functional recovery. The regenerative process is completely restored by replacing the ablated eCSCs with the progeny of one eCSC. eCSCs recovered from the host and recloned retain their regenerative potential in vivo and in vitro. After regeneration, selective suicide of these exogenous CSCs and their progeny abolishes regeneration, severely impairing ventricular performance. These data show that c-kit(pos) eCSCs are necessary and sufficient for the regeneration and repair of myocardial damage.


Long-term results of a double perfusion schedule using high dose hyperthermia and melphalan sequentially in extensive melanoma of the lower limb.
The aim of this study was to assess the results of an isolated limb perfusion (ILP) schedule with high dose hyperthermia (42-43 degrees C) and melphalan, applied sequentially in patients with advanced melanoma of the limbs. Seventeen patients with extensive recurrent or bulky melanoma of a limb were treated with hyperthermic femoral ILP (42-43 degrees C) without drugs followed by normothermic (37-38 degrees C) ILP with melphalan. Eleven patients (65%) had a complete response. Three patients (27%) had limb recurrences after 5, 6 and 18 months, respectively. The 5 year limb recurrence-free interval for patients with a complete response was 63%. Limb toxicity was mild; pressure-related blistering and transient sensory disturbances occurred after the hyperthermic ILP, and 88% of the patients had a grade II reaction (mild erythema and oedema) after the second ILP. This sequential ILP schedule resulted in a high complete response rate and a low limb-recurrence rate in patients with extensive, recurrent melanoma of the limbs at the cost of only mild toxicity. This regimen could be an alternative to ILP with tumour necrosis factor-alpha and melphalan.


["In vitro" evaluation of the action of various cavity varnishes].
The authors studied in vitro the capacity of FORP-USP cavity varnishes, COPALAINE (Prodonto), COPALITE (H. J. Bosworth Co.), CAVITINE (SS WHITE) and UNIVERSAL (SS WHITE) to promote impermeabilization. The tests were done by the use of filter paper and the impermeabilization was measured by the Rhodamine B stain infiltration. The FORP-USP cavity varnishes Copalaine and Copalite were more effective in promoting impermeabilization.


Coronary thrombolysis with K1K2Pu, a chimeric tissue-type and urokinase-type plasminogen activator: a feasibility study in six patients with acute myocardial infarction.
K1K2Pu is a recombinant chimeric tissue-type and urokinase-type plasminogen activator consisting of the two kringle domains (K1 and K2) of human tissue-type plasminogen activator (t-PA) and the serine proteinase domain (Pu) of single-chain urokinase-type plasminogen activator (scu-PA). In experimental animal models of thrombosis, its thrombolytic potency has been shown to be five- to 10-fold greater than that of its parent molecules. The effect of a bolus injection of K1K2Pu on coronary thrombolysis over 30 min was evaluated in six patients with acute myocardial infarction of less than 5 h duration in whom total occlusion of the infarct-related artery was confirmed using angiography. In two patients given an intravenous bolus of 10 mg over 5 min, persistent coronary artery recanalization was not observed within 30 min. In two out of four patients given a second bolus of 10 mg K1K2Pu, 15 min after the first, persistent coronary recanalization occurred within 30 min. The four patients without recanalization within 30 min were immediately given 100 mg t-PA over 90 min. In all patients the infarct-related artery was patent after 24 h, and the hospital course was uneventful. The bolus injections did not produce significant fibrinogen breakdown or alpha 2-antiplasmin consumption within 30 min. The plasma K1K2Pu level increased to 2-3 micrograms/ml after the first bolus injection and to 4-5 micrograms/ml after the second. K1K2Pu disappeared from the plasma with an initial half-life of 9 min and a clearance of approximately 50 ml/min. A bolus injection of 20 mg K1K2Pu is well tolerated and can induce clot-selective coronary thrombolysis in patients with acute myocardial infarction.


Age-related changes in urinary growth hormone level and its clinical application.
In order to establish the normal range of urinary growth hormone (GH) level for age and sex, which is important in the clinical application of urinary GH to diagnosis, we measured GH in the first morning urine specimens of 270 normal subjects aged 3 to 20 years. Urinary GH levels in patients with documented GH deficiency were compared with those of the normal controls. In normal subjects, urinary GH levels showed a statistically significant change with age. They were relatively high in infancy and mid-puberty, reaching a peak at 11 to 12 years in girls and at 13 to 14 years in boys. Urinary GH levels in patients with complete GH deficiency were apparently lower (less than -2.0 SD) than those of the normal children, while the levels in patients with partial GH deficiency overlapped with the normal range. When assessing GH secretion by using urinary GH measurement, consideration of age and sex is required, since the level changes significantly with these factors.


