Phenomic profiling to reveal tolerance mechanisms and regulation of ascorbate-glutathione cycle in wheat varieties (Triticum aestivum L.) under arsenic stress.
The potential of arsenic (As) tolerant and sensitive varieties of wheat (Triticum aestivum L.) has yet to be explored despite of alarming situation of arsenic toxicity. To fill this gap, the study aimed to explore the role of antioxidants, phytochelatins, and ascorbate-glutathione for As tolerance in wheat. A total of eight varieties were exposed to different arsenate treatments (0, 1, 5, 10, 50, 100, 200, 500, 1000, 2000, and 10,000 μM) initially to screen effective treatment as well as contrasting varieties via Weibull distribution frequency for further analysis. The Weibull analysis found 200 μM as the most effective treatment in the present study. Selected varieties were analyzed for accumulation of total As and As speciation, oxidative stress (malondialdehyde, hydrogen peroxide), antioxidants (superoxide dismutase, catalase, peroxidase), phytochelatins, and ascorbate-glutathione cycle (glutathione-S-transferase, glutathione reductase, glutathione peroxidase, ascorbate peroxidase). Tolerant varieties showed less accumulation and translocation of total As, arsenate, and arsenite to the shoots compared with sensitive varieties under 200 μM treatment. Low concentration in tolerant varieties correlated with better growth and development response. Tolerant varieties showed higher induction of metabolites (glutathione, phytochelatins) compared to sensitive ones. Furthermore, tolerant varieties showed better performance of antioxidant and ascorbate-glutathione cycle enzymes in response to As exposure. The findings of the present study provided great insight into the wheat tolerance mechanism upon As exposure between contrasting varieties.


Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression.
Malignant melanoma is a highly aggressive form of skin cancer with a high mortality rate if not discovered in early stages. Although a limited number of treatment options for melanoma currently exist, patients with a more aggressive form of this cancer frequently decline treatment. DM-1 is a sodium phenolate and curcumin analog with proven anticancer, anti-proliferative and anti-metastatic properties. In this paper, the DM-1 compound showed in vivo antitumor activity alone or in combination with chemotherapeutic DTIC in B16F10 melanoma-bearing mice. Beneficial effects such as melanoma tumor burden reduction with pyknotic nuclei, decreased nuclei/cytoplasmic ratio and nuclear degradation occurred after DM-1 treatment. No toxicological changes were observed in the liver, kidneys, spleen and lungs after DM-1 monotherapy or DTIC combined therapy. DTIC+DM-1 treatment induced the recovery of anemia arising from melanoma and immunomodulation. Both DM-1 treatment alone and in combination with DTIC induced apoptosis with the cleavage of caspase-3, -8 and -9. Furthermore, melanoma tumors treated with DM-1 showed a preferential apoptotic intrinsic pathway by decreasing Bcl-2/Bax ratio. Considering the chemoresistance exhibited by melanoma towards conventional chemotherapy drugs, DM-1 compound in monotherapy or in combination therapy provides a promising improvement in melanoma treatment with a reduction of side effects.


In Vitro and In Silico Approaches for the Antileishmanial Activity Evaluations of Actinomycins Isolated from Novel Streptomyces smyrnaeus Strain UKAQ_23.
Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new antileishmanial agents. The current study aimed to investigate the in vitro and in silico antileishmanial activity of two newly sourced actinomycins, X2 and D, produced by the novel Streptomyces smyrnaeus strain UKAQ_23. The antileishmanial activity conducted on promastigotes and amastigotes of Leishmania major showed actinomycin X2 having half-maximal effective concentrations (EC50), at 2.10 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and selectivity index (SI) values of 0.048 and 1, respectively, while the actinomycin D exhibited EC50 at 1.90 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and SI values of 0.052 and 1. The molecular docking studies demonstrated squalene synthase as the most favorable antileishmanial target protein for both the actinomycins X2 and D, while the xanthine phosphoribosyltransferase was the least favorable target protein. The molecular dynamics simulations confirmed that both the actinomycins remained stable in the binding pocket during the simulations. Furthermore, the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding energy calculations established that the actinomycin X2 is a better binder than the actinomycin D. In conclusion, both actinomycins X2 and D from Streptomyces smyrnaeus strain UKAQ_23 are promising antileishmanial drug candidates and have strong potential to be used for treating the currently drug-resistant leishmaniasis.


Comparative efficacy trial of cupping and serkangabin versus conventional therapy of migraine headaches: A randomized, open-label, comparative efficacy trial.
Migraine headaches are the most common acute and recurrent headaches. Current treatment of a migraine headache consists of multiple medications for control and prevention of recurrent attacks. Global emergence of alternative medicine led us to examine the efficacy of cupping therapy plus serkangabin syrup in the treatment of migraine headaches. This study was a randomized, controlled, open-label, comparative efficacy trial. We randomly assigned patients with migraine into cupping therapy plus serkangabin group (30 patients) and conventional treatment group (30 patients). An investigator assessed the severity of headache, frequency of attacks in a week and duration of attacks per hour in 5 visits (at the end of 2 weeks, 1, 3 and 6 months). Generalized estimating equations approach was used to analyze repeated measures data to compare outcomes in both groups. Average age for cupping therapy group and conventional treatment group were 31.7 (±7.6) and 32.6 (±12.7) years, respectively (P = 0.45). After treatment for 2 weeks; and 1, 3 and 6 months, severity of headache (P = 0.80), frequency of migraine attacks (P = 0.63) and duration of attacks per hours (P = 0.48) were similar in conventional and cupping groups but these symptoms were decreased in each group during the study (P < 0.001). There was no significant difference between cupping plus serkangabin therapy and conventional treatment in the treatment and prophylaxis of migraine. The alternative therapy may be used in cases of drug intolerance, no medication response, and in primary care.


Participating in the personal care of a person living with a life-limiting illness in a hospice inpatient setting: the informal caregiver's perspective.
Using semi-structured interviews, this descriptive qualitative research study examined informal caregivers' perspectives of participating in the personal care of a person living with a life-limiting illness within one hospice inpatient setting. Some 10 principal, informal caregivers of hospice inpatients were recruited by means of purposive sampling, using posters displayed in the hospice inpatient unit. Thus, participation was entirely 'opt-in'. A flash card was displayed at the beginning of each interview to determine a definition of personal care. Field notes and digital audio recording were used to capture data collected. Data were thematically analysed and demonstrated that informal caregivers' perceptions of personal care included everything that allowed the patient to remain the person they were. Informal caregivers reported an acceptable balance between being able to carry out personal care and hospice nursing staff involvement, despite no discussions being carried out to establish their wishes. Prior experiences of informal caregiving, and individual caregiver preparedness, contributed to negative and positive feelings about participating in personal care. Informal caregivers reported additional support and education needs associated with being able to participate in the personal care of patients on discharge and in the future. The emergent themes provide palliative care practitioners with direction for professional practice and research around supporting informal caregivers participating in personal care. Healthcare professionals need to clarify terminology of personal care by having dialogues with informal caregivers and acting on these accordingly. However, not all informal caregivers want such conversations. Consequently, healthcare professionals should approach this topic sensitively. Healthcare professionals ought to be asking informal caregivers if they wish to participate in personal care. Hospice nurses need to engage, support and educate informal caregivers about personal care. Furthermore, they should help to maintain and develop the skills of those informal caregivers who want to continue to play this role and not allow them to become deskilled.


A survey of deaths in Hong Kong attributed to tuberculosis.
Records obtained for 578 (96%) of the 602 patients certified as having died from tuberculosis in Hong Kong during a 1-year period were reviewed by an expert independent assessor in London, In his opinion 14 (2% of the 578) had never had tuberculosis, and in 28 (5%) it was not possible to decide whether or not the patient had ever had tuberculosis. Tuberculosis had been no more than a contributory factor in causing death in 44 (8%), in 29 (5%) it was irrelevant, and in 33 (6%) it was not possible to determine what role it had played. The remaining 430 (74%) patients were considered actually to have died from tuberculosis, 307 from active disease and 123 from the late effects of inactive disease. If all 578 patients had died from tuberculosis this would represent a death rate for the survey year of 13.1 per 100 000 of the population. The rate falls to 9.7 per 100 000 if based on the 430 patients considered by the assessor to have died from tuberculosis, a reduction of 26%. Since the annual death rate from active disease (6.9 per 100 000 in this survey) is a better index of the current efficiency of an antituberculosis programme than the total death rate, it is suggested that efforts should be made to obtain and publish separate annual rates for deaths from active and from inactive tuberculosis. An analysis of potentially avoidable delays and failures in diagnosis showed that these were mainly due to the patient's delay in seeking or accepting advice, or inadequate investigation, particularly failure to examine the sputum, by the unofficial (non-governmental) medical services. The majority of failures in management were attributable in whole or in part to the patient.


A Literature Review of Renal Surgical Anatomy and Surgical Strategies for Partial Nephrectomy.
A detailed understanding of renal surgical anatomy is necessary to optimize preoperative planning and operative technique and provide a basis for improved outcomes. To evaluate the literature regarding pertinent surgical anatomy of the kidney and related structures, nephrometry scoring systems, and current surgical strategies for partial nephrectomy (PN). A literature review was conducted. Surgical renal anatomy fundamentally impacts PN surgery. The renal artery divides into anterior and posterior divisions, from which approximately five segmental terminal arteries originate. The renal veins are not terminal. Variations in the vascular and lymphatic channels are common; thus, concurrent lymphadenectomy is not routinely indicated during PN for cT1 renal masses in the setting of clinically negative lymph nodes. Renal-protocol contrast-enhanced computed tomography or magnetic resonance imaging is used for standard imaging. Anatomy-based nephrometry scoring systems allow standardized academic reporting of tumor characteristics and predict PN outcomes (complications, remnant function, possibly histology). Anatomy-based novel surgical approaches may reduce ischemic time during PN; these include early unclamping, segmental clamping, tumor-specific clamping (zero ischemia), and unclamped PN. Cancer cure after PN relies on complete resection, which can be achieved by thin margins. Post-PN renal function is impacted by kidney quality, remnant quantity, and ischemia type and duration. Surgical renal anatomy underpins imaging, nephrometry scoring systems, and vascular control techniques that reduce global renal ischemia and may impact post-PN function. A contemporary ideal PN excises the tumor with a thin negative margin, delicately secures the tumor bed to maximize vascularized remnant parenchyma, and minimizes global ischemia to the renal remnant with minimal complications. In this report we review renal surgical anatomy. Renal mass imaging allows detailed delineation of the anatomy and vasculature and permits nephrometry scoring, and thus precise, patient-specific surgical planning. Novel off-clamp techniques have been developed that may lead to improved outcomes.


