Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism.
The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the PROKR2 gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as "dual molecular diagnosis." The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the SEMA7A and DUSP6 variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.


Predicting cognitive-language and social growth curves from early maternal behaviors in children at varying degrees of biological risk.
Growth modeling was used to examine the relation of early parenting behaviors (averaged across 6 and 12 months) with rates of change in children's cognitive-language and social response and initiating skills assessed at 6, 12, 24, and 40 months. Groups of full-term (n = 112) and very low birth weight children, divided into medically low (n = 114) and high risk (HR; n = 73), were included to evaluate whether children who vary in their rate of development are influenced in different ways by early parenting styles. Parenting behaviors that were sensitive to children's focus of interest and did not highly control or restrict their behaviors predicted greater increases and faster rates of cognitive-language and social development, with relations stronger for the HR versus the other two groups. These maternal behaviors may provide the support all infants need to establish an optimal early foundation for later development and the specific support HR children need to learn in spite of early attentional and organizational problems.


Disruption of the human SCL locus by "illegitimate" V-(D)-J recombinase activity.
A fusion complementary DNA in the T cell line HSB-2 elucidates a provocative mechanism for the disruption of the putative hematopoietic transcription factor SCL. The fusion cDNA results from an interstitial deletion between a previously unknown locus, SIL (SCL interrupting locus), and the 5' untranslated region of SCL. Similar to 1;14 translocations, this deletion disrupts the SCL 5' regulatory region. This event is probably mediated by V-(D)-J recombinase activity, although neither locus is an immunoglobulin or a T cell receptor. Two other T cell lines, CEM and RPMI 8402, have essentially identical deletions. Thus, in lymphocytes, growth-affecting genes other than immune receptors risk rearrangements.


Transcriptome Sequencing Analysis of Root in Soybean Responding to Mn Poisoning.
Manganese (Mn) is among one of the essential trace elements for normal plant development; however, excessive Mn can cause plant growth and development to be hindered. Nevertheless, the regulatory mechanisms of plant root response to Mn poisoning remain unclear. In the present study, results revealed that the root growth was inhibited when exposed to Mn poisoning. Physiological results showed that the antioxidase enzyme activities (peroxidase, superoxide dismutase, ascorbate peroxidase, and catalase) and the proline, malondialdehyde, and soluble sugar contents increased significantly under Mn toxicity stress (100 μM Mn), whereas the soluble protein and four hormones' (indolebutyric acid, abscisic acid, indoleacetic acid, and gibberellic acid 3) contents decreased significantly. In addition, the Mn, Fe, Na, Al, and Se contents in the roots increased significantly, whereas those of Mg, Zn, and K decreased significantly. Furthermore, RNA sequencing (RNA-seq) analysis was used to test the differentially expressed genes (DEGs) of soybean root under Mn poisoning. The results found 45,274 genes in soybean root and 1430 DEGs under Mn concentrations of 5 (normal) and 100 (toxicity) μM. Among these DEGs, 572 were upregulated and 858 were downregulated, indicating that soybean roots may initiate complex molecular regulatory mechanisms on Mn poisoning stress. The results of quantitative RT-PCR indicated that many DEGs were upregulated or downregulated markedly in the roots, suggesting that the regulation of DEGs may be complex. Therefore, the regulatory mechanism of soybean root on Mn toxicity stress is complicated. Present results lay the foundation for further study on the molecular regulation mechanism of function genes involved in regulating Mn tolerance traits in soybean roots.


[Cesostoma in tumors of the large intestine and a method for its closure].
Cecostomy is found to prevent effectively suture incompetency of entero-entero-anastomosis in intraabdominal resections in the large intestine in obese patients suffering diabetes and also in aged patients. The method of closing the cecostoma described may be also recommended for elimination of parietal fistulas constructed in other portions of the large intestine. Taking into account a simple technic of closure, using mechanic suture, the availability of suturing apparatuses in many hospitals, it may be recommended for a wide practical use.


Metastatic cancer involving bladder: a review.
Bladder cancer is the fourth most common cancer in men and the ninth most common cancer in women. Bladder is not a common site for metastasis of cancer and often goes undiagnosed in the clinical follow up of cancer patients. We reviewed the literature for published reports on metastatic cancer involving bladder. We searched MEDLINE, PubMed and OVID from 1953 to June 2005 for published reports on metastatic cancer involving bladder. They key words used were bladder, cancer and metastatic. A total of 2405 abstracts were reviewed. All relevant articles reporting metastatic cancer to the bladder were reviewed. We found 264 cases of metastasis to the bladder from various primary foci. We found that a majority of these malignancies had primary foci in the genitourinary tract and the colon and rectum. Of the malignancies arising from distant foci, melanomas appear to be the most common followed by breast and gastric carcinoma. The definitive diagnosis of metastatic bladder cancers is often difficult, and poses a significant challenge to the physician, pathologist and the radiologist alike. Bladder adenocarcinomas are uncommon and any adenocarcinoma of the bladder should be viewed with a high index of suspicion for a metastatic cancer from a distant focus.


Social amplification of risk in the Internet environment.
This article analyzes the dynamic process of risk amplification in the Internet environment with special emphasis on public concern for environmental risks from a high-speed railway tunnel construction project in South Korea. Environmental organizations and activists serving as social stations collected information about the project and its ecological impact, and communicated this with the general public, social groups, and institutions. The Internet provides social stations and the public with an efficient means for interactive communication and an open space for active information sharing and public participation. For example, while the website of an organization such as an environmental activist group can initially trigger local interest, the Internet allows this information to be disseminated to a much wider audience in a manner unavailable to the traditional media. Interaction among social stations demonstrates an amplifying process of public attention to the risk. Analyses of the volume of readers' comments to online newspaper articles and public opinions posted on message board of public and nonprofit organizations show the ripple effects of the amplification process as measured along temporal, geographical, and sectoral dimensions. Public attention is also influenced by the symbolic connotations of risk information. Interpretations of risk in religious, political, or legal terms intensify public concern for the environmental risk.


