The role of simple renal cysts, abdominal wall hernia, and chronic obstructive pulmonary disease as predictive factors for aortoiliac aneurysmatic disease.
This study was designed to investigate the possible predictive value of simple renal cysts (SRCs), abdominal wall hernia (AWH), and chronic obstructive pulmonary disease (COPD) for the presence of abdominal aortoiliac aneurysms (AAA). Between January 2006 and January 2011, we treated 170 consecutive patients with aortoiliac pathology. Patients' data were prospectively collected and were retrospectively analyzed. Of these patients, 110 (study group) had AAA (group 1) and 60 (control group) had aortoiliac occlusive disease (AOD; group 2). Moreover, patients of group 1 were subdivided, according to aneurysm's diameter to subgroup 1A (aortic aneurysm diameter >55 mm and/or common iliac diameter >22 mm; n = 62) and subgroup 1B (aortic aneurysm diameter ≤ 55 mm and/or common iliac diameter ≤ 22 mm; n = 48). All patients underwent a computed tomographic angiography, and datasets were analyzed for aortoiliac and SRCs' anatomical data. Additionally collected data were atherosclerotic risk factors, history of previous or current AWH, and COPD. The two groups as well as the two AAA subgroups were homogenous regarding demographics and atherosclerotic risk factors. Univariate analysis showed that incidence of SRCs, AWH, and COPD were significant predictive factors for presence of AAA. Multivariate analysis identified SRCs and AWH as independent predictive factors for the presence of AAA. In association with the aneurysm's size, multivariate analysis failed to show any predictive value of SRCs, AWH, or COPD. Results of our study showed a positive predictive value of SRCs and AWH for presence of AAA and a strong relationship but not with predictive value between COPD and AAA. These data might be helpful for the early recognition of patients at risk for an aortoiliac aneurysm formation and for establishment of AAAs population-based screening. Further research of pathophysiological commonalities between the four studied entities may be extremely helpful for designing future preventive and treatment strategy of AAAs.


Is 30-day mortality an adequate outcome statistic for patients considering heart valve replacement?
In-hospital mortality is widely used by clinicians as a benchmark measure of outcome for determining risks/benefits of cardiac surgery. Patients, however, may wish to have information on estimated longer-term outcomes. Mortality risk by 1 year after the operation may be a more meaningful outcome statistic. We therefore undertook to determine 30-day and 365-day postoperative mortality rates in a large series of consecutive patients who have undergone heart valve replacement (HVR) surgery in the United Kingdom since 1986. Data on 80,757 patients registered on the UK Heart Valve Registry were analyzed. Kaplan-Meier actuarial survival analysis was calculated to determine 30-day (group 1) and 365-day (group 2) mortality. Cox proportional hazards were calculated for each group to identify significant risk factors for mortality less than 1 year. Thirty-day mortality represents around half (56%) of the 365-day mortality. This ratio was robust for most subdivisions of the total population. Cox proportional hazards demonstrated female sex, age older than 70 years, single tricuspid valve replacement, multiple valve replacement regardless of type of valve, and subsequent valve operation as significant risk factors of early mortality (group 1). However, men were at significantly greater risk of late mortality (group 2). All other factors remained significant with the exception of subsequent valve operation, which was dropped from the model (group 2). The robustness of these data would allow cardiologists and cardiac surgeons to provide preoperative patients with a reasonably accurate estimate of survival rates at 1 year after valve replacement surgery in addition to the customary short-term 30-day outcome.


Temperature-dependent impact of thermal aminolaevulinic acid photodynamic therapy on apoptosis and reactive oxygen species generation in human dermal fibroblasts.
Actinic keratoses (AKs) are generally accepted as common precursor lesions to invasive squamous cell carcinoma. Photodynamic therapy (PDT) is a common, in-office, field therapy modality used in the treatment of AKs. Clinical and laboratory observations have demonstrated that temperature modulation can affect PDT efficacy. To demonstrate thermal PDT increases apoptotic cell death, and to investigate the mechanistic role of reactive oxygen species (ROS) free radicals in an in vitro human skin fibroblast model. This study was completed using commercially available primary human skin fibroblasts treated with aminolaevulinic acid (ALA) at specific concentrations and controlled temperatures. Cell death, apoptosis and superoxide ROS levels were quantified. We found that thermal PDT with 0·5 mmol L(-1) ALA resulted in significant temperature-dependent increases in total apoptosis and superoxide ROS generation between 33 °C and 42 °C. Our results indicate that thermal PDT significantly increases apoptotic cell death through increased generation of superoxide ROS in a temperature-dependent manner.


A formal total synthesis of the marine diterpenoid diisocyanoadociane.
[Structure: see text] A formal total synthesis of diisocyanoadociane, a marine diterpenoid with potent antimalarial properties, has been completed. The synthesis begins with a phenanthrenoid precursor that is transformed into a pyrene-derived intermediate by means of an intramolecular Michael reaction. Nitrogen functionality is introduced via a double Curtius reaction.


Structural characterization of the involvement of SigC in the regulation of the gene expression of pathogenic Mycobacterium ulcerans.
Mycobacterium ulcerans is the causative agent of the Buruli ulcers in humans. This disease is a devastating necrotic disease of the subcutaneous tissue. Currently there are very few drugs to prevent the Buruli ulcers. This human pathogen is carried by aquatic insects. The gene sequence of this pathogenic organism has recently been identified. In the present study an attempt has been made to analyze the structural characteristics of the SigC protein from Mycobacterium ulcerans. Sequence analyses of SigC reveal that it belongs to the family of sigma factors, which are involved in DNA binding at promoter sites, and play a role in transcription initiation. Homology modeling was employed to construct the three-dimensional structure of the protein and the model was analyzed. SigC protein has a distinct helix-turn-helix DNA binding motif. It is compared to other members of the DNA binding proteins. The modeled structure of SigC has been used to dock on the promoter DNA to predict the favourable binding interactions of the protein, which are responsible for the gene expressions in the organism. These interactions have been used to predict the plausible mechanism of the process. Since this is the first structural work regarding the interactions of SigC protein and its promoter DNA, this study may contribute in the realm of structure based drug design approaches to produce drugs against this harmful organism to control its proliferation and spreading of Buruli ulcer.


Sex assessment from the pelvis: a test of the Phenice (1969) and Klales et al. (2012) methods.
Sex assessment is one of the first steps of routine forensic anthropological examinations and it provides a crucial element to identify a set of human skeletal remains. In bioarchaeological contexts, this assessment is also important, as it helps in the reconstruction of past societies. Sex determination can be achieved by using several morphological or metric traits of the skull and postcranial skeleton, which have been found to have varying degrees of accuracy. In 1969 Phenice proposed a methodology focusing on three traits located on the pubis. These traits were described as either having a female or male morphology with ambiguity being rare. Phenice's method became regularly utilized as it was considered to be reliable. In 2012, Klales and colleagues published a revision of Phenice's method, as they found that it did not capture the variation in the expression of the three traits. Klales and co-authors created a visual ordinal scale of 1-5 for each of the three traits Phenice originally identified, thus adding three extra possible forms of expression. The purpose of the present research was to test both the original and revised methodologies on the same skeletal population in order to evaluate their suitability for the assessment of sex. The Luís Lopes Anthropological collection in Lisbon was used; 117 males and 117 females were scored using both methodologies. The results showed that the original method performed better (96.5% accuracy) than the revised method (92.7%).


Age-related changes in the initiation of gait: degradation of central mechanisms for momentum generation.
To investigate cross-sectionally age-related changes in the expression and biomechanical efficiency of the gait-initiation motor program. Case-control study. Twenty healthy young research subjects and 20 healthy elderly subjects who volunteered from the community participated in this study at a university research laboratory. Participants performed gait-initiation trials at three speeds from a starting position on a force platform while ground reaction force data, 3-D motion analysis data, and electromyographic data were collected. Measures included: latency of tibialis anterior (TA) activation and soleus (SOL) and gastrocnemius (GA) inhibition, magnitude of center of pressure (COP) displacement, magnitude of momentum generated, and final walking velocity. The expression of the central motor program governing gait initiation, as evidenced by the invariant timing between TA activation and SOL/GA inhibition, was seen in both the young and elderly populations, but the frequency was diminished in the latter group. The momentum-generating capacity of the COP shift mechanism was present but significantly diminished in the elderly population. These findings suggest that the central nervous system uses stable, efficient mechanisms for dealing with the inherent instability of upright bipedalism and that the integrity of these mechanisms degrades with aging.


Aggressive B cell Lymphoma: Optimal Therapy for MYC-positive, Double-Hit, and Triple-Hit DLBCL.
Approximately 10% of cases of diffuse large B cell lymphoma (DLBCL) harbor a MYC rearrangement and this has been associated with an inferior outcome following standard therapy across many different studies. Double-hit and triple-hit lymphomas harbor concurrent rearrangements of MYC and BCL2 and/or BCL6 and are also associated with a very aggressive course and poor clinical outcome. It is unclear and there is lack of consensus on how these diseases should be approached therapeutically. They are characterized typically by high tumor proliferation and likely require Burkitt lymphoma-type strategies and several retrospective studies suggest that more intensive approaches than rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) may be beneficial. One challenge in this respect is that most patients with these diseases are older than 60 years and generally have poor tolerability of regimens typically used in Burkitt lymphoma. Dose-adjusted EPOCH-R is an alternative effective immunochemotherapy platform for DLBCL and is effective in Burkitt lymphoma, and retrospective studies suggest that it is effective and feasible in patients with DLBCL that harbors a MYC rearrangement with or without a BCL-2 translocation (double-hit). A multicenter study of this approach in MYC-rearranged DLBCL is ongoing and preliminary results are very encouraging. There is a lack of consensus on the role of consolidation stem cell transplantation in patients who achieve a good response to initial therapy but at this point in time, no (retrospective) studies have demonstrated any benefit. These diseases are also associated with a high rate of CNS involvement and progression and checking for cerebrospinal fluid by cytology and flow cytometry at initial diagnosis should be considered. In summary, based on retrospective data and preliminary prospective data (as more mature data is awaited), while Burkitt-type regimens may be feasible in young patients, DA-EPOCH-R is a reasonable approach for patients with these diseases, particularly for those over the age of 60 years. CNS prophylaxis is a reasonable consideration (depending on clinical characteristics) given that the rate of CNS progression is high. Many exciting new small molecule inhibitors such as BCL-2 and MYC inhibitors are in development and are exciting for these diseases and attempts are underway to combine them with effective immunochemotherapy platforms.


Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies.
Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. These results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses, suggesting that sequencing of MCL-1 inhibitors with targeted therapies could overcome such widespread and clinically important resistance.


Distinct Cell-Cycle Control in Two Different States of Mouse Pluripotency.
Mouse embryonic stem cells (ESCs) cultured in serum are characterized by hyper-phosphorylated RB protein, lack of G1 control, and rapid progression through the cell cycle. Here, we show that ESCs grown in the presence of two small-molecule inhibitors (2i ESCs) have a longer G1-phase with hypo-phosphorylated RB, implying that they have a functional G1 checkpoint. Deletion of RB, P107, and P130 in 2i ESCs results in a G1-phase similar to that of serum ESCs. Inhibition of the ERK signaling pathway in serum ESCs results in the appearance of hypo-phosphorylated RB and the reinstatement of a G1 checkpoint. In addition, induction of a dormant state by the inhibition of MYC, resembling diapause, requires the presence of the RB family proteins. Collectively, our data show that RB-dependent G1 restriction point signaling is active in mouse ESCs grown in 2i but abrogated in serum by ERK-dependent phosphorylation.


Chemical-genetic interaction mapping links carbon metabolism and cell wall structure to tuberculosis drug efficacy.
Current chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug–drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based on in vitro assays alone. In this study, we utilized conditional Mtb knockdown mutants of essential genes as an experimentally tractable surrogate for drug treatment and probe the relationship between Mtb carbon metabolism and chemical–genetic interactions (CGIs). We examined the antitubercular drugs isoniazid, rifampicin, and moxifloxacin and found that CGIs are differentially responsive to the metabolic state, defining both environment-independent and -dependent interactions. Specifically, growth on the in vivo–relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependent in vitro CGIs could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of chemical–genetic–environmental interactions that can be used to optimize drug–drug interactions, as well as provide a framework for understanding in vitro correlates of in vivo efficacy.


Assessing of detached breakwaters and beach nourishment environmental impacts in Italy: a review.
Coastal regions are exposed to natural phenomena such as sea waves, sea level rise, climate change, and flooding events. These factors, along with human pressures, lead to an increase in coastal erosion. In response, hard engineering measures were realized as breakwaters and groins, to oppose erosion processes along the sandy beaches of the Italian coastline. These types of defense systems showed negative impacts on landscapes, ecosystems, and expected results. Additionally, the use of coastal revetments, submerged sandbars, soil bioengineering, and beach nourishment projects were used to defend seaboard areas from the risk of a growing shore withdrawal. Among these soft solutions, beach nourishment is becoming an environmentally friendly method to control shoreline erosion, increasing the width of sandy beaches to guarantee a better tourist use of coastal regions and to add a greater buffer between the shoreline and existing infrastructure. In recent times, nourishment projects have been combined with other protective measures, such as submerged sandbars and underwater detached breakwaters, limiting the loss of sediments from sandy beaches and allowing better protection from stormy events. These mixed solutions ensure effective coastal protection by maintaining the width of sandy beaches for tourist use, guaranteeing the environmental safeguard of the coastal ecosystems. In order to achieve the best result with these types of projects, a close collaboration between coastal engineers, geologists, biologists, and policymakers toward integrated coastal zone management is necessary. The study described in this paper has taken the form of a literature review regarding both the negative environmental impacts and the benefits associated with the use of old and new coastal defense systems.


Structure-activity relationships of dibenzoylhydrazines for the inhibition of P-glycoprotein-mediated quinidine transport.
We previously demonstrated that dibenzoylhydrazines (DBHs) are not only P-glycoprotein (P-gp) substrates, but also inhibitors. In the present study, we evaluated the inhibition of P-gp-mediated quinidine transport by two series of DBHs and performed a classical QSAR analysis and docking simulation in order to investigate the mechanisms underlying P-gp substrate/inhibitor recognition. The results of the QSAR analysis identified the hydrophobic factor as the most important for inhibitory activities, while electronic and steric effects also influenced the activities. The different substituent effects observed in each series suggested the different binding modes of each series of DBHs, which was supported by the results of the docking simulation.


Effectiveness of Meningococcal Vaccines at Reducing Invasive Meningococcal Disease and Pharyngeal Neisseria meningitidis Carriage: A Systematic Review and Meta-analysis.
Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, leads to significant morbidity and mortality worldwide. This review aimed to establish the effectiveness of meningococcal vaccines at preventing IMD and N. meningitidis pharyngeal carriage. A search within PubMed, Embase, Scopus, and unpublished studies up to 1 February 2020 was conducted. After removal of duplicates, 8565 studies were screened and 27 studies included. Protection was provided by meningococcal C vaccines for group C IMD (odds ratio [OR], 0.13 [95% confidence interval {CI}, .07-.23]), outer membrane vesicle (OMV) vaccines against group B IMD (OR, 0.35 [95% CI, .25-.48]), and meningococcal A, C, W, Y (MenACWY) vaccines against group ACWY IMD (OR, 0.31 [95% CI, .20-.49]). A single time series analysis found a reduction following an infant 4CMenB program (incidence rate ratio, 0.25 [95% CI, .19-.36]). Multivalent MenACWY vaccines did not reduce carriage (relative risk [RR], 0.88 [95% CI, .66-1.18]), unlike monovalent C vaccines (RR, 0.50 [95% CI, .26-.97]). 4CMenB vaccine had no effect on group B carriage (RR, 1.12 [95% CI, .90-1.40]). There was also no reduction in group B carriage following MenB-FHbp vaccination (RR, 0.98 [95% CI, .53-1.79]). Meningococcal conjugate C, ACWY, and OMV vaccines are effective at reducing IMD. A small number of studies demonstrate that monovalent C conjugate vaccines reduce pharyngeal N. meningitidis carriage. There is no evidence of carriage reduction for multivalent MenACWY, OMV, or recombinant MenB vaccines, which has implications for immunization strategies. CRD42018082085 (PROSPERO).


Oral Anticoagulant Therapy and Risk of Admission to Long-Term Care in patients With Atrial Fibrillation: A Nationwide Cohort Study.
The impact of oral anticoagulants (OACs) on the need of long-term care (LTC) in the aging and multimorbid population of patients with atrial fibrillation (AF) is unknown. We conducted a nationwide cohort study to evaluate the effect of OACs on the need of LTC. Retrospective nationwide cohort study. The registry-based FinACAF cohort study covers all patients with incident AF from all levels of care in Finland from 2007 to 2018, as well as all their OAC purchases, LTC admissions, and information on previous home care acuity. Incidence rate ratios (IRRs) of LTC admission were calculated using Poisson regression models with a Lexis-type data structure based on 3 time scales: follow-up time from AF diagnosis, calendar year, and age. We identified 188,752 patients (49.0% female; mean age 71.4 years; mean follow-up 3.6 years) with incident AF without prior LTC, of whom 143,534 (76.0 %) initiated OAC therapy and 11,775 (6.2 %) were admitted to LTC. OAC therapy was associated with lower rates of LTC admission (adjusted IRR 0.79, 95% CI 0.76-0.82). When compared to warfarin, direct oral anticoagulants (DOACs) were associated with lower LTC admission rate (adjusted IRR 0.69, 95% CI 0.61-0.79). No significant disparities were observed between different DOACs. OAC therapy, particularly with DOACs, is associated with a substantially lower risk of admission to LTC in patients with AF. Increasing guideline-based OAC coverage among patients with AF may prevent the need of LTC, lengthen survival at home, and potentially decrease health care costs.


An accurate and precise high-performance liquid chromatography method for the rapid quantification of the novel HIV integrase inhibitor raltegravir in human blood plasma after solid phase extraction.
The quantification of the HIV integrase inhibitor raltegravir in blood plasma is described using solid phase extraction (SPE) coupled with an accurate high-performance liquid chromatography assay with ultraviolet (UV) detection. The method was validated over the range of 20-10,000 ng/mL using simple sample preparation and chromatography. The SPE method was optimized to be selective and highly efficient. The buffer's ionic strength and pH were optimized for retaining RAL and the internal standard on the column, the percentage of methanol was optimized in the cleaning step to remove unwanted plasma contaminants, and the type and amount of acid was optimized for complete elution of the compounds. This method has no interference with other potentially co-administered antiretrovirals or common drugs. Average recoveries for the extraction method were consistently high: 90% for raltegravir and 90% for the internal standard diazepam. This method was found to be accurate and precise. Within day (n=6) and between day (n=18) accuracies ranged from 97.5 to 104.4%. Within-day (n=6) and between-day (n=18) precision ranged from 1.4 to 3.8%, and from 2.4 to 7.9%, respectively. This is the first published method to use simple UV technology and reliable SPE extraction methodology for the quantification of raltegravir in human plasma. This method can be easily implemented in most bioanalytical laboratories.


Estradiol induces partial desensitization of serotonin 1A receptor signaling in the paraventricular nucleus of the hypothalamus and alters expression and interaction of RGSZ1 and Gαz.
Hyperactivity of hypothalamic-pituitary mediated hormone responses, such as to stimulation with a serotonin 1A (5-HT(1A)) receptor agonist, are a feature of depression which are normalized with clinical improvement during drug therapy. We previously reported that SSRIs induce desensitization of 5-HT(1A) receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) while estradiol benzoate (EB) produces a more rapid, partial desensitization. In the current study, time course and dose-response experiments demonstrated that two once daily doses of EB is the minimum needed to induce the desensitization response as indicated by 5-HT(1A) receptor-stimulated release of oxytocin and that 10 μg/kg/day EB produces the maximal response, a partial desensitization of approximately 40%. The effects of two once daily injections of 10 μg/kg/day EB on Gαz and RGSZ1 proteins were examined as components of the 5-HT(1A) receptor signaling system, which mediates the release of oxytocin and adrenocorticotropic hormone. RGSZ1 appears to be a major target for EB-mediated responses in the 5-HT(1A) receptor signaling system. A 55 kD membrane-associate RGSZ1 protein was greatly increased in the PVN and rest of the hypothalamus and moderately increased in the dorsal hippocampus and amygdala after EB treatment as well as after an acute dose of a 5-HT(1A) receptor agonist. These results suggest that EB is a candidate for adjuvant therapy with SSRIs to hasten the therapeutic response and that RGSZ1 is a major target of EB therapy which could be explored as a target for novel therapeutic approaches for the treatment of depression.


