Alleviating Promotion of Inflammation and Cancer Induced by Nonsteroidal Anti-Inflammatory Drugs.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including aspirin are of intensive use nowadays. These drugs exert their activity via the metabolism of arachidonic acid (AA) by cyclooxygenase inhibition. Though beneficial for health in some instances, both unspecific and specific cyclooxygenase inhibitor activity interfere with AA metabolism producing also proinflammatory lipids that may promote cancer. This review is based on available literature on clinical uses, biochemical investigations, molecular medicine, pharmacology, toxicity, and epidemiology-clinical studies on NSAIDs and other drugs that may be used accordingly, which was collected from electronic (SciFinder, Medline, Science Direct, and ACS among others) and library searches of books and journals. Relevant literature supports the notion that NDSAID use may also promote proinflammatory biochemical events that are also related to precancerous predisposition. Several agents are proposed that may be employed in immediate future to supplement and optimize treatment with NSAIDs. In this way serious side effects arising from promotion of inflammation and cancer, especially in chronic NSAID users and high risk groups of patients, could be avoided.


Avenzoar's (1091-1162) clinical description of cancer.
In the 11(th) and 12(th) century the Western caliphate flourished, making Cordoba the capital of physicians and philosophers. During that period lived and practised the famous physician Ibn Zuhr or Avenzoar. In his monumental treatise Al Taysir, Avenzoar provided the first clinical description of a polypoid colorectal tumour as well as the case of a uterine cancer and a basal cell carcinoma. His medical work remained popular through middle ages, influencing the development of western medicine.


Correcting a metacognitive error: feedback increases retention of low-confidence correct responses.
Previous studies investigating posttest feedback have generally conceptualized feedback as a method for correcting erroneous responses, giving virtually no consideration to how feedback might promote learning of correct responses. Here, the authors show that when correct responses are made with low confidence, feedback serves to correct this initial metacognitive error, enhancing retention of low-confidence correct responses. In 2 experiments, subjects took an initial multiple-choice test on general knowledge facts and made a confidence judgment after each response. Feedback was provided for half of the questions, and retention was assessed by a final cued-recall test. Taking the initial test improved retention relative to not testing, and feedback further enhanced performance. Consistent with prior research, feedback improved retention by allowing subjects to correct initially erroneous responses. Of more importance, feedback also doubled the retention of correct low-confidence responses, relative to providing no feedback. The function of feedback is to correct both memory errors and metacognitive errors.


Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing.
Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.


The pharmacology of atracurium: a new competitive neuromuscular blocking agent.
Atracurium besylate, 2,2'-(3,11-dioxo-4,10-dioxatridecylene)-bis-[6,7-dimethoxy-1-(3,4-dimethoxy-benzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate, is one of a new series of competitive neuromuscular blocking agents. An i.v. dose of 0.25 mg kg-1 produced complete paralysis in anaesthetized cats, dogs and rhesus monkeys; paralysis was of medium duration and was readily antagonized by neostigmine. Vagal blockade occurred only after doses 8--16 times greater than the full neuromuscular paralysing dose and effects on sympathetic mechanisms were minimal. Hypotension and bradycardia were evident after supramaximal doses of 4 mg kg-1 i.v. and these effects, together with circulatory depression, were probably attributable to histamine release. In vitro studies have shown that the non-enzymic decomposition of atracurium by "Hofmann Elimination" was enhanced by increasing pH. In vivo neuromuscular paralysis was significantly reduced when the arterial pH was increased. There were indications that neither the liver nor the kidney plays a major role in the metabolism and elimination of unchanged drug. These results are of sufficient interest to merit the evaluation of atracurium in anaesthetized man.


Considerations for the aesthetic restoration of endodontically treated anterior teeth following intracoronal bleaching.
The major considerations in restoring the pulp chamber following bleaching of endodontically treated anterior teeth include aesthetics, function, appropriate endodontic access preparation, amount of remaining tooth structure, type of restorative material, prevention of microleakage, and prevention of iatrogenic perforation. The learning objective of this article is to review the considerations that must be made when placing aesthetic restorations in the pulp chamber and access opening of endodontically treated teeth following intracoronal bleaching. The advantages and disadvantages of the proposed techniques and materials are discussed, as are the methods for avoiding excessive removal of the tooth structure. Two case reports are used to demonstrate the clinical procedures. The authors suggest placing white gutta-percha stopping material in the pulp chamber and a composite restoration in the access opening following root canal treatment and/or bleaching procedures in the anterior dentition.


Magnetic control of electrocatalytic and bioelectrocatalytic processes.
Bioelectronics is a rapidly progressing interdisciplinary research field that has important implications for the development of biosensors, biofuel cells, biomaterial-based computers, and bioelectronic devices. Magneto-controlled molecular electronics and bioelectronics are new topics that examine the effect of an external magnetic field on electrocatalytic and bioelectrocatalytic processes of functionalized magnetic particles associated with electrodes. In this article we describe the progress in the developments of magneto-switchable electrocatalytic and bioelectrocatalytic transformations, and the effects of the rotation of the magnetic particles on the electrocatalytic and bioelectrocatalytic processes are discussed. Finally, the implications of the results on the development of biosensors, amplified immunosensors, and DNA sensors are described.


Clinical considerations in the early treatment of invasive mould infections and disease.
Different therapeutic strategies for invasive fungal diseases have been explored, each with particular strengths and weaknesses. Broad-spectrum antifungal prophylaxis seems logical, but selective use is important due to its substantial disadvantages, including interference with diagnostic assays, selection for resistance, drug toxicity and drug-drug interactions. Antimould prophylaxis should be restricted to high-risk groups, such as patients undergoing intensive chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome, allogeneic HSCT patients with prior invasive fungal infection, graft-versus-host-disease or extended neutropenia, recipients of a solid organ transplant, or patients with a high-risk inherited immunodeficiency. An empirical approach, whereby mould-active therapy is started in neutropenic patients with fever unresponsive to broad-spectrum antibiotics, is widely applied but incurs the clinical and cost penalties associated with overtreatment. A benefit for all-cause mortality using empirical therapy has not been shown, but it is recommended for high-risk patients who remain febrile after 4-7 days of broad-spectrum antibiotics and in whom extended neutropenia is anticipated. There is growing interest in delaying antifungal treatment until an invasive fungal infection is confirmed ('pre-emptive' or 'diagnostics-driven' management), prompted by the development of more sensitive diagnostic techniques. Comparisons of empirical versus pre-emptive regimens are sparse, particularly with modern triazole agents, but treatment costs are lower with pre-emptive therapy and the available evidence has not indicated reduced efficacy. Pre-emptive treatment may be appropriate in neutropenic patients who remain febrile after administration of broad-spectrum antibiotics but who are clinically stable. Further work is required to define accurately the specific patient subgroups in which each management approach is optimal.


The Long-Term Effect of Radical Prostatectomy on Erectile Function, Urinary Continence, and Lower Urinary Tract Symptoms: A Comparison to Age-Matched Healthy Controls.
Introduction. To analyze the impact of radical prostatectomy (RPE) on erectile function and lower urinary tract function in comparison to age-matched healthy men. Materials and Methods. Patients who underwent radical retropubic prostatectomy completed questionnaires containing the IIEF-5, the Bristol female LUTS questionnaire, and the International Prostate Symptom Score (IPSS). Results. Patients after RPE were included (n = 363). Age-matched healthy men (n = 363) were included. The mean IIEF-5 of patients aged 61-70 yrs after RPE was 10.4 ± 6.6 versus 18.8 ± 5.3 in the control cohort; the respective values for men aged 71-80 yrs after RPE were 7.2 ± 6.5 versus 13.6 ± 7.7 in the control cohort. Urinary incontinence after RPE was reported in 41.9% (61-70 years) and 37.7% (71-80) versus 7.5% and 15.1% in the control cohort. The mean IPSS of patients after RPE aged 61-70 yrs was 5.0 ± 4.4 versus 5.5 ± 4.9 in the control cohort; the respective values for men aged 71-80 yrs were 6.0 ± 4.9 versus 7.5 ± 5.7 in the healthy cohort. Conclusions. The negative effect of radical prostatectomy on erectile and urinary incontinence remains substantial. The physiologically declining erectile and lower urinary tract function with ageing reduces the difference between healthy men and those after surgery. Healthy men have a higher IPSS presumably due to the presence of bladder outlet obstruction.


Areca nut extract protects against ovariectomy-induced osteoporosis in mice.
Estrogen deficiency increases the generation of reactive oxygen species (ROS), which is a crucial pathogenic factor for osteoporosis. Areca nuts are rich in phenolics, which have high antioxidant activity. In the present study, an ovariectomy (OVX)-induced osteoporosis mouse model was used to investigate the protective effects of areca nut extract (ANE) on bone loss and related processes. A total of 24 8-week-old female mice were randomly divided into three groups (n=8 per group): I Sham-operated control; II, bilateral OVX; and III, bilateral OVX + ANE. Group III were treated orally with ANE at a single dose of 300 mg/kg body weight daily for 6 months. ANE supplementation for 6 months improved trabecular bone microarchitecture and significantly increased bone mineral density in the distal femur (P<0.05) compared with Group II. Furthermore, serum levels of the osteoclast differentiation-inducing factors, receptor activator of nuclear factor-κB ligand and osteoprotegerin were significantly increased and decreased, respectively (both P<0.05), in OVX mice and these effects were significantly inhibited by ANE treatment (both P<0.05). ANE supplementation also resulted in significantly decreased serum hydrogen peroxide and malondialdehyde levels compared with Group II, while the levels of glutathione and catalase activity were significantly increased (P<0.05 and P<0.01, respectively). The current study indicated that the protective effects of ANE against bone loss were mediated, at least in part, via inhibition of the release of ROS and bone resorption. These results suggested that ANE could have therapeutic value in the treatment of osteoporosis.