Outcomes of Patients With Multiple Cutaneous Squamous Cell Carcinomas: A 10-Year Single-Institution Cohort Study.
Patients with multiple cutaneous squamous cell carcinomas (CSCCs) pose a management challenge for physicians, but their prognosis is unknown because outcomes have not been compared between patients who form single vs multiple CSCCs. To compare outcomes in patients with 1 vs multiple CSCCs. A 10-year retrospective single-institution cohort study at an academic tertiary care center of patients with dermally invasive (non-in situ) primary CSCC diagnosed from January 1, 2000, through December 31, 2009. Electronic medical records were reviewed to determine the tumor stage (Brigham and Women's Hospital tumor stage) and outcomes (local recurrence [LR], nodal metastases [NM], and death due to CSCC). Outcomes were compared between patients with 1 vs more than 1 CSCC via multivariable competing-risk regression adjusted for other significant cofactors. Of 985 patients with CSCC, 727 had 1 CSCC, 239 had 2 to 9 CSCCs, and 19 had 10 or more CSCCs. Most patients with 10 or more CSCCs were immunosuppressed (15 of 19 [78.9%]). The median follow-up time was 50 months (range, 2-142 months). Patients with more than 1 CSCC had a higher risk of LR (subhazard ratio for 2-9 CSCCs, 1.8; 95% CI, 1.1-4.3; and for ≥10 CSCCs, 3.8; 95% CI, 1.4-10.0) and NM (subhazard ratio for 2-9 CSCCs, 3.0; 95% CI, 1.4-6.5; and for ≥10 CSCCs, 4.2; 95% CI, 1.4-10.4) compared with patients with 1 CSCC, adjusted for Brigham and Women's Hospital tumor stage. The 10-year cumulative incidence of LR and NM was higher in patients with 2 to 9 CSCCs and markedly higher in those with 10 or more CSCCs compared with patients who had 1 CSCC (10-year cumulative incidence for 1 CSCC: LR, 3.0%; 95% CI, 2.0%-4.5%; and NM, 2.3%; 95% CI, 1.5%-3.8%; for 2-9 CSCCs: LR, 6.7%; 95% CI, 4.2%-10.6%; and NM, 5.9%; 95% CI, 3.5%-9.6%; and for ≥10 CSCCs: LR, 36.8%; 95% CI, 19.2%-59.0%; and NM, 26.3%; 95% CI, 11.8%-48.8%). Patients with multiple CSCCs warrant frequent follow-up because they have an elevated risk of LR and NM. In particular, patients with 10 or more CSCCs have markedly elevated risks of recurrence and metastasis.


Structure of the GH76 α-mannanase homolog, BT2949, from the gut symbiont Bacteroides thetaiotaomicron.
The large bowel microbiota, a complex ecosystem resident within the gastrointestinal tract of all human beings and large mammals, functions as an essential, nonsomatic metabolic organ, hydrolysing complex dietary polysaccharides and modulating the host immune system to adequately tolerate ingested antigens. A significant member of this community, Bacteroides thetaiotaomicron, has evolved a complex system for sensing and processing a wide variety of natural glycoproducts in such a way as to provide maximum benefit to itself, the wider microbial community and the host. The immense ability of B. thetaiotaomicron as a `glycan specialist' resides in its enormous array of carbohydrate-active enzymes, many of which are arranged into polysaccharide-utilization loci (PULs) that are able to degrade sugar polymers that are often inaccessible to other gut residents, notably α-mannan. The B. thetaiotaomicron genome encodes ten putative α-mannanases spread across various PULs; however, little is known about the activity of these enzymes or the wider implications of α-mannan metabolism for the health of both the microbiota and the host. In this study, SAD phasing of a selenomethionine derivative has been used to investigate the structure of one such B. thetaiotaomicron enzyme, BT2949, which belongs to the GH76 family of α-mannanases. BT2949 presents a classical (α/α)6-barrel structure comprising a large extended surface cleft common to other GH76 family members. Analysis of the structure in conjunction with sequence alignments reveals the likely location of the catalytic active site of this noncanonical GH76.


Plasmonic hot electron enhanced MoS2 photocatalysis in hydrogen evolution.
With plasmonic hot electron doping, the molybdenum disulfide (MoS2) monolayer with deposited Au@Ag nanorattles effectively enhanced the hydrogen evolution reaction (HER) efficiency. The maximum photocatalysis is achieved under plasmon resonance excitation, and is actively controlled by the incident laser wavelength and power intensity. The localized phase transition of MoS2 is achieved and characterized to explicate this plasmon-enhanced hydrogen evolution. The proposed MoS2-nanoparticle composite combines surface plasmons and planar 2D materials, and pioneers a frontier field of plasmonic MoS2 photocatalysis.


Antiglioma effects of cytarabine on leptomeningeal metastasis of high-grade glioma by targeting the PI3K/Akt/mTOR pathway.
Leptomeningeal metastasis (LM) of high-grade glioma is a highly lethal disease requiring new effective therapeutic measures. For both de novo or relapsed glioma with LM, intrathecal cytarabine chemotherapy is not frequently used for first-line and relapse protocols. We encountered a clinical case demonstrating effective application of cytarabine in high-grade glioma with LM, prompting us to explore the effects of cytarabine on malignant glioma and molecular mechanisms of such effects through in vivo and in vitro experiments. The U87 cell line was selected to represent human glioma for studies. Cell viability was measured by MTT assay, plate colony formation assay, and trypan-blue dye exclusion test. Apoptosis was assessed by flow cytometry. Protein expression levels were detected by Western blot assay and immunohistochemistry. mRNA expression was examined by quantitative real-time reverse transcription polymerase chain reaction. Cytarabine inhibited tumor growth during the in vivo experiment. The present study confirmed that cytarabine inhibits proliferation and promotes apoptosis of U87 cells, and molecular analysis of this effect showed that cytarabine significantly reduces expression of phosphatidylinositol 3-kinase/serine/threonine kinase also known as the protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway, Ki-67, BCL2, and 4-1BB, and upregulates Bax and cleaved caspase-3. Our findings indicated that intrathecal administration of cytarabine manifests potential in prophylaxis and treatment of malignant glioma with LM. Effective medications for high-grade glioma with LM should contain cytarabine.


Use of whole body hyperthermia as a method to heat inaccessible tumours uniformly: a phase III trial in canine brain masses.
In this study, whole body hyperthermia (WBH) was assessed as a means of heating intracranial tumours uniformly. Twenty-five dogs received radiation therapy and 20 the combination of radiation and WBH. Total radiation dose was randomly assigned and was either 44, 48, 52, 56 or 60 Gy. Because of WBH toxicity, intercurrent disease or tumour progression, seven of the 45 dogs received less than the prescribed radiation dose. For WBH, the target rectal temperature was 42 degrees C for 2h and three treatments were planned. In five of the 20 dogs randomized to receive WBH, only one WBH treatment was given because of toxicity. WBH toxicity was severe in six dogs, and resulted in death or interruption in treatment. Most tumours did not undergo a complete response, making it impossible to differentiate tumour recurrence from brain necrosis as a cause of progressive neuropathy. Therefore, survival was the major study endpoint. There was no survival difference between groups. One-year survival probability (95% CI) for dogs receiving radiation therapy alone was 0.44 (0.25, 0.63) versus 0.40 (0.19, 0.63) for dogs receiving radiation and WBH. There was no difference in the incidence of brain necrosis in the two treatment groups. Results suggest that use of WBH alone to increase the temperature of intracranial tumours as a means to improve radiation therapy outcome is not a successful strategy.


Tryptophan biosynthesis in Saccharomyces cerevisiae: control of the flux through the pathway.
Enzyme derepression and feedback inhibition of the first enzyme are the regulatory mechanisms demonstrated for the tryptophan pathway in Saccharomyces cerevisiae. The relative contributions of the two mechanisms to the control of the flux through the pathway in vivo were analyzed by (i) measuring feedback inhibition of anthranilate synthase in vivo, (ii) determining the effect of regulatory mutations on the level of the tryptophan pool and the flux through the pathway, and (iii) varying the gene dose of individual enzymes of the pathway at the tetraploid level. We conclude that the flux through the pathway is adjusted to the rate of protein synthesis by means of feedback inhibition of the first enzyme by the end product, tryptophan. The synthesis of the tryptophan enzymes could not be repressed below a basal level by tryptophan supplementation of the media. The enzymes are present in excess. Increasing or lowering the concentration of individual enzymes had no noticeable influencing on the overall flux to tryptophan. The uninhibited capacity of the pathway could be observed both upon relieving feedback inhibition by tryptophan limitation and in feedback-insensitive mutants. It exceeded the rate of consumption of the amino acid on minimal medium by a factor of three. Tryptophan limitation caused derepression of four of the five tryptophan enzymes and, as a consequence, led to a further increase in the capacity of the pathway. However, because of the large reserve capacity of the "repressed" pathway, tryptophan limitation could not be imposed on wild-type cells without resorting to the use of analogs. Our results, therefore, suggest that derepression does not serve as an instrument for the specific regulation of the flux through the tryptophan pathway.


