[Epidermoid carcinoma of the penis. Review of 30 cases].
To review our series of epidermoid carcinoma of the penis. 30 cases of epidermoid carcinoma of the penis are reviewed. The clinical features, tumor stage, grade, treatment and outcome are analyzed. The time to diagnosis ranged from one month to 10 years, mean 10.3 months (1 to 36); therefore the mean diameter of the tumors was significantly greater (1.9 cm) at the time of diagnosis than at the beginning of the lesion. Eighteen patients had tumor superinfection. Twenty-four patients (80%) had low grade carcinoma; 6 had verrucous carcinoma, 6 (16.7%) intermediate and one (3.3%) high grade. Total penectomy with perineal meatus was performed in 5 cases, 23 had a partial penectomy with 2 cm margin and circumcision was done in two cases. Patients with positive lymph nodes at exploration after antibiotic treatment (13 cases) were submitted to lymphadenectomy, which was associated with chemotherapy in 4 patients. The surgical complications were mainly lymphorrhea and edema and infection of the surgical incision after lymphadenectomy. Complications at the site of penile resection were unusual. Only 6 patients have more than 5 years' follow-up (7-14), with only 1 local recurrence. The remaining patients have a mean follow-up of 22 +/- 16 months (6-60). Of these, only one patient had died from penile cancer (previously pT2pN0M0). This patient had lymph node and distant metastases 6 months following penectomy due to invasive local recurrence (pT3pN2pM1). Lymph node recurrence has been detected in three other patients. Inguinal lymphadenectomy is clearly of therapeutic value in cancer of the penis and performing it early in infiltrating tumors is likely to improve the outcome in these patients.


Ketamine Versus Etomidate and Peri-intubation Hypotension: A National Emergency Airway Registry Study.
The hemodynamic impact of induction agents is a critically important consideration in emergency intubations. We assessed the relationship between peri-intubation hypotension and the use of ketamine versus etomidate as an induction agent for emergency department (ED) intubation. We analyzed ED intubation data for patients aged >14 years from the National Emergency Airway Registry performed in 25 EDs during 2016 through 2018. We excluded patients with preintubation hypotension (systolic blood pressure <100 mm Hg) or cardiac arrest prior to intubation. The primary outcome was peri-intubation hypotension. Secondary outcomes included interventions for hypotension (e.g., intravenous fluids or vasopressors). We report adjusted odds ratios (aOR) from multivariable logistic regression models controlling for patient demographics, difficult airway characteristics, and intubation modality. There were 738 encounters with ketamine and 6,068 with etomidate. Patients receiving ketamine were more likely to have difficult airway characteristics (effect size difference = 8.8%, 95% confidence interval [CI] = 5.3% to 12.4%) and to undergo intubation with video laryngoscopy (8.1%, 95% CI = 4.4% to 12.0%). Peri-intubation hypotension incidence was 18.3% among patients receiving ketamine and 12.4% among patients receiving etomidate (effect size difference = 5.9%, 95% CI = 2.9% to 8.8%). Patients receiving ketamine were more likely to receive treatment for peri-intubation hypotension (effect size difference = 6.5%, 95% CI = 3.9% to 9.3%). In logistic regression analyses, patients receiving ketamine remained at higher risk for peri-intubation hypotension (aOR = 1.4, 95% CI = 1.2 to 1.7) and treatment for hypotension (aOR = 1.8, 95% CI = 1.4 to 2.0). There was no difference in the aOR of hypotension between patients receiving ketamine at doses ≤1.0 mg/kg versus >1.0 mg/kg or patients receiving etomidate at doses ≤0.3 mg/kg versus >0.3 mg/kg. Pending additional data, our results suggest that clinicians should not necessarily prioritize ketamine over etomidate based on concern for hemodynamic compromise among ED patients undergoing intubation.


Induced effect of Na(+) on ganoderic acid biosynthesis in static liquid culture of Ganoderma lucidum via calcineurin signal transduction.
Na(+)/Ca(2+) exchange is important to cell physiology and metabolism, but its role in the secondary metabolite biosynthesis by fungi is yet unclear. In this work, in static liquid cultures of Ganoderma lucidum, which is an efficient process for hyper-production of anti-tumor ganoderic acids (GAs), it was interestingly found that Na(+) addition could enhance the GAs production, but K(+) did not. Further investigation by intracellular Ca(2+) imaging and using a calcineurin inhibitor (i.e., cyclosporin A) revealed that addition of Na(+) led to the influx of Ca(2+) from culture broth to the cells and calcineurin signals were also triggered. Addition of 100 mM Na(+) at the beginning of the static liquid cultivation, in which the addition dosage and timing were optimized, resulted in 2.8-fold improvement of total GAs production. Quantitative gene transcription analysis indicated that the expression levels of the genes of Ca(2+) sensors and GA biosynthesis were upregulated with Na(+) induction while downregulated by using the calcineurin inhibitor, implying that higher GA production might result from higher expression of those genes. This work not only provided a simple and efficient induction strategy by Na(+) addition for the improved GAs production but also suggested the regulation mechanism of Na(+) on the GA biosynthesis through calcineurin signaling transduction.


Biological therapies for Alzheimer's disease: focus on trophic factors.
Recent revolutionary discoveries in the structure and function of the nervous system have substantiated the early optimism expressed by Ramon y Cajal on the regenerative potential of neurons. A systematic study of the mechanisms of neural injury and repair has generated exciting new ideas on how to assist the innate restorative potential of the nervous system by using substances that address specific pathogenetic events (biological or rational therapies). The greatest challenge for these interventions is the prevention of neuronal cell death, which is the inevitable outcome of many common diseases of the nervous system and which limits the efficacy of more traditional treatment approaches (i.e., approaches to restore the neuronal phenotype). Trophic factors are excellent candidates because they are naturally implemented to promote the survival of neurons in development. Among many neurological diseases, Alzheimer's disease (AD) is a model for consideration of a trophic therapy because of its grave epidemiological impact and the massive death of neurons in multiple brain sites. In the present paper, we propose an approach to design trophic therapies for AD, considering also the pertinent clinical and ethical issues. We also integrate the trophic approach with other ways to promote neural regeneration, including the use of small organic molecules. Nerve growth factor (NGF) is used as a paradigmatic trophic factor, because of a wealth of evidence for its robust effects on working memory (i.e., a type of cognition that is severely impaired in AD); other trophic factors, discussed in the text, may also have the potential as drugs for this disorder. It is likely that a comprehensive approach to treat AD will involve multiple substances selective for particular pathogenetic events and nerve cell types.


The smile is stronger than the handshake.
This article was migrated. The article was marked as recommended. Healthcare providers struggle with the timing of handwashing and the handshake during the visit with patients, we question whether the handshake is even a necessary component of the modern introduction. The Physician-Patient relationship is strongest when built on trust, and typically begins with a traditional handshake. The importance of hand hygiene has become an integral part of the patient encounter. Taking a break for hand-hygiene interrupts the natural flow of the initial introduction and non-verbal body language to our patients. In current time constrained visits, we focus on handwashing instead of on continuous eye-contact with our patient. It is arguable that the elimination of the handshake may allow one to focus on more culturally acceptable universal verbal and non-verbal communication skills that help us to build essential trust with our patients.


Age and socially related changes in fecal androgen metabolite concentrations in free-ranging male giraffes.
In many mammal species, androgen levels in males are elevated during periods of mating activity, often to facilitate aggressive behavior between males over access to fertile females. However, this pattern might be less obvious in species with a rather low male-male aggression rate, or in those that are not strictly seasonal breeders. A complex social structure, as well as additional social and environmental factors, might add more to the complexity. Here, we applied a non-invasive method to monitor fecal androgen metabolite (fAM) levels in free-ranging giraffe bulls over a period of months to examine longitudinal patterns of androgen metabolite concentrations in relation to observed male sexual behavior in different age classes. Giraffes are non-seasonal breeders, living in a fission-fusion social system and males show a roaming strategy to search for fertile females. Our results show that season has an impact on fAM levels in free-ranging giraffes, with respective steroid concentrations being higher in summer. In the presence of females, fAM levels of bulls are significantly higher compared to when found in all-male groups, with old adult bulls showing the highest fAM levels. In contrast, young adult bulls have overall slightly higher fAM levels compared to old adult bulls when residing in all male groups. Sexual behavior increases fAM levels only in old adult bulls.


Dyslipidemia in women with polycystic ovary syndrome: incidence, pattern and predictors.
One hundred forty-two women with polycystic ovary syndrome (PCOS) with an average body mass index (BMI) of 29.1 kg/m(2) and average age of 25.12 years were studied. By BMI, 30.2% were normal, 38.0% were overweight and 31.6% were obese. Thirty-one eumenorrheic women matched for BMI and age, with no evidence of hyperandrogenism, were recruited as controls. The incidence of dyslipidemia in the PCOS group was twice that of the Control group (76.1% versus 32.25%). The most frequent abnormalities were low high-density lipoprotein cholesterol (HDL-C; 57.6%) and high triglyceride (TG) (28.3%). HDL-C was significantly lower in all subgroups of women with PCOS when compared to the subgroups of normal women. No significant differences were seen in the total cholesterol (p = 0.307), low-density lipoprotein cholesterol (LDL-C; p = 0.283) and TGs (p = 0.113) levels among the subgroups. An independent effect on HDL-C was detected for glucose (p = 0.004) and fasting insulin (p = 0.01); on TG for age (p = 0.003) and homeostatic model assessment insulin resistance (p = 0.03) and on total cholesterol and LDL-C for age (p = 0.02 and p = 0.033, respectively). In conclusion, dyslipidemia is common in women with PCOS, mainly due to low HDL-C levels. BMI has a significant impact on this abnormality.