Examination of the protective roles of helmet/faceshield and directionality for human head under blast waves.
A parametric study was conducted to delineate the efficacy of personal protective equipment (PPE), such as ballistic faceshields and advanced combat helmets, in the case of a blast. The propagations of blast waves and their interactions with an unprotected head, a helmeted one, and a fully protected finite element head model (FEHM) were modeled. The biomechanical parameters of the brain were recorded when the FEHM was exposed to shockwaves from the front, back, top, and bottom. The directional dependent tissue response of the brain and the variable efficiency of PPE with respect to the blast orientation were two major results of this study.


Activity-regulated cytoskeleton-associated protein Arc is targeted to dendrites and coexpressed with mu-opioid receptors in postnatal rat caudate-putamen nucleus.
Dendritic expression of the activity-regulated cytoskeleton-associated protein (Arc) is dramatically enhanced by increased synaptic activity in adult brain. We used immunocytochemical electron microscopy to determine whether the subcellular localization of Arc in developing dendrites corresponds to the peak period of synaptogenesis in the postnatal rat caudate-putamen nucleus (CPN). The distribution was compared with that of mu-opioid receptors (MORs), whose localization in dendritic spines closely parallels excitatory synapse formation during postnatal development (Wang et al. [2003] Neuroscience 118:695-708). Sections were processed for immunocytochemical detection of antisera against Arc or MORs at the beginning (postnatal day 15; P15) and the end (P30) of the peak period of synaptogenesis in rat CPN. At P15, immunolabeling for Arc showed a punctate distribution in the cytoplasm of dendritic shafts, some of which was associated with polyribosomes. In some spiny dendrites, Arc immunoreactivity was more intensely localized in putative spines than in their parental dendrites, whereas, in other spiny dendrites, Arc labeling was restricted in the shafts. Many dendritic shafts and spines also showed immunoreactivity for MORs, although dually labeled spines were less numerous than the shafts. At P30, the proportion of singly and dually labeled spines significantly increased from 2.0% to 7.5% and from 9.5% to 21%, respectively. Arc labeling in spines was more detectable beneath the postsynaptic density or at extrasynaptic sites on the plasma membrane. Our results suggest a correlation between Arc expression in dendritic spines during postnatal development and the onset of synaptogenesis in opioid-responsive neurons in the rat CPN.


Study on defect imaging technology of optical elements based on micro-Raman spectroscopy.
An optical element defect detection imaging method based on micro-Raman spectroscopy is proposed to achieve high-precision imaging of optical element defects and their distribution. The detection precision of the system is immediately reflected in the imaging quality. The sharpness value of the mapping images is calculated using the Sum of Modulus of Gray Difference function. The selection of the Raman peak is an important step, and when a borosilicate glass sample with standard defects is measured for verification, it is found that the Raman peak light intensity changes at -37 and 28 cm-1. When these two peaks were used for 2D mapping, obvious defect contours can be obtained, while the light intensity at other sites could not be used for imaging, and remained essentially constant. Through the detection of laser burning defects, new peaks appear at the burned defect location that could be used for imaging, and the burning defect area can be clearly distinguished from the non-burning area. By changing the laser burning conditions, the Raman shift changes, which verifies that there is a certain correlation between the laser burning degree and the Raman shift, which also provides a basis for 2D mapping imaging of defect detection.


Long-term observation of porous sapphire dental implants.
We used porous sapphire dental implants made of alumina clinically for 4 years 1 month, commencing September, 1984 until September, 1988. Subjects consisted of 18 men and 42 women 20-71 years old (mean age: 35 years). Sixty-five implants were inserted in 60 patients. Of these, 20 were clinical cases of an implant connected with natural teeth and 45 were free-standing cases. We conducted a follow-up study on these patients over a 23-year period. One implant in 1 patient had to be removed because of postoperative infection and 8 implants in 7 patients had to be removed because of fracturing or detachment of the porous-part. This paper reports 3 cases where implants remained in place for 21-23 years. These cases have all shown good long-term clinical progress.


Protective Effect of N-Acetylcysteine against Oxidative Stress Induced by Zearalenone via Mitochondrial Apoptosis Pathway in SIEC02 Cells.
Zearalenone (ZEN), a nonsteroidal estrogen mycotoxin, is widely found in feed and foodstuffs. Intestinal cells may become the primary target of toxin attack after ingesting food containing ZEN. Porcine small intestinal epithelial (SIEC02) cells were selected to assess the effect of ZEN exposure on the intestine. Cells were exposed to ZEN (20 µg/mL) or pretreated with (81, 162, and 324 µg/mL) N-acetylcysteine (NAC) prior to ZEN treatment. Results indicated that the activities of glutathione peroxidase (Gpx) and glutathione reductase (GR) were reduced by ZEN, which induced reactive oxygen species (ROS) and malondialdehyde (MDA) production. Moreover, these activities increased apoptosis and mitochondrial membrane potential (ΔΨm), and regulated the messenger RNA (mRNA) expression of Bax, Bcl-2, caspase-3, caspase-9, and cytochrome c (cyto c). Additionally, NAC pretreatment reduced the oxidative damage and inhibited the apoptosis induced by ZEN. It can be concluded that ZEN-induced oxidative stress and damage may further induce mitochondrial apoptosis, and pretreatment of NAC can degrade this damage to some extent.


Current concepts in the treatment of bacterial meningitis beyond the neonatal period.
The epidemiology and treatment approach to bacterial meningitis has changed dramatically since the advent of antimicrobial therapy. New vaccines against meningeal pathogens have been implemented into national immunization programs successfully around the world. Antibiotic resistance has had a considerable impact on the efficacy of several therapeutic agents. In this review, the authors will discuss the principles of antibiotic chemotherapy, focusing on new agents for the treatment of penicillin-resistant pneumococci and adjunctive treatments to reduce the inflammatory response to bacterial infection of the meninges.


Fetal cerebral and umbilical Doppler in pregnancies complicated by late-onset placental abruption.
To evaluate whether changes in the cerebroplacental Doppler and birth weight (BW) suggestive of chronic fetal hypoxemia, precede the development of late-onset placental abruption (PA) after 32 weeks. In a multicenter retrospective study, the Doppler examinations of the fetal umbilical artery (UA) and middle cerebral artery (MCA) recorded after 32 weeks were collected in pregnancies subsequently developing PA. The BW centiles were calculated and the MCA pulsatility indices (PI), and UA PI were converted into multiples of the median (MoM). Afterwards, a comparison was made with a group of fetuses, which did not develop PA. Logistic regression was used to adjust for potential confounders and evaluate the feasibility of the prediction model. Pregnancies complicated by late-onset PA (n = 31) presented lower MCA PI (p = 0.015) and were smaller (p < 0.001) than those who did not (n = 1294). Logistic regression analysis indicated that cerebral vasodilation was more important than umbilical flow in the explanation of PA (MCA PI OR = 0.106, p = 0.014 and UA PI OR 1.901, p = 0.32). In addition, the influence of BW exerted was residual (BW centile OR = 0.989, p = 0.15). Fetuses developing late-onset PA demonstrate significant cerebral vasodilation with scarce placental dysfunction, suggesting the existence of some kind of chronic hypoxemia that follows the late-onset pattern.


Organelle Dynamics in Apicomplexan Parasites.
Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum, are the cause of many important human and animal diseases. While T. gondii tachyzoites replicate through endodyogeny, during which two daughter cells are formed within the parental cell, P. falciparum replicates through schizogony, where up to 32 parasites are formed in a single infected red blood cell and even thousands of daughter cells during mosquito- or liver-stage development. These processes require a tightly orchestrated division and distribution over the daughter parasites of one-per-cell organelles such as the mitochondrion and apicoplast. Although proper organelle segregation is highly essential, the molecular mechanism and the key proteins involved remain largely unknown. In this review, we describe organelle dynamics during cell division in T. gondii and P. falciparum, summarize the current understanding of the molecular mechanisms underlying organelle fission in these parasites, and introduce candidate fission proteins.


On the origins of the Mendelian laws.
The two laws usually attributed to Mendel were not considered as laws by him. The first law, the law of independent segregation occurs in Mendel's paper as an assumption or hypothesis. Hugo de Vries refers to this as a law discovered by Mendel. This appears to be the first use of an expression equivalent to Mendel's law. In his paper de Vries did not associate the observable characters with structures having a causitive role. That was done by Correns, who transformed the law of segregation of characters into a law of the segregation of anlagen. The second law, the law of independent assortment, is present in embryonic form in Mendel's paper. Here the independent assortment of characters appears as a secondary conclusion to a series of experiments involving several pairs of traits. Mendel repeats the primary conclusion later in the paper but not the secondary one. This leads us to believe that he considered the secondary conclusion as of lesser importance. We note in this context that the 9:3:3:1 ratio commonly associated with the idea of independent assortment, and attributed to Mendel, also does not occur in his paper. A careful reading of the papers of his discoverers shows it was Correns who first drew attention to this ratio. However, he did not formulate the second Mendelian law even though it was clearly implied. Neither was it stated by de Vries. Indeed, the first clear separation of the two laws and the naming of the second law was by T. H. Morgan some 13 years later.


[Radiotherapy of brain tumors in childhood].
External radiotherapy with high energy photons in children's brain tumors improves results of surgical treatment according to their histology. Radiotherapy treatment is a decisive factor in survival time and quality of life. Undifferentiated tumors with high radiosensitivity are treated when radiotherapy is the only means for recovery; tumors presenting histologically low malignancy in which effective radiotherapy treatment is uncertain and the risk of radiotherapy damage is the predominant factor. Radiotherapists who treat children's brains which in many cases are not yet totally myelinized , must have good technical ability. Literature and personal experience show that in medulloblastomas irradiation of the entire central nervous system associated with chemotherapy gives a survival time of 5 years in 50% of the cases; in glioblastomas and anaplastic astrocytomas, fortunately rare in children, results are poor; in brainstem tumors the association of the extracranial shunt to radiotherapy has improved results of survival time at 5 years to 50%. A good quality of life is frequent and radiological effects are rare. It is clear that radiotherapy has reached its maximum. Progress is still to be made thanks to discoveries of more effective radiosensitizer or radioprotector compounds.