Efficacy of hydrocortisone in preventing posttraumatic stress disorder following critical illness and major surgery.
Like other humans exposed to extreme trauma, patients who have been treated in an intensive care unit (ICU) often report traumatic memories. Extremely traumatic memories from the ICU in some of these patients are associated with the development of posttraumatic stress disorder (PTSD), which results in significant impairments in health-related quality of life (HRQL) outcomes of ICU therapy. Severely ill patients in the ICU often show insufficient endogenous glucocorticoid signaling, which has recently been termed critical illness-related corticosteroid insufficiency (CIRCI). We performed several controlled trials in ICU patients with suspected CIRCI from septic shock or cardiac surgery, which indicated that the administration of glucocorticoids (stress doses of hydrocortisone) during ICU treatment results in a significant reduction of PTSD symptoms in long-term survivors as well as improvements in HRQL outcomes. Stress doses of hydrocortisone could help to surmount impaired glucocorticoid signaling from CIRCI during critical illness resulting in a downregulation of the stress response as well as inhibition of traumatic memory retrieval and facilitated extinction of aversive information.


Direct measurement of the self-exchange rate of stellacyanin by a novel e.p.r. method.
A method for reconstituting the blue copper protein stellacyanin with the stable copper isotopes 63Cu and 65Cu is reported. Small differences in the e.p.r. spectra of the two isotopic forms of stellacyanin have been used to monitor the electron self-exchange reaction of stellacyanin by rapid-freeze e.p.r. methods. The self-exchange rate constant (k11) for stellacyanin has been determined as 1.2 X 10(5) M-1 X S-1 at 20 degrees C. This value is in close agreement with values obtained from less-direct methods.


A Rare Clinical Presentation With a Difficult Imaging Diagnosis of an Intra-articular Clear Cell Sarcoma of the Knee.
Clear cell sarcoma, a highly aggressive cell sarcoma with melanotic differentiation, typically occurs in the tendon and aponeuroses of the lower extremities and rarely develops in the intra-articular region. Herein, we present an extremely rare case of clear cell sarcoma originating from the intra-articular knee and suspected as benign tumors due to the benign-looking findings on MRI and PET/CT. The image results in our case were completely consistent with a tenosynovial giant cell tumor, resulting in the misdiagnosis. For differential diagnosis, especially malignant melanoma, histopathology, including IHC and FISH, was indispensable.


Multi-frequency differential absorption LIDAR system for remote sensing of CO2 and H2O near 1.6 µm.
The specifications and performance of a ground-based differential absorption LIDAR (light detection and ranging) system (DIAL) using an optical parametric oscillator (OPO) are presented. The OPO is injection-seeded with the output of a confocal filter cavity at frequencies generated by an electro-optic phase modulator (EOM) from a fixed-frequency external cavity diode laser (ECDL). The number of seed frequencies, frequency spacings, and duration is controlled with an arbitrary waveform generator (AWG) driving the EOM. Range resolved data are acquired using both photon current and photon counts from a hybrid detection system. The DIAL measurements are performed using a repeating sequence of 10 frequencies spanning a range of 37.5 GHz near 1602.2 nm to sequentially sample CO2 and H2O at 10 Hz. Dry air mixing ratios of CO2 and H2O with a resolution of 250 m and an averaging time of 10 min resulted in uncertainties as low as 6 µmol/mol (ppm) and 0.44 g/kg, respectively. Simultaneous measurements using an integrated path differential absorption (IPDA) LIDAR system and in situ point sensor calibrated to WMO (World Meteorological Organization) gas standards are conducted over two 10 hr nighttime periods to support traceability of the DIAL results. The column averaged DIAL mixing ratios agree with the IPDA LIDAR results to within the measured uncertainties for much of two measurement periods. Some of the discrepancies with the in situ point sensor results are revealed through trends observed in the gradients of the range resolved DIAL data.


Niels Stensen (1638-1686): scientist, neuroanatomist, and saint.
Niels Stensen (1638-1686) was a prominent Danish scientist who laid the foundations of paleontology, geology, and crystallography. He undertook a personal search for the truth, rejecting many assumptions of his time, and he struggled to acquire a firm foundation of knowledge based on close observation and rigorous experimentation. Niels Stensen is known eponymously for the discovery of the duct of the parotid gland (ductus stenonianus) but most clinicians are not familiar with his contributions to anatomy beyond his studies on the glands. In 1665, he delivered a lecture in Paris on the anatomy of the brain, the Discours sur l'anatomie du cerveau ("A Dissertation on the Anatomy of the Brain"), which is a seminal investigation on methods in neuroscience. His scientific letter on a hydrocephalic calf represents an early pathophysiological investigation on hydrocephalus. In 1667 Stensen converted to Catholicism and in 1677 he was consecrated titular bishop of Titiopolis. He spent the last years of his life in poverty and traveled continuously trying to bring back northern Europe to Catholicism. This essay highlights the life and the scientific contributions of Niels Stensen, with emphasis on his contributions to neuroscience.