Pneumonia in the tropics.
Pneumonia in the tropics poses a heavy disease burden. The complex interplay of climate change, human migration influences and socio-economic factors lead to changing patterns of respiratory infections in tropical climate but also increasingly in temperate countries. Tropical and poorer countries, especially South East Asia, also bear the brunt of the global tuberculosis (TB) pandemic, accounting for almost one-third of the burden. But, as human migration patterns evolve, we expect to see more TB cases in higher income as well as temperate countries, and rise in infections like scrub typhus from ecotourism activities. Fuelled by the ease of air travel, novel zoonotic infections originating from the tropics have led to global respiratory pandemics. As such, clinicians worldwide should be aware of these new conditions as well as classical tropical bacterial pneumonias such as melioidosis. Rarer entities such as co-infections of leptospirosis and chikungunya or dengue will need careful consideration as well. In this review, we highlight aetiologies of pneumonia seen more commonly in the tropics compared with temperate regions, their disease burden, variable clinical presentations as well as impact on healthcare delivery.


Testing effects of consumer richness, evenness and body size on ecosystem functioning.
1. Numerous studies have revealed (usually positive) relationships between biodiversity and ecosystem functioning (B-EF), but the underpinning drivers are rarely addressed explicitly, hindering the development of a more predictive understanding. 2. We developed a suite of statistical models (where we combined existing models with novel ones) to test for richness and evenness effects on detrital processing in freshwater microcosms. Instead of using consumer species as biodiversity units, we used two size classes within three species (six types). This allowed us to test for diversity effects and also to focus on the role of body size and biomass. 3. Our statistical models tested for (i) whether performance in polyculture was more than the sum of its parts (non-additive effects), (ii) the effects of specific type combinations (assemblage identity effects) and (iii) whether types behaved differently when their absolute or relative abundances were altered (e.g. because type abundance in polyculture was lower compared with monoculture). The latter point meant we did not need additional density treatments. 4. Process rates were independent of richness and evenness and all types performed in an additive fashion. The performance of a type was mainly driven by the consumers' metabolic requirements (connected to body size). On an assemblage level, biomass explained a large proportion of detrital processing rates. 5. We conclude that B-EF studies would benefit from widening their statistical approaches. Further, they need to consider biomass of species assemblages and whether biomass is comprised of small or large individuals, because even if all species are present in the same biomass, small species (or individuals) will perform better.


Species richness and food-web structure jointly drive community biomass and its temporal stability in fish communities.
Biodiversity-ecosystem functioning and food-web complexity-stability relationships are central to ecology. However, they remain largely untested in natural contexts. Here, we estimated the links among environmental conditions, richness, food-web structure, annual biomass and its temporal stability using a standardised monitoring dataset of 99 stream fish communities spanning from 1995 to 2018. We first revealed that both richness and average trophic level are positively related to annual biomass, with effects of similar strength. Second, we found that community stability is fostered by mean trophic level, while contrary to expectation, it is decreased by species richness. Finally, we found that environmental conditions affect both biomass and its stability mainly via effects on richness and network structure. Strikingly, the effect of species richness on community stability was mediated by population stability rather than synchrony, which contrasts with results from single trophic communities. We discuss the hypothesis that it could be a characteristic of multi-trophic communities.


Enteric fever in young Yoruba children.
Ninety-seven Nigerian children under 5 years of age had typhoid or paratyphoid fever proved by blood culture. The presented with fever, anaemia, gastrointestinal or neurological disturbances, and typhoid and paratyphoid appeared clinically indistinguishible. In this holoendemic malarial area, malaria was the most important differential diagnosis, and may have contributed to the concomitant anaemia seen in the majority of patients. Despite vigorous therapy with chloramphenicol or trimethoxazole, and blood transfusion where indicated, the mortality in both typhoid and paratyphoid was high (18% in both groups).


Calcium phosphate coatings for dental implants. Current status and future potential.
The initial experience with high-quality HA coatings has been positive. The application of HA coatings to metallic substrate implants represents the first time that the body can be directed as to where, and to some extent how, it should respond to their implantation, representing a truly incremental increase from metals material technology and an interim step towards more tailorable, biologically active systems. It remains clear at this writing that all HA-coatings are not created equal and it remains an environment of "buyer beware." There is cause for optimism as new advances in the three essential criteria will only improve the current success rate. These advances and increases in efficacy will, as always, be pioneered in the dental and oral surgical disciplines.


Blindness and autonomic instability following Russell's viper bite - A case report.
Autonomic instability is a rare complication following elapid bites. Blindness too is a rare complication following Russell's viper bite and is most likely due to cerebral infarction or direct ocular toxicity. We report a case of a young male from Sri Lanka who developed both transient blindness and autonomic instability following severe envenomation by a Russell's viper bite.


Suicides in Turkey between 1996 and 2005: general perspective.
Suicide is a significant problem in the world. Sharing the information about the national suicide rates in the international scientific area is an important issue for not only the solution of the problem, but also improving the efforts for decreasing the suicidal deaths. We aimed to add the statistical information about the rates, the risk factors, and the methods of suicides in Turkey to the literature. The suicide rates in Turkey increased in the period between 1996 and 2005 years; it was 3.8 per 100,000 populations in 2005. The average ratio of male to female was 1.58/1 between 1996 and 2005 years. The suicidal deaths increased above the age of 75, especially in male population. In females, the most dangerous period was 15 to 24 age group. The major risk factor for suicides was found to be illness (29.6%) for both genders and especially for above middle ages. Hanging was the most preferred method for both genders and for most of the age groups in Turkey. Suicides increased in the spring and summer.


Ejection time: influence of hemodynamics and site of measurement in the arterial tree.
The left ventricular ejection time is routinely measured from a peripheral arterial waveform. However, the arterial waveform undergoes constant transformation as the pulse wave propagates along the arterial tree. Our goal was to determine if the left ventricular ejection time measured peripherally in the arterial tree accurately reflected the ejection time measured through the aortic valve. Moreover, we examined/accessed the modulating influence of hemodynamics on ejection time measurements. Continuous wave Doppler waveform images through the aortic valve and the simultaneously obtained radial artery pressure waveforms were analyzed to determine central and peripheral ejection times, respectively. The peripheral ejection time was significantly longer than the simultaneously measured central ejection time (174.5±25.2 ms vs. 120.7±14.4 ms; P<0.0001; 17.4±8.7% increase). Moreover, the ejection time prolongation was accentuated at lower blood pressures, lower heart rate and lower pulse wave velocity. The time difference between centrally and peripherally measured ejection times likely reflects intrinsic vascular characteristics. Moreover, given that the ejection time also depends on blood pressure, heart rate and pulse wave velocity, peripherally measured ejection times might need to be adjusted to account for changes in these variables.


Bacteriophage Q replicase contains the protein biosynthesis elongation factors EF Tu and EF Ts.
The enzyme, Qbeta replicase, responsible for the replication of the RNA of Escherichia coli pahge Qbeta, is composed of four nonidentical subunits, three of which, I, III, and IV, are coded for by the bacterial genome, while subunit II is phage-specific. SUBUNIT IV IS SHOWN TO BE IDENTICAL TO THE PROTEIN SYNTHESIS ELONGATION FACTOR EF TS BY THE FOLLOWING CRITERIA: coelectrophoresis on polyacrylamide gels in sodium dodecyl sulfate and in urea buffers, identity of the first seven amino acids at the amino-terminus, precipitation of sub-unit IV by anti-EF T-factor serum, and stimulation of EF Tu-GDP exchange by subunit IV. Subunit III is shown to be identical to the protein synthesis elongation factor EF Tu by the following criteria: coelectrophoresis on sodium dodecyl sulfate gels, precipitation of EF Tu by anti-Qbeta replicase serum, binding of guanine nucleotides, and binding of phenylalanyl-tRNA. In addition, Qbeta replicase activity can be reconstituted from subunits I and II with EF Tu and EF Ts.


Relationship between markers of activated coagulation, their correlation with inflammation, and association with coronary heart disease (NPHSII).
To determine whether activation of coagulation increases in parallel with inflammation and whether coagulation activation markers (CAMs) are independently associated with coronary heart disease (CHD), in the prospective study, NPHSII. Surveillance of 2997 men between 50 and 63 years yielded 314 first CHD events during 36507 person-years of observation. The plasma levels of activated factor XII (FXIIa), the peptides released upon activation of factor X (FXpep) and factor IX (FIXpep), activated factor VII (FVIIa), prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FpA) served as indices of activity along the coagulation pathway. C reactive protein (CRP) provided a marker of inflammatory activity. While borderline or significant correlations were identified for each CAM with inflammation, as determined by CRP levels, these did not reach as high a numerical value as was shown for fibrinogen with CRP. FVIIa and FIXpep possessed independent associations with CHD: a one SD increase in adjusted FIXpep and FVIIa level was associated with a relative hazard of 1.20 (95% CI 1.00-1.43) and 0.70 (CI 0.58-0.86), respectively, using a group including all CHD events, compared with 'no-event'. Inflammation has significant but minimal impact upon CAMs of the extrinsic coagulation pathway. Reduced FVIIa and increased FIXpep levels were found to be significant, independent, predictors of CHD.


Determination of phthalate esters in liquor samples by vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction followed by GC-MS.
A novel method using vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction has been developed for the extraction of phthalate esters (PAEs) in Chinese liquor samples prior to analysis by GC-MS. In the proposed method, a high-density extraction solvent (carbon tetrachloride) was dispersed into samples with the aid of a surfactant (Triton X-100) and vortex agitation, resulting in a short extraction equilibrium (30 s). After centrifugation, a single microdrop of solvent was easily collected for GC-MS analysis. Key factors that affected the extraction efficiency were optimized. Under the optimum conditions, linearity was found in the range from 0.05 to 50 μg/L. Coefficients of determination varied from 0.9938 to 0.9971. LODs, based on an S/N of 3, ranged from 4.9 to 13 ng/L. Enrichment factors varied from 140 to 184. Reproducibility and recoveries were assessed by testing a series of three liquor samples that were spiked with different concentration levels. Finally, the proposed method was successfully applied to the determination of PAEs in 16 Chinese liquor samples. In this work, high-density-solvent vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction was applied for the first time for the extraction of PAEs in Chinese liquor samples and was proved to be simple, rapid, and sensitive.