Innovation flows at Friville facility.
The key steps that can be taken to minimise the risk of harmful waterborne bacteria such as Legionella and Pseudomonas proliferating widely through water systems in healthcare premises were discussed in detail during a recent two-day event staged by Delabie, one of Europe's leading water control and sanitary equipment suppliers, at the company's Friville headquarters in Picardy, northern France. As HEJ editor, Jonathan Baillie, reports, the event, held in an impressive training centre close to a sizeable factory that exports products ranging from antibacterial taps and showers to grab rails to over 70 countries worldwide, also provided the opportunity for sharing of expertise and experience between the host personnel and a group of 17 public health engineers from throughout England and Scotland, who attended as guests.


A microRNA-initiated DNAzyme motor operating in living cells.
Synthetic DNA motors have great potential to mimic natural protein motors in cells but the operation of synthetic DNA motors in living cells remains challenging and has not been demonstrated. Here we report a DNAzyme motor that operates in living cells in response to a specific intracellular target. The whole motor system is constructed on a 20 nm gold nanoparticle (AuNP) decorated with hundreds of substrate strands serving as DNA tracks and dozens of DNAzyme molecules each silenced by a locking strand. Intracellular interaction of a target molecule with the motor system initiates the autonomous walking of the motor on the AuNP. An example DNAzyme motor responsive to a specific microRNA enables amplified detection of the specific microRNA in individual cancer cells. Activated by specific intracellular targets, these self-powered DNAzyme motors will have diverse applications in the control and modulation of biological functions.


Identification of the ferroptosis regulator HELLS with prognostic value for adrenocortical carcinoma based on integrated analysis and experimental validation.
For adrenocortical carcinoma (ACC), a rare endocrine malignancy with a high rate of mortality and recurrence, it is difficult for clinicians to predict overall survival and select the most effective treatment. Targeting ferroptosis, a form of cell death, has been reported to be a promising therapeutic strategy for ACC; however, the core ferroptosis regulator and its prognostic value in ACC remain unknown. RNA sequencing data and clinical information were downloaded from public databases. Differentially expressed gene and survival analyses were performed to identify candidate ferroptosis regulators. A multivariate Cox regression model was used to construct a gene signature, and a nomogram was constructed to predict the overall survival of patients with ACC. Gene set variation analysis (GSVA) was used to identify underlying aberrant pathways and the relative immune cell infiltration levels of each ACC sample. Immunohistochemistry staining was performed in formalin-fixed paraffin-embedded tumor tissue sections. Ultimately, 23 differentially expressed ferroptosis regulators were identified between normal adrenal gland and ACC tissues, and 50 ferroptosis regulators were related to prognosis, with 13 ferroptosis regulators being simultaneously found to satisfy the differential expression and prognostic value. According to the multivariate Cox regression model, a ferroptosis regulator signature was constructed from 3 genes in The Cancer Genome Atlas (TCGA; hazard ratio =9.01; P=1.39×10-10), and the area under the curve (AUC) values of 3-, 5-, 8-year overall survival were 0.924, 0.906, and 0.866, respectively. The survival analysis and the receiver operating characteristic (ROC) analysis validated the prognostic value of the ferroptosis regulator signature in 3 validation datasets. Moreover, metabolism-, E2F-, MYC-, and G2/M checkpoint-related pathways and aberrant immune cell infiltration levels were identified as being responsible for the different prognosis of risk groups in ACC. HELLS was found to be a significantly differentially expressed ferroptosis-suppressor gene with a prognostic value in ACC and to be highly associated with immune cell infiltration levels and multiple biological functions. A ferroptosis regulator signature showed promising power for predicting the prognosis of ACC, and HELLS was identified as a hub ferroptosis regulator in the initiation and progression of ACC.


Relationship between low-frequency aircraft noise and annoyance due to rattle and vibration.
A near-replication of a study of the annoyance of rattle and vibration attributable to aircraft noise [Fidell et al., J. Acoust. Soc. Am. 106, 1408-1415 (1999)] was conducted in the vicinity of Minneapolis-St. Paul International Airport (MSP). The findings of the current study were similar to those reported earlier with respect to the types of objects cited as sources of rattle in homes, frequencies of notice of rattle, and the prevalence of annoyance due to aircraft noise-induced rattle. A reliably lower prevalence rate of annoyance (but not of complaints) with rattle and vibration was noted among respondents living in homes that had been treated to achieve a 5-dB improvement in A-weighted noise reduction than among respondents living in untreated homes. This difference is not due to any substantive increase in low-frequency noise reduction of acoustically treated homes, but may be associated with installation of nonrattling windows. Common interpretations of the prevalence of a consequential degree of annoyance attributable to low-frequency aircraft noise may be developed from the combined results of the present and prior studies.


Unsuspected Active Ulcerative Colitis in a Patient With Dermatomyositis: A Rare Association Detected on 18F-FDG PET/CT During the Search for an Occult Malignancy.
Dermatomyositis is an inflammatory myopathy with the characteristic features of skin rash and myopathy. We here present a known case of dermatomyositis evaluated with 18F-FDG PET/CT for the presence of any occult malignancy. The scan was negative for the presence of any malignancy. However, it revealed multiple intensely FDG avid colonic strictures that were later proven on colonoscopic biopsy to be ulcerative colitis. Also, a well-known association of bilateral sacroilitis was simultaneously demonstrated on the scan. The present case demonstrates that 18F-FDG PET/CT imaging can serve as a one-stop shop imaging modality in dermatomyositis by facilitating detection of occult primary if any and by providing insight into other rare systemic associations.


Chemical cross-linking and mass spectrometry as structure determination tools.
Chemical cross-linking is becoming a valuable tool for the high-order structure determination of proteins and protein complexes. Cross-linking methodology is able to provide low-resolution structures when at least something is known already about the proteins under investigation. The suitability of top-down and bottom-up methodologies is discussed and further potential applications of chemical cross-linking of proteins, as well as combinations with other techniques such as hydrogen/deuterium exchange and molecular modeling, are suggested.


Amikacin therapy for severe gram-negative sepsis. Emphasis on infections with gentamicin-resistant organisms.
Amikacin (BB-K8) is a semisynthetic derivative of kanamycin which is active in vitro against many gentamicin-resistant Gram-negative bacilli. Twenty-three patients with 25 serious Gram-negative infections were treated with this new aminoglycoside. Twelve infections involved organisms that were resistant to gentamicin. Twenty patients satisfied the criteria for bacteriological and clinical cure. This included 11 of the 12 infections involving gentamicin-resistant Gram-negative bacilli. In 4 urinary tract infections there was a good clinical response, but routine follow-up urine cultures at 30 days were positive. One patient failed on amikacin therapy. Eighth nerve toxicity was detected in two patients. These results indicate that amikacin is effective in the treatment of serious Gram-negative infections and is particularly useful in those involving resistant organisms. Further studies are indicated to evaluate ototoxic potential.


Risk of MS relapse after yellow fever vaccination: A self-controlled case series.
To determine whether live-attenuated yellow fever vaccine (YFV) was associated with MS relapse, we evaluated the clinical courses of 23 patients in the year before and the year after immunization at the university hospital of Geneva, Switzerland. This self-controlled retrospective cohort included adult patients with MS receiving YFV between 2014 and 2018 and defined the year before vaccination, the 3 months thereafter, and the 9 months following as the pre-exposure (PEP), exposure-risk (ERP), and postrisk (PRP) periods, respectively. The primary outcome was the relative incidence of relapse in the ERP vs the PEP. Secondary end points included the presence of new T2-weighted (T2) or T1-weighted gadolinium-positive (T1Gd+) MRI lesions. Of 23 patients with MS receiving YFV (20 relapsing MS and 3 primary progressive MS), 17 (74%) were women; mean age was 34 years (SD ±10); and 10 of 23 (40%) were treated with disease-modifying therapies (DMTs). Although 9 patients experienced 12 relapses in the PEP, only one experienced a relapse in the ERP; 3 other patients experienced one relapse each in the PRP. None of the 8 patients receiving natalizumab at the time of vaccination experienced relapse thereafter. In the PEP, ERP, and PRP, 18, 2, and 9 patients had new brain and/or spinal cord lesions on T2 or T1Gd + MRI, respectively. In this cohort, YF vaccination was associated with neither an increase in MS relapse nor emergence of brain and/or spinal lesions. Further studies are warranted to confirm these findings. This study provides Class IV evidence that for persons with MS, YFV may not increase relapse risk.


Effect of maternal antibody on the infant immune response to inactivated poliovirus vaccines made from Sabin strains.
This study aimed to evaluate the effect of maternally derived antibody on the immunogenicity of Sabin IPV. A total of 600 infants were randomized to receive one of the five different vaccines: the high- (group A), medium- (group B) or low-dose (group C) of investigational Sabin IPV, the control Salk IPV (group D) or the control Sabin IPV (group E), at 2, 3 and 4 months of age. The post-vaccination GMTs, GMIs and seroconversion rates of poliovirus type-specific neutralizing antibody were analyzed for different maternal antibody levels. The correlations between maternal antibody levels and post-vaccination antibody responses were also modeled by linear regressions. The post-vaccination GMTs were significantly lower among infants with high maternal antibody titers for poliovirus type 1 or 2 mainly in the groups B, C, D and E. The GMIs and seroconversion rates decreased significantly with the increase of maternal antibody levels in all the five groups. In the groups A, B and C, maternal antibody levels were negatively associated with the post-vaccination antibody titers (for poliovirus type 1 and 2) and the fold increases of post-vaccination antibody (for all the 3 poliovirus types). With the reduce of potency of the investigational Sabin IPVs, the linear regression coefficients increased accordingly in the groups A, B and C. In conclusion, high levels of maternal poliovirus antibody could attenuate the immune responses to the Sabin IPVs. Altering the potency of the investigational Sabin IPVs could alter the associations between maternal antibody levels and the serologic responses of infants.