Comparing the toxic mechanism of synthesized zinc oxide nanomaterials by physicochemical characterization and reactive oxygen species properties.
We studied the toxicity of ZnO nanomaterials in terms of physicochemical characteristics and reactive oxygen species (ROS) properties. ZnO nanorods [synthesized at room temperature (ZnO-RT, length; 18.0±4.2 nm) and at 60 °C (ZnO-60, length; 80.5±6.8 nm)] were used to evaluate the potential toxicity upon growth velocity-related particle size. The cytotoxicity of ZnO-60 was higher than that of ZnO-RT. We observed that the toxicity of ZnO-RT and ZnO-60 was related with ROS formation by using antioxidant N-acetylcysteine and electron spin resonance. Also, we found that the source of toxicity was not related to Zn(2+) ions released from ZnO in 24h treatment. Our results indicate that toxicity of ZnO nanorods is caused by the amounts of ROS. Our study strongly suggests that size of nanomaterial is not the sole factor to be considered, thus, the development of appropriate criteria based on morphological/physicochemical characteristics as well as synthesis procedures is needed to evaluate the precise toxicity.


Plant cell wall composition modulates the gut microbiota and metabolites in in-vitro fermentation.
This research investigated the effect of different types of plant cell wall fibres, including cereal (i.e., barley, sorghum, and rice), legume (i.e., pea, faba bean, and mung bean), and tuber (potato, sweet potato, and yam) cell wall fibres on in vitro faecal fermentation profiles and gut microbiota composition. The cell wall composition, specifically the content of lignin and pectin, was found to have a significant influence on the gut microbiota and fermentation outcomes. Compared with type I cell walls (legume and tuber) which have high pectin content, the type II cell walls (cereal) which are high in lignin but low in pectin had a lower fermentation rates and less short-chain fatty acid production. The redundancy analysis showed samples with similar fibre composition and fermentation profiles clustered together, and the principal coordinate analysis revealed separation among different types of cell walls and closer proximity among the same cell wall types. These findings emphasize the importance of cell wall composition in shaping the microbial community during fermentation and contribute to a better understanding of the relationship between plant cell walls and gut health. This research has practical implications for the development of functional foods and dietary interventions.


Pressurized hydrogenotrophic denitrification reactor for small water systems.
The implementation of hydrogenotrophic denitrification is limited due to safety concerns, poor H2 utilization and low solubility of H2 gas with the resulting low transfer rate. The current paper presents the main research work conducted on a pressurized hydrogenotrophic reactor for denitrification that was recently developed. The reactor is based on a new concept suggesting that a gas-liquid equilibrium is achieved in the closed headspace of denitrifying reactor, further produced N2 gas is carried out by the effluent and gas purging is not required. The feasibility of the proposed reactor was shown for two effluent concentrations of 10 and 1 mg NO3--N/L. Hydrogen gas utilization efficiencies of 92.8% and 96.9% were measured for the two effluent concentrations, respectively. Reactor modeling predicted high denitrification rates above 4 g NO3--N/(Lreactor·d) at reasonable operational conditions. Hydrogen utilization efficiency was improved up to almost 100% by combining the pressurized reactor with a following open-to-atmosphere polishing unit. Also, the potential of the reactor to remove ClO4- was shown.


Immunoreactivity profiling of Anti-Chinese hamster ovarian host cell protein antibodies by isobaric labeled affinity purification-mass spectrometry reveals low-recovery proteins.
We evaluated the immunoreactivity profiles of eight commercial anti-host cell protein (anti-HCP) antibodies from different host animals and their antigens used for immunization by an isobaric labeled affinity purification-mass spectrometry (AP-MS) method. As a result, 34 proteins with high abundance but low recovery from harvest cell culture fluid were identified. Since they are likely to be underestimated in biopharmaceutical quality assessment, the features common to these proteins were investigated. Compared to other immunoprecipitated HCP proteins, proteins exhibiting lower molecular weight (ΔMW = -14600), lower isoelectric point (ΔpI = -0.86), and lower hydrophobicity (ΔGRAVY = -0.13) were enriched. This AP-MS method provides important information for HCP control strategies using immunological methods and is expected to contribute to the development of safe biopharmaceutics.


Olefin metathesis for chemical biology.
Chemical biology relies on effective synthetic chemistry for building molecules to probe and modulate biological function. Olefin metathesis in organic solvents is a valuable addition to this armamentarium, and developments during the previous decade are enabling metathesis in aqueous solvents for the manipulation of biomolecules. Functional group-tolerant ruthenium metathesis catalysts modified with charged moieties or hydrophilic polymers are soluble and active in water, enabling ring-opening metathesis polymerization, cross metathesis, and ring-closing metathesis. Alternatively, conventional hydrophobic ruthenium complexes catalyze a similar array of metathesis reactions in mixtures of water and organic solvents. This strategy has enabled cross metathesis on the surface of a protein. Continuing developments in catalyst design and methodology will popularize the bioorthogonal reactivity of metathesis.


Compounds from diverse natural origin against triple-negative breast cancer: A comprehensive review.
Triple-negative breast cancer (TNBC) is caused due to the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor 2 (HER2) expression. Triple-negative breast cancer is the most aggressive heterogeneous disease that is capable of producing different clones and mutations. Tumorigenesis in TNBC is caused due to the mutation or overexpression of tumor suppressor genes. It is also associated with mutations in the BRCA gene which is linked to hereditary breast cancer. In addition, PARP proteins and checkpoint proteins also play a crucial function in causing TNBC. Many cell signaling pathways are dysregulated in TNBC. Even though chemotherapy and immunotherapy are good options for TNBC treatment, the response rates are still low in general. Many phytochemicals that are derived from natural compounds have shown very good inhibitions for TNBC. Natural compounds have the great advantage of being less toxic, having lesser side effects, and being easily available. The secondary metabolites such as alkaloids, terpenoids, steroids, and flavonoids in natural products make them promising inhibitors of TNBC. Their compositions also offer vital insights into inhibitory action, which could lead to new cancer-fighting strategies. This review can help in understanding how naturally occurring substances and medicinal herbs decrease specific tumors and pave the way for the development of novel and extremely efficient antitumor therapies.


Ecological aspects of potential arbovirus vectors (Diptera: Culicidae) in an urban landscape of Southern Amazon, Brazil.
Amazon has been under intense human pressure, especially in the so-called "Arc of Deforestation" in the Eastern and Southern regions. Changes in biodiversity due to landscape disturbance in municipalities at the Arc of Deforestation are likely to impact mosquito species leading to the potential for emergence of arboviruses. Our aim was to describe the composition and structure of culicids in Sinop, a municipality located in the Southern Amazon at the State of Mato Grosso, as well as their presence in urban habitats, analyzing climate variables and potential risk of arbovirus transmission. Mosquitoes were collected in four habitats located in urban environments for 12 months. We recovered 5,210 adult mosquitoes from mosquito traps. Among the 33 species identified, 19 are associated with arbovirus transmission. Higher abundance, richness, diversity, and equitability of mosquito species were observed in urban forest parks and in new neighborhoods located in the outskirts of the city, nearby forest fragments and agricultural areas. As the environment consolidates as urban, both abundance and richness decrease. Highly urbanized neighborhoods had higher dominance of Culex quinquefasciatus, a mosquito associated with different arboviruses, including West Nile and Saint Louis encephalitis virus. The medically important species Cx. declarator, Cx. (Melanoconion) ssp., Aedeomyia squamipennis and Aedes scapularis were found in the four habitats. It is possible that these mosquitoes are adapting to different habitats and as a consequence, they are reaching urbanized areas. Mosquito abundance was higher in the days of high temperature and low precipitation in urban forest parks and in highly urbanized neighborhoods. These results suggest that Sinop region is a key area for surveillance of arbovirus vectors.


Anticoagulation Holiday: Resumption of Direct Oral Anticoagulants for Atrial Fibrillation in Patients with Index Traumatic Intracranial Hemorrhage.
The optimal time to restart direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) after traumatic intracranial hemorrhage (tICH) is unknown. Physicians must weigh the risk of recurrent hemorrhage against ischemic stroke. We investigated rates of stroke while holding anticoagulation, hemorrhage after anticoagulation resumption, and factors associated with the decision to restart anticoagulation. Patients presenting to our level I trauma center for tICH while on a DOAC for NVAF were retrospectively reviewed over 2 years. Age, sex, DOAC use, antiplatelet use, congestive heart failure, hypertension, age, diabetes, previous stroke, vascular disease, sex score for stroke risk in NVAF, injury mechanism, bleeding pattern, Injury Severity Score, use of a reversal agent, Glasgow Coma Scale at 24 hours, hemorrhage expansion, neurosurgical intervention, Morse Fall Risk, DOAC restart date, rebleed events, and ischemic stroke were recorded to study rates of recurrent hemorrhage and stroke, and factors that influenced the decision to restart anticoagulation. Twenty-eight patients sustained tICH while on a DOAC. Fall was the most common mechanism (89.3%), and subdural hematoma was the predominant bleeding pattern (60.7%). Of the 25 surviving patients, 16 patients (64%) restarted a DOAC a median 29.5 days after tICH. One patient had recurrent hemorrhage after resuming anticoagulation. One patient had an embolic stroke after 118 days off anticoagulation. Age >80, Injury Severity Score ≥16, and expansion of tICH influenced the decision to indefinitely hold anticoagulation. The low stroke rate observed in this study suggests that holding DOACs for NVAF for 1 month is sufficient to reduce the risk of stroke after tICH. Additional data are required to determine optimal restart timing.