Neural Differentiation of Incorrectly Predicted Memories.
When an item is predicted in a particular context but the prediction is violated, memory for that item is weakened (Kim et al., 2014). Here, we explore what happens when such previously mispredicted items are later reencountered. According to prior neural network simulations, this sequence of events-misprediction and subsequent restudy-should lead to differentiation of the item's neural representation from the previous context (on which the misprediction was based). Specifically, misprediction weakens connections in the representation to features shared with the previous context and restudy allows new features to be incorporated into the representation that are not shared with the previous context. This cycle of misprediction and restudy should have the net effect of moving the item's neural representation away from the neural representation of the previous context. We tested this hypothesis using human fMRI by tracking changes in item-specific BOLD activity patterns in the hippocampus, a key structure for representing memories and generating predictions. In left CA2/3/DG, we found greater neural differentiation for items that were repeatedly mispredicted and restudied compared with items from a control condition that was identical except without misprediction. We also measured prediction strength in a trial-by-trial fashion and found that greater misprediction for an item led to more differentiation, further supporting our hypothesis. Therefore, the consequences of prediction error go beyond memory weakening. If the mispredicted item is restudied, the brain adaptively differentiates its memory representation to improve the accuracy of subsequent predictions and to shield it from further weakening.SIGNIFICANCE STATEMENT Competition between overlapping memories leads to weakening of nontarget memories over time, making it easier to access target memories. However, a nontarget memory in one context might become a target memory in another context. How do such memories get restrengthened without increasing competition again? Computational models suggest that the brain handles this by reducing neural connections to the previous context and adding connections to new features that were not part of the previous context. The result is neural differentiation away from the previous context. Here, we provide support for this theory, using fMRI to track neural representations of individual memories in the hippocampus and how they change based on learning.


Priming with γ-Aminobutyric Acid against Botrytis cinerea Reshuffles Metabolism and Reactive Oxygen Species: Dissecting Signalling and Metabolism.
The stress-inducible non-proteinogenic amino acid γ-aminobutyric acid (GABA) is known to alleviate several (a)biotic stresses in plants. GABA forms an important link between carbon and nitrogen metabolism and has been proposed as a signalling molecule in plants. Here, we set out to establish GABA as a priming compound against Botrytis cinerea in Arabidopsis thaliana and how metabolism and reactive oxygen species (ROS) are influenced after GABA treatment and infection. We show that GABA already primes disease resistance at low concentrations (100 µM), comparable to the well-characterized priming agent β-Aminobutyric acid (BABA). Treatment with GABA reduced ROS burst in response to flg22 (bacterial peptide derived from flagellum) and oligogalacturonides (OGs). Plants treated with GABA showed reduced H2O2 accumulation after infection due to increased activity of catalase and guaiacol peroxidase. Contrary to 100 µM GABA treatments, 1 mM exogenous GABA induced endogenous GABA before and after infection. Strikingly, 1 mM GABA promoted total and active nitrate reductase activity whereas 100 µM inhibited active nitrate reductase. Sucrose accumulated after GABA treatment, whereas glucose and fructose only accumulated in treated plants after infection. We propose that extracellular GABA signalling and endogenous metabolism can be separated at low exogenous concentrations.


The vigabatrin-associated brain abnormalities on MRI and their differential diagnosis.
Vigabatrin is an anti-epileptic drug that inhibits the enzyme γ-aminobutyric acid (GABA)-transaminase. The anticonvulsant effect of vigabatrin involves increasing GABA levels and attenuating glutamate-glutamine cycling. Vigabatrin indications include infantile spasms and refractory focal seizures. Despite having a significant role in paediatric epileptology, vigabatrin has adverse effects, such as retinal toxicity, in up to 30% of patients after 1 year of use and brain abnormalities on magnetic resonance imaging (MRI). The percentage of patients with brain abnormalities on MRI varies between 22-32% of children using vigabatrin to treat infantile spasms. Risk factors for presenting these imaging abnormalities are cryptogenic infantile spasms, age <12 months old, high dosage, and possible concomitant hormonal therapy. Clinically, these abnormalities are usually asymptomatic. Histopathological analysis reveals white matter vacuolation and intramyelinic oedema. The typical findings of vigabatrin-associated brain abnormalities on MRI are bilateral and have a symmetrical hyperintense signal on T2-weighted imaging, with diffusion restriction, that often compromise the globi pallidi, thalami, subthalamic nuclei, cerebral peduncles, midbrain, dorsal brainstem, including the medial longitudinal fasciculi, and dentate nuclei of the cerebellum. In this article, the authors intend to review the clinical manifestations, histopathological features, imaging aspects, and differential diagnosis of vigabatrin-associated brain abnormalities on MRI.


A Case Report of Congenital Fiber Type Disproportion with an Increased Level of Anti-ACh Receptor Antibodies.
Congenital fiber type disproportion (CFTD) is a form of congenital myopathy, which is defined by type 1 myofibers that are 12% smaller than type 2 myofibers, as well as a general predominance of type 1 myofibers. Conversely, myasthenia gravis (MG) is an acquired immune-mediated disease, in which the acetylcholine receptor (AChR) of the neuromuscular junction is blocked by antibodies. Thus, the anti-AChR antibody is nearly specific to MG. Herein, we report on a case of CFTD with increased anti-AChR antibody levels. A 23-month-old boy exhibited muscle hypotonia and weakness. Although he could walk by himself, he easily fell down and could not control his head for a long time. His blood test was positive for the anti-AChR antibody, while a muscle biopsy revealed characteristics of CFTD. We could not explain the relationship between MG and CFTD. However, we considered different diagnoses aside from MG, even when the patient's blood is positive for the anti-AChR antibody.


Pd-catalyzed carbonylation for the construction of tertiary and quaternary carbon centers with sp(3) carbon partners.
The first examples of a Pd-catalyzed carbonylation of aryl boronic acids with sp(3) carbon partners are presented. Various boronic acids were shown to react with 1,3-diesters and 1,3-diketones to afford structurally unique carbonyl compounds. By employing 2-substituted 1,3-diesters, synthetically-challenging quaternary carbon centres were accessed. In total, 42 examples of aryl carbonyl compounds were prepared in moderate to good yields. The catalytic system features the use of a bidentated phosphine ligand and a relatively low CO pressure (5 atm), providing an easy, alternative method for the preparation of triketones.


Increased productivity in wet years drives a decline in ecosystem stability with nitrogen additions in arid grasslands.
Adding nutrients to nutrient-limited ecosystems typically lowers plant diversity and decreases species asynchrony. Both, in turn, decrease the stability of productivity in the response to negative climate fluctuations such as droughts. However, most classic studies examining stability have been done in relatively wet grasslands dominated by perennial grasses. We examined how nutrient additions influence the stability of productivity to rainfall variability in an arid grassland with a mix of perennial and annual species. Of the nutrients, only nitrogen increased productivity, and only in wet years. In addition, only nitrogen decreased the stability of productivity. Thus, nutrient addition makes ecosystem productivity less stable in both wet and arid grasslands. However, the mechanism is very different. In contrast to wet grasslands, adding nitrogen to an arid grassland did not decrease diversity. Rather, stability decreased with nitrogen addition due to an increase in annual species that increased productivity. In other words, in our arid grassland, nitrogen addition decreased ecosystem stability because of increased ecosystem responsiveness to positive climate fluctuations. These climate fluctuations were facilitated by annual species that take advantage of wet years and can escape dry years as seeds. Our data support the conclusion that nutrient additions decrease the stability of productivity in both wet and arid grasslands. Nutrient enrichment increases the sensitivity of productivity to low rainfall years in wet grasslands, whereas nutrient enrichment in arid grasslands increases the sensitivity of productivity to high rainfall years.


Induction of constitutive melanogenesis in amelanotic mouse melanoma cells by transfection of the human melanocortin-1 receptor gene.
The human melanocortin-1 (MC1) receptor was stably expressed in the amelanotic mouse melanoma cell clone B16-G4F which does not express its own (mouse) MC1 receptor and hence is unresponsive to alpha melanocyte stimulating hormone (alpha MSH). From several stable transfectant cell lines expressing the human MC1 receptor in relatively high numbers, three melanin producing clones (G4F-12, 14, and 15) and one amelanotic clone (G4F-7) were further analyzed in competition binding experiments and in cAMP and melanin assays. The dissociation constants (KD) for [Nle4, D-Phe7]-alpha MSH in all four clones ranged from 0.187 to 0.705 nmol/l, thus corresponding to the KD observed with the different human melanoma cell lines so far studied. Intracellular cAMP content was 3- to 5-fold higher than that of control cells, and alpha MSH induced an additional 1.5- to 1.7-fold increase. G4F-15 cells secreted melanin into the medium whereas the other clones did not secrete melanin. The extent of melanin secretion was similar to that of fully alpha MSH-stimulated B16-F1 mouse melanoma cells but the onset of secretion was delayed. alpha MSH induced an additional dose-related increase (up to 1.3-fold) in melanin production which could be suppressed by the addition of specific alpha MSH antibodies without altering the constitutive part of melanogenesis. Human and mouse agouti proteins, which inhibit basal and alpha MSH-induced melanogenesis in B16-F1 cells, both reduced alpha MSH-induced melanin production in G4F-15 cells but did not affect the constitutive melanogenesis. These results indicate that human MC1 receptor expressed in mouse B16-G4F cells induces constitutive activation of the signalling pathway controlling melanogenesis, most likely by tightly coupling to Gs alpha, in a similar manner to that reported for constitutively active receptor mutants in other systems.


[Tricuspid annuloplasty, pulmonary valve replacement, ventricular septal defect (VSD) patch closure, and right-sided maze procedure 23-years after corrective repair of tetralogy of Fallot].
Postoperative pulmonary valve regurgitation, stenosis of the right ventricular outflow tract, conduit failure, ventricular septal patch leak, secondary tricuspid valve regurgitation, and various arrhythmias are the major complications that develop after surgical repair of tetralogy of Fallot in adults. A 27-year-old male with pulmonary regurgitation, tricuspid regurgitation, residual ventricular septal defect (VSD), low left ventricular function, and chronic atrial fibrillation underwent tricuspid annuloplasty, pulmonary valve replacement with a stentless aortic valve, VSD patch closure, and right-sided maze procedure, and the postoperative course was uneventful. The cardiothoracic ratio decreased, sinus rhythm was restored, and the patient's complaints were relieved. Reoperation at the optimal time after corrective repair of tetralogy of Fallot in adults may improve the outcome.