Mechanism-Driven Elaboration of an Enantioselective Bromocyclopropanation Reaction of Allylic Alcohols.
A stereoselective bromocyclopropanation of allylic alcohols using dibromomethylzinc bromide is described. Spectroscopic studies to monitor the formation of transient intermediates not only led to the development of a more-atom-economical halocyclopropanation reaction, but also highlighted the unique role of ether additives in the process. The desired bromo-substituted cyclopropanes were isolated in high yields and excellent diastereo- as well as enantioselectivities using readily available reagents.


Cloning of human erythroid dematin reveals another member of the villin family.
Dematin is an actin-bundling protein originally identified in the human erythroid membrane skeleton. Its actin-bundling activity is abolished upon phosphorylation by the cAMP-dependent protein kinase and is restored after dephosphorylation. Here we report the complete primary structure of human erythroid dematin, whose sequence includes a homologue of the "headpiece" sequence found at the C terminus of villin. This headpiece is essential for villin function in inducing microvillar development and actin redistribution. The widespread expression of dematin transcripts in human tissues suggests that dematin and its homologues may substitute for villin in villin-negative tissues to regulate actin reorganization by a phosphorylation-regulated mechanism.


Contamination assessment of mercury, lead, cadmium and arsenic in surface sediments of Chabahar Bay.
This study aimed to investigate heavy metals content of mercury (Hg), lead (Pb), cadmium (Cd) and arsenic (As) in surface sediments of Chabahar Bay. Sediment samples were taken from 13 stations and then analyzed. The concentration of Hg, Pb, Cd and As ranged between 0.06 and 0.14ppm, 8 and 23ppm, 0.05 and 0.9ppm and 5 and 22ppm, respectively. Arsenic content was more than ERL at some stations. Statistical analyses indicated critical importance of organic matter and mud in metal dispersion. Also, positive correlation of Al with Pb, Hg and Cd probably implies their terrestrial origination. Average enrichment factor of Hg, Pb, Cd and As were 2.67±0.95, 0.77±0.28, 6.56±9.9, and 7.53±3.44, respectively. Most stations were classified as moderately polluted and non-polluted sites.


Electronic health records: turning research into decision support for quality care.
Much has been written and discussed about low clinical and decision-support tools can help providers deliver quality care to their patients. But there are theories--and then there are realities--about what will actually work in the real world and how useful they will be. When incorporating decision-support tools into electronic health records, the results may not always be predictable.


Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3.
Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases (RTKs) regulate a variety of dynamic cellular events, including cell protrusion, migration, proliferation, and cell-fate determination. Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the physiological and pathological roles of Eph. However, there is a lack of small-molecule inhibitors that are selective for individual Eph isoforms due to the high homology within the family. Herein, we report the development of the first potent and specific inhibitors of a single Eph isoform, EphB3. Through structural bioinformatic analysis, we identified a cysteine in the hinge region of the EphB3 kinase domain, a feature that is not shared with any other human kinases. We synthesized and characterized a series of electrophilic quinazolines to target this unique, reactive feature in EphB3. Some of the electrophilic quinazolines selectively and potently inhibited EphB3 both in vitro and in cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed the covalent linkage between the protein and the inhibitors. A "clickable" version of an optimized inhibitor was created and employed to verify specific target engagement in the whole proteome and to probe the extent and kinetics of target engagement of existing EphB3 inhibitors. Furthermore, we demonstrate that the autophosphorylation of EphB3 within the juxtamembrane region occurs in trans using a specific inhibitor. These exquisitely specific inhibitors will facilitate the dissection of EphB3's role in various biological processes and disease contribution.


Utility of the Powerball in the invigoration of the musculature of the forearm.
In order to ascertain the utility of a 250 Hz NSD Powerball gyroscope in increasing the maximum grip force and muscular endurance of the forearm, ten adults without pathology in their upper limbs exercised one forearm with the device during a period of one month. We evaluated grip strength and forearm muscle endurance with a Jamar dynamometer both at the end of the month as well as after a resting period of one month. There was a tendency (not statistically significant p = 0.054), for the volunteers to increase their maximum grip strength. There was also highly significant increase in muscle endurance (p = 0.00001), a gain that remained slightly unchanged after the rest. Because the gyroscope generates random multidirectional forces to the forearm, the reactive muscle contraction is likely to stimulate more efficient neuromuscular contro of the wrist, a conclusion which our work appears to validate. The use of Powerball in forearm proprioception deficient patients is, therefore, justified.


Does skeletal maturity predict sequential contralateral involvement after fixation of slipped capital femoral epiphysis?
The management of the uninvolved hip after fixation of unilateral slipped capital femoral epiphysis (SCFE) remains controversial. The purpose of this study was to determine the relationship of sequential contralateral slip to the initial patient presentation, specifically skeletal maturity. The medical records and radiographs for all patients who underwent fixation of unilateral SCFE between June 1996 and October 2003 were reviewed retrospectively. Data were gathered on age, sex, stability, chronicity, body mass index, modified Oxford bone age (mOBA), physeal slope angle, grade, and contralateral involvement as determined by need for fixation. Seventy-one children underwent fixation of unilateral SCFE. At initial presentation, the triradiate cartilage was open in 43 patients and closed in 28 patients. There was no difference in the rate of contralateral involvement based on any measured parameter. Although not statistically significant, closure of the triradiate cartilage and increased mOBA were associated with lower rates of sequential slip progression. Only 1 patient with a mOBA greater than 22 had contralateral progression. The rate of contralateral slip was 23% when the triradiate cartilage was open. When the triradiate cartilage was closed, 93% demonstrated no sequential contralateral slip. In this series, 23% of patients with open triradiate cartilage went on to contralateral slip, but all sequential slips were classified as mild. No studied variable proved to be a statistically significant predictor in this group of patients, including skeletal maturity. Further study to identify useful predictive factors would be beneficial to these patients, but our results question the need for prophylactic pinning in this population. Level IV.


Semiclassical "Divide-and-Conquer" Method for Spectroscopic Calculations of High Dimensional Molecular Systems.
A new semiclassical "divide-and-conquer" method is presented with the aim of demonstrating that quantum dynamics simulations of high dimensional molecular systems are doable. The method is first tested by calculating the quantum vibrational power spectra of water, methane, and benzene-three molecules of increasing dimensionality for which benchmark quantum results are available-and then applied to C_{60}, a system characterized by 174 vibrational degrees of freedom. Results show that the approach can accurately account for quantum anharmonicities, purely quantum features like overtones, and the removal of degeneracy when the molecular symmetry is broken.


Surface Engineered PLGA Nanoparticle for Threshold Responsive Glucose Monitoring and "Self-Programmed" Insulin Delivery.
We have developed a reversible, biocompatible, "self-programmed" PLGA [poly(lactic-co-glycolic acid)] nanoparticle-based optical biosensor capable of sensing and continuous monitoring of glucose above the physiologically relevant threshold value (100-125 mg/dL) as well as "on-demand" insulin delivery via an "On-Off" technique. We have carefully surface engineered the PLGA nanoparticle using amino dextran-fluorescein (A-DexFl) and amino-phenyl boronic acid (A-PBA) to exploit the binding affinity of boronic acids with that of cis-1,2 diols of dextran/glucose. Initially, the dextran chains wrap the nanoparticle surface due to its high affinity toward A-PBA (Kb = 6.1 × 106 M-1). The close proximity of the fluorophores with that of A-PBA quenches the fluorescence, resulting in an "Off" state. On the addition of glucose, it competes with A-DexFl to bind with A-PBA. Above a certain threshold concentration of glucose, the binding affinity overcomes (Kb = 6.3 × 107 M-1) the dextran-A-PBA binding. This opens-up the wrapped A-DexFl chains from the nanoparticle surface and results in an increased distance between the fluorophore and A-PBA, triggering the "On" state. The activation of the On-Off state can be finely tuned in the desired range of physiologically relevant glucose concentrations by varying the ligand ratios on the PLGA surface. The nanoparticle core has also been used as an insulin reservoir to trigger the drug release in the "On" state. We have obtained ∼53% encapsulation efficiency and ∼20% loading efficiency for insulin loading. Once the glucose concentration falls beyond the detection range, the dextran chains collapse on the nanoparticle surface with a suspension in drug release. The process is solely controlled by the competition and multivalent binding affinity between glucose, A-DexFl, and A-PBA, which allows it to be "self-programmed" and "self-regulated" with continuous monitoring up to 8-10 cycles over a 72 h time period. A sustained drug release has been found with ∼70% of released drug over a period of 72 h, although this release is insignificant in the absence of glucose. Several control experiments have been performed to optimize the sensor design.


Peculiarities of occupational mental health care in kindergarten teachers.
The purpose of this paper is to quantify the factors that disrupt the mental health of kindergarten (KG) teachers. For this, the researchers conducted an electronic survey of preschool teachers (n = 587) on a popular educational platform with the Symptom Checklist-90-R and content analysis of interviews in practicing KG teachers (n = 105) with an open discussion of the main stressors during professional activities. Self-reports indicated that depression, interpersonal sensitivity, and anxiety were the main mental health symptoms. ANOVA has revealed that total teaching experience is a statistically significant factor for the mental health of KG teachers: F(2.60) = 5.99. According to respondents, the main stressors included concern for the children's health, fear of injuries, and difficulties in communicating with parents. The synthesis of results allowed for proposing six specific steps for mental health care in KG teachers. The findings are important for administrators and officials of preschool education. The proposed approach can become a theoretical basis for finding ways of mental health care for practicing teachers in further research.


The primary cilium as sensor of fluid flow: new building blocks to the model. A review in the theme: cell signaling: proteins, pathways and mechanisms.
The primary cilium is an extraordinary organelle. For many years, it had the full attention of only a few dedicated scientists fascinated by its uniqueness. Unexpectedly, after decades of obscurity, it has moved very quickly into the limelight with the increasing evidence of its central role in the many genetic variations that lead to what are now known as ciliopathies. These studies implicated unique biological functions of the primary cilium, which are not completely straightforward. In parallel, and initially completely unrelated to the ciliopathies, the primary cilium was characterized functionally as an organelle that makes cells more susceptible to changes in fluid flow. Thus the primary cilium was suggested to function as a flow-sensing device. This characterization has been substantiated for many epithelial cell types over the years. Nevertheless, part of the central mechanism of signal transduction has not been explained, largely because of the substantial technical challenges of working with this delicate organelle. The current review considers the recent advances that allow us to fill some of the holes in the model of signal transduction in cilium-mediated responses to fluid flow and to pursue the physiological implications of this peculiar organelle.