Preparation of sodium alginate/Cur-PLA hydrogel beads for curcumin encapsulation.
The low bioavailability of hydrophobic compounds, however, limits their medicinal use. Hydrogel beads made of biopolymers can be employed as controlled delivery systems and as a carrier to carry curcumin molecules. In this study, encapsulation of curcumin is done within the hydrogel by using Polylactic acid. The prepared SA/Cur-PLA and SA/Cur beads were examined using FTIR, SEM, TGA, NMR, and, XRD to study the interaction between drug and polymer. The developed bead's curcumin encapsulation efficiency was found to be 81.47 % in SA/Cur-PLA. Curcumin's release kinetics have been studied in systems (SGF, pH 1.2, and SCF, pH 7.4) that simulate oral consumption, which possess good pH sensitivity. The in vitro drug release studies of SA/Cur-PLA beads suggest that the curcumin release was significantly increased in a controlled manner and within 12 h, the cumulative release of curcumin was accomplished. In vitro hemolysis study shows a 7.93 % hemolysis rate which suggests that the produced bead is hemocompatible. For SA/Cur-PLA and SA/Cur, cytotoxicity evaluation and antimicrobial study was performed. Results show that both hydrogels are cytocompatible and antimicrobial in nature. It was found that biopolymer-based hydrogel beads enhanced the bioavailability of curcumin, antioxidant, biodegradable, and considered an effective carrier for the oral delivery of several hydrophobic nutraceuticals.


Characteristics of hair loss in COVID-19 patients in Thailand.
There is still a scarcity of data on hair loss caused by coronavirus disease 2019 (COVID-19) infection. This study aims to determine the characteristics of hair loss in Thai individuals after COVID-19 infection and to identify associated factors. From March to June 2022, a retrospective review of medical records and telephone interviews was conducted to determine the details of hair loss, the severity of infection, and the associated treatments of patients with an abrupt onset of hair loss after the diagnosis of COVID-19 infection at Siriraj Hospital in Bangkok, Thailand. This study included 43 patients who experienced hair loss within 4 months after COVID-19 infection. The mean age was 46.5 ± 14.5 years, predominantly women. Most had mild COVID-19 symptoms (59.3%), and 59.1% experienced weight loss, with a mean weight loss of 4.3 ± 2.0 kg per month. Preexisting hair loss was reported in 31.0% of participants, with approximately 3-quarters diagnosed with androgenetic alopecia. The median onset of hair loss after COVID-19 infection was 30 days (interquartile range 30-60). Telogen effluvium was the most common acute hair loss diagnosis, and topical minoxidil was the predominant treatment (95.3%). Female gender was correlated with a more severe shedding scale (adjusted odd ratio 24.76, 95% CI 1.67-168.86). Patients with a history of androgenetic alopecia tended to have a lower hair shedding scale (adjusted odd ratio 0.03, 95% CI 0.01-0.38). This study reviewed the characteristics of hair loss after COVID-19 infection during Omicron outbreaks in Thailand. The COVID-19-associated telogen effluvium, which is the primary cause in our patients, manifested with earlier onset at approximately 30 days.


Does the in vitro egg hatch test predict the failure of benzimidazole treatment in Haemonchus contortus?
Considerable research has been directed towards optimising in vitro tests that can diagnose resistance in pre-parasitic stages of parasites. The objective of this study was to compare the in vivo faecal egg count reduction test (FECRT), the in vitro egg hatch test (EHT), and the molecular determination of the frequency of a codon 200 allele of β-tubulin isotype 1 associated with benzimidazole resistance in larval stages of Haemonchus contortus obtained from infected goats. Animals were infected with composite infective doses representing 10, 20, 30, 40, 60, and 80% resistant alleles. Faecal samples for the EHT were collected on 28, 33, and 35 days post-infection. The results of the in vivo FECRT indicated that albendazole treatment reduced infections consisting of composite doses of 10, 20, 30, 40, 60, and 80% larvae of the resistant isolate by 91.3, 78.0, 63.3, 48.4, 36.5, and 41.4%, respectively. The drug concentration at which 50% of the eggs were prevented from developing hatching larvae (ED50) in the in vitro EHT varied from 0.09 ± 0.01 to 15.63 ± 12.10 μg/mL thiabendazole. The results of the in vitro EHT indicated that the test could estimate in vivo resistance well. The EHT could thus accurately estimate the in vivo efficacy of the drug and percentage of the resistance allele in the population using hatching parameters in delineation doses. This finding was also supported by comparing the FECRT data to the hatching percentages in the EHT on 30 goat farms in Slovakia with natural mixed infections of gastrointestinal parasites.


Intraoperative use of gamma-detecting probes to localize neuroendocrine tumors.
Neuroendocrine tumors are characterized by the expression of different peptides and biogenic amines. These rare tumors tend to grow slowly and are notoriously difficult to localize, at least in the early stages. Surgical removal is the only definitive therapeutic option for neuroendocrine tumors and relief from hyperfunctional status. The effectiveness of surgical treatment is invariably dependent upon the complete surgical excision of all tumor tissue, because microscopic and occult disease not readily seen by the surgeon may remain in situ, leading to shortened survival. Therefore, pre- and intraoperative localization of the primary as well as of metastatic tumors is of utmost importance. Radioguided surgery (RGS) is an intraoperative technique that enables the surgeon to localize radiolabelled tissue based on the characteristics of the various tissues. Concerning gastroenteropancreatic tumors (GEP), intraoperative gamma probe examination is able to reveal small tumor sites accumulating (111In-DTPA-D-Phe1)-pentetreotide more efficiently (> 90%) than somatostatin receptor scintigraphy (68%-77%), because lesions with a size smaller than 5 mm in greatest dimension could be identified. Furthermore, RGS identified 57% more lesions when compared to the "palpating finger" of the surgeon. In medullary thyroid cancer (MTC), surgical removal of the tumor is the first and most efficient treatment of the disease. Persistent or increasing serum calcitonin and carcinoembryonic antigen (CEA) levels imply tumor recurrence after thyroid ablation. For imaging recurrent MTC many radiopharmaceuticals have been used to visualize tumor sites, but none of them has shown excellent sensitivity. Preoperative somatostatin receptor scintigraphy and intraoperative RGS in patients with recurrent MTC demonstrate only part of the tumor sites and cannot visualize small tumor sites (less than 10 mm). In comparison, RGS using 99mTc(V)-DMSA detects metastases with a size of 5 mm in diameter, whereas the "palpating finger" of the surgeon localized metastases with a size of more than 1 cm in diameter. In patients with recurrent MTC, intraoperative gamma probe examination is able to localize over 30% more tumor lesions when compared with conventional preoperative imaging modalities and surgical findings. MIBG scintigraphy is the most sensitive technique for the detection and staging of neuroblastoma (sensitivity 92%; specificity nearly 100%). Intraoperative RGS with iodine labelled MIBG has been developed to improve the definition of tumor limits or to localize small, nonpalpable tumors. Comparison of 123I- and 125I-labelled MIBG revealed a sensitivity of 91% and 92%, respectively; the specificity of 125I (85%) was significantly higher than that of 123I (55%). In addition to scintigraphy of the adrenal glands by precusors of adrenal hormones, imaging with a radiolabelled somatostatin analogue is possible; however, (111In-DTPA-D-Phe1)-pentetreotide is not specific for any adrenal disease or function and the relatively high radioligand accumulation in the kidneys limited the use for detection of tumors in the area of the adrenal glands.


Developmental toxicity of carboxylic acids to Xenopus embryos: a quantitative structure-activity relationship and computer-automated structure evaluation.
The developmental toxicity for each of 45 carboxylic acids was determined for Xenopus embryos. Acids tested included 12 unbranched, saturated aliphatics, 12 branched, saturated aliphatics, 12 unsaturated aliphatics, and 9 aromatics. Embryos were collected following hormone-induced breeding and exposed to at least eight concentrations of the acid, along with a control. For each concentration, 25 properly developing embryos were exposed to the acid solution for 96 h. Each acid was tested on at least three separate occasions and the data were pooled to calculate 96-h LC50 (lethality), 96-h EC50 (malformation), and DHI (developmental hazard index = 96-h LC50/96-h EC50) values. The endpoint data were subjected to quantitative structure-activity relationship (QSAR) analyse: and computer-automated structure evaluation (CASE). Variation in acid-induced lethality was effectively explained by partitioning and ionizability of the acids, while partitioning alone was somewhat effective in explaining variation for acid-induced malformation. The results indicated that developmental hazard of the acids to Xenopus embryos is primarily dependent on carbon-chain length, with acids containing five carbon atoms in the chain tending to be the most potent. Unsaturation reduced the hazard in comparison with the corresponding unbranched saturated acid. Developmental hazard was highest for 2-position branched compounds with a 5- or 6-C chain, but was reduced for 2-position branched acids with a 3- or 4-C chain. Hazard of the non-2 position branched acids was variable. Valproic (2-propylpentanoic) acid showed the highest developmental hazard with Xenopus, twice that of any other acid tested.


Patient acceptance and perceived utility of pre-consultation prevention summaries and reminders in general practice: pilot study.
Patients attending general practices receive only about sixty per cent of the preventive services that are indicated for them. This pilot study explores patient acceptability and perceived utility of automatically generated prevention summary and reminder sheets provided to patients immediately before consultations with their general practitioners. Adult patients attending a general practitioner in a practice in Adelaide and a general practitioner in a practice in Melbourne, Australia for consultations in January and February 2009 received automatically-generated prevention summary and reminder sheets that highlighted indicated preventive activities that were due to be performed, and that encouraged the patient to discuss these with the general practitioner in the consultation. Patients completed a post-consultation questionnaire and were interviewed about their experience of receiving the sheets. Sixty patients, median age 53 years (interquartile range 40-74) years, and 58% female, were recruited. Seventy eight per cent of patients found the sheets clear and easy to understand, 75% found them very or quite useful, 72% reported they had addressed with their general practitioner all of the preventive activities that were listed on the sheets as being due to be performed. A further 13% indicated that they had addressed most or some of the activities. 78% of patients said that they would like to keep receiving the sheets. Themes emerging from interviews with patients included: patient knowledge was enhanced; patient conceptions of health and the GP consultation were broadened; the consultation was enhanced; patient pro-activity was encouraged; patients were encouraged to plan their health care; the intervention was suitable for a variety of patients. Most patients reported that they found the prevention summary and reminder sheets acceptable and useful. The actual increase in performance of preventive activities that may result from this new intervention needs to be tested in randomised controlled trials.


A Low-Cost Paper Glucose Sensor with Molecularly Imprinted Polyaniline Electrode.
For the hundreds of millions of worldwide diabetic patients, glucose test strips are the most important and commonly used tool for monitoring blood glucose levels. Commercial test strips use glucose oxidases as recognition agents, which increases the cost and reduces the durability of test strips. To lower the cost of glucose sensors, we developed a paper-based electrical sensor with molecularly imprinted glucose recognition sites and demonstrated the determination of various glucose concentrations in bovine blood solutions. The sensing electrode is integrated with molecular recognition sites in the conductive polymer. A calibration graph as a function of glucose concentration in aqueous solution was acquired and matched with a correlation coefficient of 0.989. We also demonstrated the determination of the added glucose concentrations ranging from 2.2 to 11.1 mM in bovine blood samples with a linear correlation coefficient of 0.984. This non-enzymatic glucose sensor has the potential to reduce the health care cost of test strips as well as make glucose sensor test strips more accessible to underserved communities.