A sustainable approach to cathode delamination using a green solvent.
Designing an environment-friendly delamination process for an end-of-life (EoL) composite cathode is a crucial step in direct cathode recycling. In this study, the green solvent dimethyl isosorbide (DMI) is explored to extract cathode active materials (AMs) from the Al current collector via dissolving the polyvinylidene fluoride (PVDF) binder. Mechanistic insight suggests that binder removal from the Al substrate proceeds via reducing polymer interchain interaction through DMI penetrating into the PVDF crystalline region. Polymer-solvent interaction may increase via establishing hydrogen bond between PVDF and DMI, which facilitates binder removal. Analytical characterizations including 1H NMR, FTIR, XRD and SEM-EDS reveal that the molecular, micro, and crystal structures of the recovered cathode AMs, PVDF and Al foil are preserved. This finding is expected to provide a replacement for the toxic organic solvent N-methylpyrrolidone (NMP) and offers an effective, ecofriendly, and sustainable direct cathode recycling approach for spent Li-ion batteries.


Senior place at the VNA.
Adult day care enhances the lives of a diverse population that benefits from the socialization and stimulation provided in a structured therapeutic group setting. The key to a successful program is to individualize as much as possible the care to each client while taking into consideration the needs of his or her support system.


Nonsurgical management of patients with stage D1 adenocarcinoma of prostate: risks vs benefits.
Within two years of diagnosis, 50 per cent of patients with Stage D1 prostatic adenocarcinoma will have clinically overt metastatic disease. Any purely local therapy (e.g., radical prostatectomy) appears to offer little in terms of the risk:benefit ratio. However, some form of local therapy is appropriate, since the untreated primary may continue to act as a source of metastases. 125I implantation with concomitant systemic therapy is an excellent therapeutic option for the majority of these patients. If one accepts the premise that local therapy is of limited value in metastatic disease, systemic treatment at the time of initial diagnosis should be considered. According to the data presented by the Mayo Clinic Group, immediate orchiectomy may be the best form of therapy. An alternative to orchiectomy is estrogen therapy or the more recently introduced GnRH analogues. Finally, the issue of identifiable tumor characteristics is addressed. The course of treatment may well be influenced by the identification of biologically aggressive tumors, using indicators such as elevated acid phosphatase. It is still undetermined whether stereology or flow cytometric analysis will further identify slower growing tumors from the more aggressive ones.


[The characteristics of urinary tract infection with urosepsis].
Urinary tract infections (UTIs) are frequently complicated with bacteremia. Many cases of this infection are diagnosed and treated by general practitioners. We retrospectively exam- ined the characteristics of UTIs presenting with urosepsis. We assigned 57 UTI patients into two groups according to the results of the blood cultures. Patients were admitted to the Department of General Practice at Sakai City Hospital from January 1, 2011 to December 31, 2011. We investigated the medical records retrospectively. 22 patients presented with urosepsis and 35 did not. Urosepsis in the patients was significantly associated with diabetes mellitus and ureteral stones (diabetes: 32 vs. 3%, p = 0.004; ureteral stone: 23 vs. 3%, p = 0.03). Nausea or vomiting and hydronephrosis were seen in about one half of the patients with urosepsis and were significantly more frequent (nausea or vomiting: 45 vs. 17%, p = 0.03; hydronephrosis: 36 vs. 11%, p = 0.04). Leukocytosis (white blood cell (WBC) count > 12,000/gL) or leukopenia (WBC count < 4,000 /μL) were significantly more frequent (68% vs. 29%) but no significant association was found between urosepsis and body temperature or C-reactive proteins. Nausea or vomiting, ureteral stones or hydronephrosis, diabetes mellitus and leukocytosis or leukopenia had significantly higher rates in the patients with urosepsis.


RSTFC: A Novel Algorithm for Spatio-Temporal Filtering and Classification of Single-Trial EEG.
Learning optimal spatio-temporal filters is a key to feature extraction for single-trial electroencephalogram (EEG) classification. The challenges are controlling the complexity of the learning algorithm so as to alleviate the curse of dimensionality and attaining computational efficiency to facilitate online applications, e.g., brain-computer interfaces (BCIs). To tackle these barriers, this paper presents a novel algorithm, termed regularized spatio-temporal filtering and classification (RSTFC), for single-trial EEG classification. RSTFC consists of two modules. In the feature extraction module, an l2 -regularized algorithm is developed for supervised spatio-temporal filtering of the EEG signals. Unlike the existing supervised spatio-temporal filter optimization algorithms, the developed algorithm can simultaneously optimize spatial and high-order temporal filters in an eigenvalue decomposition framework and thus be implemented highly efficiently. In the classification module, a convex optimization algorithm for sparse Fisher linear discriminant analysis is proposed for simultaneous feature selection and classification of the typically high-dimensional spatio-temporally filtered signals. The effectiveness of RSTFC is demonstrated by comparing it with several state-of-the-arts methods on three brain-computer interface (BCI) competition data sets collected from 17 subjects. Results indicate that RSTFC yields significantly higher classification accuracies than the competing methods. This paper also discusses the advantage of optimizing channel-specific temporal filters over optimizing a temporal filter common to all channels.


Vertebroplasty: clinical experience and follow-up results.
This study was undertaken to report the clinical experience with percutaneous minimal invasive vertebroplasty using polymethyl-methacrylcate (PMMA) for a consecutive group of patients. Over the period of the last 4 years, 40 patients were treated at 68 vertebral segment levels with the intention to relieve pain related to vertebral body lesions. Reduced vertebral body height and destruction of the posterior vertebral wall were not considered to be exclusion criterias. The vertebroplasty procedure was performed under general anesthesia and in prone position with imaging control using mostly biplane DSA fluoroscopic guidance, and rarely with single-plane mobile DSA combined with computed tomographic guidance. Unilateral, but more frequently bilateral, transpedicular introduction of a 2-3-mm OD needle was followed by an injection of polymethyl-methacrylcate (PMMA). PMMA preparation involved a diluted mixture (20 mL powder for 5 mL liquid) allowing for an extended polymerization time of up to 8 min. The PMMA was mixed with metallic powder to enhance its radio-opacity. Before PMMA injection, a vertebral phlebography was obtained to evaluate the filling pattern and identify sites of potential PMMA leakage. Injection of opacified PMMA was performed under continuous visual control with fluoroscopy to obtain adequate filling and to avoid important PMMA leakage. Clinical follow-up involved an evaluation using a questionnaire for assessment of pain, pain medication, and mobility. One to six levels were treated in one to three treatment sessions for patients with metastatic, osteoporotic, and hemangiomatous lesions of the vertebral bodies who presented with pain. The results observed matched those reported previously with a success rate of approximately 80% and a complication rate below 6% per treated level. Treatment failure and complications observed were related to leakage, insufficient pretreatment evaluation, anesthesia, or patient position during treatment. Image guidance with fluoroscopy was efficient both for precise transpedicular approach and PMMA implantation control. Vertebroplasty is very efficient for treatment of pain. Treatment failure was mostly related to insufficient pretreatment clinical evaluation, and complication due to excessive PMMA volume injection. Control of PMMA volume seems to be the most critical point for avoiding complications. A good fluoroscopy control is therefore mandatory.


Contemporary perspectives on vital pulp therapy: views from the endodontists and pediatric dentists.
The purpose of this study was to determine the level of agreement between pediatric dentists and endodontists at a pulp therapy symposium conjointly sponsored by the American Association of Endodontists (AAE) and the American Academy of Pediatric Dentistry (AAPD) on November 2-3, 2007. Presymposium and postsymposium tests were administered, and respondent answers were compared between pediatric dentists and endodontists. Opinions on 3 areas were sought: pulp therapy for cariously involved primary teeth; indirect pulp treatment (IPT) for cariously involved immature permanent teeth; and innovative treatment options including pulpal revascularization and regeneration. Results were analyzed with chi2 tests. Comparisons of presymposium and postsymposium responses and between the 2 groups of attendees indicated that the pediatric dentistry and endodontic communities agree that formocresol will be replaced as a primary tooth pulpotomy agent, that mineral trioxide is the first choice to take its place, that IPT in primary teeth holds hope as a replacement for pulpotomy, and that IPT is an acceptable pulp therapy technique for cariously involved young permanent teeth. Both groups believe that pulp revascularization and regeneration will be viable treatment modalities in the future. The AAE and the AAPD are positioned to begin preparation of best practice guidelines that share common language and treatment recommendations for pulp therapies performed by both specialties.


Recurrence after gross-total resection of low-grade pediatric brain tumors: the frequency and timing of postoperative imaging.
Low-grade glial and glioneuronal brain tumors are frequently encountered in the pediatric population and can be effectively treated by resection. The authors aimed to use imaging to evaluate how often tumors recurred and to determine if recurrences were associated with any clinical symptoms, along with the financial costs of imaging, in patients with radiographically proven gross-total resection (GTR) at Boston Children's Hospital. These data were assessed to propose guidelines regarding postoperative surveillance. The authors performed a retrospective cohort analysis of the Pediatric Brain Tumor Program database from 1993 to 2003 to identify patients with glial or glioneuronal tumors initially evaluated at Boston Children's Hospital. Among the 888 patients evaluated for any type of brain tumor during this period, 67 patients had WHO Grade I glial or glioneuronal lesions with radiographically proven GTR and available follow-up data. The frequency and timing of postoperative imaging was compared with the institutional protocol. Recurrence-free survival was calculated using the Kaplan-Meier method. Financial costs of imaging were available from 2001 to 2009 and were averaged to extrapolate the postoperative surveillance costs. Among the 67 patients with GTR, 13 recurrences were detected radiographically with a mean time to recurrence of 32.4 months (range 2.9-128.5 months). The mean duration of follow-up after surgery was 6.6 years. The recurrence-free survival at 2 and 5 years after GTR for all low-grade glial and glioneuronal tumors was 0.90 (95% CI 0.82-0.97) and 0.82 (95% CI 0.73-0.92), respectively. No clinical symptoms were associated with any of the recurrences, and no deaths occurred. Under the institutional protocol of surveillance imaging, the estimated cost per recurrence at 5 years was $104,094 per patient. The proposed protocol would reduce the number of MR scans in the first 5 years from 10 to 5, providing a potential cost savings of $52,047 per recurrence. Given the slow-growing, clinically asymptomatic nature of low-grade glial and glioneuronal tumors coupled with the financial and psychological costs of repeated imaging, the authors propose a postoperative surveillance MRI schedule that is less intensive than current institutional practice.