Non-Edg family LPA receptors: the cutting edge of LPA research.
Lysophosphatidic acid (LPA) is a bioactive lipid mediator with diverse physiological and pathological actions on many types of cells. Originally, LPA was thought to elicit its biological functions through three subtypes of endothelial differentiation gene (Edg) family G protein-coupled receptors (LPA1, LPA2 and LPA3) until our group identified a fourth subtype, LPA4. The discovery of this receptor, which is structurally distinct from the Edg family LPA receptors, led to the identification of two additional LPA receptors, LPA5 and LPA6, homologous to LPA4. These 'non-Edg family' LPA receptors now provide a new framework for understanding the diverse functions of LPA, including vascular development, platelet activation and hair growth. In this review, we summarize the identification, intracellular signalling and biological functions of this novel cluster of LPA receptors.


3D Bioprinting Phototunable Hydrogels to Study Fibroblast Activation.
Phototunable hydrogels can transform spatially and temporally in response to light exposure. Incorporating these types of biomaterials in cell-culture platforms and dynamically triggering changes, such as increasing microenvironmental stiffness, enables researchers to model changes in the extracellular matrix (ECM) that occur during fibrotic disease progression. Herein, a method is presented for 3D bioprinting a phototunable hydrogel biomaterial capable of two sequential polymerization reactions within a gelatin support bath. The technique of Freeform Reversible Embedding of Suspended Hydrogels (FRESH) bioprinting was adapted by adjusting the pH of the support bath to facilitate a Michael addition reaction. First, the bioink containing poly(ethylene glycol)-alpha methacrylate (PEGαMA) was reacted off-stoichiometry with a cell-degradable crosslinker to form soft hydrogels. These soft hydrogels were later exposed to photoinitator and light to induce the homopolymerization of unreacted groups and stiffen the hydrogel. This protocol covers hydrogel synthesis, 3D bioprinting, photostiffening, and endpoint characterizations to assess fibroblast activation within 3D structures. The method presented here enables researchers to 3D bioprint a variety of materials that undergo pH-catalyzed polymerization reactions and could be implemented to engineer various models of tissue homeostasis, disease, and repair.


Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin.
The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.


Compulsive Internet Use Scale for assessment of self-reported problematic internet use in primary school-aged children.
The tremendous growth of internet use during past few decades has been primarily led by young people. Despite a plenitude of studies reporting the pros and cons of excessive internet use by adolescents, the internet use of primary school-aged children is under-researched. First, there is lack of reliable and valid cultural invariant self-report instruments for children younger than 11-years-old. Secondly, there is no consensus on whether primary school-aged children can reliably report on their internet use. This study aimed to examine the psychometric properties of the Compulsive Internet Use Scale (CIUS) as reported by primary school-aged children in three different countries/regions. Paper-pencil format CIUS questionnaires were completed by a total of 691 children aged 8 to 10 years old, 236 of them Latvian, 207 Lithuanian, and 248 Taiwanese, as well as by one of their parents, at two-time points, separated by a one-year interval. The parents also reported on the child's emotional and behavioral difficulties. Confirmatory factor analysis indicated that for the child self-report, a 10-item CIUS showed the best fit and good psychometric properties: solid structural validity; very good internal consistency; appropriate stability and predictive validity after 1 year; as well as sound sensitivity and specificity when compared to the 14-item CIUS parent-report form. Child self-report CIUS ratings correlated with time online reported by the child and parent and with emotional and behavioral problems reported by the parent. This study indicates that children as young as 8-10 years old can reliably and consistently provide valuable information on their problematic use of the internet.


Metabolomic Profiling of 13 Diatom Cultures and Their Adaptation to Nitrate-Limited Growth Conditions.
Diatoms are very efficient in their use of available nutrients. Changes in nutrient availability influence the metabolism and the composition of the cell constituents. Since diatoms are valuable candidates to search for oil producing algae, measurements of diatom-produced compounds can be very useful for biotechnology. In order to explore the diversity of lipophilic compounds produced by diatoms, we describe the results from an analysis of 13 diatom strains. With the help of a lipidomics platform, which combines an UPLC separation with a high resolution/high mass accuracy mass spectrometer, we were able to measure and annotate 142 lipid species. Out of these, 32 were present in all 13 cultures. The annotated lipid features belong to six classes of glycerolipids. The data obtained from the measurements were used to create lipidomic profiles. The metabolomic overview of analysed cultures is amended by the measurement of 96 polar compounds. To further increase the lipid diversity and gain insight into metabolomic adaptation to nitrogen limitation, diatoms were cultured in media with high and low concentrations of nitrate. The growth in nitrogen-deplete or nitrogen-replete conditions affects metabolite accumulation but has no major influence on the species-specific metabolomic profile. Thus, the genetic component is stronger in determining metabolic patterns than nitrogen levels. Therefore, lipid profiling is powerful enough to be used as a molecular fingerprint for diatom cultures. Furthermore, an increase of triacylglycerol (TAG) accumulation was observed in low nitrogen samples, although this trend was not consistent across all 13 diatom strains. Overall, our results expand the current understanding of metabolomics diversity in diatoms and confirm their potential value for producing lipids for either bioenergy or as feed stock.


Does adiposity mediate the relationship between socioeconomic position and non-allergic asthma in childhood?
Despite its high prevalence, early onset and chronic nature, the causes of asthma are not clearly established. The present study examined a plausible but untested relationship in the development of non-allergic asthma; an asthma phenotype closely linked to deprivation and other preventable risk factors. Our aim was to determine the mediating role of adiposity in the relationship between socioeconomic position in infancy and non-allergic asthma emergence in mid-childhood. To estimate the causal indirect effect of adiposity we applied the parametric g-computational procedure to 6203 singleton children from the UK Millennium Cohort Study. Adiposity was measured at age 7 by body mass index, waist circumference and waist circumference-to-height ratio. Children who developed non-allergic asthma between the age of 7 and 14 were compared with children without allergies or allergic asthma at these ages. We found no evidence to suggest that adiposity is a mediator in the relationship between socioeconomic position and the development of non-allergic asthma in mid-childhood. After adjustment for risk factors, the direct effect of socioeconomic position remained; children in the lowest tertile of socioeconomic position had a 43% (OR 1.43, 95% CI 1.38 to 1.49) greater odds of developing non-allergic asthma compared with the highest tertile. Adiposity at age 7 does not mediate the relationship between socioeconomic position and non-allergic asthma. The results suggest that improving socioeconomic conditions and promoting healthy weight are both important in reducing the development of non-allergic asthma in early to mid-childhood.


A Boron Dipyrromethene (BODIPY)-Based Cu(II) -Bipyridine Complex for Highly Selective NO Detection.
A BODIPY-containing Cu(II) -bipyridine complex for the simple selective fluorogenic detection of NO in air and in live cells is reported. The detection mechanism is based on NO-promoted Cu(II) to Cu(I) reduction, followed by demetallation of the complex, which results in the clearly enhanced emission of the boron dipyrromethene (BODIPY) unit.


Development of olmesartan medoxomil lipid-based nanoparticles and nanosuspension: preparation, characterization and comparative pharmacokinetic evaluation.
The aim was to enhance the oral bioavailability of olmesartan medoxomil (OM) by preparing solid lipid nanoparticles (SLNs) and comparing with nanosuspension (OM-NS). OM-SLNs and OM-NS were prepared by known methods. Prepared SLNs were evaluated for physical characters and in vivo pharmacokinetic (PK) performance in rats. OM-NS showed more than four-fold increase in the solubility. During DSC and XRD studies, drug incorporated in SLNs was found to be in amorphous form. The relative bioavailability of OM-SLN and OM-NS was 7.21- and 3.52-fold when compared with that of coarse suspension. Further, OM-SLNs also increased the oral bioavailability by two-fold over that of OM-NS.


Hypereosinophilic Syndrome After Liver Transplantation: A Case Report and a Review of the Literature.
Persistently elevated eosinophil granulocytes in the peripheral blood in children is challenging because of a complex diagnosis especially after solid organ transplantation and can lead to difficulties in finding an underlying causative factor.We report a 12-year-old boy who developed severe hypereosinophilia 11 years after liver transplantation due to biliary atresia. Accompanying symptoms were recurrent fever, fatigue, elevated liver enzymes, abdominal pain, and significant weight loss. After exclusion of secondary causes of eosinophilia, an idiopathic hypereosinophilic syndrome (I-HES) was diagnosed. Treatment with prednisolone resulted in an immediate response with rapid reduction of eosinophils, normalization of liver enzymes, and amelioration of any clinical symptoms. A hypereosinophilic syndrome in patients after liver transplantation is rare, and a broad differential diagnosis has to be considered. Prednisolone may lead to a prompt amelioration of eosinophilia and associated symptoms.


[Traditional experiences and modern cognition on primary processing of traditional Chinese medicinal materials].
Primary processing is important links and closely related to the quality of traditional Chinese medicinal materials. The methods and technologies system of traditional primary processing were derived from the long-term practices and experiences, which is distinctive, colorful and diverse, and scientific, it is not only to cleaning of remove the non-officinal parts, drying for termination the physiological status of organisms, but also to retain the most active substances, decrease the toxic components, and promote the transformation among chemical ingredients through primary processing. So the traditional primary processing endowed with characters, quality, specifications and properties of traditional Chinese medicine, and embodied some important science truth. This paper analyzed the traditional experiences and modern cognition on primary processing of TCM materials based on the changes of chemical compositions and explored the scientific truth. These data may be providing foundation and support for process of normalization and standardization of primary processing of TCM materials.