Posterior cruciate ligament removal contributes to abnormal knee motion during posterior stabilized total knee arthroplasty.
Abnormal anterior translation of the femur on the tibia has been observed in mid flexion (20-60 degrees ) following posterior stabilized total knee arthroplasty. The underlying biomechanical causes of this abnormal motion remain unknown. The purpose of this study was to isolate the effects of posterior cruciate ligament removal on knee motion after total knee arthroplasty. We posed two questions: Does removing the posterior cruciate ligament introduce abnormal anterior femoral translation? Does implanting a posterior stabilized prosthesis change the kinematics from the cruciate deficient case? Using a navigation system, we measured passive knee kinematics of ten male osteoarthritic patients during surgery after initial exposure, after removing the anterior cruciate ligament, after removing the posterior cruciate ligament, and after implanting the prosthesis. Passively flexing and extending the knee, we calculated anterior femoral translation and the flexion angle at which femoral rollback began. Removing the posterior cruciate ligament doubled anterior translation (from 5.1 +/- 4.3 mm to 10.4 +/- 5.1 mm) and increased the flexion angle at which femoral rollback began (from 31.2 +/- 9.6 degrees to 49.3 +/- 7.3 degrees). Implanting the prosthesis increased the amount of anterior translation (to 16.1 +/- 4.4 mm), and did not change the flexion angle at which femoral rollback began. Abnormal anterior translation was observed in low and mid flexion (0-60 degrees) after removing the posterior cruciate ligament, and normal motion was not restored by the posterior stabilized prosthesis.


Brain training habits are not associated with generalized benefits to cognition: An online study of over 1000 "brain trainers".
The foundational tenet of brain training is that general cognitive functioning can be enhanced by completing computerized games, a notion that is both intuitive and appealing. Moreover, there is strong incentive to improve our cognitive abilities, so much so that it has driven a billion-dollar industry. However, whether brain training can really produce these desired outcomes continues to be debated. This is, in part, because the literature is replete with studies that use ill-defined criteria for establishing transferable improvements to cognition, often using single training and outcome measures with small samples. To overcome these limitations, we conducted a large-scale online study to examine whether practices and beliefs about brain training are associated with better cognition. We recruited a diverse sample of over 1000 participants, who had been using an assortment of brain training programs for up to 5 years. Cognition was assessed using multiple tests that measure attention, reasoning, working memory and planning. We found no association between any measure of cognitive functioning and whether participants were currently "brain training" or not, even for the most committed brain trainers. Duration of brain training also showed no relationship with any cognitive performance measure. This result was the same regardless of participant age, which brain training program they used, or whether they expected brain training to work. Our results pose a significant challenge for "brain training" programs that purport to improve general cognitive functioning among the general population. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Photon beam quality variations of a flattening filter free linear accelerator.
Recently, there has been an increasing interest in operating conventional linear accelerators without a flattening filter. The aim of this study was to determine beam quality variations as a function of off-axis ray angle for unflattened beams. In addition, a comparison was made with the off-axis energy variation in flattened beams. Two Elekta Precise linear accelerators were modified in order to enable radiation delivery with and without the flattening filter in the beam line. At the Medical University Vienna (Vienna, Austria), half value layer (HVL) measurements were performed for 6 and 10 MV with an in-house developed device that can be easily mounted on the gantry. At St. Luke's Hospital (Dublin, Ireland), measurements were performed at 6 MV in narrow beam geometry with the gantry tilted around 270 degrees with pinhole collimators, an attenuator, and the chamber positioned on the table. All attenuation measurements were performed with ionization chambers and a buildup cap (2 mm brass) or a PMMA mini phantom (diameter 3 cm, measurement depth 2.5 cm). For flattened 6 and 10 MV photon beams from the Elekta linac the relative HVL(theta) varies by about 11% for an off-axis ray angle theta = 10 degrees. These results agree within +/- 2% with a previously proposed generic off-axis energy correction. For unflattened beams, the variation was less than 5% in the whole range of off-axis ray angles up to 10 degrees. The difference in relative HVL data was less than 1% for unflattened beams at 6 and 10 MV. Off-axis energy variation is rather small in unflattened beams and less than half the one for flattened beams. Thus, ignoring the effect of off-axis energy variation for dose calculations in unflattened beams can be clinically justified.


An ab initio study of the nickel-catalyzed transformation of amorphous carbon into graphene in rapid thermal processing.
Ab initio molecular dynamics (AIMD) simulations are employed to investigate the chemical mechanism underlying the Ni-catalyzed transformation of amorphous carbon (a-C) into graphene in the rapid thermal processing (RTP) experiment to directly grow graphene on various dielectric surfaces via the evaporation of surplus Ni and C at 1100 °C (below the melting point of bulk Ni). It is found that the a-C-to-graphene transformation entails the metal-induced crystallization and layer exchange mechanism, rather than the conventional dissolution/precipitation mechanism typically involved in Ni-catalyzed chemical vapor deposition (CVD) growth of graphene. The multi-layer graphene can be tuned by changing the relative thicknesses of deposited a-C and Ni thin films. Our AIMD simulations suggest that the easy evaporation of surplus Ni with excess C is likely attributed to the formation of a viscous-liquid-like Ni-C solution within the temperature range of 900-1800 K and to the faster diffusion of C atoms than that of Ni atoms above 600 K. Even at room temperature, sp(3)-C atoms in a-C are quickly converted to sp(2)-C atoms in the course of the simulation, and the graphitic C formation can occur at low temperature. When the temperature is as high as 1200 K, the grown graphitic structures reversely dissolve into Ni. Because the rate of temperature increase is considerably faster in the AIMD simulations than in realistic experiments, defects in the grown graphitic structures are kinetically trapped. In this kinetic growth stage, the carbon structures grown from sp(3)-carbon or from sp(2)-carbon exhibit marked differences.


SMARCB1 involvement in the development of leiomyoma in a patient with schwannomatosis.
Germline SMARCB1 mutations predispose in schwannomatosis patients to the development of multiple benign schwannomas and, in some cases, meningiomas. Here, we report on a 34-year-old female patient who developed multiple schwannomas at various locations and in addition a leiomyoma of the cervix uteri. She carried a c.362+1G>A mutation that inactivates the donor splice site of exon 3. This mutation caused the schwannomatosis phenotype in this patient and was also demonstrated to be present in her affected mother. The leiomyoma displayed the genetic features that are characteristic for germline SMARCB1 mutation-associated tumors. The mutant allele retained in the tumor, whereas the wild-type allele was lost by loss of heterozygosity. Furthermore, the loss of heterozygosity involved net loss of chromosome 22. An NF2 mutation was not found. However, quantitative polymerase chain reaction suggested that both NF2 copies were lost in the tumor. Immunostaining with a SMARCB1 antibody revealed the mosaic expression pattern that is typical for schwannomatosis-associated tumors. To our knowledge, this is the first reported case of leiomyoma associated with a germline SMARCB1 mutation. As such, it widens the spectrum of benign tumors associated with a germline SMARCB1 mutation.


Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies.
During the past 5 years, high-throughput technologies have been successfully used by epidemiology studies, but almost all have focused on sequence variation through genome-wide association studies (GWAS). Today, the study of other genomic events is becoming more common in large-scale epidemiological studies. Many of these, unlike the single-nucleotide polymorphism studied in GWAS, are continuous measures. In this context, the exercise of searching for regions of interest for disease is akin to the problems described in the statistical 'bump hunting' literature. New statistical challenges arise when the measurements are continuous rather than categorical, when they are measured with uncertainty, and when both biological signal, and measurement errors are characterized by spatial correlation along the genome. Perhaps the most challenging complication is that continuous genomic data from large studies are measured throughout long periods, making them susceptible to 'batch effects'. An example that combines all three characteristics is genome-wide DNA methylation measurements. Here, we present a data analysis pipeline that effectively models measurement error, removes batch effects, detects regions of interest and attaches statistical uncertainty to identified regions. We illustrate the usefulness of our approach by detecting genomic regions of DNA methylation associated with a continuous trait in a well-characterized population of newborns. Additionally, we show that addressing unexplained heterogeneity like batch effects reduces the number of false-positive regions. Our framework offers a comprehensive yet flexible approach for identifying genomic regions of biological interest in large epidemiological studies using quantitative high-throughput methods.


Cellular corepressor TLE2 inhibits replication-and-transcription- activator-mediated transactivation and lytic reactivation of Kaposi's sarcoma-associated herpesvirus.
Replication and transcription activator (RTA) encoded by open reading frame 50 (ORF50) of Kaposi's sarcoma-associated herpesvirus (KSHV) is essential and sufficient to initiate lytic reactivation. RTA activates its target genes through direct binding with high affinity to its responsive elements or by interaction with cellular factors, such as RBP-Jkappa, Ap-1, C/EBP-alpha, and Oct-1. In this study, we identified transducin-like enhancer of split 2 (TLE2) as a novel RTA binding protein by using yeast two-hybrid screening of a human spleen cDNA library. The interaction between TLE2 and RTA was confirmed by glutathione S-transferase (GST) binding and coimmunoprecipitation assays. Immunofluorescence analysis showed that TLE2 and RTA were colocalized in the same nuclear compartment in KSHV-infected cells. This interaction recruited TLE2 to RTA bound to its recognition sites on DNA and repressed RTA auto-activation and transactivation activity. Moreover, TLE2 also inhibited the induction of lytic replication and virion production driven by RTA. We further showed that the Q (Gln-rich), SP (Ser-Pro-rich), and WDR (Trp-Asp repeat) domains of TLE2 and the Pro-rich domain of RTA were essential for this interaction. RBP-Jkappa has been shown previously to bind to the same Pro-rich domain of RTA, and this binding can be subject to competition by TLE2. In addition, TLE2 can form a complex with RTA to access the cognate DNA sequence of the RTA-responsive element at different promoters. Intriguingly, the transcription level of TLE2 could be upregulated by RTA during the lytic reactivation process. In conclusion, we identified a new RTA binding protein, TLE2, and demonstrated that TLE2 inhibited replication and transactivation mediated by RTA. This provides another potentially important mechanism for maintenance of KSHV viral latency through interaction with a host protein.