Genome Sequences of Mycobacteriophages Luchador and Nerujay.
Luchador and Nerujay are two newly isolated mycobacteriophages recovered from soil samples using Mycobacterium smegmatis. Their genomes are 53,387 bp and 53,455 bp long and have 96 and 97 predicted open reading frames, respectively. Nerujay is related to subcluster A1 phages, and Luchador represents a new subcluster, A14.


Transcranial magnetic stimulation combined with endogenous human hippocampal and motor cortical activity enhances memory.
The hippocampus is a fundamental cortical structure in the memory process of encoding, retaining, and recalling information. Transcranial Magnetic Stimulation (TMS) following a Paired Associative Stimulation (PAS) enhances nervous system excitability and promotes cortical plasticity mechanisms by synchronizing two stimuli in the same neural pathway. However, PAS has not been shown to improve memorization capacity yet. Here, we present an innovative protocol stemming from the PAS paradigm, which combines single-pulse TMS to the hippocampus with endogenous hippocampal activity during a working memory (WM) task. 96 volunteers were randomized across one experimental group and three parallel groups (motor cortex stimulation, sham stimulation, and no stimulation) in a single session. This combined-stimuli configuration resulted in an increased memorization capacity in the WM task, which was dependent on the stimulated brain location and subjects' basal memory performance. These results are potentially significant for clinical research on memory dysfunction and its related neurological disorders. Future research on paired associative or combined stimulation is required to unveil stimulation-derived neural mechanisms that enhance the ability to memorize.


Unspoken: Child-Perpetrator Dynamic in the Context of Intrafamilial Child Sexual Abuse.
The literature on child sexual abuse (CSA) has contributed greatly to the understanding of child-perpetrator dynamic while mainly addressing the concepts of grooming and manipulation. Considerably less attention has been dedicated, however, to child-perpetrator dynamic in intrafamilial child sexual abuse (IFCSA). The current study examined how children perceive and experience the dynamic with their perpetrator parents in the context of IFCSA, as conveyed by victims. Analysis of 29 forensic interviews with children aged 8 to 14 years suggested above all, across all identified themes, the unspoken nature of IFCSA. Specifically, the children shared their surprise at the abusive incidents despite having described a long and unspoken grooming process. The children shared their understanding of the secretive nature of IFCSA although that too was unspoken, while illustrating the fear and terror in the family dynamic. Finally, the children discussed the elusiveness of the dynamic in terms of the natural and unnatural aspects of the relationship. The discussion addresses the unique nature of IFCSA and the family dynamic. The main implication for practice is the urgent need to modify existing instruction and training programs for practitioners to better adjust them to IFCSA survivors. More specifically, the elusive nature of IFCSA must be conveyed to both clinical and forensic practitioners who need to evaluate and intervene in with child survivors of IFCSA. In addition, the fear and terror that characterize the family dynamic and the unspoken, unbridled rule of the perpetrator fathers are of central importance in adapting interventions to children and their families in the context of IFCSA.


Irritability Predicts Hyperactive/Impulsive Symptoms Across Adolescence for Females.
Irritability is common in Attention-Deficit Hyperactivity Disorder (ADHD), but little is known about whether irritability predicts the course of ADHD symptoms over time. Adolescence is a dynamic period of emotional development as well as shifts in ADHD symptoms; an important goal is to identify youth at risk of increasing or persisting symptoms. We examined irritability as a longitudinal predictor of change in adolescents' ADHD symptoms, as well as how this link may differ in females versus males. The sample included 108 youth (72 males) age 12-16 years (M = 14.21 years, SD = 1.44 years), 62 of whom met criteria for ADHD. Approximately 18 months later, 80 participants (48 males) were followed up at Time 2. A dimensional approach was used to examine changes over time in parent-reported inattentive and hyperactive/impulsive symptoms. Longitudinal path analysis revealed that irritability at Time 1 predicted higher relative hyperactive/impulsive symptoms at Time 2 after controlling for age and longitudinal stability in all variables. A multiple-group analysis examining moderation by sex/gender revealed that this association was significant only for females. These results suggest that irritability may play a key role in the persistence and worsening of hyperactive/impulsive symptoms across adolescence for females, with potential implications for the diagnosis and treatment of females with ADHD.


Shaping dynamical neural computations using spatiotemporal constraints.
Dynamics play a critical role in computation. The principled evolution of states over time enables both biological and artificial networks to represent and integrate information to make decisions. In the past few decades, significant multidisciplinary progress has been made in bridging the gap between how we understand biological versus artificial computation, including how insights gained from one can translate to the other. Research has revealed that neurobiology is a key determinant of brain network architecture, which gives rise to spatiotemporally constrained patterns of activity that underlie computation. Here, we discuss how neural systems use dynamics for computation, and claim that the biological constraints that shape brain networks may be leveraged to improve the implementation of artificial neural networks. To formalize this discussion, we consider a natural artificial analog of the brain that has been used extensively to model neural computation: the recurrent neural network (RNN). In both the brain and the RNN, we emphasize the common computational substrate atop which dynamics occur -- the connectivity between neurons -- and we explore the unique computational advantages offered by biophysical constraints such as resource efficiency, spatial embedding, and neurodevelopment.


Initial blood pressure response to enalapril in hospitalized patients (Studies of Left Ventricular Dysfunction [SOLVD]).
Studies of Left Ventricular Dysfunction (SOLVD) is a randomized trial of enalapril versus placebo in reducing mortality in patients with cardiac dysfunction (defined as left ventricular ejection fraction less than or equal to 35%). Before randomization, patients at risk for hypotension were hospitalized for a test dose of 2.5 mg of enalapril administered orally at baseline and again 12 hours later. As of February 1989, 89 of 7,539 (1.2%) patients had been studied during hospitalization. Baseline systolic and diastolic blood pressures were 115 +/- 18 and 73 +/- 10 mm Hg, respectively. After enalapril, systolic blood pressure decreased slightly but significantly 8 to 20 hours after the initial dose (mean reduction 8 to 11 mm Hg). In this highly selected group of 89 patients, symptoms relating to decrease in blood pressure were noted in 13 (15%). It is emphasized that most patients with cardiac dysfunction readily tolerate enalapril. However, the agent should be administered with caution to patients with advanced congestive failure and diminished baseline blood pressure, owing to a significant incidence of symptomatic hypotension.


Evaluation of Systematic Reviews of Interventions for Retina and Vitreous Conditions.
Patient care and clinical practice guidelines should be informed by evidence from reliable systematic reviews. The reliability of systematic reviews related to forthcoming guidelines for retina and vitreous conditions is unknown. To summarize the reliability of systematic reviews on interventions for 7 retina and vitreous conditions, describe characteristics of reliable and unreliable systematic reviews, and examine the primary area in which they appeared to be lacking. A cross-sectional study of systematic reviews was conducted. Systematic reviews of interventions for retina- and vitreous-related conditions in a database maintained by the Cochrane Eyes and Vision United States Satellite were identified. Databases that the reviewers searched, whether any date or language restrictions were applied, and bibliographic information, such as year and journal of publication, were documented. The initial search was conducted in March 2007, and the final update was performed in July 2018. The conditions of interest were age-related macular degeneration; diabetic retinopathy; idiopathic epiretinal membrane and vitreomacular traction; idiopathic macular hole; posterior vitreous detachment, retinal breaks, and lattice degeneration; retinal and ophthalmic artery occlusions; and retinal vein occlusions. The reliability of each review was evaluated using prespecified criteria. Data were extracted by 2 research assistants working independently, with disagreements resolved through discussion or by 1 research assistant with verification by a senior team member. Proportion of reviews that meet all of the following criteria: (1) defined eligibility criteria for study selection, (2) described conducting a comprehensive literature search, (3) reported assessing risk of bias in included studies, (4) described using appropriate methods for any meta-analysis performed, and (5) provided conclusions consistent with review findings. A total of 327 systematic reviews that addressed retina and vitreous conditions were identified; of these, 131 reviews (40.1%) were classified as reliable and 196 reviews (59.9%) were classified as not reliable. At least 1 reliable review was found for each of the 7 retina and vitreous conditions. The most common reason that a review was classified as not reliable was lack of evidence that a comprehensive literature search for relevant studies had been conducted (149 of 196 reviews [76.0%]). The findings of this study suggest that most systematic reviews that addressed interventions for retina and vitreous conditions were not reliable. Systematic review teams and guideline developers should work with information professionals who can help navigate sophisticated and varied syntaxes required to search different resources.


ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes.
ETS1 has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1 high BRCA patients showed better prognosis and longer survival compared to ETS1 low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.


The effect of fearful expressions on recognition memory for faces: Behavioral and electrophysiological data.
Facial expressions affect memory for face identity. We tested how fearful expressions modulate recognition memory for faces. In two studies, participants completed a continuous recognition task with fearful and neutral faces while their electroencephalogram was recorded. Each face stimulus was presented twice and participants were instructed to indicate whether it was presented for the first ('new') or second time ('old'). The false alarm rate was higher for fearful than neutral faces, which is opposite to the emotion enhancement effect on memory but in line with the liberal response bias for emotional information. There was no evidence of emotional modulation of the N400 old/new effect, which suggests that the sense of familiarity was not affected by fearful facial expressions. The LPC old/new effect, however, was modulated by facial expression, as it was absent for fearful faces because of a greater positivity in response to new fearful than new neutral faces. This LPC old/new effect finding may reflect that the emotional salience of fearful new faces is mistaken for a sense of recollection, resulting in an increased false alarm rate. In short, people seem more likely to (mistakenly) think that they have encountered a person before when the person looks scared compared to non-emotional, which has relevance for daily life and forensic situations such as police lineups.