Application of FAIMS to anabolic androgenic steroids in sport drug testing.
Mass spectrometric identification of anabolic androgenic steroids challenges standard doping-control methods. To reveal a doping offence the presence of prohibited anabolic androgenic steroids at trace levels in the picogram-per-millilitre range must be confirmed as reliable. Human urine samples containing epitrenbolone, metandienone metabolite (17beta -hydroxymethyl-17alpha-methyl-18-norandrost-1,4,13-trien-3-one), stanozolol, 16beta-hydroxystanozolol and 4beta-hydroxystanozolol were analysed using LC-FAIMS-MS/MS. These substances are prohibited in sport according to World Anti-Doping Agency (WADA) regulations. Glucuronides were hydrolysed and prepared by liquid-liquid extraction. Excellent recovery and precision were obtained for all compounds. Linear calibration results for epitrenbolone and metandienone metabolite were obtained and concentration information could be determined in the ranges of reliable response between 750-1200 and 100-600 pg/mL, respectively. Limits of detection were estimated at 25 pg/mL (stanozolol), 50 pg/mL (metandienone metabolite, 16beta-hydroxystanozolol), 100 pg/mL (4beta-hydroxystanozolol) and 500 pg/mL (epitrenbolone). The assay was applied to doping-control samples. For all analytes, LC-FAIMS-MS/MS resulted in excellent interference removal, which effectively extends the post-dose detection time.


Preparation and characterization of a novel pyrrole-benzophenone copolymerized silica nanocomposite as a reagent in a visual immunologic-agglutination test.
Biological sensing is explored through novel stable colloidal dispersions of pyrrole-benzophenone and pyrrole copolymerized silica (PPy-SiO(2)-PPyBPh) nanocomposites, which allow covalent linking of biological molecules through light mediation. The mechanism of nanocomposite attachment to a model protein is studied by gold labeled cholera toxin B (CTB) to enhance the contrast in electron microscopy imaging. The biological test itself is carried out without gold labeling, i.e., using CTB only. The protein is shown to be covalently bound through the benzophenone groups. When the reactive PPy-SiO(2)-PPyBPh-CTB nanocomposite is exposed to specific recognition anti-CTB immunoglobulins, a qualitative visual agglutination assay occurs spontaneously, producing as a positive test, PPy-SiO(2)-PPyBPh-CTB-anti-CTB, in less than 1 h, while the control solution of the PPy-SiO(2)-PPyBPh-CTB alone remained well-dispersed during the same period. These dispersions were characterized by cryogenic transmission microscopy (cryo-TEM), scanning electron microscopy (SEM), FTIR and X-ray photoelectron spectroscopy (XPS).


Academics explore humidity's benefits.
The effects of humidification on hospital superbugs are being explored by some of the UK's top academics, in what Dave Mortimer, national sales manager for Vapac Humidity Control, explains are the UK's first such studies.


[Diagnosis and treatment of myocarditis].
Myocarditis is a focal or diffuse inflammatory process of the myocardium. Along with the deepening of research, there are new technological advances which are useful to the diagnosis and treatment of myocarditis. Cardiovascular magnetic resonance imaging has become a useful noninvasive imaging tool for diagnosis of myocarditis, but does not replace endomyocardial biopsy. The supportive treatment has remained the mainstay of therapy for patients with myocarditis, especially with fulminant myocarditis, including the comprehensive treatment of shock, heart failure, and arrhythmia. Due to the lack of large clinical data, diagnosis and treatment for myocarditis remains to be further explored.


Rare variants of Cutaneous Leishmaniasis: whitlow, paronychia, and sporotrichoid.
Cutaneous Leishmaniasis is endemic in certain areas of Pakistan, with the wet form of the disease being the most prevalent. It has a number of morphological variants, which are dependent on the immune status of the host, the subspecies of the Leishmania, and also, to some extent, on the site of involvement. We describe here a case of Leishmaniasis showing two very rare variants, whitlow and paronychial lesions, occurring concurrently with sporotrichoid spread. The patient responded to intramuscular sodium stibogluconate with resolution of the skin lesions.


Nonintrusive, noncontacting frequency-domain photothermal radiometry and luminescence depth profilometry of carious and artificial subsurface lesions in human teeth.
Nonintrusive, noncontacting frequency-domain photothermal radiometry (FD-PTR or PTR) and frequency-domain luminescence (FD-LUM or LUM) have been used with 659-nm and 830-nm laser sources to detect artificial and natural subsurface defects in human teeth. The major findings of this study are (1) PTR is sensitive to very deep (>5 mm) defects at low modulation frequencies (5 Hz). Both PTR and LUM amplitudes exhibit a peak at tooth thicknesses of ca. 1.4 to 2.7 mm. Furthermore, the LUM amplitude exhibits a small trough at ca. 2.5 to 3.5 mm. (2) PTR is sensitive to various defects such as a deep carious lesion, a demineralized area, an edge, a crack, and a surface stain, while LUM exhibits low sensitivity and spatial resolution. (3) PTR frequency scans over the surface of a fissure into demineralized enamel and dentin show higher amplitude than those for healthy teeth, as well as a pronounced curvature in both the amplitude and phase signal channels. These can be excellent markers for the diagnosis of subsurface carious lesions. (4) PTR amplitude frequency scans over the surface of enamels of variable thickness exhibit strong thickness dependence, thus establishing depth profilometric sensitivity to subsurface interfaces such as the dentin/enamel junction.


A rationale for biopsying embryos reaching the morula stage on Day 6 in women undergoing preimplantation genetic testing for aneuploidy.
Is there a benefit to assessing ploidy in delayed embryos reaching the morula stage on Day 6 of development? Day-6 morulae should be considered for biopsy in women <40 years old undergoing preimplantation genetic testing for aneuploidy (PGT-A) because they are associated with acceptable, albeit reduced, euploidy and implantation rates (IRs). Embryo development and morphology have been shown to correlate with aneuploidy and pregnancy rates. During PGT-A cycles, embryos are biopsied if they reach the blastocyst stage by Day 5 or 6, whereas slow-developing embryos are typically deselected and discarded. Determining the viability of slow-developing embryos is particularly relevant for women undergoing PGT-A who have diminished ovarian reserve and a relatively low blastocyst yield. This is a retrospective cohort study that was performed at an academic medical center. Patients who underwent IVF with PGT-A were reviewed for inclusion. A total of 1615 cycles were reviewed. All cycles which involved a biopsy of a cavitating or compacted morula on Day 6 were included (n = 763). PGT-A was performed using array comparative genomic hybridization. The aneuploidy and implantation of morulae were compared to those of blastocysts originating from the same couples. The study included 763 cycles in which 1260 morulae and 3014 blastocysts were biopsied. Women were divided into four age groups (<35, 35-37, 38-39 and ≥40 years): the prevalence of aneuploidy was consistently lower among blastocysts (40.3, 50.8, 56 and 78.3%, respectively) than among compacted morulae (68.7, 75.5, 88.9 and 98.1%, respectively) and cavitating morulae (57, 66.4, 81 and 91.6%, respectively) throughout the different age groups (P < 0.001). Of note, the majority of compacted morulae (98.1%) and cavitating morulae (91.6%) were aneuploid in women aged ≥40 years. Compacted and cavitating morulae had significantly higher rates of complex aneuploidy, which involves ≥3 chromosomes, compared with blastocysts (P < 0.001). Furthermore, euploid morulae were associated with a significantly lower IR (28.2 versus 54.6%; P = 0.002) and live birth rate (23.1 versus 55.0%; P = 0.001) compared to euploid blastocysts. This study confirms that Day-6 morulae should not be discarded in young women undergoing PGT-A. However, a potential drawback of biopsying embryos at the morula stage is the inability to distinguish between inner cell mass and trophectoderm cell origin. The sample size of euploid morula transfer cycles in this study was limited. Thus, a larger cohort would be beneficial to validate the reassuring live birth and spontaneous abortion rates reported here. Furthermore, the reproducibility of our findings should be determined at different centers. Although Day-6 morulae are associated with higher aneuploidy rates and lower IRs compared to blastocysts, they still yielded successful pregnancies. Therefore, testing Day-6 morulae should be considered, especially for women <40 years old who are undergoing PGT-A with a small cohort of available blastocysts for biopsy. The authors have nothing to disclose. They received no specific funding for this work. N/A.


Effects of exercise training on plasma androgens in men.
An increased risk for coronary artery disease (CAD) is associated with a reduced plasma androgen concentration in men. The purpose of the present study was to determine if plasma testosterone (T), sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS) concentration were altered with an exercise training program which reduced CAD risk. Thirteen men (mean +/- SE, age 47.2 +/- 1.5 yrs) were examined before and after 14 weeks of endurance-oriented physical training (3-4 days/week, 30-45 min/day). There were no changes in basal plasma T, SHBG and DHEAS concentration despite a significant (p < 0.05) increase in insulin sensitivity, plasma HDL cholesterol, and a decrease in plasma triglyceride and adiposity. Exercise training thus appears to reduce CAD risk irrespective of androgen concentration in men.


Infective endocarditis with left to right intracardiac fistula due to Streptococcus anginosus - a rare complication caused by an even rarer bacterium.
Although infective endocarditis (IE) has been described in reports dating from the Renaissance, the diagnosis still challenges and the outcome often surprises. In the course of time, diagnostic criteria have been updated and validated to reduce misdiagnosis. Some risk factors and epidemiology have shown dynamic changes since degenerative valvular disease became more predominant in developed countries, and the mean age of the affected population increased. Despite streptococci have been being well known as etiologic agents, some groups, although rare, have been increasingly reported (e.g., Streptococcus milleri.) Intracardiac complications of IE are common and have a worse prognosis, frequently requiring surgical treatment. We report a case of a middle-aged diabetic man who presented with prolonged fever, weight loss, and ultimately severe dyspnea. IE was diagnosed based on a new valvular regurgitation murmur, a positive blood culture for Streptococcus anginosus, an echocardiographic finding of an aortic valve vegetation, fever, and pulmonary thromboembolism. Despite an appropriate antibiotic regimen, the patient died. Autopsy findings showed vegetation attached to a bicuspid aortic valve with an associated septal abscess and left ventricle and aortic root fistula connecting with the pulmonary artery. A large thrombus was adherent to the pulmonary artery trunk and a pulmonary septic thromboemboli were also identified.