Endogenous tumor-reactive CD8+ T cells are differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor growth.
Immunotherapies aimed at enhancing natural or endogenous antitumor T-cell immunity in patients affected by advanced malignancies are currently being implemented in the clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, reliable biomarkers are needed. We used CD11a, an integrin that is upregulated on the surface of effector and memory CD8+ T cells, and PD-1, an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantify and monitor endogenous tumor-reactive cytotoxic T lymphocytes (CTLs) in two mouse tumor models and in the peripheral blood of 12 patients affected by Stage IV melanoma. High expression levels of CD11a and PD-1 were detected among CD8+ T cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the peripheral blood of melanoma patients, tumor antigen-specific CD8+ T cells were associated with a population of CD11ahigh CD8+ T cells that co-expressed high levels of PD-1. Healthy donors exhibited a comparatively much lower frequency of such PD-1+CD11ahighCD8+ T cells. Phenotypic analyses demonstrated that CD11ahighCD8+ T cells are proliferating (Ki67+) and activated (CD62L-CD69+). Increased CD11ahighCD8+ T cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector functions of CD8+ T cells is compromised by an elevated expression of PD-1. The CD11ahighCD8+ T-cell population expresses high levels of PD-1 and presumably constitutes the cellular target of PD-1 blockade therapy. The expression level of CD11a and PD-1 by CD8+ T cells may therefore represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of immunotherapy but also contribute to the selection of cancer patients who are likely to benefit from anti-PD-1 therapy.


Persistent poor glycaemic control in adult Type 1 diabetes. A closer look at the problem.
Around 25% of the adult Type 1 diabetes population is in persistent poor glycaemic control and thus at increased risk of developing microvascular complications. We here discuss correlates of long-standing poor glycaemic control and review the efficacy of clinical strategies designed to overcome persistent poor control. Only a few studies have identified determinants and correlates of long-standing poor glycaemic control in Type 1 diabetes. There is some evidence implicating genetic factors, as well as lower economic status, and psychological factors, including lack of motivation, emotional distress, depression and eating disorders. Ways of improving glycaemic control include strategies to enable self-management, e.g. motivational strategies, coping-orientated education, psychosocial therapies, and/or intensifying insulin injection therapy plus continuous subcutaneous insulin infusion. Long-standing poor glycaemic control appears to be a heterogeneous and complex phenomenon, for which there is no simple, single solution. Comprehensive psycho-medical assessment in diabetes care may prove useful in tailoring interventions. Further research is warranted, to increase our understanding how psychosocial and biomedical factors, separately and in interaction, determine poor outcomes in Type 1 diabetes.


The frequency of lymphocytic and reflux esophagitis in non-human primates.
We previously reported in humans a novel histologic phenotype of non-gastro-esophageal reflux disease called lymphocytic esophagitis. In this work, the esophagi of 121 non-human primates (103 baboons and 18 macaques) were investigated. 45 baboons (43.7%) and 9 macaques (50%) had lymphocytic esophagitis. The lymphocytic infiltration in the squamous epithelium involved not only papillary but also inter-papillary fields. Microscopic examination around the papillae revealed a mean of 52 intraepithelial lymphocytes (IELs) per high power field. Of the remaining baboons, 29 had reflux esophagitis (GERD). Among them, 25 (24.3%) 2 (1.9%) and 2 (1.9%) had grade1, 2 and 3 esophagitis, respectively. Of the remaining macaques, 4 had GERD: 1 (5.5%) with grade 1 and 3 (16.7%) with grade 2 esophagitis. None of the macaques had grade 3 esophagitis. The IEL population in lymphocytic esophagitis was composed of T cells, a subset of natural killer cells and of helper and inflammatory T cells. This investigation in non-human primates substantiates the identity of lymphocytic esophagitis as a subset of chronic esophagitis, as well as of reflux esophagitis. The antigenic agent(s) responsible for the marked immunological reaction in lymphocytic esophagitis in non-human primates (and in humans) remains unknown.


[Humanization in health care: knowledge disseminated in Brazilian nursing literature].
This qualitative research aims to analyze the scientific production about "humane health care/nursing", understanding what views on humanization have been developing. A bibliographic survey was carried out, covering the period from the end of the 1950's until today, in the periodicals Revista Brasileira de Enfermagem, Revista Paulista de Hospitais and Texto e Contexto, examining 42 articles, which were then subject to analysis and integrative synthesis. The issue has been developing from a charitable perspective to the current preoccupation with the valuation of health as a civil right, inserted in a political health project. Articles from all decades reveal the need to invest in workers, valuing the subjective dimension. Nevertheless, humanization receives little attention in education. Care humanization supposes the meeting of subjects who share knowledge, power and experiences, implying political, administrative and subjective transformations.


QTL detection for rice grain storage protein content and genetic effect verifications.
Rice grain quality is a multifarious attribute mainly governed by multiple nutritional factors. Grain protein is the central component of rice grain nutrition dominantly affecting eating-cooking qualities. Grain protein content is quantitatively influenced by its protein fractions. Genetic quantification of five protein fractions-albumins, globulins, prolamins, glutelin, and grain protein content-were evaluated by exploiting two BC3F2 mapping populations, derived from Kongyu131/TKM9 (population-I) and Kongyu131/Bg94-1 (population-II), which were grown in a single environment. Correlation studies among protein fractions and grain protein content were thoroughly investigated. A genetic linkage map was developed by using 146 single sequence repeat (SSR) markers in population-I and 167 markers in population-II. In total, 40 QTLs were delineated for five traits in both populations. Approximately 22 QTLs were dissected in population-I, derived from Kongyu131/TKM9, seven QTLs for albumin content, four QTLs for globulin content, three QTLs for prolamin content, four QTLs for glutelin content, and four QTLs for grain protein content. In total, 18 QTLs were detected in population-II, derived from Kongyu131/Bg94-1, five QTLs for albumin content, three QTLs for globulin content, four QTLs for prolamin content, two QTLs for glutelin content, and four QTLs for grain protein content. Three QTLs, qAlb7.1, Alb7.2, and qGPC7.2, derived from population-II (Kongyu131/Bg94-1) for albumin and grain protein content were successfully validated in the near isogenic line (NIL) populations. The localized chromosomal locus of the validated QTLs could be helpful for fine mapping via map-based cloning to discover underlying candidate genes. The functional insights of the underlying candidate gene would furnish novel perceptivity for the foundation of rice grain protein content and trigger the development of nutritionally important rice cultivars by combining marker-assisted selection (MAS) breeding. The online version contains supplementary material available at 10.1007/s11032-023-01436-7.


Developmental changes in the membrane current pattern, K+ buffer capacity, and morphology of glial cells in the corpus callosum slice.
Recent studies indicated that glial cells in tissue culture can express a variety of different voltage-gated channels, while little is known about the presence of such channels in glial cells in vivo. We used a mouse corpus callosum slice preparation, in which after postnatal day 5 (P5) more than 99% of all perikarya belong to glial cells (Sturrock, 1976), to study the current patterns of glial cells during their development in situ. We combined the patch-clamp technique with intracellular labeling using Lucifer yellow (LY) and subsequent ultrastructural characterization. In slices of mice from P6 to P8, we predominantly found cells expressing delayed-rectifier K+ currents. They were similar to those described for cultured glial precursor cells (Sontheimer et al., 1989). A-type K+ currents or Na+ currents were not or only rarely observed, in contrast to cultured glial precursors. LY labeling revealed that numerous thin processes extended radially from the perikaryon of these cells, and ultrastructural observations suggested that they resemble immature glial cells. In slices of older mice (P10-13), when myelination of the corpus callosum has already commenced, many cells were characterized by an almost linear current-voltage relationship. This current pattern was similar to cultured oligodendrocytes (Sontheimer et al., 1989). Most processes of LY-filled cells with such a current profile extended parallel to each other. Electron microscopy showed that these processes surround thick, unmyelinated axons. We suggest that cells with oligodendrocyte-type electrophysiology are promyelinating oligodendrocytes. In contrast to cultured oligodendrocytes, membrane currents of promyelinating oligodendrocytes in the slice decayed during the voltage command. This decay was due not to inactivation, but to a marked change in the potassium equilibrium potential within the voltage jump. This implies that, in the more mature corpus callosum, small membrane polarizations in a physiological range can lead to extensive changes in the K+ gradient across the glial membrane within a few milliseconds.


Culling a Self-Assembled Quantum Dot as a Single-Photon Source Using X-ray Microscopy.
Epitaxially grown self-assembled semiconductor quantum dots (QDs) with atom-like optical properties have emerged as the best choice for single-photon sources required for the development of quantum technology and quantum networks. Nondestructive selection of a single QD having desired structural, compositional, and optical characteristics is essential to obtain noise-free, fully indistinguishable single or entangled photons from single-photon emitters. Here, we show that the structural orientations and local compositional inhomogeneities within a single QD and the surrounding wet layer can be probed in a screening fashion by scanning X-ray diffraction microscopy and X-ray fluorescence with a few tens of nanometers-sized synchrotron radiation beam. The presented measurement protocol can be used to cull the best single QD from the enormous number of self-assembled dots grown simultaneously. The obtained results show that the elemental composition and resultant strain profiles of a QD are sensitive to in-plane crystallographic directions. We also observe that lattice expansion after a certain composition-limit introduces shear strain within a QD, enabling the possibility of controlled chiral-QD formation. Nanoscale chirality and compositional anisotropy, contradictory to common assumptions, need to be incorporated into existing theoretical models to predict the optical properties of single-photon sources and to further tune the epitaxial growth process of self-assembled quantum structures.


Clinical application of cytokine-induced killer (CIK) cell therapy in colorectal cancer: Current strategies and future challenges.
Colorectal cancer (CRC) remains a significant global health burden and is the second leading cause of cancer-related death. Cytokine induced killer (CIK) cell therapy is an immunotherapy which has the potential to meet this need. Clinical trials of CIK cell therapy for the management of CRC have reported improved clinical outcomes. However, production and delivery protocols varied significantly, and many studies were reported only in Chinese language journals. Here we present the most comprehensive review of the clinical CIK cell therapy trials for CRC management to date. We accessed both English and Chinese language clinical studies, and summarise how CIK cell therapy has been implemented, from manufacturing to patient delivery. We discuss current challenges that impede wider adoption of CIK cell therapy in CRC management.