Honeycomb-structured fabric with enhanced photothermal management and site-specific salt crystallization enables sustainable solar steam generation.
The emerging of solar-driven interfacial evaporation provides new opportunities to alleviate the shortage of fresh water resource. Nevertheless, in practical solar desalination, salt precipitation will lead to the decrease of evaporation rate due to reduced light absorption and blocked evaporation channels of evaporator. It still remains a challenge to eliminate salt accumulation and simultaneously maintain high-efficient evaporation. In this work, a solar evaporator was prepared based on reduced graphene oxide and chitosan coated honeycomb-structured fabric (rCHF). The rCHF showed a high light absorbance of 97.2% due to enhanced light trapping of the honeycomb structure and ultra-low thermal conductivity of 0.044 W m-1 K-1. Furthermore, the temperature gradient generated inside the honeycomb unit can induce the Marangoni effect, which led to the site-specific salt crystallization on rCHF in seawater evaporation. As a result, the rCHF realized an excellent solar evaporation rate of 2.02 kg m-2h-1 under one sun irradiation (1 kW m-2). The site-specific salt crystallization on the surface of rCHF ensured stable evaporation even in 20% brine, and the isolated salt can be removed by natural dissolution owing to the excellent hydrophilicity of rCHF. This work provides a new perspective for the design of solar evaporator for practical solar seawater desalination.


Tumor-derived exosomal microRNA-15b-5p augments laryngeal cancer by targeting TXNIP.
Tumor-derived exosomes (EXO) are information carriers of microRNA (miR) in cancer development. Here, we explored the synergism of tumor-derived EXO and miR-15b-5p in laryngeal cancer (LCa). miR-15b-5p and thioredoxin-interacting protein (TXNIP) levels were firstly measured in clinical LCa tissues. The association between miR-15b-5p and TXNIP was determined. miR-15b-5p mimic was transfected into HEP-2 cells, and the corresponding exosomes were extracted. miR-15b-5p mimic-modified EXO were co-cultured with HEP-2 cells, and TXNIP low expression/high expression vector was transfected into HEP-2 cells Finally, cell growth was observed in vitro and in vivo. miR-15b-5p level was high while TXNIP level was low in LCa, and miR-15b-5p negatively modulated TXNIP expression. HEP-2 cells-derived EXO or inhibition of TXNIP enhanced HEP-2 cell growth in vitro and in vivo. Up-regulated miR-15b-5p further strengthened the pro-tumor effect of EXO, but this effect was reversed by overexpression of TXNIP. Overall, tumor-derived exosomal miR-15b-5p augments LCa through targeting down-regulation of TXNIP.


Empirical estimation of the normative blood pressure in infants <28 weeks gestation using a massive data approach.
To determine the expected systolic, mean and diastolic blood pressures at birth and respective rates of change during the first 72 h of life in infants born at <28 weeks estimated gestational age (EGA) with a favorable short-term outcome, defined as survival to 14 days with grade II or less intraventricular hemorrhage (IVH). Systolic, mean and diastolic blood pressures were continuously sampled at 0.5 Hz via umbilical artery catheter from birth through 72 h. The raw data were aligned by postnatal hour and underwent error correction. For each infant, the mean values of systolic, mean and diastolic blood pressure were calculated for each postnatal hour. The slope and intercept of best-fit line for each of the three blood pressure parameters was then calculated. Infants that received inotropic medications, died in the first 14 days of life, or had IVH grade III or IV were excluded. Using 11.9 million valid data points from 35 infants (mean EGA=25.7 ± 1.5 weeks, mean birth weight=865 ± 201 g), we found independent associations of African-American race (P<0.01) and a complete course of antenatal steroids (P<0.01) with higher blood pressures at birth and a slower rate of increase. Acute chorioamnionitis was independently associated (P=0.02) with lower blood pressures at birth and a faster rate of increase. EGA and birth weight were not independently predictive of blood pressure parameters. We found that (i) the estimated mean blood pressure at birth is ~33 mmHg in a cohort of very preterm infants, (ii) blood pressure gradually increases with postnatal age, (iii) systolic blood pressure increases at a faster rate than diastolic blood pressure, (iv) race, antenatal steroid exposure and chorioamnionitis are independent modulators of blood pressure whereas EGA and birth weight are not.


Systematic biases and Type I error accumulation in tests of the race model inequality.
In simple, go/no-go, and choice reaction time (RT) tasks, responses are faster to two redundant targets than to a single target. This redundancy gain has been explained in terms of a race model assuming that whichever target is processed faster determines RT (Raab, 1962). Miller (1982) presented a race model inequality to test the race model by comparing the RT distributions of single and redundant target conditions. Here, we present simulations indicating that the standard tests of this inequality (for a description of the testing algorithm, see Ulrich, Miller, & Schröter, 2007) are afflicted with systematic biases and Type I error accumulation. Systematic biases tend to produce violations of the race model inequality, but they decrease as the numbers of observations increase. Reasonably unbiased tests of the race model inequality are obtained for sample sizes of at least 20 for each target condition. In addition, Type I error accumulates because of testing the inequality at multiple percentiles. To reduce Type I error, the race model inequality should be tested in a restricted range of percentiles, preferably in the percentile range 10% to 25%.