Targeted free energy perturbation.
In this paper generalization of the free energy perturbation identity is derived, and a computational strategy based on this result is presented. A simple example illustrates the efficiency gains that can be achieved with this method.


Cell-cell adhesion interface: rise of the lateral membrane.
The lateral membrane plays an important role in the mechanical stability of epithelial cell sheet in steady state. In addition, the lateral membrane is continuously remodeled during dynamic processes such as cell extrusion, cytokinesis, and intercellular cell movement. In wound healing, the lateral membrane must be built from flat and spread cells that had crawled into the area of the wound. Thus, forming the lateral membrane is a phenomenon that occurs not only in development but also during homeostatic maintenance and regeneration of differentiated epithelial tissues.


Application of frog (Rana tigerina Daudin) skin collagen as a novel substrate in cell culture.
Collagen and collagen-based materials have extensive application in biomedical devices and tissue engineering. The current paper pertains to the application of frog (Rana tigerina Daudin) skin collagen as a novel substrate in cell culture. The study deals with the behavior, morphology, and physiology of keratinocytes and fibroblasts over dry and reconstituted collagen substratum, which are the key cells involved in wound repair. The advantage of using frog skin collagen as a substratum lies in the ease with which the reconstituted gel can be formed. Further, frog skin collagen is highly hydrophilic, which may be attributed to the fact that amphibians, as the first vertebrates connecting water and land, must have evolved certain physiologic specializations. These studies also contribute to the hypothesis that part of the healing efficacy of frog skin may be due to the collagen since proliferation, migration, and differentiation of epithelial cells are prime requisites for a normal healing mechanism.


Sleep in Wilson's disease: a polysomnography-based study.
Wilson's disease (WD) has neuro-anatomical, pathophysiological and neurochemical basis for sleep disturbances. The aim of the study was objective evaluation of the frequency and nature of sleep abnormalities using polysomnography (PSG) in patients with WD. The study included 25 subjects with WD (males, 18; age , 24.4 ± 9.25 years) and 25 healthy controls (all males; age, 33.1 ± 9.7 years). After phenotypic assessment and magnetic resonance imaging (MRI), sleep-related questionnaires were administered, and PSG was performed. Patients had significantly reduced total sleep-time (P=.001), sleep-efficiency (P=.001), percentage of deep sleep (P=.01), and REM-sleep (P=.04) with prolonged sleep-onset latency (P=.05) and latency to stage 2 (P=.02). Subgroup analyses of patients based on demographic and clinical parameters were done. Men had significantly more bradycardia both during awake (P=.002) and sleep (P=.03) states. Younger patients (<20 years) had frequent tachycardia (P=.01), higher Periodic Limb Movement (PLM) Index (P=.01) and lesser REM% sleep (P=.05). Patients on de-coppering therapy had prolonged REM-sleep-onset latency (P=.03) and mixed apnea events (P=.04). The isolated limb movements were more in the severe form of disease (P=.05) and in patients taking anticonvulsants (P=.03). This study, the first of its kind in literature, revealed significant sleep disturbances in patients with Wilson's disease.


Expression of carboxymethylcellulase on the surface of Escherichia coli using Pseudomonas syringae ice nucleation protein.
Ice-nucleation protein (INP), an outer membrane protein from Pseudomonas syringae, is able to catalyze the ice crystal formation of supercooled water. It was exploited for anchoring of Bacillus subtilis carboxymethylcellulase (CMCase) on the surface of Escherichia coli. A surface anchoring vector, pGINP21M, was created that contains the multicloning sites including BamHI, SmaI and EcoRI at the end of the 3' flanking region encoding the C-terminus of INP instead of the stop codon for subcloning the foreign genes. The CMCase gene was in-frame subcloned for making INP-CMCase fusion proteins. The ability of this vector for directing the actual synthesis of INP-CMCase fusion proteins was confirmed by Western blotting analysis. CMCase targeted on the surface of cells was verified by measuring whole cell CMCase activity and ice-nucleation activity. CMCase activity was mainly detected on the cell surface whereas no enzyme activity was detected in the culture supernatant. Ice-nucleation activity was also maintained even if an INP-CMCase hybrid was made. This means that the fusion protein is functionally expressed and has its biological conformation on the surface. INP-CMCase fusion proteins were stable in the stationary phase. INP deleted of the repeating domain, thus producing no ice-nucleation activity, could also direct CMCase on the cell surface. This suggests that it has the secretion and targeting signal to the outer membrane.


It ain't over till it's over: the case for offering relapse-prevention interventions to former smokers.
Most people who attempt to quit tobacco smoking eventually relapse. Although treatment strategies have been developed to prevent smoking relapse, they tend to be available only to the small proportion of smokers who enroll in intensive smoking cessation treatments. It is argued that freestanding relapse-prevention interventions could be offered to persons who recently ceased smoking, whether they used a formal treatment program or quit on their own. A line of research is described demonstrating that a series of relapse-prevention booklets mailed to recent quitters significantly reduces smoking relapse. Moreover, the intervention seems to be highly cost-effective. If disseminated widely, such an approach has the potential to make a significant public health impact.


Anion Exchange Renders Hydrophobic Capsules and Cargoes Water-Soluble.
Control over the solubility properties of container molecules is a central challenge in host-guest chemistry. Herein we present a simple anion-exchange protocol that allows the dissolution in water of various hydrophobic metal-organic container molecules prepared by iron(II)-templated subcomponent self-assembly. Our process involved the exchange of less hydrophilic trifluoromethanesulfonate anions for hydrophilic sulfate; the resulting water-soluble cages could be rendered water-insoluble through reverse anion exchange. Notably, this strategy allowed cargoes within capsules, including polycyclic aromatic compounds and complex organic drugs, to be brought into water. Hydrophobic effects appeared to enhance binding, as many of these cargoes were not bound in non-aqueous media. Studies of the scope of this method revealed that cages containing tetratopic and tritopic ligands were more stable in water, whereas cages with ditopic ligands disassembled.


[Construction and activities of suilysin mutants].
To construct the suilysin mutant without hemolytic activity and evaluate its functions. The proline in 353 site of suilysin was site-directed mutated to alanine, leucine and valine, respectively. The recombinant mutants were renaturated and purified by immobilized metal ion affinity chromatography, and the purified proteins were evaluated in the hemolytic activity and immunogenicity. We obtained three mutants, SLY(P353A), SLY(P353L) and SLY(P353V). The SLY(P353V) mutant had non-hemolytic activity. Western blotting and animal experiments showed that SLY(P353V) mutant still had immunogenicity. Suilysin mutant SLY(P353V) has no hemolytic activity but remains immunogenicity.


Comparison of metronidazole with doxycycline prophylaxis in elective colorectal surgery. A prospective, randomized multicentre study.
In a series of 157 patients undergoing elective colorectal surgery, metronidazole or doxycycline was given to prevent infectious complications. The prophylaxis was started just before the operation and was administered for a total of three days. Excluding mild, negligible infections, 39 (25%) of the 157 patients had infectious complications, 23 from the metronidazole group (28%) and 16 from the doxycycline group (21%). The type of infection varied according to the medication. In four cases of the metronidazole group and 16 of the doxycycline group, anaerobic bacteria were found. The corresponding figures for aerobes were 36 and 20. Doxycycline thus was significantly more effective in preventing complications in general, but metronidazole gave superior protection against anaerobes.


Upper airway obstruction induced by warfarin sodium.
I report a patient in whom warfarin sodium induced upper airway obstruction secondary to a spontaneous nontraumatic hemorrhage into the sublingual space. Treatment of this obstructive sublingual space hematoma with conservative medical management is reviewed. I discuss the role of warfarin sodium in coagulation and in the production of this pseudo-Ludwig phenomenon.


Nonconscious indirect inferences in encoding.
Indirect (transitive) inference (i.e., if A is related to B, and B is related to C, then C is related to A) is a ubiquitous component of thinking and reasoning. This research demonstrates that a mechanism at least functionally similar to drawing indirect inferences can also be observed in unintentional processes of encoding. The 2 studies followed the same design and used modified versions of procedures tested in previous research on nonconscious information processing (P. Lewicki, T. Hill, & M. Czyzewska, 1992). In the first learning phase, Ss acquired an encoding algorithm relating Variables A and B. In the second learning phase, Variable A was removed from the material and replaced with Variable C, allowing Ss to acquire the second encoding algorithm (relating B and C). Consistent with the original studies, Ss were not aware that there were any consistencies in the material. In the testing phase material, Variable B was removed, and Ss were asked to make intuitive judgments regarding Variable A. The data from both experiments confirmed the expectation that Ss would implicitly draw indirect inferences (A on the basis of C). This process is discussed as one of the mechanisms that may trigger the development of various components of procedural knowledge.


HIV screening among newly diagnosed TB patients: a cross sectional study in Lima, Peru.
Since 2006, the Peruvian National TB program (NTP) recommends voluntary counseling and testing (VCT) for all tuberculosis (TB) patients. Responding to the differential burden of both diseases in Peru, TB is managed in peripheral health facilities while HIV is managed in referral centers. This study aims to determine the coverage of HIV screening among TB patients and the characteristics of persons not screened. From March 2010 to December 2011 we enrolled new smear-positive pulmonary TB adults in 34 health facilities in a district in Lima. NTP staff offered VCT to all TB patients. Patients with an HIV positive result were referred for confirmation tests and management. We interviewed patients to collect their demographic and clinical characteristics and registered if patients opted in or out of the screening. Of the 1295 enrolled TB patients, nine had a known HIV diagnosis. Of the remaining, 76.1% (979) were screened for HIV. Among the 23.9% (307) not screened, 38.4% (118) opted out of the screening. TB patients at one of the health care facilities of the higher areas of the district (OR = 3.38, CI 95% 2.17-5.28 for the highest area and OR = 2.82, CI 95% 1.78-4.49 for the high area) as well as those reporting illegal drug consumption (OR = 1.65, CI 95% 1.15-2.37) were more likely not to be screened. Twenty-four were HIV positive (1.9% of all patients 1295, or 2.4% of those screened). Of 15 patients diagnosed with HIV during the TB episode, ten were enrolled in an HIV program. The median time between the result of the HIV screening and the first consultation at the HIV program was 82 days (IQR, 32-414). The median time between the result of the HIV screening and antiretroviral initiation was 148.5 days (IQR 32-500). An acceptable proportion of TB patients were screened for HIV in Lima. Referral systems of HIV positive patients should be strengthened for timely ART initiation.