The Use of Closed Suction Drainage in Lumbar Spinal Surgery: Is It Really Necessary?
Closed wound suction drainage after spine surgery is commonly used in clinical practice. However, no consensus has been reached for using drainage versus nondrainage after lumbar spinal surgery until now. The purpose of this study was to determine the clinical outcomes of using closed suction drainage versus nondrainage after lumbar spinal surgery. We conducted a systematic review and meta-analysis to identify relevant studies from PubMed, MEDLINE, EMBASE, Cochrane Library, and Google scholar up to September 2015. All randomized, quasi-randomized, and controlled clinical studies, which compared the clinical outcomes of using closed suction drainage versus nondrainage in patients who underwent lumbar spinal surgery, were included. Data extraction and quality assessment were according to Cochrane Collaboration guidelines. Five studies involving 1295 patients were included in this meta-analysis. By pooling the clinical outcomes, there were no significant differences between patients with drainage and nondrainage in terms of the incidence of wound infection (odds ratio [OR], 1.48; 95% confidence interval [CI], 0.47-4.71; P = 0.50), wound hematoma (OR, 0.45; 95% CI, 0.01-29.31, P = 0.71), and reoperation (OR, 1.36; 95% CI, 0.22-8.27; P = 0.74). Drainage after lumbar surgery was associated with more blood loss and significantly greater blood transfusions (OR, 3.68; 95% CI, 1.80-7.54; P < 0.01) compared with nondrainage. However, more patients contracted postoperative fever in the nondrainage group than did those in drainage group. Based on this systematic review and meta-analysis, there is insufficient evidence to suggest routine use of prophylactic closed suction drainage after lumbar spinal surgery. However, a decision to use or not use drainage should be individualized for each patient because many factors affect the outcomes.


Amides and formamidines with antinociceptive activity (note II).
Forty amides, formamidines and trifluoromethylsulfonylamides bearing on the nitrogen a cyclohexyl residue, eventually 2-substituted, were prepared and tested for analgesic activity against a chemical stimulus. Good activity was exhibited by amides 9, 11 and 28, by formamidine 34, as well as by triflyamide 40. Eleven additional compounds exhibited a moderate activity.


Glucocorticoid treatment facilitates development of a metabolic syndrome in ovariectomized Macaca Mulatta fed a high fat diet.
Metabolic syndrome (MetS) is characterized by a cluster of key features, which include abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The aim of this study was to assess the impact of elevated glucocorticoid levels on the development of MetS in middle-aged female rhesus monkeys (Macaca Mulatta) after ovariectomy. Six female ovariectomized rhesus monkeys (9-13years) were randomly assigned to either a control group (normal diet, n=3) or a group in which MetS was facilitated (n=3). The MetS group fed with HFD (15% fat) and received oral prednisone acetate treatment (50mg/day). After 24months, the GCs treatment was withdrawn with continuation of high-fat feeding for a further 12months. After 24months, the MetS group displayed a significant increase in body weight and abdominal circumference. Additionally, the MetS animals displayed abnormal serum lipids, insulin resistance and impaired glucose tolerance. Histology of liver biopsies indicated marked accumulation of lipid droplets in hepatocytes of MetS animals. Withdrawal of GCs treatment led to recovery from above-mentioned metabolic disorders. Whereas GCs treatment increased leptin expression, it lowered expression of adiponectin and other factors in adipose tissue. Expression of Hydroxy-steroid dehydrogenase-1 and glucose transporter type-4 in the livers of MetS animals were reduced. We conclude that in the context of high fat diet, high levels of exogenous GCs contribute to the development of MetS in non-human primates.


Chronic brain toxicity response of juvenile Chinese rare minnows (Gobiocypris rarus) to the neonicotinoid insecticides imidacloprid and nitenpyram.
Imidacloprid and nitenpyram are widely used neonicotinoid pesticides worldwide and were observed to adversely affect non-target aquatic organisms. In this study, the toxic effect of imidacloprid and nitenpyram on the brain of juvenile Chinese rare minnows (Gobiocypris rarus) was investigated by determining the oxidative stress, 8-hydroxy-2-deoxyguanosine (8-OHdG) content and acetylcholinesterase (AChE) activity. The superoxide dismutase (SOD) activities did not significantly change after long-term exposure to imidacloprid and nitenpyram. A noticeable increase of catalase (CAT) activities was observed on the brain tissues under 0.1 mg/L imidacloprid and under all nitenpyram treatments (p < 0.05). The malondialdehyde (MDA) content increased markedly under 2.0 mg/L imidacloprid and 0.1 mg/L nitenpyram treatments (p < 0.05). The glutathione (GSH) content in the brain significantly increased under 0.5 and 2.0 mg/L imidacloprid (p < 0.05). A significant decrease was observed in the mRNA levels of Cu/Zn-sod under 2.0 mg/L imidacloprid and those of cat under 0.1 and 0.5 mg/L nitenpyram (p < 0.05). The mRNA levels of gpx1 clearly decreased under 2.0 mg/L imidacloprid and under 0.1 mg/L nitenpyram (p < 0.05). The treatments of 0.1 and 0.5 mg/L nitenpyram decreased cat expression levels markedly (p < 0.05). 2.0 mg/L imidacloprid raised the 8-OHdG content. The AChE activities increased markedly under 0.5 and 2.0 mg/L imidacloprid while clearly decreasing under 2.0 mg/L nitenpyram (p < 0.05). Therefore, our results indicate that imidacloprid and nitenpyram might cause adverse effects on juvenile Chinese rare minnows brain. Notably, imidacloprid had greater impacts on juvenile rare minnows compared to nitenpyram.


MRI with Magnetic Resonance Spectroscopy of multiple brain abscesses secondary to Scedosporium apiospermum in two immunocompromised patients.
Scedosporium apiospermum is a deadly fungal infection that can infect the central nervous system, particularly in immunocompromised patients. We present two cases of Scedosporium brain abscesses. The first case was fatal and relevant conventional MRI and MR spectroscopy findings are discussed. To our knowledge, this is the first reported case of MR spectroscopy in Scedosporium apiospermum abscesses. In the second case, the patient recovered and conventional MR findings are followed over several months. In the appropriate clinical setting, conventional MR imaging and MR spectroscopy may facilitate diagnosis, earlier initiation of antifungal pharmacotherapy and surgical intervention in this frequently fatal infection.


Resveratrol facilitates pain attenuation in a rat model of neuropathic pain through the activation of spinal Sirt1.
Little research has been conducted regarding the implications of Sirt1 (a classic III HDAC) in neuropathic pain. The aim of this study was to investigate the variation in the expressions of spinal Sirt1 and acetyl-histone H3 in a rat model of chronic constriction injury. A neuropathic pain model of chronic constriction injury (CCI) was established in a unilateral hind limb in Sprague-Dawley rats. Western blot analysis and immunohistochemistry revealed that Sirt1 (silent information regulator) expression decreased, whereas acetyl-histone H3 increased in the spinal cord following CCI surgery. The intrathecal administration of resveratrol, an activator of Sirt1, attenuated CCI-induced mechanical allodynia and thermal hyperalgesia, increased Sirt1 expression, and decreased acetyl-histone H3 in the spine. Resveratrol induced no obvious histopathological changes in the spinal cord. Our data provide new evidence for the contribution of spinal Sirt1 to the initiation and maintenance of neuropathic pain. The antinociceptive effects of resveratrol may be mediated through the activation of spinal Sirt1 in CCI rats.


Hair mercury level in smokers and its influence on blood pressure and lipid metabolism.
Smoking is a major risk factor for the development and progression of cardiovascular disease and cigarettes contain a slight amount of mercury. Mercury has been causally linked to cardiovascular diseases. This study evaluated the mercury content in hair according to smoking exposure status and the influence of the mercury level on blood pressure and lipid metabolism. We examined mercury concentration in the hair samples from 236 healthy people 16-75-years-of-age who had visited the health promotion center of a university hospital from January 2004 to January 2007. Self-reported cigarette smoking status and baseline health information were obtained using a questionnaire. Blood pressure and serum lipid level according to the mercury concentration were assessed. The mean systolic blood pressure in the smoking exposure group and non-exposure group were 123.2±15.4mmHg and 117.2±15.9mmHg, respectively (p=0.005). The mean diastolic pressure in the smoking exposure group and non-exposed group were 80.2±10.9mmHg and 75.1±11.3mmHg, respectively (p<0.001). Mercury concentration had a positive relationship with systolic and diastolic blood pressure. Compared with the normal and high mercury groups, the normal mercury group demonstrated lower blood pressure, lower triglyceride, and lower smoking amount, but higher high density lipoprotein cholesterol than the high mercury group. There was an increase of mercury concentration in the smoking exposure group. The 20-29 packyear group showed significantly increased odds ratio of mercury content, compared with the non-exposure group (14.00, 95% confidence interval, 5.03-38.96). Smoking is positively associated with mercury accumulation, and high mercury concentration is associated with increased blood pressure and abnormal lipid metabolism.


Viability maintenance of mammary epithelial cells in vitro.
Mammary epithelial cells were isolated from mice lactating for 6 to 10 days and incubated in plastic culture dishes for 10 days. Viability of the cells was tested daily for 8 different treatment regimens including control (Minimum Essential Medium and antibiotics). Tested in cultures were horse serum, a collagen gel matrix, the lactogenic hormones prolactin, insulin, cortisol and all combinations of the above. Effectiveness of treatment was compared each day using the Duncan's New Multiple Range Test (DNMRT) and over the entire 10 day experimental period using regression analysis. After 1 day the collagen gel matrix was the most effective treatment followed by lactogenic hormones and horse serum. On days 2, 4 and 5, horse serum alone was the best treatment while day 3 demonstrated a slight superiority for hormones only. By day 6, and until day 10, a combination of horse serum and hormones maintained viability most successfully. The second and third most effective treatments during this portion of the experimental period were a combination of all three components and hormones alone, respectively. These data support the concept of complex support for mammary epithelial cell viability by a collagen gel matrix accompanied by three known hormones and unknown factors in horse serum.


Neurotrophins: potential therapeutic tools for the treatment of spinal cord injury.
Spinal cord injury permanently disrupts neuroanatomical circuitry and can result in severe functional deficits. These functional deficits, however, are not immutable and spontaneous recovery occurs in some patients. It is highly likely that this recovery is dependent upon spared tissue and the endogenous plasticity of the central nervous system. Neurotrophic factors are mediators of neuronal plasticity throughout development and into adulthood, affecting proliferation of neuronal precursors, neuronal survival, axonal growth, dendritic arborization and synapse formation. Neurotrophic factors are therefore excellent candidates for enhancing axonal plasticity and regeneration after spinal cord injury. Understanding growth factor effects on axonal growth and utilizing them to alter the intrinsic limitations on regenerative growth will provide potent tools for the development of translational therapeutic interventions for spinal cord injury.