The role of thioredoxin reductase 1 in melanoma metabolism and metastasis.
Although significant progress has been made in targeted and immunologic therapeutics for melanoma, many tumors fail to respond, and most eventually progress when treated with the most efficacious targeted combination therapies thus far identified. Therefore, alternative approaches that exploit distinct melanoma phenotypes are necessary to develop new approaches for therapeutic intervention. Tissue microarrays containing human nevi and melanomas were used to evaluate levels of the antioxidant protein thioredoxin reductase 1 (TR1), which was found to increase as a function of disease progression. Melanoma cell lines revealed metabolic differences that correlated with TR1 levels. We used this new insight to design a model treatment strategy that creates a synthetic lethal interaction wherein targeting TR1 sensitizes melanoma to inhibition of glycolytic metabolism, resulting in a decrease in metastases in vivo. This approach holds the promise of a new clinical therapeutic strategy, distinct from oncoprotein inhibition.


The role of retinoid X receptor alpha in regulating alcohol metabolism.
There is substantial overlap in retinol and alcohol metabolism. Mice that lack retinoic acid (RA) receptor retinoid X receptor alpha (RXRalpha) expression in the liver are more susceptible to alcoholic liver disease. To investigate the interaction between RXRalpha and alcoholic liver disease, ethanol metabolism was studied in hepatocyte RXRalpha-deficient [RXRalpha knockout (KO)] mice. Hepatocyte RXRalpha deficiency resulted in a significant increase in hepatic alcohol dehydrogenase (ADH) activity, ADH1 protein, but not Adh1 mRNA. Polysomal distribution analysis indicated that more polysome-associated Adh1 mRNA was present in the mutant mouse livers, suggesting increased ADH1 protein synthesis in RXRalpha KO mice compared with wild-type mice. However, ADH2 and ADH3 enzyme activities were not affected by RXRalpha deficiency. Although ethanol clearance was increased, acetaldehyde elimination was reduced when RXRalpha was not expressed in the liver. Both mitochondrial aldehyde dehydrogenase (ALDH) 2 and cytosolic ALDH activities were reduced in the mutant mice compared with the wild type. Western blot analysis revealed that the levels of ALDH1A1 and ALDH1A2 were decreased in the mutant mice. Semiquantitative reverse transcriptase-polymerase chain reaction indicated that liver Aldh1a1 mRNA level was also reduced due to the lack of RXRalpha expression. Thus, RXRalpha differentially affects ADH and ALDH activity, leading to an increase in alcohol clearance, but a reduction in acetaldehyde elimination. In addition, CYP2E1 as well as mitochondrial and cytosolic glutathione S-transferase activities were significantly lower in RXRalpha KO mice than in wild-type mice. Our results reveal the central role of RXRalpha in ethanol metabolism.


Effects of N-Glycosylation of the human cation channel TRPA1 on agonist-sensitivity.
Determining the functional significance of post-translational modifications advances our understanding of many broadly-expressed proteins, and particularly ion channels. The enzymes that catalyze these modifications are often expressed in a cell-type specific manner, resulting in considerable structural diversity among post-translationally modified proteins that are expressed across a variety of cell types. TRP channels exhibit notably variable behavior between cell types in vitro and in vivo , and they are frequently modified with N-glycans that contribute to protein function. TRPA1 possesses two putative N-linked glycosylation sites at N747 and N753 that have not yet been studied in detail. Here, we show that both of these sites can be modified with an N-glycan and that the glycan at position N747 modulates agonist-sensitivity of TRPA1 in vitro Additionally, we found that N-glycosylation also modulates cooperative effects of temperature and the agonist cinnamaldehyde on TRPA1 channel activation. Collectively, these findings suggest a dynamic role played by the N-glycosylation of human TRPA1. They also provide further evidence of the versatility of N-glycans and will assist in efforts to fully understand the complex regulation of TRPA1 activity.


Presence of chelonid herpesvirus 5 (ChHV5) in sea turtles in northern Sinaloa, Mexico.
The presence of fibropapilloma and its associated chelonid herpesvirus 5 (ChHV5) was assessed in 82 wild sea turtles. Olive ridley turtles Lepidochelys olivacea (n = 58) were caught in the pelagic Area of Marine Influence (AMI) (off the coast of Guasave, Sinaloa), and black turtles Chelonia mydas agassizii (n = 24) were captured in the Navachiste Lagoon System. The apparent physical condition was evaluated as 'good' or 'poor' by physical examination. The population structure and general health status was determined by condition index, hematocrit and total plasma protein. Detection of ChHV5 from skin samples was done by PCR. The overall physical condition of black turtles was good and all the individuals were tumor-free. Likewise, the physical condition of most olive ridley turtles was good, except for 10 individuals with poor condition. Of these, 4 had fibropapilloma-like tumors. PCR analyses showed that 3 tumors were ChHV5-positive. The DNA sequence showed 96% identity with ChHV5. All other skin samples from black or olive ridley turtles were ChHV5-negative. This is the first report of fibropapillomatosis-ChHV5 in foraging grounds off northern Sinaloa. The virus was present in a small proportion of L. olivacea individuals, a free-ranging species. It is suggested that infected turtles acquired the virus at a different location somewhere during their development before arriving in the AMI zone. This finding makes the case for setting up a health monitoring program for turtle populations in the area, enforcing sanitary measures to reduce the spread of the pathogen.


Differential pathlength spectroscopy for the quantitation of optical properties of gold nanoparticles.
An accurate estimation of optical absorption coefficient (microabs) and scattering coefficient (microsca) is important in characterizing nanoparticles for identifying or optimizing applications such as photothermal therapy and photoacoustic imaging. In this exciting period where several fascinating methods have been unveiled for the synthesis of various nanoparticles, the field is still lacking in the availability of efficient characterization methods. We introduce an accurate and simple methodology to optically characterize nanoparticles which could fill the gap. This is based on differential pathlength spectroscopy (DPS), a dual optical fiber approach, originally developed to detect cancer endoscopically by measuring the optical properties of tissue in small interrogation volumes. We expand its use to nanoparticles in a method that allows us to resolve the effects of microabs and microsca in the extinction coefficient of low concentration samples. We outline the measurement protocol using the DPS system and describe the analysis of the data taking additional inputs from electron microscopy and discrete dipole approximation (DDA) simulations. The DPS signal from the sample is first translated into the backscattering coefficient using a calibration constant. Further, the backscattering coefficient is converted via the simulated scattering phase function into the scattering coefficient. With this knowledge and extinction coefficient measured using a conventional photospectrometer, the absorption coefficient is calculated. We prove the validity of the method using spherical and rod-shaped gold nanoparticles, comparing the results with outputs from DDA simulations. We also briefly touch upon the dilemma of the choice of the appropriate dielectric function for gold at the nanoscale.


Effectiveness of problem-based learning on academic performance in genetics.
This study aimed at comparing the effectiveness of problem-based learning (PBL)1 and traditional lecture-based instruction on elementary school students' academic achievement and performance skills in a science unit on genetics while controlling for their reasoning ability. For the specified purpose, twoinstructional methods were randomly assigned to intact classes of two different teachers. Each teacher had both PBL classes and traditional classes. Although students in PBL classes (n = 126) worked on ill-structured problems cooperatively with the guidance of the teacher, students in traditional classes (n = 91) received instruction based on teacher's explanations, discussions, and textbooks. Genetics Achievement Test was developed by researchers to measure the academic achievement and performance skills. Multivariate Analysis of Covariance results showed that the PBL students had higher academic achievement and performance skills scores (M = 11.44 and M = 2.67, respectively) when compared with those in traditional classes (M = 10.91 and M = 2.20, respectively). This indicated that the PBL students tend to better acquire scientific conceptions related to genetics and integrate and organize the knowledge. Moreover, it was found that the reasoning ability explained a significant portion of variance in the scores of academic achievement and performance skills.


Urinary excretion of platinum from platinum industry workers.
Assessment of level of exposure to platinum and platinum concentration in urine from platinum industry workers to evaluate internal exposures and excretion kinetics. Platinum concentrations in urine samples from 34 workers were measured by adsorptive voltammetry after UV-photolysis. Morning and evening samples were taken two to six times during six months. Individual exposures were assessed by personal air sampling. Also, two male volunteers were exposed to platinum dust for four hours at a typical platinum refinery workplace. Urinary platinum excretion after a shift in platinum industry workers was found to be up to 6270 ng/g creatinine--that is, 1000 times above the median value of unexposed people. Urinary excretion reached the maximum nearly 10 hours after inhalative exposure to dust containing platinum. Elimination corresponded to a first half life of about 50 (95% confidence interval (95% CI) 36 to 66) hours, but there were indications that a part of the incorporated platinum is stored longer. The amount of urinary platinum excretion showed a close correlation with the exposure level monitored by personal air sampling. A newly developed analytical method enabled the detection of even natural background concentrations of platinum. Thus, increased urinary platinum concentrations could be detected early, which is important to avoid damaging health of exposed workers.


Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial.
To report results from VISIBLE 2, a randomised, double-blind, placebo-controlled, phase 3 trial evaluating a new subcutaneous [SC] vedolizumab formulation as maintenance treatment in adults with moderately to severely active Crohn's disease [CD]. Following open-label vedolizumab 300 mg intravenous induction therapy at Weeks 0 and 2, Week 6 clinical responders (≥70-point decrease in CD Activity Index [CDAI] score from baseline) were randomised 2:1 to receive double-blind maintenance vedolizumab 108 mg SC or placebo every 2 weeks until Week 50. Assessments at Week 52 included clinical remission [primary endpoint; CDAI ≤150], enhanced clinical response [≥100-point decrease in CDAI from baseline], corticosteroid-free clinical remission among patients using a corticosteroid at baseline, clinical remission in anti-tumour necrosis factor [anti-TNF]-naïve patients, and safety. Following vedolizumab intravenous induction, 275 patients were randomised to vedolizumab SC and 135 to placebo maintenance. At Week 52, 48.0% of patients receiving vedolizumab SC versus 34.3% receiving placebo were in clinical remission [p = 0.008]. Enhanced clinical response at Week 52 was achieved by 52.0% versus 44.8% of patients receiving vedolizumab SC versus placebo, respectively [p = 0.167]. At Week 52, 45.3% and 18.2% of patients receiving vedolizumab SC and placebo, respectively, were in corticosteroid-free clinical remission, and 48.6% of anti-TNF-naïve patients receiving vedolizumab SC and 42.9% receiving placebo were in clinical remission. Injection site reaction was the only new safety finding observed for vedolizumab SC [2.9%]. Vedolizumab SC is an effective and safe maintenance therapy in patients with CD who responded to two infusions of vedolizumab intravenous induction therapy.