Platelet-derived growth factor inhibits bone regeneration induced by osteogenin, a bone morphogenetic protein, in rat craniotomy defects.
Platelet-derived growth factor (PDGF) is a potent moderator of soft tissue repair through induction of the inflammatory phase of repair and subsequent enhanced collagen deposition. We examined the effect of recombinant BB homodimer PDGF (rPDGF-BB) applied to rat craniotomy defects, treated with and without bovine osteogenin (OG), to see if bone regeneration would be stimulated. Implants containing 0, 20, 60, or 200 micrograms rPDGF-BB, reconstituted with insoluble rat collagenous bone matrix containing 0, 30, or 150 micrograms OG, were placed into 8-mm craniotomies. After 11 d, 21 of the 144 rats presented subcutaneous masses superior to the defect sites. The masses, comprised of serosanguinous fluid encapsulated by fibrous connective tissue, were larger and occurred more frequently in rats treated with 200 micrograms rPDGF-BB, and were absent in rats not treated with rPDGF-BB. The masses underwent resorption within 28 d after surgery. OG (2-256 micrograms) caused a dose-dependent increase in radiopacity and a marked regeneration of calcified tissue in a dose-dependent fashion within defect sites. However, OG-induced bone regeneration was inhibited 17-53% in the presence of rPDGF-BB. These results suggest that rPDGF-BB inhibited OG-induced bone regeneration and stimulated a soft tissue repair wound phenotype and response.


The new epoch of structural insights into radical SAM enzymology.
The Radical SAM (RS) superfamily of enzymes catalyzes a wide array of enzymatic reactions. The majority of these enzymes employ an electron from a reduced [4Fe-4S]+1 cluster to facilitate the reductive cleavage of S-adenosyl-l-methionine, thereby producing a highly reactive 5'-deoxyadenosyl radical (5'-dA⋅) and l-methionine. Typically, RS enzymes use this 5'-dA⋅ to extract a hydrogen atom from the target substrate, starting the cascade of an expansive and impressive variety of chemical transformations. While a great deal of understanding has been gleaned for 5'-dA⋅ formation, because of the chemical diversity within this superfamily, the subsequent chemical transformations have only been fully elucidated in a few examples. In addition, with the advent of new sequencing technology, the size of this family now surpasses 700,000 members, with the number of uncharacterized enzymes and domains also rapidly expanding. In this review, we outline the history of RS enzyme characterization in what we term "epochs" based on advances in technology designed for stably producing these enzymes in an active state. We propose that the state of the field has entered the fourth epoch, which we argue should commence with a protein structure initiative focused solely on RS enzymes to properly tackle this unique superfamily and uncover more novel chemical transformations that likely exist.


The clinical features of Fournier's gangrene and the predictivity of the Fournier's Gangrene Severity Index on the outcomes.
Fournier's gangrene (FG) is a rare, rapidly progressive, fulminant form of necrotizing fasciitis of the genital, perianal and perineal regions. Several factors have been reported to contribute to the clinical outcomes. The primary aims of this study were to examine the clinical features of patients with FG and evaluate the predictivity of the Fournier's Gangrene Severity Index (FGSI) score on the outcomes. We carried out a collective retrospective chart review of patients diagnosed and treated for FG in three reference centers between January 1995 and July 2007. Seventy-two patients with FG with were included to the study. Data were collected on medical history, symptoms, physical examination findings, admission and final laboratory tests, timing and extent of surgical debridement and antibiotic therapy. Perianal and perirectal abscess, scrotal abscess and urethral stenosis were the leading etiological factors. Diabetes mellitus was the predominant risk factor. Etiological factors and risk factors did not significantly contribute to survival or mortality, and duration of the symptoms was significantly longer in the non-survivor's group (P < 0.05). The FGSI scores were higher in the non-survivor's group. Regression analysis showed a FGSIS score of 10.5 as the cut-off to the outcome. Based on these results, we conclude that a patient's metabolic status and the extent of disease at presentation are the most important factors determining the prognosis of FG. The FGSI score may be considered as an objective and simple tool to predict the outcome in the patient with FG and should be used in further studies of FG patient series for comparison purposes.


Two-dimensional pentagonal CrX (X = S, Se or Te) monolayers: antiferromagnetic semiconductors for spintronics and photocatalysts.
Two dimensional (2D) materials with hexagonal building blocks have received tremendous interest in recent years and show promise as nanoscale devices for versatile applications. Herein, we propose a new family of 2D pentagonal CrX (X = S, Se or Te) monolayers (penta-CrX) for applications in electronics, spintronics and photocatalysis. We find that the 2D penta-CrX monolayers are thermally, structurally and mechanically stable. The penta-CrX monolayers are antiferromagnetic and semiconducting. We show that the magnetism is attributed to the super-exchange induced by the ionic interactions between the Cr and X atoms and can be enhanced upon applying tension. We further show that the penta-CrS and penta-CrSe monolayers show good redox potentials versus a normal hydrogen electrode, and their band gaps are comparable to the energy of a photon in the visible light region, indicating their capability of maximal utilization of solar energy for water splitting. With intrinsic semiconducting and controllable magnetic properties, the proposed penta-CrX monolayers may hold promise as flexible spintronics and photocatalysts.


Impact of Background Noise and Sentence Complexity on Processing Demands during Sentence Comprehension.
Speech comprehension in adverse listening conditions can be effortful even when speech is fully intelligible. Acoustical distortions typically make speech comprehension more effortful, but effort also depends on linguistic aspects of the speech signal, such as its syntactic complexity. In the present study, pupil dilations, and subjective effort ratings were recorded in 20 normal-hearing participants while performing a sentence comprehension task. The sentences were either syntactically simple (subject-first sentence structure) or complex (object-first sentence structure) and were presented in two levels of background noise both corresponding to high intelligibility. A digit span and a reading span test were used to assess individual differences in the participants' working memory capacity (WMC). The results showed that the subjectively rated effort was mostly affected by the noise level and less by syntactic complexity. Conversely, pupil dilations increased with syntactic complexity but only showed a small effect of the noise level. Participants with higher WMC showed increased pupil responses in the higher-level noise condition but rated sentence comprehension as being less effortful compared to participants with lower WMC. Overall, the results demonstrate that pupil dilations and subjectively rated effort represent different aspects of effort. Furthermore, the results indicate that effort can vary in situations with high speech intelligibility.


Effect of Adrenoreceptor Stimulation on Peptidergic Regulation of Cardiac Activity in Newborn Rats.
We studied the effect of adrenoreceptor stimulation on the frequency of spontaneous activity and amplitude-time parameters of isometric contraction of the atrial myocardial strips from newborn rats, as well as the effect of Y receptor stimulation against the background of adrenoreceptor activation. After addition of Y1,5 receptor agonist [Leu31, Pro34] NPY (10-7 M), a tendency to a decrease in the effect of β1,2-adrenoreceptor agonist isoproterenol (10-5 M) on the frequency of spontaneous activity and atrial myocardial contractility was observed. The age-related features of the effect of NPY on the frequency of spontaneous activity and contractility of myocardial strips from newborn and adult rats were revealed.


Adverse birth outcomes associated with open dumpsites in Alaska Native Villages.
This retrospective cohort study evaluated adverse birth outcomes in infants whose birth records indicated maternal residence in villages containing dumpsites potentially hazardous to health and environment. Birth records from 1997 to 2001 identified 10,073 eligible infants born to mothers in 197 Alaska Native villages. Outcomes included low or very low birth weight, preterm birth, and intrauterine growth retardation. Infants from mothers in villages with intermediate (odds ratio (OR) = 1.73, 95% confidence interval (CI): 1.06, 2.84) and high (OR = 2.06, 95% CI: 1.28, 3.32) hazard dumpsites had a higher proportion of low birth weight infants than did infants from mothers in the referent category. More infants born to mothers from intermediate (OR = 4.38, 95% CI: 2.20, 8.77) and high (OR = 3.98, 95% CI: 1.93, 8.21) hazard villages suffered from intrauterine growth retardation. On average, infants weighed 36 g less (95% CI: -71.2, -0.8) and 55.4 g less (95% CI: -95.3, -15.6) when born to highly exposed mothers than did infants in the intermediate and low exposure groups, respectively, an effect even larger in births to Alaska Native mothers only. No differences in incidence were detected across exposure levels for other outcomes. This is the first study to evaluate adverse pregnancy outcomes associated with open dumpsites in Alaska Native villages.


Forty-year follow-up of coronary heart disease mortality and its predictors: the Corfu cohort of the seven countries study.
The authors examined the effect of several risk factors in relation to coronary heart disease (CHD) mortality in the Corfu cohort of the Seven Countries Study. The population studied in this analysis consisted of 529 rural men (age 40-59 years) enrolled in 1961. Multivariate analysis was performed with CHD death as the end point; age, blood pressure, heart rate, serum total cholesterol, smoking, physical activity, body mass index, skinfold thickness, vital capacity, and forced expiratory volume were the predictors. The 40-year CHD survival rate was 63% (108 deaths). Age (hazard ratio [HR]=1.093; p<0.001), smoking (HR=1.79; p<0.05), body mass index (HR=1.05; p<0.1), and serum total cholesterol (HR=1.004; p<0.2) were independently associated with 40-year CHD mortality. Conclusively, in men from the Corfu cohort, age, lifestyle habits (expressed as smoking and body mass index), and serum cholesterol levels were consistently associated with 40-year CHD mortality. In addition, the current status of men in the Corfu cohort is marked by long-term adoption of a Mediterranean type of diet, physical activity, and optimism.