Low-sodium dry-cured rabbit leg: A novel meat product with healthier properties.
Dry-cured rabbit legs were produced with a 50% reduction or replacement of NaCl by KCl and with the addition of monosodium glutamate (MG). The effect of this reformulation on technological, nutritional, and sensory characteristics was evaluated. The sodium reformulation did not show a great impact on Aw, pH, weight loss, and volatile profile of the samples. The samples presented high protein (31.5 to 36.1%) and low fat contents (3.2 to 5.7%). In addition, all essential amino acids presented an amino acid score greater than 1.0. The reformulated samples showed a sodium reduction of 46.2% while the addition of KCl to the formulations provided a healthy Na/K ratio. Oleic acid was the major fatty acid (FA) (31.3% of total FA) and healthy lipid indexes were observed for all samples. Finally, the addition of MG was effective to compensate for the sensory defects caused by sodium reformulation.


Cortical blindness following hypoxia during cardiac arrest.
Two patients with cortical blindness following hypoxic episodes are reported. The characteristics of the syndrome are described. Attention is drawn to the lack of awareness of this complication of hypoxia.


A novel assay to assess the effects of estrogen on the cardiac calmodulin binding equilibrium.
The Ca2+-binding protein calmodulin (CaM) modulates numerous target proteins but is produced insufficiently to bind all of them, generating a limiting CaM equilibrium. Menopause increases cardiac morbidity; however, it is unknown if the cardiac CaM equilibrium is affected by estrogen. We devised an assay to assess the effects of ovariectomy and estrogen treatment on the cardiac CaM equilibrium. Sprague-Dawley rats received sham surgery or ovariectomy, followed by 2-week treatment with vehicle or 17β-estradiol. Ca2+-saturated left ventricular (LV) lysates were processed through CaM sepharose columns, which retained CaM-binding proteins unoccupied by endogenous CaM. Eluants therefrom were subjected to a competitive binding assay against purified CaM and a CaM biosensor to assess the amounts of unoccupied CaM-binding sites. LV cellular composition was assessed by immunohistochemistry. LV eluants processed from sham animals reduce biosensor response by ~32%, indicating baseline presence of unoccupied CaM-binding sites and a limiting CaM equilibrium. Ovariectomy exacerbates the limiting CaM equilibrium, reducing biosensor response by ~65%. 17β-estradiol treatment equalizes the difference between sham and ovariectomized animals. These changes reflect whole tissue responses and are not mirrored by changes in total surface areas of cardiomyocytes and fibroblasts. Consistently, Ca2+-dependent, but not Ca2+-independent, interaction between CaM and the cardiac inositol trisphosphate receptor (IP3R) is reduced following ovariectomy and is restored by subsequent 17β-estradiol treatment. Our assay provides a new parameter to assess tissue CaM equilibrium. The exacerbated limiting CaM equilibrium following estrogen loss may contribute to cardiac morbidity and is prevented by estrogen treatment.


Lesions caused by Africanized honeybee stings in three cattle in Brazil.
We report three cases of stings by Africanized bees in cattle in the state of Rio de Janeiro, Brazil. Erythema, subcutaneous edema, necrosis accompanied by skin detachment, and subsequent skin regeneration were observed, especially on the head and dewlap. Histopathological examinations performed 45 days later revealed complete skin reepithelialization with moderate dermal fibrosis. The clinical picture and differential diagnosis are discussed in the present manuscript, with a focus on photosensitization, which causes cutaneous lesions on the head (sequela) with cicatricial curving of the ears and can be very similar to what is observed in cattle attacked by swarms of bees. The distinction between photosensitization and bee sting lesions can be made with a focus on history and clinical and pathological aspects.


JC Polyomavirus Attachment and Entry: Potential Sites for PML Therapeutics.
JC polyomavirus (JCPyV) is a significant human pathogen that causes an asymptomatic infection in the kidney in the majority of the population. In immunosuppressed individuals, the virus can become reactivated and spread to the brain, causing the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). There are currently limited treatment options for this fatal disease. Attachment to receptors and entry into host cells are the initiating events in JCPyV infection and therefore an attractive target for therapeutics to prevent or treat PML. This review provides the current understanding of JCPyV attachment and entry events and the potential therapeutics to target these areas. JCPyV attachment and entry to host cells is mediated by α2,6-linked lactoseries tetrasaccharide c (LSTc) and 5-hydroxytryptamine receptors (5-HT2Rs), respectively, and subsequent trafficking to the endoplasmic reticulum is required for infection. Recently, vaccines, monoclonal antibodies, and small molecules have shown promise as anti-viral and PML therapies. This review summarizes our current understanding of JCPyV attachment, entry, and trafficking and the development of potential PML therapeutics that inhibit these critical steps in JCPyV infection.


Distribution of 14C after topical application of 14C-labeled 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) in mice.
Following topical application of 14C-labeled 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine) to the skin of mice radioactivity was found in all viscera and tissues examined. Exclusive of the gut, highest values were recorded for the liver, kidney and lung.


Resumption of electrical conduction in previously isolated pulmonary veins: rationale for a different strategy?
Atrial fibrillation (AF) may recur after pulmonary vein isolation (PVI) as the result of either recurrent PV conduction or non-PV foci. This study characterized the electrophysiological findings of patients with recurrent AF after initially successful PVI and the clinical outcome after a repeat procedure. Among 185 patients undergoing PVI, 52 reported no significant improvement in their clinical course. We analyzed PV conduction in 51 PVs (15 patients) at repeat PVI. All PVs were isolated with either RF (30 W, 50 degrees C, 60 seconds) or cryoablation (-80 degrees C for 5 minutes). At repeat study, 42 of the previously isolated 51 PVs had return of conduction. All patients had recurrent conduction in > or =2 PVs, with only 1 non-PV focus identified. The mean number of RF applications required to re-isolate the PVs was fewer at the repeat compared with the initial procedure (10+/-6 versus 4+/-2, P<0.005). Over a period of 15+/-6 months, all but 1 patient was clinically improved by the second procedure. In patients with recurrent AF after PVI, return of PV conduction can be expected. Repeat PVI provides significant clinical benefit for these patients. These results suggest that if permanent PV isolation is the ablation strategy, different techniques may be required to improve long-term efficacy.


Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead.
In order to expedite the availability of drugs to treat cancers in a cost-effective manner, repurposing of old drugs for oncological indications is gathering momentum. Revolutionary advances in pharmacology and genomics have demonstrated many old drugs to have activity at novel antioncogenic pharmacological targets. We decided to investigate whether prospective studies support the promises of nonclinical and retrospective clinical studies on repurposing three old drugs, namely metformin, valproate and astemizole. We conducted an extensive literature search through PubMed to gather representative nonclinical and retrospective clinical studies that investigated the potential repurposing of these three drugs for oncological indications. We then searched for prospective studies aimed at confirming the promises of retrospective data. While evidence from nonclinical and retrospective clinical studies with these drugs appears highly promising, large scale prospective studies are either lacking or have failed to substantiate this promise. We provide a brief discussion of some of the challenges in repurposing. Principal challenges and obstacles relate to heterogeneity of cancers studied without considering their molecular signatures, trials with small sample size and short duration, failure consider issues of ethnicity of study population and effective antioncogenic doses of the drug studied. Well-designed prospective studies demonstrating efficacy are required for repurposing old drugs for oncology indications, just as they are for new chemical entities for any indication. Early and ongoing interactions with regulatory authorities are invaluable. We outline a tentative framework for a structured approach to repurposing old drugs for novel indications in oncology.


Estimation of Chinese hamster ovary cell density in packed-bed bioreactor by lactate production rate.
A method is described for estimating recombinant Chinese hamster ovary (rCHO) cell density in a packed-bed bioreactor by lactate production rate. The lactate production rate, which depended on both the cell numbers and cell growth rate, was modeled by segregating the cell population into two parts: one growing at a maximum specific growth rate and another non-growing. The individual cell in each part had the same lactate production rate. The established rate equation of lactate production matched the experimental data reasonably well and could be used to estimate the cell growth in the batch culture with microcarriers. Furthermore, in the perfusion culture of rCHO cells in a packed-bed bioreactor, the final cell density, 1.3 x 10(10) cells l(-1), estimated by lactate production rate, was comparable to the direct sample counting of 1.2 x 10(10) cells l(-1), showing that lactate production rate method would be useful in tracing the cell growth in packed-bed bioreactors.


Development of statistical learning ability across modalities, domains, and languages.
Statistical learning (SL) is defined as our ability to use statistics (e.g., frequencies or transitional probabilities) to detect implicit regularities in the environment. Limited research has examined the developmental trajectory of SL across domains and modalities, and no previous research has made systematic comparisons across domains, modalities, and languages using comparable tasks. The current study investigated the development of SL ability across 9-, 11-, and 13-year-old native Chinese-speaking children in non-linguistic visual and auditory SL, first-language Chinese visual and auditory SL, and second-language English visual and auditory SL. Results showed that children across the three age groups achieved all types of SL, and they performed better in visual modality than in auditory modality. Furthermore, while visual SL constantly improved from 9- to 11- to 13-year-olds, auditory SL improved only from 11- to 13-year-olds but not from 9- to 11-year-olds, which could be explained by the discrepancy in developmental trajectory between auditory language and working memory. This pattern of age and modality interaction was similar across non-linguistic Chinese and English SL. A significant interaction between modality and language type also showed that better learning was achieved in visual SL as compared with auditory SL in both non-linguistic and English stimuli. However, children performed similarly across the two modalities in Chinese, possibly due to the contribution of tonal information. Together, our findings point to the joint function of age, modality, and language type in SL development.


The efficacy of glatiramer acetate in beta-interferon-intolerant MS patients.
Glatiramer acetate (GA) is routinely used in multiple sclerosis (MS) patients who cannot tolerate or fail to respond to beta-interferon (IFN-beta). The aim of this study was to assess the efficacy and tolerability of GA in these patients. Fifteen relapsing-remitting MS patients who had discontinued IFN-beta therapy due to side effects were included in this open, 1-year prospective study. Neurologic examinations and laboratory assessments were performed every 3 months. The induction of MxA protein production was also evaluated. Eleven of fifteen patients (73%) tolerated GA well whereas four patients (27%) discontinued treatment due to side effects. The relapse rate reduced from 1.86 per year to 0.91 per year. Neither laboratory abnormalities nor MxA protein induction was found. GA can be considered as a good treatment alternative to IFN-beta-intolerant MS patients. However, some patients were not able to use available immunomodulative treatments, which emphasizes the need for new therapeutic options. The lack of MxA protein induction confirms the different mechanisms of action of GA and IFN-beta.