Color induction in equiluminant flashed stimuli.
Color induction is the influence of the surrounding color (inducer) on the perceived color of a central region. There are two different types of color induction: color contrast (the color of the central region shifts away from that of the inducer) and color assimilation (the color shifts towards the color of the inducer). Several studies on these effects have used uniform and striped surrounds, reporting color contrast and color assimilation, respectively. Other authors [J. Vis.12(1), 22 (2012)1534-736210.1167/12.12.1] have studied color induction using flashed uniform surrounds, reporting that the contrast is higher for shorter flash duration. Extending their study, we present new psychophysical results using both flashed and static (i.e., non-flashed) equiluminant stimuli for both striped and uniform surrounds. Similarly to them, for uniform surround stimuli we observed color contrast, but we did not obtain the maximum contrast for the shortest (10 ms) flashed stimuli, but for 40 ms. We only observed this maximum contrast for red, green, and lime inducers, while for a purple inducer we obtained an asymptotic profile along the flash duration. For striped stimuli, we observed color assimilation only for the static (infinite flash duration) red-green surround inducers (red first inducer, green second inducer). For the other inducers' configurations, we observed color contrast or no induction. Since other studies showed that non-equiluminant striped static stimuli induce color assimilation, our results also suggest that luminance differences could be a key factor to induce it.


[Haemostaseological aspects of perioperative blood management].
Recent studies in humans have shown that tissue factor on the surface of endothelial cells, monocytes, or subendothelial structures sparks plasmatic coagulation. In vivo, there is no functional separation of an "endogenous" and "exogenous" pathway of the coagulation cascade. However, global laboratory tests run along such pathways due to preincubation with specific activators and, hence, allow localization of inherited coagulation defects. Coagulation inhibitors such as antithrombin or activated protein C are accelerated in their activity by cell surface glycoproteins and almost completely inactivate procoagulant activity in the microcirculation. Antithrombin binds to endothelial glycosaminoglycans and then significantly increases anticoagulant activity. Protein C is activated by the thrombin-thrombomodulin-complex and inactivates factors V a and VIII a, respectively. Additionally, activated protein C has a profibrinolytic effect. Both systems physiologically counteract the procoagulant transformation of endothelial and monocyte cell surfaces which occurs in critically ill patients due to induction of tissue factor, suppression of thrombomodulin, and removal of glycosaminoglycans from the cell surface. The distinction of static and dynamic coagulation disorders is useful since static disorders seldom require therapeutic interventions although global laboratory tests may continuously deteriorate. Dynamical disorders are symptoms of an underlying disease, and consumption coagulopathy with disseminated fibrin deposition and oozing occurs when coagulation turnover cannot be stopped. Antithrombin substitution is a well documented therapeutic option along with fresh frozen plasma and erythrocyte concentrate transfusion for blood substitution. Recent case reports in patients with irreversible bleeding complications favour the application of a recombinant factor VII concentrate. A rising perspective to decrease the use of heterologous blood and blood products may be intraoperative plasma retransfusion. The quality of such plasma undergoing consecutive filtration steps has to be clinically studied. The application of a synthetic platelet substitute, the "plateletsome", containing platelet glycoproteins led to significantly improved haemostasis without generating systemic procoagulant activity. In a far future, procoagulant cell surface transformation may be influenced by topic application of inhaled thrombomodulin loaded liposomes or by sense or antisense oligonucleotides inducing thrombomodulin expression or suppressing tissue factor expression, respectively.


The impact of patient safety culture on handover in rural health facilities.
Effective handover is crucial for patient safety. Rural health care organisations have particular challenges in relation to handover of information, placing them at higher risk of adverse events. Few studies have examined the relationship between handover and patient safety in rural contexts, particularly in Australia. This study aimed to explore the effect of handover on overall perceptions of patient safety and the effect of other patient safety dimensions on handover in a rural Australian setting. A cross-sectional online survey using The Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture was implemented across six rural Local Health Districts in NSW, Australia and resulted in 1587 respondents. Hierarchical multiple linear regression analysis was conducted to account for the nested nature of the data. Models were developed to assess the effect of handover on patient safety perceptions, and the effect of other patient safety culture composites on handover variables. Open-ended questions about patient safety were inductively analyzed for themes. Quotes from the handover theme are presented. All models were significant overall (p < .001), with explanatory powers ranging from 29 to 48%. Within rural health settings, effective handover is significantly related to patient safety perceptions (R2 = .29). A strong teamwork culture and management support culture was found to enhance effective handover of patient information (R2 = .47), and effective handover of personal responsibility (R2 = .37). A strong teamwork, management support, and open communication culture enhances handover of department accountability (R2 = .41). Despite the implementation of standardised communication tools and frameworks for handover, patient safety is compromised by inadequate coordination, poor or absent documentation between departments, between other health care agencies and in transfer of care from acute facilities to primary/community care. Approaches to handover need to consider the particular challenges associated with rurality and strengthening elements found to be associated with increased safety, such as a strong teamwork and management culture and good reporting practices. Research is required to examine how communication at transition of care, particularly between facilities, is conducted and ways in which to enhance patients' and families' participation.


Connective tissues: matrix composition and its relevance to physical therapy.
In the last 2 decades, the understanding of CT structure and function has increased enormously. It is now clear that the cells of the various CTs synthesize a variety of ECM components that act not only to underpin the specific biomechanical and functional properties of tissues, but also to regulate a variety of cellular functions. Importantly for the physical therapist, and as discussed above, CTs are responsive to changes in the mechanical environment, both naturally occurring and applied. The relative proportions of collagens and PGs largely determine the mechanical properties of CTs. The relationship between the fibril-forming collagens and PG concentration is reciprocal. Connective tissues designed to resist high tensile forces are high in collagen and low in total PG content (mostly dermatan sulphate PGs), whereas CTs subjected to compressive forces have a greater PG content (mostly chondroitin sulphate PGs). Hyaluronan has multiple roles and not only provides tissue hydration and facilitation of gliding and sliding movements but also forms an integral component of large PG aggregates in pressure-resisting tissues. The smaller glycoproteins help to stabilize and link collagens and PGs to the cell surface. The result is a complex interacting network of matrix molecules, which determines both the mechanical properties and the metabolic responses of tissues. Patients with CT problems affecting movement are frequently examined and treated by physical therapists. A knowledge of the CT matrix composition and its relationship to the biomechanical properties of these tissues, particularly the predictable responses to changing mechanical forces, offers an opportunity to provide a rational basis for treatments. The complexity of the interplay among the components, however, requires that further research be undertaken to determine more precisely the effects of treatments on the structure and function of CTs.