Analgesic activity of Piper longum Linn. root.
Piper longum root, commonly called Kandantippili, is traditionally used to treat rheumatism, insomnia, palsy and epilepsy. But a scientific study on its central actions is not available. This study screens P. longum root for opioid type analgesia using rat tail-flick method and for NSAID type analgesia using acetic-acid writhing method. Pentazocine (ip) and ibuprofen (oral) are used as respective drug controls. An aqueous suspension of P. longum root powder is given orally to mice and rat in doses of 200, 400 and 800 mg/kg. The delay in reaction time for thermal stimulus in rats and the number of writhings to chemical stimulus in mice are determined in each group. The results are analysed statistically. The 400 and 800 mg/kg doses of P. longum show significant NSAID type of analgesia (P < 0.001). Both Ibuprofen (40 mg/kg) and P. longum (800 mg/kg) show 50% protection against writhing. The delay in reaction time to thermal stimulus was less than 6% for different doses of P. longum as against 100% for pentazocine. This indicates that P. longum root has weak opioid but potent NSAID type of analgesic activity.


Familial, isolated, complete right bundle-branch block.
An electrocardiographic study of the families of two children with isolated complete right bundle-branch block is presented. Several cases of classical complete right bundle-branch block were disclosed (17/69 and 3/22 respectively) in three generations of the two families. Personal interviews and parish registers showed that the two families were related, being descendants 8 generations back from a glass-blower who has emigrated to Sweden in the eighteenth century. It is concluded that complete right bundle-branch block can be an autosomal, genetic anomaly which is inherited dominantly but with reduced penetrance and/or expressivity.


Gender in Science and Engineering Faculties: Demographic Inertia Revisited.
The under-representation of women on faculties of science and engineering is ascribed in part to demographic inertia, which is the lag between retirement of current faculty and future hires. The assumption of demographic inertia implies that, given enough time, gender parity will be achieved. We examine that assumption via a semi-Markov model to predict the future faculty, with simulations that predict the convergence demographic state. Our model shows that existing practices that produce gender gaps in recruitment, retention, and career progression preclude eventual gender parity. Further, we examine sensitivity of the convergence state to current gender gaps to show that all sources of disparity across the entire faculty career must be erased to produce parity: we cannot blame demographic inertia.


Human dihydrolipoamide dehydrogenase (E3) deficiency: Novel insights into the structural basis and molecular pathomechanism.
This review summarizes our present view on the molecular pathogenesis of human (h) E3-deficiency caused by a variety of genetic alterations with a special emphasis on the moonlighting biochemical phenomena related to the affected (dihydro)lipoamide dehydrogenase (LADH, E3, gene: dld), in particular the generation of reactive oxygen species (ROS). E3-deficiency is a rare autosomal recessive genetic disorder frequently presenting with a neonatal onset and premature death; the highest carrier rate of a single pathogenic dld mutation (1:94-1:110) was found among Ashkenazi Jews. Patients usually die during acute episodes that generally involve severe metabolic decompensation and lactic acidosis leading to neurological, cardiological, and/or hepatological manifestations. The disease owes its severity to the fact that LADH is the common E3 subunit of the alpha-ketoglutarate (KGDHc), pyruvate (PDHc), and branched-chain α-keto acid dehydrogenase complexes and is also part of the glycine cleavage system, hence the malfunctioning of LADH simultaneously incapacitates several central metabolic pathways. Nevertheless, the clinical pictures are usually not unequivocally portrayed through the loss of LADH activities and imply auxiliary mechanisms that exacerbate the symptoms and outcomes of this disorder. Enhanced ROS generation by disease-causing hE3 variants as well as by the E1-E2 subcomplex of the hKGDHc likely contributes to selected pathogeneses of E3-deficiency, which could be targeted by specific drugs or antioxidants; lipoic acid was demonstrated to be a potent inhibitor of ROS generation by hE3 in vitro. Flavin supplementation might prove to be beneficial for those mutations triggering FAD loss in the hE3 component. Selected pathogenic hE3 variants lose their affinity for the E2 component of the hPDHc, a mechanism which warrants scrutiny also for other E3-haboring complexes.


Validity of the use of a subfascial vessel as the recipient vessel in a second free flap transfer: A retrospective clinical review.
Performing a greater number of free flap procedures inevitably results in an increase in the number of cases that experience free flap failure. In cases that require a second free flap after the failure of the first, recipient vessel selection becomes difficult. Furthermore, recipient vessel selection can be complicated if the vessel is deep in the recipient site, or if there is an increased risk of vessel damage during the dissection. Thus, we present our experience where a subfascial vessel beneath the deep fascia was used as a recipient vessel for a second free flap in lower extremity reconstruction due to total or partial first flap failure.Between January 2010 and April 2015, 5 patients underwent second free flap reconstruction using a subfascial vessel as the recipient vessel. The flaps were anastomosed in a perforator-to-perforator manner, using the supermicrosurgery technique. We measured the sizes of the flaps, which varied from 5 × 3 to 15 × 8 cm, and the recipient subfascial vessel diameters.The mean time for the dissection of the recipient perforator was 45 minutes. All the flaps exhibited full survival, although a partial loss of the skin graft at the flap donor site was observed in 1 patient; this defect healed with conservative management.We recommend using a subfascial vessel as the recipient vessel for both first and second free flaps, especially if access to the major vessel is risky or challenging.


tRNA splicing in yeast and wheat germ. A cyclic phosphodiesterase implicated in the metabolism of ADP-ribose 1",2"-cyclic phosphate.
Adenosine diphosphate (ADP)-ribose 1",2"-cyclic phosphate (Appr > p) is produced as a result of transfer RNA (tRNA) splicing in the yeast Saccharomyces cerevisiae and probably in other eukaryotes. Endonucleolytic cleavage and ligation result in a mature length tRNA with a 2'-phosphate at the splice junction. This 2'-phosphate is transferred to NAD to produce Appr > p. Metabolism of Appr > p requires hydrolysis of the 1",2"-cyclic phosphate linkage. We show here that yeast has a unique cyclic phosphodiesterase that can hydrolyze Appr > p, ribose 1,2-cyclic phosphate, and ribose 1,3-cyclic phosphate to the corresponding ribose 1-phosphate derivatives. The cyclic phosphodiesterase is highly specific for Appr > p; there is 20-fold less activity on ribose 1,3-cyclic phosphate and no detectable activity on nucleoside 2',3'-cyclic phosphates. A similar cyclic phosphodiesterase is present in wheat germ. The wheat germ cyclic phosphodiesterase activity co-chromatographs with a 2',3'-cyclic nucleotide 3'-phosphodiesterase that was previously identified and purified. The purified wheat germ enzyme has a distinct preference for Appr > p and ribose cyclic phosphate compared to guanosine 2',3'-cyclic phosphate and shares other biochemical characteristics with the yeast enzyme.


Assertive outreach nurses' experience of engagement.
There are currently no studies available in the literature to highlight nurses' experiences of the assertive outreach (AO) engagement process. This study aimed to understand how AO nurses experience this process and what can be learned from it. The participants were five nurses working in a rural AO service in one county. Methodological considerations were rooted in the work of Martin Heidegger and the data analysed using the hermeneutic phenomenological thematic method. The data-gathering tool was semi-structured interviews. Seven major themes emerged to construct the nurses' understanding of their experience of assertive engagement. These were: (1) having time; (2) anticipatory persistence and tired dejection; (3) pressure, relief and satisfaction; (4) being the human professional confluence; (5) accepting anxiety and fear; (6) working and learning together; and (7) bringing the caring attitude. This paper focuses on the seven emerging themes and discusses the implications and recommendations for nurses practising in the AO setting.


Risks and Benefits of Dual Antiplatelet Therapy Beyond 12 Months After Coronary Stenting: A Prospective Randomized Cohort Study.
The optimal duration of dual antiplatelet therapy (DAT) after coronary stenting remains poorly define. The aim of this study was to evaluate the impact of longer than 24 months DAT in patients who received drug-eluting and bare-metal stents.A total of 1010 individuals who underwent elective, urgent or emergency coronary angioplasty with intended stent implantation at reference or specialized cardiac hospitals were randomized to receive long-term and short-term DAT to determine the benefits and adverse effects of long-term DAT. Total of 508 patients were randomized to long-term and 502 patients to <1 year DAT, and all of them were followed for more than 36 months for major adverse cardiac and cerebvascular events and bleeding major adverse cardiac and cerebvascular events (MACCE)Mean age of the 1010 patients (364 women and 646 men) was 60 years. Stent reocclusion occurred in 15 patients. Mean Syntax score was 23.00 ± 5.08 for whole samples, 25.00 ± 5.27 in 28 patients with MACCE and 23 ± 5.00 in 982 patients without MACCE (P = 0.057). According to all specified bleeding definitions, clopidogrel therapy for >12 months was not associated with a greater risk of hemorrhage. A regimen of >12 months of clopidogrel therapy in patients who had received drug-eluting or bare-metal stents did not differ significantly from a regimen of <12 months on clopidogrel with regard to MACCE.Long-term DAT might not significantly affect the reduction in the risk of death from any cause, myocardial infarction, or stroke, and not associated with minor or major bleeding events.