From mango by-product to food packaging: Pectin-phenolic antioxidant films from mango peels.
The objective of the study was to prepare active films based on pectin and polyphenol-rich extracts from Tommy Atkins mango peels. Aqueous and methanolic extracts showed a variety of phenolic compounds that were identified by UPLC-MS analysis, and a high content of total phenolics that were quantified by the Folin-Ciocalteau method. The methanolic extract showed better results in antioxidant tests and was more effective in inhibiting the growth of Gram-positive and Gram-negative bacteria. The pectin extracted from mango peels showed good thermal stability and a degree of methoxylation of 58.3% by 1H NMR. The films containing the phenolic extracts showed lower water vapor permeability when compared to the control film (without any phenolic extracts). The incorporation of the extracts led to an increase in elongation (ε) and a decrease in tensile strength (σ) and modulus of elasticity (Y). The films with aqueous or methanolic extracts showed higher antioxidant activity in terms of inhibition of the DPPH radical. Therefore, the films developed in this work are presented as a promising alternative for food packaging and/or coating applications.


The obstructed kidney: correlation between renal function and urodynamic assessment.
In 20 patients with pelvi-ureteric junction obstruction the results of quantification of the change in renal pelvis size during high-dose intravenous urography with a diuretic, pressure/flow studies, standard renography and deconvolution analysis of the gamma camera renogram have been compared. The results of high-dose intravenous urography and pressure/flow studies correlated well. Renography was unreliable in diagnosing obstruction unless deconvolution analysis of the gamma camera renogram was used to differentiate those showing an obstructive uropathy from those with an obstructing nephropathy.


Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers.
The oral hypoglycaemic drug nateglinide is eliminated from the human body via hepatic biotransformation and renal tubular secretion. According to in vitro data, about 70% of nateglinide intrinsic clearance may be mediated by cytochrome P450 (CYP) 2C9 and a smaller fraction by CYP3A4 and CYP2D6. To assess the impact of CYP2C9 polymorphisms and of the CYP2D6 poor metaboliser genotype on the pharmacokinetics of nateglinide and its effects on insulin, glucose and glucagon in plasma. A prospective clinical study in 26 healthy volunteers chosen for their CYP2C9 and CYP2D6 genotype was conducted with individuals carrying wild-type genotype as reference group. Serial plasma nateglinide, glucose, insulin and glucagon concentrations were measured over 34 hours after a 180 mg dose of nateglinide under challenge with 75 g of oral glucose at 0, 4 and 8 hours after nateglinide intake. Kinetics were evaluated by nonparametric methods and by population pharmacokinetic-pharmacodynamic modelling. Significantly reduced oral nateglinide clearance was found in carriers of CYP2C9*3 alleles, (p < 0.01), whereas carriers of CYP2C9*2 alleles had kinetic parameters similar to those of carriers of the wild-type allele (p = nonsignificant). Median total clearances were 7.9, 8.4, 6.5, 6.9, 5.8 and 4.1 L/h in carriers of the CYP2C9 genotypes *1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3. Median clearance in three carriers of two deficient CYP2D6 alleles was 9.4 L/h. These differences in nateglinide kinetics due to CYP2C9 genotypes did not result in statistically significant differences in plasma glucose, insulin and glucagon. Pharmacokinetic-pharmacodynamic modelling revealed a minor effect of CYP2C9 genotype on insulin and glucose, and extrapolations indicated that carriers of the CYP2C9*3/*3 genotype may be at a slightly higher risk of hypoglycaemia compared with carriers of CYP2C9*1, particularly when taking nateglinide doses above 120 mg. The effect of CYP2C9 polymorphisms on nateglinide kinetics may cause a slightly increased risk for hypoglycaemia, which may become relevant in diabetic patients.


Demonstration of tissue-specific antigens shared by normal pancreas and pancreatic neoplasms.
Xenoantiserum raised against extracts of normal hamster pancreas, after absorption with normal tissues, reacted specifically with normal hamster and human pancreas by immunodiffusion. Absorbed antiserum also reacted with hamster and human pancreatic carcinoma but not with other neoplasms. Immunization of hamsters with normal pancreas extracts prevented growth of transplantable pancreatic carcinomas.


Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Asymptomatic Infections in 2 Large Academic Health Systems in Wisconsin.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) asymptomatic infections may play a critical role in disease transmission. We aim to determine the prevalence of asymptomatic SARS-CoV-2 infection at 2 hospital systems in 2 counties in Wisconsin. The SARS-CoV-2 prevalence was 1% or lower at both systems despite the higher incidence of coronavirus disease 2019 (COVID-19) in Milwaukee County.


Role of Microenvironment in Resistance to Therapy in AML.
As part of the dynamic interactions between leukemic cells and cells of the bone marrow microenvironment, specific niches provide a sanctuary where subpopulations of leukemic cells evade chemotherapy-induced death and acquire a drug-resistant phenotype. This review focuses on the cellular and molecular biology of the leukemia stem cell (LSC) niche and of microenvironment/leukemia interactions. Key emerging therapeutic targets include chemokine receptors, adhesion molecules, the sympathetic nervous system, and hypoxia-related proteins, as well as the genetic and epigenetic abnormalities of the leukemia-associated stroma. The complex interplay between LSCs and microenvironment components provides a rationale for appropriately tailored molecular therapies designed to improve outcomes in leukemia. Further understanding of the contribution of the bone marrow niche to the process of leukemogenesis may provide new targets that allow destruction of LSCs without adversely affecting normal stem cell self-renewal.


[Oncorna-like virus particles in the cochlear spiral ganglion of guinea pigs (author's transl)].
Virus particles in spiral ganglion cells of the guinea pig have been grouped with herpes viruses. The purpose of this study was to evaluate this classification of the viruses and their influence on cell morphology. 20 healthy, adult guinea pigs from different breeds were studied. The spiral ganglion was serially sectioned and examined electron micoscopically. All examined spiral ganglions of several guinea pig populations from different breeds showed intracytoplasmic viruses in some granular spiral ganglion cells. According to their localization and morphology we classify these viruses with the oncorna virus group. This is not in agreement with the classification of other authors. Apparently there is a world-wide latent viral infection in guinea pigs. The accumulation of lysosomal-like vacuoles in vicinity to the viruses indicates an increased local lysosomal activity of the infected ganglion cells. Considering the otherwise normal ultrastructure of the infected cells an additional influence of these viruses on the intracellular metabolism can neither be demonstrated nor denied.


The ptotic tongue-imaging appearance and pathology localization along the course of the hypoglossal nerve.
CT and MRI findings of tongue ptosis and atrophy should alert radiologists to potential pathology along the course of the hypoglossal nerve (cranial nerve XII), a purely motor cranial nerve which supplies the intrinsic and extrinsic muscles of the tongue. While relatively specific for hypoglossal nerve pathology, these findings do not accurately localize the site or cause of denervation. A detailed understanding of the anatomic extent of the nerve, which crosses multiple anatomic spaces, is essential to identify possible underlying pathology, which ranges from benign postoperative changes to life-threatening medical emergencies. This review will describe key imaging findings of tongue denervation, segmental anatomy of the hypoglossal nerve, imaging optimization, and comprehensive imaging examples of diverse pathology which may affect the hypoglossal nerve. Armed with this knowledge, radiologists will increase their sensitivity for detection of pathology and provide clinically relevant differential diagnoses when faced with findings of tongue ptosis and denervation.


Goitrogens and thyroid follicular cell neoplasia: evidence for a threshold process.
Thyroid neoplasia can result from many different causes. These include low iodine diets, subtotal thyroidectomy, radioactive iodine, natural goitrogens such as rape seed and cabbage, chemotherapeutic agents such as sulfathiazole, and pesticides such as amitrole. All of these appear to act through either direct or indirect interference with thyroid hormone synthesis. Decreased circulating levels of thyroid hormones in the blood result in increased release of thyroid-stimulating hormone by the anterior pituitary gland. This, in turn, results in hypertrophy and hyperplasia of the thyroid without a corresponding increase in blood thyroid hormone levels. Hyperplasia of the pituitary is also observed due to increased functional demand for continued production of thyroid-stimulating hormone. After prolonged stimulation of the pituitary/thyroid axis, hyperplasia may progress to neoplasia. Cessation of exposure prior to the induction of neoplasia results in a return to the normal state. It is clear that some degree of thyroid inhibition can be accommodated within the bounds of the normal feedback mechanism without the induction of either hyperplasia or neoplasia. A threshold for thyroid follicular neoplasia is therefore indicated.


Application of the positive matrix factorization approach to identify heavy metal sources in sediments. A case study on the Mexican Pacific Coast.
During the last two decades, sediments collected in different sources of water bodies of the Tehuantepec Basin, located in the southeast of the Mexican Pacific Coast, showed that concentrations of heavy metals may pose a risk to the environment and human health. The extractable organic matter, geoaccumulation index, and enrichment factors were quantified for arsenic, cadmium, copper, chromium, nickel, lead, vanadium, zinc, and the fine-grained sediment fraction. The non-parametric SiZer method was applied to assess the statistical significance of the reconstructed metal variation along time. This inference method appears to be particularly natural and well suited to temperature and other environmental reconstructions. In this approach, a collection of smooth of the reconstructed metal concentrations is considered simultaneously, and inferences about the significance of the metal trends can be made with respect to time. Hence, the database represents a consolidated set of available and validated water and sediment data of an urban industrialized area, which is very useful as case study site. The positive matrix factorization approach was used in identification and source apportionment of the anthropogenic heavy metals in the sediments. Regionally, metals and organic matter are depleted relative to crustal abundance in a range of 45-55 %, while there is an inorganic enrichment from lithogenous/anthropogenic sources of around 40 %. Only extractable organic matter, Pb, As, and Cd can be related with non-crustal sources, suggesting that additional input cannot be explained by local runoff or erosion processes.