Body composition and exercise performance in patients with chronic obstructive pulmonary disease.
To investigate whether a compromised nutritional state may limit exercise performance in patients with chronic obstructive pulmonary disease we studied 54 such patients (FEV1 less than 50% and arterial oxygen tension (PaO2) greater than 7.3 kPa) whose clinical condition was stable and who were admitted to a pulmonary rehabilitation centre. Fat free mass was assessed anthropometrically (from skinfold measurements at four sites) and by bioelectrical impedance; creatinine height index and arm muscle circumference were also assessed. The mean (SD) distance walked in 12 minutes was 845 (178) m. No association was established between the distance walked and spirometric measures. A good correlation was found between the distance walked and fat free mass in the whole group (r = 0.73 for impedance measurements and 0.65 for skinfold thickness) and in a subgroup of 23 lean patients (body weight less than 90% of ideal weight; r = 0.66 for impedance measurements and 0.46 for skinfold thickness). Body weight correlated with the distance walked only in the whole group (r = 0.61). On stepwise regression analysis fat free mass measured by bioelectrical impedance, maximal inspiratory mouth pressure, and PaO2 accounted for 60% of the variation in the distance walked in 12 minutes. We conclude that fat free mass, independently of airflow obstruction, is an important determinant of exercise performance in patients with severe chronic obstructive pulmonary disease.


Emergent cortical circuit dynamics contain dense, interwoven ensembles of spike sequences.
Temporal codes are theoretically powerful encoding schemes, but their precise form in the neocortex remains unknown in part because of the large number of possible codes and the difficulty in disambiguating informative spikes from statistical noise. A biologically plausible and computationally powerful temporal coding scheme is the Hebbian assembly phase sequence (APS), which predicts reliable propagation of spikes between functionally related assemblies of neurons. Here, we sought to measure the inherent capacity of neocortical networks to produce reliable sequences of spikes, as would be predicted by an APS code. To record microcircuit activity, the scale at which computation is implemented, we used two-photon calcium imaging to densely sample spontaneous activity in murine neocortical networks ex vivo. We show that the population spike histogram is sufficient to produce a spatiotemporal progression of activity across the population. To more comprehensively evaluate the capacity for sequential spiking that cannot be explained by the overall population spiking, we identify statistically significant spike sequences. We found a large repertoire of sequence spikes that collectively comprise the majority of spiking in the circuit. Sequences manifest probabilistically and share neuron membership, resulting in unique ensembles of interwoven sequences characterizing individual spatiotemporal progressions of activity. Distillation of population dynamics into its constituent sequences provides a way to capture trial-to-trial variability and may prove to be a powerful decoding substrate in vivo. Informed by these data, we suggest that the Hebbian APS be reformulated as interwoven sequences with flexible assembly membership due to shared overlapping neurons.NEW & NOTEWORTHY Neocortical computation occurs largely within microcircuits comprised of individual neurons and their connections within small volumes (<500 μm3). We found evidence for a long-postulated temporal code, the Hebbian assembly phase sequence, by identifying repeated and co-occurring sequences of spikes. Variance in population activity across trials was explained in part by the ensemble of active sequences. The presence of interwoven sequences suggests that neuronal assembly structure can be variable and is determined by previous activity.


Infant sleep placement after the back to sleep campaign.
The Back to Sleep campaign has been credited with recent declines in the incidence of sudden infant death syndrome. Using survey data for the 1996-1998 birth cohorts, this epidemiologic study examines infant sleep position in a large, population-based sample. Data concerning infant sleep position are drawn from the 1996-1998 Pregnancy Risk Assessment Monitoring System for 15 states. Weighted multiple logistic regression analysis is used to examine correlates of infant sleep position. The prevalence of prone infant sleeping significantly declined between 1996 and 1998 (adjusted odds ratio [AOR] = 0.70; 95% confidence interval [CI] = [0.63, 0.78]). African Americans were more likely than non-Hispanic whites to sleep prone, (AOR = 1.45; 95% CI = 1.33,1.59), and were less likely to sleep supine (AOR = 0.52; 95% CI = 0.48, 0.57). Hispanic/Latinos were less likely overall than non-Hispanic whites to sleep prone (AOR = 0.81; 95% CI = 0.69, 0.95), but were also less likely to sleep supine (AOR = 0.78; 95% CI = 0.69, 0.87). Adherence to sleep position recommended by the American Academy of Pediatrics increased sharply among Hispanic/Latino infants. Very low birth weight infants and infants in larger families were less likely to sleep in the recommended supine position. Infants born between 1001 and 1500 g (AOR = 0.67; 95% CI = 0.57, 0.79), and extremely low birth weight infants between 500 and 1000 g (AOR = 0.57; 95% CI = 0.45, 0.72) were especially unlikely to sleep supine. Infants in households with more than 3 other children (AOR = 1.72; 95% CI = 1.08, 2.74) were more likely to sleep prone. The prevalence of supine infant sleep increased between 1996 and 1998. Low adherence to sleep position recommendations of the American Academy of Pediatrics among African Americans, very low birth weight infants, and infants in large families remain public health concerns.