No effect of transfer factor in juvenile rheumatoid arthritis by double-blind trial.
A previously pilot study of treatment with transfer factor in 3 patients with juvenile rheumatoid arthritis (JRA) gave promising results. However, in this small and open study no definite conclusions could be drawn. Therefore, a double-blind group trial was performed in 12 JRA patients treated with transfer factor, and in 12 placebo-treated control patients. The patients were evaluated clinically, by laboratory tests, and by estimation of different lymphocyte populations and cell-mediated immunity in vitro and in vivo. Transfer factor was not found to be of significant therapeutic value in patients with JRA. The only statistically significant difference between the two groups was a greater reduction in the percentage of T lymphocytes in transfer factor-treated patients than in control patients. The significance of this is difficult to explain and could have appeared by chance. No side effects of treatment with transfer factor were noted.


Reproducibility of measuring lamina cribrosa pore geometry in human and nonhuman primates with in vivo adaptive optics imaging.
The ability to consistently resolve lamina cribrosa pores in vivo has applications in the study of optic nerve head and retinal disease mechanisms. Repeatability was assessed in imaging laminar pores in normal living eyes with a confocal adaptive optics scanning laser ophthalmoscope (AOSLO). Reflectance images (840 nm) of the anterior lamina cribrosa were acquired using the AOSLO in four or more different sessions in two normal rhesus monkey eyes and three normal human eyes. Laminar pore areas, elongations (ratio of major to minor axes of the best-fit ellipse) and nearest neighbor distances were calculated for each session. Measurement repeatability was assessed across sessions. Pore areas ranged from 90 to 4365 μm(2) in monkeys and 154 to 6637 μm(2) in humans. Mean variabilities in measuring pore area and elongation (i.e., mean of the standard deviation of measurements made across sessions for the same pores) were 50 μm(2) (6.1%) and 0.13 (6.7%), respectively, in monkeys and 113 μm(2) (8.3%) and 0.17 (7.7%), respectively, in humans. Mean variabilities in measuring nearest neighbor distances were 1.93 μm (5.2%) in monkeys and 2.79 μm (4.1%) in humans. There were no statistically significant differences in any pore parameters across sessions (ANOVA, P > 0.05). The anterior lamina cribrosa was consistently imaged in vivo in normal monkey and human eyes. The small intersession variability in normal pore geometry suggests that AOSLO imaging could be used to measure and track changes in laminar pores in vivo during glaucomatous progression.


Accountability Assessment of Health Improvements in the United States Associated with Reduced Coal Emissions Between 2005 and 2012.
National, state, and local policies contributed to a 65% reduction in sulfur dioxide emissions from coal-fired power plants between 2005 and 2012 in the United States, providing an opportunity to directly quantify public health benefits attributable to these reductions under an air pollution accountability framework. We estimate ZIP code-level changes in two different-but related-exposure metrics: total PM2.5 concentrations and exposure to coal-fired power plant emissions. We associate changes in 10 health outcome rates among approximately 30 million US Medicare beneficiaries with exposure changes between 2005 and 2012 using two difference-in-difference regression approaches designed to mitigate observed and unobserved confounding. Rates per 10,000 person-years of six cardiac and respiratory health outcomes-all cardiovascular disease, chronic obstructive pulmonary disorder, cardiovascular stroke, heart failure, ischemic heart disease, and respiratory tract infections-decreased by between 7.89 and 1.95 per (Equation is included in full-text article.)decrease in PM2.5, with comparable decreases in coal exposure leading to slightly larger rate decreases. Results for acute myocardial infarction, heart rhythm disorders, and peripheral vascular disease were near zero and/or mixed between the various exposure metrics and analyses. A secondary analysis found that nonlinearities in relationships between changing health outcome rates and coal exposure may explain differences in their associations. The direct analyses of emissions reductions estimate substantial health benefits via coal power plant emission and PM2.5 concentration reductions. Differing responses associated with changes in the two exposure metrics underscore the importance of isolating source-specific impacts from those due to total PM2.5 exposure.


Panel discussion: regional action priorities.
Action priorities for reducing iron deficiency vary across regions. Some regions have limited experience with national programs, such as in the republics of Central Asia, where the focus since independence has been on assessment, advocacy and scaling up of interventions. In more developed regions the priorities are improving established programs and addressing the needs of the remaining subpopulations with high rates of iron deficiency. The etiology of anemia, whether multi-factorial as in Sub-Saharan Africa or mostly due to iron deficiency as in the Middle East and North Africa, is an important factor shaping the choice of strategies. Some interventions are particularly feasible in some settings and are being promoted aggressively, such as flour fortification in Latin America and the Middle East and North Africa, or the fortification of condiments in Asia. The quality of the health infrastructure and resources in general also determine the mix and scale of interventions implemented. A lesson for all regions is that countries in North America and Europe, where diets are varied and abundant and infections nearly absent, generally support multiple strategies that include nutrition education, supplementation and fortification of a variety of staples consumed by toddlers and the general population. Monitoring and evaluation efforts have proven necessary for improving quality and for advocacy.


Phosphoric acid catalyzed diastereo- and enantioselective synthesis of substituted 1,3-diaminotetralins.
The reaction of anilines and phenylacetaldehydes in the presence of chiral phosphoric acid afforded optically active 1,2-trans, 2,3-cis 1,3-diaminotetralins in high yields with excellent diastereo- and enantioselectivities. The trans/cis product was readily isomerized to a trans/trans stereoisomer with no significant loss of enantiomeric purity.


Intuitive Assessment of Mortality Based on Facial Characteristics: Behavioral, Electrocortical, and Machine Learning Analyses.
Studies of various characteristics of the human face indicate that it contains a wealth of information about health status. Most studies involve objective measurement of facial features as correlated with historical health information. But some individuals also claim to be adept at intuitively gauging mortality based solely upon a quick glance at a person's photograph. To test this claim, we invited 12 such individuals to see if they could tell if a person was alive or dead based solely on a brief examination of his or her photograph. All photos used in the experiment were transformed into a uniform gray scale and counterbalanced across eight categories as follows: gender, age, gaze direction, glasses, head position, smile, hair color, and image resolution. Participants examined 404 photographs displayed on a computer monitor, one photo at a time, each shown for a maximum of 8seconds. Half of the individuals in the photos were deceased, and half were alive at the time the experiment was conducted. Participants were asked to indicate if they thought the person in a photo was living or deceased by pressing an appropriate button. Overall, mean accuracy on this task was 53.6%, where 50% was expected by chance (P = .005, two tail). Statistically significant accuracy was independently obtained in 5 of the 12 participants. We also collected 32-channel electrocortical recordings and observed a robust difference between images of deceased individuals correctly vs. incorrectly classified in the early event related potential at 100ms post-stimulus onset. We then applied machine learning techniques to classify the photographs based on 11 image characteristics; both random forest and logistic regression machine learning approaches were used, and both classifiers failed to achieve accuracy above chance level. Our results suggest that some individuals can intuitively assess mortality based on some as-yet unknown features of the face.


Analysis of diaphragmatic movement before and after pulmonary rehabilitation using fluoroscopy imaging in patients with COPD.
The diaphragm is the principal inspiratory muscle. The purpose of this study was to assess improvements in diaphragmatic movement before and after pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD), using a fluoroscopy-guided chest X-ray. Among 117 patients with COPD receiving pulmonary rehabilitation who underwent the initial fluoroscopy-guided chest X-ray and pulmonary function test, 37 of those patients who underwent both initial and follow-up fluoroscopy and pulmonary function tests were enrolled in this study. After hospital education, participants received pulmonary rehabilitation through regular home-based training for at least 3 months by the same physiatrist. We assessed the changes in diaphragm area with fluoroscopy-guided posteroanterior chest X-rays between pre- and postpulmonary rehabilitation. To minimize radiation hazards for subjects, the exposure time for fluoroscopy to take chest X-rays was limited to less than 5 seconds. There were significant improvements (2,022.8±1,548.3 mm(2) to 3,010.7±1,495.6 mm(2) and 2,382.4±1,475.9 mm(2) to 3,315.9±1,883.5 mm(2); right side P=0.001 and left side P=0.019, respectively) in diaphragmatic motion area during full inspiration and expiration in both lungs after pulmonary rehabilitation. Pulmonary function tests showed no statistically significant difference between pre- and postpulmonary rehabilitation. The study suggests that the strategy to assess diaphragm movement using fluoroscopy is a relatively effective tool for the evaluation of pulmonary rehabilitation in COPD patients in terms of cost and time savings compared with computed tomography or magnetic resonance imaging.


Impact of Obeticholic acid Exposure on Decompensation and Mortality in Primary Biliary Cholangitis and Cirrhosis.
Obeticholic acid (OCA) is approved for the treatment of patients with primary biliary cholangitis (PBC) who are partial responders or intolerant to ursodeoxycholic acid. Reports of serious liver injury have raised concerns about its safety in cirrhosis. We investigated the effects of treatment with OCA on hepatic decompensation and liver-related mortality or transplantation in a cohort with compensated PBC cirrhosis. This was a retrospective cohort study using national data of US veterans with PBC and cirrhosis. We performed a propensity score model using variables associated with OCA prescription to control for baseline risk of decompensation. New OCA users were matched to nonusers. We identified 509 subjects with compensated PBC cirrhosis. We developed a propensity score model using variables associated with OCA prescription; 21 OCA users were matched with 84 nonusers. Over 569 and 3,847 person-months, respectively, of follow-up, 5 (23.8%) OCA users and 22 (26.2%) OCA nonusers decompensated. The C-statistic of the propensity score model was 0.87. On multivariable analysis, after adjusting for potential confounders, OCA use was associated with an increased risk of hepatic decompensation (adjusted hazard ratio, 3.9; 95% confidence interval, 1.33-11.57; P = 0.01). There was no association between OCA use and liver-related mortality or transplantation (adjusted hazard ratio, 1.35; 95% confidence interval, 0.35-5.21; P = 0.66). Conclusion: OCA use was associated with an increase in hepatic decompensation but not liver-related mortality or transplantation in patients with compensated PBC cirrhosis. Additional studies are recommended to prospectively investigate these findings.