[Current data on tiagabine].
To review current data regarding the mode of action, pharmacokinetics, clinical efficacy and tolerance of tiagabine (TGB). TGB is a drug which boosts gabergic inhibition by blocking the re-uptake of synaptic GABA by the glia and neurones. This specific mode of action leads to an antiepileptic effect in patients of all ages with partial seizures. The efficacy of TGB is complemented by good tolerance, especially when it is introduced slowly, over a period of eight weeks. This form of administration is also used with other new antiepileptic drugs, such as lamotrigine and topiramate. We consider the data regarding efficacy and tolerance found in the clinical trials and studies reported in the literature. TGB is an effective, well-tolerated drug when used in patients with difficult-to-control partial crises. However, it should also be used in patients with less difficult-to-control seizures and in previously untreated patients so as to properly define its efficacy and tolerance.


The development of the Belgian paediatric clinical trial network.
Paediatric clinical trials are critical to ensure that medications prescribed to children are safe and effective. However, evidence-based dosing and labelling of such medications remain limited, and most clinical trials in paediatrics fail. Factors for lack of trial completion include performance at site level (limited patient recruitment, limited site staff experience and lack of infrastructure), the sponsor team (limited paediatric specific expertise in design, uncertainties on robustness of biomarkers or outcome variables) as well as regulatory and administrative burdens. As a result of the growing demand for site support, the Belgian Paediatric Clinical Research Network (BPCRN) established in 2009 has been relaunched in 2018 to improve paediatric clinical trials, with the support of innovative-medicines-initiative 2 (IMI2) pan-European network conect4children (c4c) and the transatlantic network I-ACT for Children (US).This paper highlights the formation of the BPCRN and the practical insights it offers for advancing paediatric clinical trials through national networks. A national network can improve trial quality, safety and efficiency, provide clinical research expertise, identify suitable sites, and help with troubleshooting of common trial issues. The BPCRN's centralized approach has advanced paediatric clinical trials by streamlining communication and standardizing trial conduct. Challenges and opportunities have arisen, including a relaunch in 2018, orphan medicine trials, and network sustainability. Collaboration between network activities, government support, site-level improvements, efficient communication, and interaction with industry are key to achieve lasting transformation in paediatric medicine research.


Application of a novel highly sensitive activity-based probe for detection of cathepsin G.
Cathepsins are crucial in antigen processing in the major histocompatibility complex class II (MHC II) pathway. Within the proteolytic machinery, three classes of proteases (i.e., cysteine, aspartic, and serine proteases) are present in the endocytic compartments. The combined action of these proteases generates antigenic peptides from antigens, which are loaded to MHC II molecules for CD4+ T cell presentation. Detection of active serine proteases in primary human antigen-presenting cells (APCs) is restricted because of the small numbers of cells isolated from the peripheral blood. For this purpose, we developed a novel highly sensitive α-aminoalkylphosphonate diphenyl ester (DAP) activity-based probe to detect the serine protease cathepsin G (CatG) in primary APCs and after Epstein-Barr virus (EBV) exposure. Although CatG activity was not altered after short-term exposure of EBV in primary myeloid dendritic cells 1 (mDC1s), the aspartic protease cathepsin D (CatD) was reduced, suggesting that EBV is responsible for mitigating the presentation of a model antigen tetanus toxoid C-fragment (TTCF) by reduction of CatD. In addition, CatG activity was reduced to background levels in B cells during cell culture; however, these findings were independent of EBV transformation. In conclusion, our activity-based probe can be used for both Western blot and 96-well-based high-throughput CatG detection when cell numbers are limited.


Tycho Brahe: astronomer of Renaissance Denmark.
As the result of a duel early in the life of this flamboyant scientist, Tycho Brahe lost his nose and soon after began to wear a prosthesis. Although evidence is impressionistic at best, Tycho's case can be seen as an example of how the use of a prosthesis produced significant biographic changes.


Ankle joint arthroscopy.
The arthroscope has been used clinically on the knee for quite some time. The history of arthroscopy is reviewed. The technique of arthroscopic surgery on the knee is summarized. The applications of its use on the ankle joint is discussed as well as technique for arthroscopy. A case report is presented and experiences with arthroscope for diagnosis of ankle problems at Harrison Community Hospital are summarized.


Understanding why GPs see pharmaceutical representatives: a qualitative interview study.
Doctors are aware of the commercial bias in pharmaceutical representative information; nevertheless, such information is known to change doctors' prescribing, and augment irrational prescribing and prescribing costs. To explore GPs, reasons for receiving visits from pharmaceutical representatives. Qualitative study with semi-structured interviews. One hundred and seven general practitioners (GPs) in practices from two health authorities in the North West of England. The main outcome measures of the study were: reasons for receiving/not receiving representative visits; advantages/disadvantages in receiving visits; and quality of representative-supplied information. Most GPs routinely see pharmaceutical representatives, because they bring new drug information speedily; they are convenient and accessible; and can be consulted with a saving of time and effort. Many GPs asserted they had the skills to critically appraise the evidence. Furthermore, the credibility and social characteristics of the representative were instrumental in shaping GPs' perceptions of representatives as legitimate information providers. GPs also received visits from representatives for reasons other than information acquisition. These reasons are congruent with personal selling techniques used in marketing communications. The study draws attention to the social and cultural contexts of GP-representative encounters and the way in which the acquisition of pharmacological information within the mercantile context of representative visits is legitimated. This highlights the need for doctors to critically appraise information supplied by representatives in relation to other information sources.


The Salmon in Pregnancy Study: study design, subject characteristics, maternal fish and marine n-3 fatty acid intake, and marine n-3 fatty acid status in maternal and umbilical cord blood.
Oily fish provides marine n-3 (omega-3) fatty acids that are considered to be important in the growth, development, and health of the fetus and newborn infant. The objectives were to increase salmon consumption among pregnant women and to determine the effect on maternal and umbilical cord plasma marine n-3 fatty acid content. Women (n = 123) with low habitual consumption of oily fish were randomly assigned to continue their habitual diet or were provided with 2 portions of farmed salmon/wk to include in their diet from week 20 of pregnancy until delivery. Median weekly consumption frequency of study salmon in the salmon group was 1.94 portions, and total fish consumption frequency was 2.11 portions/wk in the salmon group and 0.47 portions/wk in the control group (P < 0.001). Intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the diet, from seafood, and from oily fish were higher in the salmon group (all P < 0.001). Percentages of EPA and DHA in plasma phosphatidylcholine decreased during pregnancy in the control group (P for trend = 0.029 and 0.008, respectively), whereas they increased in the salmon group (P for trend for both < 0.001). EPA and DHA percentages were higher in maternal plasma phosphatidylcholine at weeks 34 and 38 of pregnancy and in umbilical cord plasma phosphatidylcholine in the salmon group (P < 0.001 for all). If pregnant women, who do not regularly eat oily fish, eat 2 portions of salmon/wk, they will increase their intake of EPA and DHA, achieving the recommended minimum intake; and they will increase their and their fetus' status of EPA and DHA. This trial was registered at clinicaltrials.gov as NCT00801502.


Virtual screening using combinatorial cyclic peptide libraries reveals protein interfaces readily targetable by cyclic peptides.
Protein-protein and protein-peptide interactions are responsible for the vast majority of biological functions in vivo, but targeting these interactions with small molecules has historically been difficult. What is required are efficient combined computational and experimental screening methods to choose among a number of potential protein interfaces worthy of targeting lead macrocyclic compounds for further investigation. To achieve this, we have generated combinatorial 3D virtual libraries of short disulfide-bonded peptides and compared them to pharmacophore models of important protein-protein and protein-peptide structures, including short linear motifs (SLiMs), protein-binding peptides, and turn structures at protein-protein interfaces, built from 3D models available in the Protein Data Bank. We prepared a total of 372 reference pharmacophores, which were matched against 108,659 multiconformer cyclic peptides. After normalization to exclude nonspecific cyclic peptides, the top hits notably are enriched for mimetics of turn structures, including a turn at the interaction surface of human α thrombin, and also feature several protein-binding peptides. The top cyclic peptide hits also cover the critical "hot spot" interaction sites predicted from the interaction crystal structure. We have validated our method by testing cyclic peptides predicted to inhibit thrombin, a key protein in the blood coagulation pathway of important therapeutic interest, identifying a cyclic peptide inhibitor with lead-like activity. We conclude that protein interfaces most readily targetable by cyclic peptides and related macrocyclic drugs may be identified computationally among a set of candidate interfaces, accelerating the choice of interfaces against which lead compounds may be screened.


Correlations for the acute toxicity of multiple nitrogen substituted aromatic molecules.
Twenty-nine compounds, including amino and nitro derivatives of aromatic hydrocarbons as well as azaarenes and indole analogs, were assayed. The biological activity was monitored as population growth to axenic cultures of the ciliate Tetrahymena pyriformis. Structure-activity relationships were examined by linear regression analysis of log biological activity (Y) and log 1-octanol/water partition coefficient (X). Partition coefficients were determined by linear regression analysis of the retention time index of HPLC data. Attempts to generate linear predictive correlations for all the test compounds (n = 29; r2 = 0.325; P greater than 0.0013) and groups, subdivided based on the following chemical classes: aromatic hydrocarbons (n = 13; r2 = 0.122; P greater than 0.2417), azaarenes (n = 9; r2 = 0.348; P greater than 0.0946) and indole analogs (n = 7; r2 = 0.743; P greater than 0.0126), met with little success. Similarly, subdivisions based on the presence of a single (n = 14; r2 = 0.514; P greater than 0.0039) or multiple H-polar groups, i.e., NO2, NH2 (n = 15; r2 = 0.195; P greater than 0.0996), met with little success also. However, if one segregates the compounds which have para oriented H-polar substituents one gets a strong linear predictive correlation (n = 11; r2 = 0.889; P greater than 0.0001). A subdivision of the remaining data set leads to two models (n = 11; r2 = 0.845; P greater than 0.0001) and (n = 7; r2 = 0.965; P greater than 0.0001). An examination of the toxicity partitioning product values suggests the three-line predictive correlation model of these data is valid.