Climatic variability and its impact on the indigenous agricultural system using panel data analysis in the Sikkim Himalaya, India.
Climate-induced extreme events with fluctuations in climatic indicators like temperature and precipitation highly influence crop productivity. This study deals with quantitative analysis of climatic variability and crop production (1990-2018) using panel data regression analysis. The focus is on variability of three crops, i.e., paddy, maize, and wheat in the Rangit river basin of Sikkim Himalaya, India. Meterological data were acquired from the Indian Meteorological Department, agricultural data from the state agricultural department and a field survey were also conducted with the farmers, using a structured questionnaire, focused group discussion, and key informant observations. The acquired data was analyzed with the help of correlation and multiple linear regression analysis to analyze the relationship between climatic variability and crop production. The result of the study shows that all three crops are dependent on rainfall; however, paddy was the most sensitive to climatic variability. It was found that the overall grain production had an inverse relation to temperature, but it had a positive correlation with rainfall. It was observed that there was a continuous decline in the overall production of paddy and wheat. During deficiency years, it was found that when - 11.33% rainfall was deficient, paddy yield declined by - 1.52%. Further, a deviation of - 13.48% led to a decline of - 54.78% in wheat. The study advocates that timely policy interventions and strategies shall reduce climatic shocks and improve productivity. This would strengthen the livelihood security of the local communities, overcome the challenges of food security, and ensure long-term sustainability of Rangit River basin.


The effects of vocational noise exposure on hearing aid battery subjective life.
This study examined the effects of vocational training noise on subjective battery life and on battery current drain, in 5 different class B hearing aids worn by students at a school for the deaf. Each S used a mercury battery in the morning in an average listening school environment with a 2-hr period of vocational noise exposure included, and another battery in an average school listening environment from after lunch to bed time. Voltage measurements and usage hrs were recorded until S reported the battery was not working. There were no mean differences in subjective battery life nor in recorded voltage drop between the two conditions. Battery life in 2 batteries exposed to vocational noise may have been extended due to a 10-day rest period during the spring break for these 2 students.


Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase.
NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.


Long-term stability of retreated defective restorations in patients with vertical food impaction.
Vertical food impaction (VFI) is a common complaint among patients receiving interproximal restorations. However, there is a gap in the literature regarding outcomes of treating defective restorations with VFI. This study sought to determine 10-year stability of retreated defective restorations in patients diagnosed with VFI. A total of 150 teeth (75 pair), in 38 patients comprised our study population. All the participants had been diagnosed with VFI due to faulty restorations and treated by means of redoing the restoration to build a stable contact in at least one restored tooth. The criteria for building an optimum dental contact were defined. Demographic characteristics, date and frequency of redoing the restoration, type and material of restoration, number of restored surfaces, occlusal intercuspal relationship, missing adjacent and/or opposing teeth, cemento enamel junction to alveolar crest distance, recurrence of VFI symptoms, recurrent caries, and periapical pathology as well as periodontal variables were recorded. Kaplan-Meier estimator revealed that the mean ± standard deviation of 1, 3, 5, and 10-year stability of reconstructed contacts was 89/2% ± 3/6%, 79/2% ± 5%, 70/7% ± 0/06%, and 66/3% ± 7/1%, respectively. The overall cumulative stability rate was 74/4%. Further analysis predicted that over a 12-year period, restored contacts were stable for 8.86 ± 0.6 years. Cox regression model indicated that having cusp to marginal ridge occlusal relationship (95% confidence interval [CI] for hazard risk (HR) = 1/1-13/9, HR = 3/93), and being over 40 years of age (95% CI for HR = 0/88-17/66, HR = 3/95) were major determinants of contact stability. Long-term stability of retreated and restructured tooth contacts with a history of VFI was 66%-89% in this specific sample.


Effects of age on mortality and antibiotic efficacy in cecal ligation and puncture.
The incidence and mortality of sepsis increase with age, consequently, 80% of the clinical mortality from sepsis occurs in patients over age 65. Despite this aged clinical population, most research models of sepsis use 6- to 16-week-old mice as patient surrogates. This age range of mice corresponds to human ages 10 to 17 years. To assess the influence of age on rodent CLP and on antibiotic therapy, we studied young (4 month), mature (12 month), and aged (24 month) mice. Male C57BL/6 mice (n = 27-30 in each age group) were subjected to cecal ligation and puncture (CLP), two punctures with a 25-gauge needle. Mice were observed untreated for 10 days. Young mice had 20% mortality, mature mice had 70% mortality (P = 0.0013 vs. young), and aged mice had 75% mortality (P = 0.0001 vs. young). To assess the effects of age on antibiotic therapy, mice were subjected to CLP as above (n = 38-40 in each age group). Mice were then randomized to treatment with intraperitoneal injections of ceftriaxone and metronidazole or normal saline. Therapy was initiated 12 h after CLP, and injections were repeated every 12 h for 7 days. Young mice saw a 56% decrease in mortality from CLP with antibiotic therapy (P = 0.001), and mature mice had a 30% decrease in mortality (P = 0.06). Aged mice saw no benefit from antibiotic therapy. We also compared plasma cytokine levels between young and aged mice after CLP. When compared with young mice, aged mice had higher levels of IL-6 and TNF-alpha 24 h after CLP. However, high IL-6 was predictive of mortality at any age. Mice appear to have age-dependent responses to intra-abdominal sepsis and to appropriate therapy.