Marathon running and vision.
Sixteen optometric tests were administered to 29 athletes prior to and following their running the 1974 26-mile B.A.A. Boston Marathon. The tests included amplitude of accommodation, near point of convergence, stereopsis, depth perception, near phorias, ACA, near ductions, peripheral fields, and suppression. It appears that the systemic fatigue did not significantly affect the test values and it is reasonable to assume similar findings for other forms of athletics. While few optometrists' or ophthalmologists' patients are marathon runners, this study's findings may be extrapolatable to more common conditions.


Assessment of a photon-counting detector for a dual-energy C-arm angiographic system.
This article presents the implementation and assessment of photon-counting dual-energy x-ray detector technology for angiographic C-arm systems in interventional radiology. A photon-counting detector was successfully integrated into a clinical C-arm CT system. Detector performance was assessed using image uniformity metrics in both 2D projections and 3D cone-beam computed tomography (CBCT) images. Uniform exposure fields were acquired to analyze projection images and scans of a homogeneous cylinder phantom were taken to analyze 3D reconstructions. Image uniformity was assessed over a broad range of imaging parameters. Detector calibration greatly improved image uniformity, reducing image variation from 8.8% to 0.5% in an ideal scenario, but image uniformity degraded when imaging parameters varied strongly from values set at calibration: the tube voltage, low-high energy threshhold, and tube current had the greatest impact. Material discrimination and dynamic angiography capabilities were successfully demonstrated in separate phantom and in vivo experiments. The uniformity results identified major factors degrading image quality. The quantitative results will guide selection of calibration points to mitigate the loss of uniformity. The unique combination of dual-energy and fluoroscopy imaging capabilities with a flat-panel photon-counting detector may enable new applications in interventional radiology.


Development of α-tocopherol surface-modified targeted delivery of 5-fluorouracil-loaded poly-D, L-lactic-co-glycolic acid nanoparticles against oral squamous cell carcinoma.
The aim of the study to develop surface modified targeted moiety α-tocopherol (α-t) encapsulated with 5-fluorouracil (5-FU)-poly-D, L-lactic-co-glycolic acid nanoparticles (PLGA NPs) toward the anticancer activity against oral squamous cell carcinoma (OSCC). 5-FU was conjugated with the polymer, PLGA by ionic cross-linking and α-tocopherol use as a functionalized surface moiety. Characterization, drug entrapment efficiency, and in-vitro drug release system were optimized at different pH 7.4 and pH 4.5. The in-vitro cell was performed to optimize the anticancer activity through MTT assay and apoptotic staining assay was also performed by flow cytometry to evaluate the cellular apoptotic activity and cellular uptake. The particle size was distributed within an average range of 145-162 nm, the polydispersity index values lie 0.16-0.30, and the surface charge was at the negative side, -17mV to -23mV. The in vitro drug release system showed more sympathetic situation at pH 7.4 as compared to pH 4.5, for targeted NPs, approximately 86% and 69%, respectively. The non-targeted 5-FU-PLGA NPs showed drug release of 83% and 64% at pH 7.4 and 4.5 subsequently. In vitro anticancer activity confirmed the intense inhibition by α-t-FU-PLGA NPs of 79.98% after 96 h treatment of SCC15 cells and confirmed the steady-state inhibition of 83.74% after 160 h incubation in comparison to 5-FU-PLGA NPs. Subsequently, the early apoptosis, 27.98%, and 16.45%, and late apoptosis, 47.29%, and 32.57%, suggested the higher apoptosis rate in targeted NPs against OSCC. The surface modified α-t-FU-PLGA NP was treated over SCC15 cells, and the oral cancer cells have shown the high intensity of cellular uptake, which confirmed that the target moiety has successfully invaded over the surface of cancer cells and shown advanced targeted delivery against OSCC.


Recent Advances in the Development of Pharmaceutical Agents for Metabolic Disorders: A Computational Perspective.
Metabolic disorders comprise a set of different disorders varying from epidemic diseases such as diabetes mellitus to inborn metabolic orphan diseases such as phenylketonuria. Despite considerable evidence showing the importance of the computational methods in discovery and development of new pharmaceuticals, there are no systematic reviews outlining how they are utilized in the field of metabolic disorders. This review aims to discuss the necessity of the development of web-based tools and databases by integration of available information for solving Big Data problems in network pharmacology of metabolic disorders. We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The alterations in metabolic pathways cause various cardiovascular, hematological, neurological, gastrointestinal, immune disorders and cancer. In this regard, informatics, Big Data and modeling techniques aid in the design of novel therapeutic agents for metabolic diseases by addressing various Big Data problems in the network polypharmacology (drugs/pharmaceutical agents, proteins, genes, diseases, bioassays, ADMET and metabolic pathways), identification of privileged scaffolds, developing new diagnostic biomarkers, understanding the pathophysiology of disease and progress in personalized medicine. The recent advances of developing pharmaceutical agents for various metabolic disorders by considering their pathogenesis, mechanisms of action, therapeutic and adverse effects have been summarized. We have highlighted the role of computational techniques, drug repurposing, and network-based polypharmacological approaches in the identification of new/existing medicines with improved drug-likeness properties for the rare metabolic disorders.


Unique Molecular Characteristics of Visceral Afferents Arising from Different Levels of the Neuraxis: Location of Afferent Somata Predicts Function and Stimulus Detection Modalities.
Viscera receive innervation from sensory ganglia located adjacent to multiple levels of the brainstem and spinal cord. Here we examined whether molecular profiling could be used to identify functional clusters of colon afferents from thoracolumbar (TL), lumbosacral (LS), and nodose ganglia (NG) in male and female mice. Profiling of TL and LS bladder afferents was also performed. Visceral afferents were back-labeled using retrograde tracers injected into proximal and distal regions of colon or bladder, followed by single-cell qRT-PCR and analysis via an automated hierarchical clustering method. Genes were chosen for assay (32 for bladder; 48 for colon) based on their established role in stimulus detection, regulation of sensitivity/function, or neuroimmune interaction. A total of 132 colon afferents (from NG, TL, and LS ganglia) and 128 bladder afferents (from TL and LS ganglia) were analyzed. Retrograde labeling from the colon showed that NG and TL afferents innervate proximal and distal regions of the colon, whereas 98% of LS afferents only project to distal regions. There were clusters of colon and bladder afferents, defined by mRNA profiling, that localized to either TL or LS ganglia. Mixed TL/LS clustering also was found. In addition, transcriptionally, NG colon afferents were almost completely segregated from colon TL and LS neurons. Furthermore, colon and bladder afferents expressed genes at similar levels, although different gene combinations defined the clusters. These results indicate that genes implicated in both homeostatic regulation and conscious sensations are found at all anatomic levels, suggesting that afferents from different portions of the neuraxis have overlapping functions.SIGNIFICANCE STATEMENT Visceral organs are innervated by sensory neurons whose cell bodies are located in multiple ganglia associated with the brainstem and spinal cord. For the colon, this overlapping innervation is proposed to facilitate visceral sensation and homeostasis, where sensation and pain are mediated by spinal afferents and fear and anxiety (the affective aspects of visceral pain) are the domain of nodose afferents. The transcriptomic analysis performed here reveals that genes implicated in both homeostatic regulation and pain are found in afferents across all ganglia types, suggesting that conscious sensation and homeostatic regulation are the result of convergence, and not segregation, of sensory input.


Static and Dynamic Synthesis of Bengali and Devanagari Signatures.
Developing an automatic signature verification system is challenging and demands a large number of training samples. This is why synthetic handwriting generation is an emerging topic in document image analysis. Some handwriting synthesizers use the motor equivalence model, the well-established hypothesis from neuroscience, which analyses how a human being accomplishes movement. Specifically, a motor equivalence model divides human actions into two steps: 1) the effector independent step at cognitive level and 2) the effector dependent step at motor level. In fact, recent work reports the successful application to Western scripts of a handwriting synthesizer, based on this theory. This paper aims to adapt this scheme for the generation of synthetic signatures in two Indic scripts, Bengali (Bangla), and Devanagari (Hindi). For this purpose, we use two different online and offline databases for both Bengali and Devanagari signatures. This paper reports an effective synthesizer for static and dynamic signatures written in Devanagari or Bengali scripts. We obtain promising results with artificially generated signatures in terms of appearance and performance when we compare the results with those for real signatures.


Chronic social isolation signals starvation and reduces sleep in Drosophila.
Social isolation and loneliness have potent effects on public health1-4. Research in social psychology suggests that compromised sleep quality is a key factor that links persistent loneliness to adverse health conditions5,6. Although experimental manipulations have been widely applied to studying the control of sleep and wakefulness in animal models, how normal sleep is perturbed by social isolation is unknown. Here we report that chronic, but not acute, social isolation reduces sleep in Drosophila. We use quantitative behavioural analysis and transcriptome profiling to differentiate between brain states associated with acute and chronic social isolation. Although the flies had uninterrupted access to food, chronic social isolation altered the expression of metabolic genes and induced a brain state that signals starvation. Chronically isolated animals exhibit sleep loss accompanied by overconsumption of food, which resonates with anecdotal findings of loneliness-associated hyperphagia in humans. Chronic social isolation reduces sleep and promotes feeding through neural activities in the peptidergic fan-shaped body columnar neurons of the fly. Artificial activation of these neurons causes misperception of acute social isolation as chronic social isolation and thereby results in sleep loss and increased feeding. These results present a mechanistic link between chronic social isolation, metabolism, and sleep, addressing a long-standing call for animal models focused on loneliness7.