Assessing vascular effects of adding bevacizumab to neoadjuvant chemotherapy in osteosarcoma using DCE-MRI.
The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI. Six DCE-MRI and three (18)F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (K(trans), v(p), and v(e)) were examined for correlation with FDG-PET (SUV(max)) and association with drug exposure, and evaluated with clinical outcome. K(trans) (P=0.041) and v(p) (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72 h. Greater exposure to bevacizumab was correlated with larger decreases in v(p) at day 5 (P=0.04) and week 10 (P=0.02). A lower K(trans) at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034). This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.


Twisted ovarian tumor causing progressive hemothorax: a case report of porous diaphragm syndrome.
Porous diaphragm syndrome is caused by a defect in the diaphragm. The defect may induce pleural effusion in a patient with an ovarian tumor. A 59-year-old Japanese woman with an ovarian tumor and right hemothorax underwent thoracotomy and presented with a fenestra in the right diaphragm through which bloody fluids were flowing from the peritoneal cavity into the pleural space. Following suturing of the fenestra, laparotomy revealed intraabdominal bleeding due to torsion of an ovarian tumor. This is the first report in which the diaphragmatic defect was identified in a patient with an ovarian tumor and hemothorax. Porous diaphragm syndrome may be involved in the pathophysiology of right pleural effusion observed in other medical conditions such as Meigs' syndrome, ovarian hyperstimulated syndrome, and ovarian cancer.


Prostaglandins H1 and H2. Convenient biochemical synthesis and isolation. Further biological and spectroscopic characterization.
An easy biochemical preparation of the prostaglandin endoperoxides, PGH1 and PGH2, is described. Both of the endoperoxides are potent contractors of isolated gerbil colon smooth muscle. Contracture with PGH2 is about equal to that caused by the standard, PGE1, while contracture with PGH1 is about half of that caused by PGE1. PGH1 was found to inhibit platelet aggregation induced by PGH2 and is about 1/10 as potent a stimulator of cAMP accumulation as is PGE1. The mass spectra of the methyl esters of both PGH1 and PGH2 were obtained, as were the infrared spectra of the two compounds. The nuclear magnetic resonance spectrum of PGH2 is characterized by signals at 4.58 delta and 4.47 delta for the C-9 and C-11 protons, respectively.


Corrigendum: Optimization of Genomic Selection to Improve Disease Resistance in Two Marine Fishes, The European Sea Bass (Dicentrarchus labrax) and the Gilthead Sea Bream (Sparus aurata).
[This corrects the article DOI: 10.3389/fgene.2021.665920.].


Thyroid T4 5'-deiodinase activity in normal and abnormal human thyroid glands.
To investigate the activity of the thyroid gland to convert T4 to T3, we measured the activity of thyroid T4 5'-deiodinase in the following human thyroid glands: 9 normal glands, 5 Hashimoto's thyroiditis, 13 follicular adenomas, 11 methimazole (MMI)-treated Graves' disease (GD), 11 propranolol iodide-treated GD, and 8 propylthiouracil (PTU)-treated GD. The enzyme activity was determined by the ability of 100,000 X g pellet of the thyroid homogenate to convert T4 to T3 in vitro. Normal thyroids showed the enzyme activity of 1.59 +/- 0.18 (mean +/- SEM) pmol T3/mg protein/min. Euthyroid Hashimoto's thyroiditis displayed the enzyme activity of 1.01 +/- 0.15 pmol T3/mg protein/min, which was similar to the normal thyroid enzyme activity. The hypothyroid gland of Hashimoto's thyroiditis showed the enzyme activity of 1.8 pmol T3/mg protein/min. Follicular adenomas showed a wide range of enzyme activity with the mean level of 3.24 +/- 0.82 pmol T3/mg protein/min that did not differ significantly from that of the normal thyroids. Interestingly, one adenoma, despite TSH suppression that ordinarily decreases enzyme activity, showed the greatest activity of 11.0 pmol T3/mg protein/min. Graves' thyroids following treatment with MMI, PTU, and propranolol-iodide showed enzyme activities of 4.61 +/- 0.53, 3.95 +/- 0.43, and 3.51 +/- 0.46 pmol T3/mg protein/min, respectively; all these values were greater than that of the normal thyroids (P less than 0.01), but did not differ significantly when compared with each other. In summary, thyroid glands with Hashimoto's thyroiditis had activities of T4 to T3 conversion similar to the normal thyroid glands.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of SOST expression using large minigenes reveals the MEF2C binding site in the evolutionarily conserved region (ECR5) enhancer mediates forskolin, but not 1,25-dihydroxyvitamin D3 or TGFβ1 responsiveness.
Transcribed from the SOST gene, sclerostin is an osteocyte-derived negative regulator of bone formation that inhibits osteoblastogenesis via antagonism of the Wnt pathway. Sclerostin is a promising therapeutic target for low bone mass diseases and neutralizing antibody therapies that target sclerostin are in development. Diverse stimuli regulate SOST including the vitamin D hormone, forskolin (Fsk), bone morphogenic protein 2 (BMP-2), oncostatin M (OSM), dexamethasone (Dex), and transforming growth factor (TGFβ1). To explore the mechanisms by which these compounds regulate SOST expression, we examined their ability to regulate a SOST reporter minigene containing the entire SOST locus including the downstream regionor mutant minigenes containing a deletion of the -1kb to -2kb promoter proximal region (-1kb), ECR2, ECR5, or two point mutations in the MEF2 binding site of ECR5 (ECR5/MEF2). Previous reports suggest that both the PTH and TGFβ1 effects on SOST are mediated through ECR5 and that the action of PTH is mediated specifically via the MEF2 binding site at ECR5. Consistent with these reports, the suppressive effects of Fsk were abrogated following both ECR5 deletion and ECR5/MEF2 mutation. In contrast, we found that TGFβ1 negatively regulated SOST and that neither ECR5 nor ECR5/MEF2 was involved. Surprisingly, none of these four deletions/mutations abrogated the suppressive effects of the vitamin D hormone, OSM, Dex, or TGFβ1, or the positive effects of BMP-2. These data suggest that we need to move beyond ECR5 to understand SOST regulation.


Evaluation of CD4+CD25+FOXP3+ regulatory T cells function in patients with common variable immunodeficiency.
Common variable immunodeficiency (CVID) is one of the predominant antibody disorders where abnormalities in regulatory T cells (Tregs) may result in autoimmunity and chronic inflammation. To evaluate Tegs frequency and function, 13 CVID patients and 10 age- and sex-matched healthy volunteer were enrolled. The percentages of Tregs were calculated using flow cytomety method. For assessment of Treg function, Tregs were isolated and their suppressive functions were determined using Tregs suppression assay. The levels of immunoregulatory cytokines IL-10 and TGF-β produced by Tregs were also measured. Our results revealed that Tregs frequency (P<0.001) and their suppressive functions (P<0.001) were impaired in CVID patients. The level of TGF-β did not differ between CVID patients and controls (p=0.09); while the amount of IL-10 was remarkably decreased in CVID patients (P=0.007). Our findings suggest that disturbed Tregs frequency and their functional characteristics might account for aberrant immune responses observed in CVID patients.


Early macular ganglion cell-inner plexiform layer analysis in non-arteritic anterior ischemic optic neuropathy.
To investigate the potential usefulness of early macular ganglion cell-inner plexiform layer (mGCIPL) measurement for detecting retinal ganglion cell damage in eyes with non-arteritic anterior ischemic optic neuropathy (NAION). Thirteen patients with NAION were examined within 1 month of visual disturbance onset and underwent spectral domain optical coherence tomography (SD-OCT) measurement of the mGCIPL and peripapillary retinal nerve fiber layer (pRNFL). Complete ophthalmologic evaluations, including visual acuity and visual field (VF) test, were performed. The time to minimum and average mGCIPL and pRNFL thinning were investigated. The correlation between the area of mGCIPL thinning and the affected VF area was also analyzed. Thirteen eyes of 13 patients with NAION were included. The length of time from visual disturbance onset to minimum and average mGCIPL thinning was 32.5 ± 12.1 days and 46.1 ± 23.2 days, respectively, and the time to pRNFL thinning was 79.2 ± 19.7 days. There was a significant regional correlation between the area of mGCIPL loss and that of the VF defect in the early phase (r = 0.610; p = 0.027). However, the area of mGCIPL thinning in the late phase did not correlate with that of late VF defects. In the early phase, mGCIPL thinning was observed, and the area of mGCIPL thinning correlated with that of the VF defect in eyes with NAION. Therefore, early retinal ganglion cell damage and dysfunction may be detected in NAION by measurement of mGCIPL using SD-OCT.


Stratified patient-centered care in type 2 diabetes: a cluster-randomized, controlled clinical trial of effectiveness and cost-effectiveness.
Diabetes treatment should be effective and cost-effective. HbA1c-associated complications are costly. Would patient-centered care be more (cost-) effective if it was targeted to patients within specific HbA1c ranges? This prospective, cluster-randomized, controlled trial involved 13 hospitals (clusters) in the Netherlands and 506 patients with type 2 diabetes randomized to patient-centered (n=237) or usual care (controls) (n=269). Primary outcomes were change in HbA1c and quality-adjusted life years (QALYs); costs and incremental costs (USD) after 1 year were secondary outcomes. We applied nonparametric bootstrapping and probabilistic modeling over a lifetime using a validated Dutch model. The baseline HbA1c strata were <7.0% (53 mmol/mol), 7.0-8.5%, and >8.5% (69 mmol/mol). Patient-centered care was most effective and cost-effective in those with baseline HbA1c>8.5% (69 mmol/mol). After 1 year, the HbA1c reduction was 0.83% (95% CI 0.81-0.84%) (6.7 mmol/mol [6.5-6.8]), and the incremental cost-effectiveness ratio (ICER) was 261 USD (235-288) per QALY. Over a lifetime, 0.54 QALYs (0.30-0.78) were gained at a cost of 3,482 USD (2,706-4,258); ICER 6,443 USD/QALY (3,199-9,686). For baseline HbA1c 7.0-8.5% (53-69 mmol/mol), 0.24 QALY (0.07-0.41) was gained at a cost of 4,731 USD (4,259-5,205); ICER 20,086 USD (5,979-34,193). Care was not cost-effective for patients at a baseline HbA1c<7.0% (53 mmol/mol). Patient-centered care is more valuable when targeted to patients with HbA1c>8.5% (69 mmol/mol), confirming clinical intuition. The findings support treatment in those with baseline HbA1c 7-8.5% (53-69 mmol/mol) and demonstrate little to no benefit among those with HbA1c<7% (53 mmol/mol). Further studies should assess different HbA1c strata and additional risk profiles to account for heterogeneity among patients.