Survey of physician diagnostic practices for patients with acute diarrhea: clinical and public health implications.
To understand physician practices regarding the diagnosis of acute diarrheal diseases, we conducted a survey, in 1996, of 2839 physicians in Connecticut, Georgia, Minnesota, Oregon, and California. Bacterial stool culture was requested for samples from the last patient seen for acute diarrhea by 784 (44%; 95% confidence interval, 42%-46%) of 1783 physicians. Physicians were more likely to request a culture for persons with acquired immune deficiency syndrome, bloody stools, travel to a developing country, diarrhea for >3 days, intravenous rehydration, or fever. Substantial geographic and specialty differences in culture-request practices were observed. Twenty-eight percent of physicians did not know whether stool culture included testing for Escherichia coli O157:H7; 40% did not know whether Yersinia or Vibrio species were included. These variabilities suggest a need for clinical diagnostic guidelines for diarrhea. Many physicians could benefit from education to improve their knowledge about tests included in routine stool examinations.


Arthrodesis of the knee with intramedullary fixation.
The application of intramedullary fixation for arthrodesis of the knee has been limited by the technical problems of rod failure and fracture of the femur at the rod insertion site. Improved implant design and rod insertion technique were utilized in seven patients with uniformly successful results. Intramedullary fixation provides prolonged stable fixation and is an alternative to the external fixation techniques currently used to achieve knee arthrodesis.


The metabolism of 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid in two siblings with cholestasis due to intrahepatic bile duct anomalies. An apparent inborn error of cholic acid synthesis.
Studies were carried out in a family in which two children with cholestasis due to intrahepatic bile duct anomalies were shown to have increased amounts of the cholic acid precursor, 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid (THCA). The metabolism of THCA was studied in one of these patients after an intravenous injection of (3H)THCA, and the cause of the increased amounts of THCA in this condition was found to be due to a metabolic defect in the conversion of this compound into cholic acid. A small amount of (3H)cholic acid was also identified after (3H)THCA administration, confirming that this metabolic defect was incomplete. Varanic acid (3alpha, 7alpha, 12alpha, 24xi-tetrahydorxy-5beta-cholestan-26-oic acid), a metabolite of THCA, could not be identified in either of these patients. By assuming that this compound would be conjugated and excreted if the metabolic block occurred after the formation of varanic acid, the defect in these patients appears to be due to a deficiency of a 24-hydroxylating enzyme system required to convert THCA into varanic acid. This condition appears to be transmitted in an autosomal recessive fashion, because the two affected patients were of opposite sex, and neither a normal sibling nor the two parents have increased amount of THCA in their bile.


Cardio-hepatic metabolic derangements and valproic acid.
Valproic acid (VPA) is an anti-epileptic and mood-stabilizing compound successfully used in the clinics since many decades. During the last few years, research on VPA revitalized. VPA has profound impact on nuclear chromatin structure in target cells by impinging on epigenetic mechanisms such as inhibition of histone deacetylase HDAC1, with implications for HIV and cancer treatment, and for the direct reprogramming in generation of induced pluripotent stem (iPS) cells. VPA can thus act at multiple levels and in several cellular systems. In addition to its established applications for the treatment of neurological and psychiatric disorders, and its newly discovered epigenetic mechanisms of action, the peripheral metabolic effects of VPA administration, in particular impinging on the heart and on the liver, are now starting to be understood. These have important consequences for the management of therapy and also for investigation purposes. The aim of this article is on one hand to summarize the emerging knowledge on the role of VPA during the occurrence of cardio-metabolic dysfunctions and on the other hand to describe concisely the VPA-induced epigenetic modifications in target cells.


Identification of dendrobium species used for herbal medicines based on ribosomal DNA internal transcribed spacer sequence.
Stems of genus Dendrobium (Orchidaceae) have been traditionally used as an herbal medicine (Dendrobii Herba) in Eastern Asia. Although demand for Dendrobium is increasing rapidly, wild resources are decreasing due to over-collection. This study aimed to identify plant sources of Dendrobii Herba on the market based on sequences of the internal transcribed spacer (ITS) regions of nuclear ribosomal DNA. We constructed an ITS1-5.8S-ITS2 sequence database of 196 Dendrobium species, and the database was employed to identify 21 herbal samples. We found that 13 Dendrobium species (D. catenatum, D. cucullatum, D. denudans, D. devonianum, D. eriiflorum, D. hancockii, D. linawianum, D. lituiflorum, D. loddigesii, D. polyanthum, D. primulinum, D. regium, and D. transparens) were possibly used as plant sources of Dendrobii Herba, and unidentified species allied to D. denudans, D. eriiflorum, D. gregulus, or D. hemimelanoglossum were also used as sources. Furthermore, it is clear that D. catenatum is one of the most important sources of Dendrobii Herba (5 out of 21 samples).


Posttranscriptional regulation and assembly into ribosomes of a Saccharomyces cerevisiae ribosomal protein-beta-galactosidase fusion.
To study the regulation of ribosomal protein genes, we constructed a 'lacZ fusion of the Saccharomyces cerevisiae RP51A gene, containing the first 64 codons of RP51A. In a strain lacking an intact RP51A gene (cells are viable due to the presence of an active RP51B gene), beta-galactosidase activity is 10-fold greater than in a strain containing RP51A. RP51A-lacZ mRNA levels are equal in the two strains, indicating that regulation is posttranscriptional. In the absence of the RP51A gene, the fusion protein is predominantly cytoplasmic and associated with polysomes, whereas in the presence of RP51A, the fusion protein is predominantly nuclear, and none is associated with polysomes. Deletions were made in the RP51A-coding portion of the fusion gene. The most extensively deleted gene, containing only the first seven RP51A codons fused to lacZ, produced a high level of beta-galactosidase activity in both the presence and the absence of the RP51A gene. In both cases, little or none of this shorter fusion protein was found associated with polysomes. Thus, a regulatory site (or sites) lies in the protein-coding region of RP51A. We suggest that posttranscriptional regulation of the rp51 fusion protein is related to assembly of the protein into ribosomes.