Mismatched summation mechanisms in older adults for the perception of small moving stimuli.
Previous studies have found evidence for reduced cortical inhibition in aging visual cortex. Reduced inhibition could plausibly increase the spatial area of excitation in receptive fields of older observers, as weaker inhibitory processes would allow the excitatory receptive field to dominate and be psychophysically measureable over larger areas. Here, we investigated aging effects on spatial summation of motion direction using the Battenberg summation method, which aims to control the influence of locally generated internal noise changes by holding overall display size constant. This method produces more accurate estimates of summation area than conventional methods that simply increase overall stimulus dimensions. Battenberg stimuli have a checkerboard arrangement, where check size (luminance-modulated drifting gratings alternating with mean luminance areas), but not display size, is varied and compared with performance for a full field stimulus to provide a measure of summation. Motion direction discrimination thresholds, where contrast was the dependent variable, were measured in 14 younger (24-34 years) and 14 older (62-76 years) adults. Older observers were less sensitive for all check sizes, but the relative sensitivity across sizes, also differed between groups. In the older adults, the full field stimulus offered smaller performance improvements compared to that for younger adults, specifically for the small checked Battenberg stimuli. This suggests aging impacts on short-range summation mechanisms, potentially underpinned by larger summation areas for the perception of small moving stimuli.


Nitric oxide: news from stem cells to platelets.
Nitric oxide (NO) is a diffusible, short-lived, diatomic free radical ubiquitously produced by mammalian cells. The generation of NO from L-arginine is enzymatically regulated by three different isoforms of NO synthases. The NO signaling pathway involves mainly the activation of soluble guanylyl cyclase to produce cyclic GMP (cGMP) as a second messenger and downstream mediator. In addition, the free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. NO is a pleiotropic biomodulator in several systems, including the cardiovascular, nervous and immune systems. In the hematopoietic system, NO is thought to be an autocrine or paracrine messenger but also an intracellular effector molecule. Megakaryopoiesis and subsequent thrombopoiesis occur through complex biologic steps that involve hematopoietic stem cell commitment to megakaryocytic lineage, megakaryocyte maturation and finally, platelet release. Here, we summarize the current knowledge regarding the role of exogenous and endogenous NO in hematopoietic stem cell biology, megakaryocyte development and platelet biogenesis as well as relevance of platelet-derived NO generation on platelet function. Dysregulation of NO synthesis has been observed in several diseases, and the evaluation of a series of pharmacological agents with the ability to modulate the NO/cGMP pathway in platelets will also be discussed.


Novel "ruthenium cyclopentadienyl"-peptide conjugate complexes against human FGFR(+) breast cancer.
In this work we explored the possibility of improving the selectivity of a cytotoxic Ru complex [RuCp(PPh3)(2,2'-bipy)][CF3SO3] (where Cp = η5-cyclopentadienyl) TM34 towards FGFR(+) breast cancer cells. Molecular dynamics (MD) simulations of TM34 in a phosphatidylcholine membrane model pinpointed the cyclopentadienyl group as a favorable derivatization position for the peptide conjugation approach. Three new Ru(ii) complexes presenting a functionalized η5-cyclopentadienyl were synthesized, namely [Ru(η5-C5H4COOH)(2,2'-bipy)(PPh3)][CF3SO3] (TM281) and its precursors, [Ru(η5-C5H4COOCH2CH3)(η2-2,2'-bipy)(PPh3)][CF3SO3] (3) and [Ru(η5-C5H4COOCH2CH3)(PPh3)2Cl] (2). Complex TM281 was prepared by the hydrolysis of the ethyl ester group appended to the η5-cyclopentadienyl ligand of complex 3 with K2CO3 in water/acetonitrile, followed by mild protonation using an ion exchange resin. The newly synthesized complexes were fully characterized by NMR, FTIR and UV-vis spectroscopic techniques. Also, electrochemical studies were carried out by means of cyclic voltammetry in order to evaluate the stability of the compounds. Single crystal X-ray diffraction studies were carried out for compounds 3 and TM281 which crystallized in the monoclinic system, space group P21/n. The unprecedented synthesis and characterization of three half-sandwich ruthenium(ii)-cyclopentadienyl peptide conjugates and their preliminary biological evaluation against human FGFR(+) and FGFR(-) breast cancer cells are also reported.


Role of cytokines in the regulation of plasminogen activator inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes.
Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are characteristic for obesity and are associated with increased risk of thromboembolic complications. PAI-1 recently was reported to be expressed and secreted by human adipocytes, but little is known about regulation of PAI-1 in human adipose tissue. Therefore, we examined the effects of selected cytokines present in adipose tissue on expression and secretion of PAI-1 in in vitro, differentiated subcutaneous human adipocytes in primary culture. Transforming growth factor-beta1 (TGF-beta1) increased PAI-1 secretion in a dose- and time-dependent manner. PAI-1 protein increased by 3.2-fold and PAI-1 mRNA by 1.9-fold after a 6-hour exposure to 400 pmol/L TGF-beta1. This effect is probably mediated by TGF-beta1 type 2 and 3 receptors, which were found to be expressed in cultured human adipocytes. Moreover, TNF-alpha and interkeukin-1beta (IL-1beta) also exerted a stimulatory effect on PAI-1 release and increased PAI-1 mRNA levels. As assessed by a semiquantitative reverse transcription-polymerase chain reaction technique, TGF-beta1 mRNA is expressed by differentiation of human preadipocytes and is moderately upregulated by TNF-alpha and IL-1beta. In conclusion, our results clearly indicate that TGF-beta1 is a potent inducer of PAI-1 production in subcutaneous human adipocytes. In addition, data suggest that TNF-alpha and IL-1beta also have stimulatory effects on PAI-1 protein secretion and may contribute to the elevated PAI-1 levels observed in obesity.


Galbanic acid: Induced antiproliferation in estrogen receptor-negative breast cancer cells and enhanced cellular redox state in the human dermal fibroblasts.
Galbanic acid (GA) is a natural bioactive compound abundantly distributed in Ferula species (Apiaceae), with a wide range of biological functions. The present study investigated the anticancer properties of GA in human breast carcinoma MCF-7 and MDA-MB-231 cell lines using MTT (3,4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay. Further, the antioxidant activity of GA was determined in vitro. The plausible mechanisms of action of GA were further investigated using flow cytometry and gene expression analysis. Our study indicated that treatment with GA resulted in inhibition of proliferation and induction of apoptosis in MDA-MB-231 cells. The obtained results indicated that GA has strong cytotoxicity on MDA-MB-231 cells (IC50 = 48.75 µg/mL) compare to MCF-7 (IC50 = 56.65 µg/mL) and decrease cancer cell viability in the dose- and time-dependent manner. Meanwhile, microscopic examination and flow cytometry analysis confirmed the apoptosis cell death upon treatment with GA. The gene expression analysis revealed that GA could induce apoptosis-mediated proliferation inhibition in MDA-MB-231 cells through upregulation of bax and caspase-3 and downregulation of bcl2 genes. Besides, the GA exhibited free radical-scavenging activity and enhanced the cellular redox state in human dermal fibroblasts. The elevation of cellular redox status was confirmed by upregulating superoxide dismutase, catalase, and glutathione peroxidase genes. The results obtained in this study indicated that GA could be considered as a promising anticancer agent in breast cancer therapy and a bioactive antioxidant compound to be used in pharmaceutical and cosmetic industries.


Is the ross procedure a suitable choice for aortic valve replacement in children with rheumatic aortic valve disease?
Ross procedure is the aortic valve replacement of choice in children. Nonetheless, late autograft reoperation for dilatation and/or regurgitation is concerning. We examine whether Ross procedure is suitable in children with rheumatic fever. Medical records of 104 children with rheumatic fever who underwent Ross procedure were reviewed (1991-2004). Competing risks methodology determined time-related prevalence and associated factors for two mutually exclusive end states: autograft reoperation and death prior to subsequent reoperation. Mean age was 13.8 ± 2.7, 83 (80%) were males. Hemodynamic dysfunction was primarily regurgitation (n = 92, 88%) and stenosis/mixed (n = 12, 12%). Competing risks analysis showed that in ten years after the Ross procedure, 1% of patients died, 32% underwent autograft reoperation, and 67% were alive and free from reoperation. Ten-year freedom from aortic regurgitation greater than or equal to moderate was 63%. Ten-year freedom from autograft reoperation was 65% for regurgitation versus 90% for stenosis/mixed disease. Risk factors for autograft reoperation were earlier surgery year (PE: 0.26 ± 0.06 per year; P < .001), additional surgery (PE: 0.82 ± 0.39, P = .04), no annular stabilization (PE: 1.21 ± 0.61, P = .05). Ten-year freedom from homograft replacement was 83%. Risk factors were fresh homografts (PE: 1.36 ± 0.71; P = .06) and aortic homografts (PE: 1.15 ± 0.59; P = .05). Ten-year freedom from any cardiac reoperation was 53%. Concomitant cardiac surgery was risk factor (PE: 1.37 ± 0.47; P = .004). Ross procedure in children with rheumatic fever is associated with excellent survival but results are plagued by aortic regurgitation and frequent autograft reoperation. Risk factors include preoperative regurgitation, concomitant surgery, dilated annulus, and earlier surgery era. Better patient selection in later era has mitigated autograft reoperation risk. Continued, improved candidate selection, along with modifications in autograft implantation and root/sinotubular stabilization techniques, may further decrease late autograft failure.


The association of body mass index, weight gain and central obesity with activity-related breathlessness: the Swedish Cardiopulmonary Bioimage Study.
Breathlessness is common in the population, especially in women and associated with adverse health outcomes. Obesity (body mass index (BMI) >30 kg/m2) is rapidly increasing globally and its impact on breathlessness is unclear. This population-based study aimed primarily to evaluate the association of current BMI and self-reported change in BMI since age 20 with breathlessness (modified Research Council score ≥1) in the middle-aged population. Secondary aims were to evaluate factors that contribute to breathlessness in obesity, including the interaction with spirometric lung volume and sex. We included 13 437 individuals; mean age 57.5 years; 52.5% women; mean BMI 26.8 (SD 4.3); mean BMI increase since age 20 was 5.0 kg/m2; and 1283 (9.6%) reported breathlessness. Obesity was strongly associated with increased breathlessness, OR 3.54 (95% CI, 3.03 to 4.13) independent of age, sex, smoking, airflow obstruction, exercise level and the presence of comorbidities. The association between BMI and breathlessness was modified by lung volume; the increase in breathlessness prevalence with higher BMI was steeper for individuals with lower forced vital capacity (FVC). The higher breathlessness prevalence in obese women than men (27.4% vs 12.5%; p<0.001) was related to their lower FVC. Irrespective of current BMI and confounders, individuals who had increased in BMI since age 20 had more breathlessness. Breathlessness is independently associated with obesity and with weight gain in adult life, and the association is stronger for individuals with lower lung volumes.