Efficacy and Safety of Apatinib Treatment for Patients with Advanced Intrahepatic Cholangiocarcinoma.
Effective treatment options for intrahepatic cholangiocarcinoma (ICC) are limited. This study was intended to explore the efficacy and safety of apatinib in advanced ICC with lymph node metastasis or distant metastasis. The efficacy and toxicity of apatinib were evaluated in patients with ICC between November 2017 and March 2020 at the Second Affiliated Hospital of Anhui Medical University. Survival analysis was estimated using Kaplan-Meier method. Ten patients with advanced ICC were enrolled. The median progression-free survival (PFS) was 3.0 months (95% CI: 1.450-4.550). No patient achieved a complete response (CR). One patient gained partial response (PR), and 6 patients had stable disease (SD). The objective response rate (ORR) was 10%, and the disease control rate (DCR) was 70%. The common treatment-related adverse events were hypertension (20%), proteinuria (30%), hand and foot syndrome (10%) or emesis (10%). No grade 3/4 toxicities occurred. Toxicities were mild and tolerable. Apatinib is potentially an effective treatment option with tolerable toxicities for patients with advanced ICC.


Cavernous hemangioma in the pineal region.
A cavernous hemangioma in the pineal region of a 22-year-old man is reported. Because the patient had diabetes insipidus and a contrast-medium-enhanced mass in his pineal region on computed tomography, a germinoma was suspected. A ventricular shunt was made and the tumor was irradiated, but without a response. After irradiation the tumor was entirely removed, and postoperatively the diabetes insipidus improved.


The pre membrane and envelope protein is the crucial virulence determinant of Japanese encephalitis virus.
After sequence comparison, it was found that there are multiple amino acid mutations in pre-M and envelope (E) protein of Japanese encephalitis virus vaccine strain comparison with wild type (WT) strain SA14. It is generally acknowledged it is the mutations that have caused the virulence attenuation of vaccine strain, but lack of sufficient experimental evidences. For a better understanding of the mechanism of attenuation of Japanese encephalitis virus (JEV), in this study, we assessed whether prM/E is critical neurovirulence determinants of JEV with infectious cDNA clones technique. Substitutions prM/E of vaccine strain with that of WT SA14 did significantly increase the virulence of JEV to the similar level of wild type SA14, and simultaneously, replacement prM/E of JEV WT strain SA14 with that of vaccine strain SA14-14-2 decreased the virulence of JEV significantly to the similar level of vaccine stain. The results indicate that the prM/E protein is the crucial virulence determinant of Japanese encephalitis virus, although other proteins take part in the process to some extent.


Future perspectives in specific immunotherapy of melanoma.
With the discovery of T-cell recognised tumour-associated antigens (TAAs), interest in specific immunotherapy for treatment of malignancies has increased substantially. The majority of studies investigating TAAs have focused on melanoma-associated antigens because of evidence that the immune system influences the pathogenesis of melanoma. This paper reviews the different types of melanoma antigens, their in vitro and in vivo immunogenicity and clinical data regarding the use of specific immunotherapy in patients with stage I-IV melanoma. Results of clinical studies are highly variable but encourage further research in these patients. Developing and perfecting laboratory and clinical correlates of response to these specific immunotherapies are vital to determining their role in clinical practice.


Molecular targeting of angiogenesis.
The majority of pharmacological approaches for the treatment of solid tumors suffer from poor selectivity, thus limiting dose escalation (i.e., the doses of drug which are required to kill tumor cells cause unacceptable toxicities to normal tissues). The situation is made more dramatic by the fact that the majority of anticancer drugs accumulate preferentially in normal tissues rather than in neoplastic sites, due to the irregular vasculature and to the high interstitial pressure of solid tumors. One avenue towards the development of more efficacious and better tolerated anti-cancer drugs relies on the targeted delivery of therapeutic agents to the tumor environment, thus sparing normal tissues. Molecular markers which are selectively expressed in the stroma and in neo-vascular sites of aggressive solid tumors appear to be particularly suited for ligand-based tumor targeting strategies. Tumor blood vessels are accessible to agents coming from the bloodstream, and their occlusion may result in an avalanche of tumor cell death. Furthermore, endothelial cells and stromal cells are genetically more stable than tumor cells and can produce abundant markers, which are ideally suited for tumor targeting strategies. This review focuses on recent advances in the development of ligands for the selective targeting of tumor blood vessels and new blood vessels in other angiogenesis-related diseases.