Healthy Vegan Lifestyle Habits among Argentinian Vegetarians and Non-Vegetarians.
Although current research has contributed to the promotion of whole-food plant-based diets, few studies have examined healthy vegan dietary and lifestyle factors, especially in South America. Therefore, we aimed at investigating the adherence to healthy vegan lifestyle habits among Argentinian vegetarians and omnivorous, using a recently developed vegetarian lifestyle index adapted to the vegan dietary pattern. Also, accessibility of vegetarian foods, and the proportion of household income spent on food were assessed in a cross-sectional approach with 1454 participants. The population was comprised of females (84.9%), singles (55.0%), young-adults (mean age 32.1, standard deviation (SD) = 13.6), employed (50.8%), with high educational levels (50.4%), and low prevalence of both tobacco smoking (7.0%) and frequent alcohol consumption (7.6%). The mean score of adherence to healthy vegan lifestyle habits was 6.64 (SD = 1.72), with higher scores indicating better adherence. Non-vegetarians (5.75; 95% confidence interval (CI), 5.61⁻5.89) had a significantly lower adjusted mean score compared to semi-(6.32; 95% CI, 6.17⁻6.47), pesco-(6.99; 95% CI, 6.59⁻7.39), lacto-ovo-vegetarians (7.10; 95% CI, 6.96⁻7.24), as well as vegans (8.59; 95% CI, 8.35⁻8.83). The mean proportion of household income spent on food was significantly lower among vegans compared with other dietary patterns. The whole studied population showed a low consumption of whole grains, legumes, vegetables, nuts, and seeds. Although vegans showed a better diet and lifestyle pattern there is a need to improve eating and lifestyle habits to address risk factors for non-communicable diseases in Argentina.


[Testicular function during prolonged corticotherapy].
Prolonged corticosteroid therapy produces a major degree of protein catabolism. Short-term treatment with ACTH or glucocorticoids results, in males, in a fall in plasma testosterone levels. In order to determine the origin of this hypogonadism, the testicular function was investigated in 18 men under prolonged glucocorticoid treatment. The mean plasma testosterone level in men treated for less than 3 months (5.9 +/- 0.8 ng/ml) was not statistically different from that obtained in controls (7.5 +/- 0.5 ng/ml; P greater than 0.05). However, the mean plasma luteinizing hormone level was significantly higher in these patients than in controls (8.2 +/- 1.9 mUl/ml vs 3.6 +/- mUl/ml respectively; P less than 0.001). In patients treated for more than 2 years, the mean plasma testosterone level (3.8 +/- 0.6 ng/ml) was significantly lower than in controls (P less than 0.001), but the mean plasma luteinizing hormone level was normal (5 +/- 1 mUl/ml). Plasma testosterone levels are negatively correlated with the daily dose of glucocorticoid (r = -0.81; P less than 0.001). The free testosterone index was within normal range in 5 of the 9 men under prolonged steroid therapy, near the lower limit of normality in 2 men and definitely low in 2 other men. The gonadotrophin response to the luteinizing hormone releasing hormone was normal, whereas the testicular response to human chorionic gonadotrophin was reduced. These data suggest that prolonged treatment with steroidal anti-inflammatory agents influences both gonadotrophic and testicular function and may be associated with true hypoandrogenism.


Collaborative retrospective macula society study of photodynamic therapy for chronic central serous chorioretinopathy.
To assess the visual and anatomic outcomes of central serous chorioretinopathy (CSC) after verteporfin photodynamic therapy (PDT). Retrospective case series. Patients with CSC who underwent PDT. Members of the Macula Society were surveyed to retrospectively collect data on PDT treatment for CSC. Patient demographic information, PDT treatment parameters, fluorescein angiographic information, optical coherence tomography (OCT) metrics, pre- and post-treatment visual acuity (VA), and adverse outcomes were collected online using standardized forms. Visual acuities over time and presence or absence of subretinal fluid (SRF). Data were submitted on 265 eyes of 237 patients with CSC with a mean age of 52 (standard deviation [± 11]) years; 61 were women (26%). Mean baseline logarithm of the minimum angle of resolution (logMAR) VA was 0.39±0.36 (20/50). Baseline VAs were ≥20/32 in 115 eyes (43%), 20/40 to 20/80 in 97 eyes (37%), and ≤20/100 in 47 eyes (18%). Normal fluence was used for PDT treatment in 130 treatments (49%), half-fluence was used in 128 treatments (48%), and very low fluence or missing information was used in 7 treatments (3%). The number of PDT treatments was 1 in 89%, 2 in 7%, and 3 in 3% of eyes. Post-PDT follow-up ranged from 1 month to more than 1 year. Post-PDT VA was correlated with baseline VA (r = 0.70, P < 0.001). Visual acuity improved ≥3 lines in <1%, 29%, and 48% of eyes with baseline VA ≥20/32, 20/40 to 20/80, and ≤20/100, respectively. Subretinal fluid resolved in 81% by the last post-PDT visit. There was no difference in the response to PDT when analyzed by age, race, fluence setting, fluorescein angiography (FA) leakage type, corticosteroid exposure, or fluid location (subretinal or pigment epithelial detachment; all P > 0.01). Complications were rare: Retinal pigment epithelial atrophy was seen in 4% of patients, and acute severe visual decrease was seen in 1.5% of patients. Photodynamic therapy was associated with improved VA and resolution of SRF. Adverse side effects were rare.