[Accompanying the search for origins, a legislated but complex and delicate task].
For a long time, France has allowed women to ask for the secrecy of their identity during childbirth, but this can generate questions in the child who has become an adult. The legislator therefore intervened in 2002 so that women who prefer to give birth secretly can benefit from specific support and are invited to leave information about their identity if they wish.


Emergence of coronavirus disease 2019 (COVID-19) in Austria.
This is a report on the first identified cases of coronavirus disease 2019 (COVID-19) in Austria. The first documented case was a person who stayed in Kühtai, Tyrol, from 24 to 26 January 2020, and had been infected by a Chinese instructor in Starnberg (Germany) between 20 and 22 January. This counts as a German case since her diagnosis was eventually made in Munich (Germany) on 28 January. On 25 February, two cases imported from Italy were diagnosed in Innsbruck but again no secondary cases were identified in Austria. The first three infections of Austrian inhabitants were detected on 27 February in Vienna. The two resulting clusters finally included 6 (source of initial infection unknown) and 61 cases. Most likely, Italy was the source of the latter cluster. On 12 March the first fatal case of COVID-19 in Austria was reported, a 69-year-old Viennese who died in a Vienna hospital after returning from a cruise ship tour in Italy. On 6 March three autochthonously acquired cases were reported in the Tyrol, all related to the ski resort Ischgl. Of the first 14 Islandic COVID-19 cases infected in Ischgl, 11 had already returned to Iceland on 29 February. We consider that the incriminated barkeeper, who tested PCR positive on 7 March, was neither the primary case nor a superspreader. In our opinion, undetected transmission of SARS-CoV‑2 had been ongoing in Ischgl prior to the first laboratory confirmed cases. Our data also underline that the introduction of SARS-CoV‑2 into Austria was not one single event.


Collagen deposition in a non-fibrotic lung granuloma model after nitric oxide inhibition.
Recent studies support the concept that pulmonary granulomatous inflammation directed by interferon (IFN)-gamma, interleukin (IL)-12, and nitric oxide usually resolves in the absence of fibrosis. To determine whether nitric oxide participates in modulating the fibrotic response during the development of pulmonary granulomas in response to purified protein derivative (PPD), mice presensitized to PPD received daily intraperitoneal injections of N(G)-nitro-D-arginine-methyl ester (D-NAME), N(G)-nitro-L-arginine-methyl ester (L-NAME), or aminoguanidine after delivery of PPD-coated beads to the lungs. Eight days later, morphometric analysis of lung granulomas revealed that L-NAME-treated mice when challenged with PPD in vitro for 36 hours had the largest pulmonary granulomas and the greatest collagen deposition among the treated groups. In addition, equivalent numbers of dispersed lung cells from L-NAME- and aminoguanidine-treated mice produced significantly higher levels of IL-4, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1alpha and significantly lower levels of eotaxin compared with D-NAME-treated mice. Cultures of dispersed lung cells from L-NAME-treated mice also produced significantly more IL-10 and less IL-12 compared with similar numbers of dispersed lung cells from D-NAME-treated mice. Cultures of isolated lung fibroblasts from L-NAME-treated mice expressed higher levels of C-C chemokine receptor 2 (CCR2) and CCR3 mRNA and contained less MCP-1 and eotaxin protein than a similar number of fibroblasts from D-NAME-treated mice. Thus, nitric oxide appears to regulate the deposition of extracellular matrix in lung granulomas through the modulation of the cytokine and chemokine profile of these lesions. Alterations in the cytokine, chemokine, and procollagen profile of this lesion may be a direct effect of nitric oxide on the pulmonary fibroblast and provide an important signal for regulating fibroblast activity during the evolution of chronic lung disease.


[Application of microsurgical technique to hepatic artery reconstruction in liver transplantation].
To explore the value of the microsurgical technique in the reconstruction of hepatic artery. From September 2000 to June 2001, we performed liver transplantation for 11 patients including living related liver transplantation (4) and 7 orthotopic liver transplantation (7). Arterial reconstruction was performed under an operating microscope. No patients developed hepatic arterial thrombosis and serious complication, nor death for multiple organ failure. Microsurgical technique in reconstruction of the hepatic artery can improve surgical outcome, not only in orthotopic liver transplantation but also in living related liver transplantation.


Splenic extramedullary hematopoietic proliferation in Philadelphia chromosome-negative myeloproliferative neoplasms: heterogeneous morphology and cytological composition.
We studied 24 spleens with extramedullary hematopoietic proliferation (EMHP), a key feature of advanced-stage Philadelphia chromosome-negative myeloproliferative neoplasms, obtained from 24 patients (14 primary myelofibrosis, 7 polycythemia vera and 3 unclassifiable). Hematoxylin and eosin, reticulin and trichrome stains, and immunohistochemical stains for myeloperoxidase, glycophorin-C, CD42b, CD34, CD117, CD8, nerve growth factor receptor and smooth muscle actin were evaluated. Clinical information was correlated with the morphological findings. Three distinct histological patterns of EMHP were recognized: diffuse (12), nodular (5), and mixed-nodular and diffuse (7). The preponderant lineage was granulocytic in diffuse, trilineage in nodular and erythroid in mixed EMHP. Erythropoiesis was largely intravascular, granulopoiesis was within the splenic cords and megakaryopoiesis was observed in both locations. The stromal changes paralleled the histological pattern with preservation of the splenic stromal and vascular architecture in the diffuse areas as opposed to areas of nodular EMHP. The morphological features of the splenic EMHP did not correlate with specific subtypes of myeloproliferative neoplasms. The mean duration of follow-up from initial diagnosis was 80 months. A total of 15 of the 24 patients died of disease: 8 of 12 (67%) with diffuse, 2 of 5 (40%) with nodular and 5 of 7 (71%) with mixed growth patterns. The mean duration from diagnosis to splenectomy was shorter in patients with diffuse (83 months) as compared with those with nodular EMHP (127 months). Our study demonstrates that splenic extramedullary hematopoietic proliferation in Philadelphia chromosome-negative myeloproliferative neoplasms shows distinct histological patterns that do not correlate with disease subtypes, but appear to suggest a trend between the histological patterns and clinical behavior. These results suggest a different biology of the disease in the nodular and diffuse extramedullary hematopoietic proliferation groups.


Regional myocyte hypertrophy and increased interstitial myocardial fibrosis in hypertrophic cardiomyopathy.
The purpose of this study was to determine if the thickened cardiac walls of patients with hypertrophic cardiomyopathy (HC) are due to increased size or number of myocytes or increased amounts of fibrous tissue. Eight patients, aged 18 to 42 years, who died from complications of HC and 8 age-matched control subjects without heart disease were studied. A 1.5-cm3 block of tissue was removed from the left ventricular free wall, right ventricular free wall and ventricular septum (VS). Each region of each wall was evaluated for fibrous tissue by point counting; cell diameter was measured using an ocular micrometer disc. Cell layers were counted across the walls. The results revealed that increased cell size, cell layers and fibrous tissue are characteristic of HC, but only in the VS are all 3 significantly increased. The fibrous tissue was most extensive in the VS (19 +/- 9%), but it was more extensive than in the control subjects in all 3 walls. Cell diameters were largest in the layers closest to the left ventricular cavity.


[Detection of gas embolism in neurosurgery by capnography. Apropos of 32 patients surgically treated in seated position].
Hitherto dreaded and dreadful, air embolism has since the past few years a better prognosis owing to new techniques of early detection. The present study concerns a series of 32 neurosurgical patients who were operated in the sitting position under continuous capnography. This method not only provides global monitoring (metabolic, haemodynamic and respiratory) but also allows early detection of any significant migration of air or gas into the blood vessels. The incidence of air embolism in this series was 31% (10 patients out of 32). The onset of air embolism was diagnosed on a rapidly progressive fall in the expired fraction of CO2 (FECO2), in spite of a normal blood pressure. Early treatment prevented further complications. Therefore capnography is a sensitive and reliable method of air embolism detection intraoperatively. Its use in the operating room and intensive care unit should be systematic whenever air embolism may occur.


Quail Rathke's pouch differentiation an electron microscopic study.
Adenohypophyseal region of quail embryo has been examined by electron microscopy from stage 12 to stage 21 of Zacchei (1961). The Seessel's pouch develops prior to the early stages of adenohypophysis formation, then regresses while Rathke's pouch proliferates and differentiates. From Rathke's pouch formation by stage 12 (48 h of incubation) until appearance of the first secretory granules by stage 21 (6 days of incubation), there are no major ultrastructural modifications in adenohypophyseal cells. Mitochondria, Golgi vesicles, polysomic ribosomes, pinocytotic vesicles, and mitotic figures become more numerous while nucleocytoplasmic ratio and the number of ribosomes and lipid droplets decreases. The major change is the appearance of secretory granules by day 6 of incubation. This phenomenon occurs at the same time as in chick embryo, despite an incubation period shorter for quail than for chick. Mitotic figures are mainly distributed near the pouch lumen, while secretory granules are first located in the peripheral cells of the cephalic part of pars distalis primordium. The hypothetical role of mesenchyme and vascularization is discussed.


Identification of the influenza virus transcriptase by affinity-labeling with pyridoxal 5'-phosphate.
Pyridoxal 5'-phosphate (PLP), a reversible inhibitor of in vitro transcription by fowl plaque virus, has been used to identify the transcriptase. Kinetic analyses showed that PLP competitively inhibits the addition of each nucleoside triphosphate in ApG-primed reactions, suggesting that both initiation and elongation are affected. The irreversible inhibition by PLP following reduction with borohydride was prevented by preincubation with the first substrate: GTP in unprimed reactions or CTP in the presence of ApG. On reaction of FPV proteins with PLP and [3H]borohydride the core protein PB1 was preferentially labeled and the labeling was selectively blocked by GTP or ApG + CTP. These data suggest that PB1 has the nucleotide-binding site of the transcriptase, is responsible for both initiation and elongation, and is apparently associated with the 3' ends of template RNAs in virions.