Inhalant Cannabidiol Inhibits Glioblastoma Progression Through Regulation of Tumor Microenvironment.
Introduction: Glioblastoma (GBM) is the most common invasive brain tumor composed of diverse cell types with poor prognosis. The highly complex tumor microenvironment (TME) and its interaction with tumor cells play important roles in the development, progression, and durability of GBM. Angiogenic and immune factors are two major components of TME of GBM; their interplay is a major determinant of tumor vascularization, immune profile, as well as immune unresponsiveness of GBM. Given the ineffectiveness of current standard therapies (surgery, radiotherapy, and concomitant chemotherapy) in managing patients with GBM, it is necessary to develop new ways of treating these lethal brain tumors. Targeting TME, altering tumor ecosystem may be a viable therapeutic strategy with beneficial effects for patients in their fight against GBM. Materials and Methods: Given the potential therapeutic effects of cannabidiol (CBD) in a wide spectrum of diseases, including malignancies, we tested, for the first time, whether inhalant CBD can inhibit GBM tumor growth using a well-established orthotopic murine model. Optical imaging, histology, immunohistochemistry, and flow cytometry were employed to describe the outcomes such as tumor progression, cancer cell signaling pathways, and the TME. Results: Our findings showed that inhalation of CBD was able to not only limit the tumor growth but also to alter the dynamics of TME by repressing P-selectin, apelin, and interleukin (IL)-8, as well as blocking a key immune checkpoint-indoleamine 2,3-dioxygenase (IDO). In addition, CBD enhanced the cluster of differentiation (CD) 103 expression, indicating improved antigen presentation, promoted CD8 immune responses, and reduced innate Lymphoid Cells within the tumor. Conclusion: Overall, our novel findings support the possible therapeutic role of inhaled CBD as an effective, relatively safe, and easy to administer treatment adjunct for GBM with significant impacts on the cellular and molecular signaling of TME, warranting further research.


The effects, safety and acceptability of compact, pre-filled, autodisable injection devices when delivered by lay health workers.
To systematically assess (i) the effects and safety and (ii) the acceptability of using lay health workers (LHWs) to deliver vaccines and medicines to mothers and children through compact pre-filled autodisable devices (CPADs). We searched electronic databases and grey literature. For the systematic review of effects and safety, we sought randomised and non-randomised controlled trials, controlled before-after studies and interrupted time series studies. For the systematic review of acceptability, we sought qualitative studies. Two researchers independently carried out data extraction, study quality assessment and thematic analysis of the qualitative data. No studies met our criteria for the review exploring the effects and safety of using LHWs to deliver CPADs. For the acceptability review, six qualitative studies assessed the acceptability of using LHWs to deliver hepatitis B vaccine, tetanus toxoid vaccine, gentamicin or oxytocin using Uniject™ devices. All studies took place in low- or middle-income countries and explored the perceptions of community members, LHWs, supervisors, health professionals or programme managers. Most of the studies were of low quality. Recipients generally accepted the intervention. Most health professionals were confident that LHWs could deliver the intervention with sufficient training and supervision, but some had problems delivering supervision. The LHWs perceived Uniject™ as effective and important and were motivated by positive responses from the community. However, some LHWs feared the consequences if harm should come to recipients. Evidence of the effects and safety of using CPADs delivered by LHWs is lacking. Evidence regarding acceptability suggests that this intervention may be acceptable although LHWs may feel vulnerable to blame.


CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways.
White matter (WM) is injured in most strokes, which contributes to functional deficits during recovery. Casein kinase 2 (CK2) is a protein kinase that is expressed in brain, including WM. To assess the impact of CK2 inhibition on axon recovery following oxygen glucose deprivation (OGD), mouse optic nerves (MONs), which are pure WM tracts, were subjected to OGD with or without the selective CK2 inhibitor CX-4945. CX-4945 application preserved axon function during OGD and promoted axon function recovery when applied before or after OGD. This protective effect of CK2 inhibition correlated with preservation of oligodendrocytes and conservation of axon structure and axonal mitochondria. To investigate the pertinent downstream signaling pathways, siRNA targeting the CK2α subunit identified CDK5 and AKT as downstream molecules. Consequently, MK-2206 and roscovitine, which are selective AKT and CDK5 inhibitors, respectively, protected young and aging WM function only when applied before OGD. However, a novel pan-AKT allosteric inhibitor, ARQ-092, which targets both the inactive and active conformations of AKT, conferred protection to young and aging axons when applied before or after OGD. These results suggest that AKT and CDK5 signaling contribute to the WM functional protection conferred by CK2 inhibition during ischemia, while inhibition of activated AKT signaling plays the primary role in post-ischemic protection conferred by CK2 inhibition in WM independent of age. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, our results will provide rationale for repurposing these drugs as therapeutic options for stroke patients by adding novel targets.


It's not only for the money: an analysis of adolescent versus adult entry into street prostitution.
Numerous studies examine the causal factors of entrance into prostitution and find economic marginalization, substance addiction, and interpersonal networks are common reasons women enter the trade. However, we know less about the role that age of onset plays in shaping female pathways into prostitution. Here, we build from insights into previous research by analyzing not only entry pathways but also how age categories are linked to time spent in the trade and whether the length of time in prostitution exacts a greater "toll" on women. Drawing from the feminist and age of onset literatures, we analyze 40 in-depth interviews with female street prostitutes from five U.S. cities. Our results underscore the importance of age as an organizing feature of women's pathways into prostitution and the potential associated consequences of working in this trade.


The Effect of Muscle Artifact Reduction Methods on Few-channel SSVEPs during Head Movements.
Brain-computer interfaces (BCIs) with steady-state visual evoked potentials (SSVEPs) caused by flickering stimuli have caught attention as communication tools between human brains and external machines through a head-mounted display (HMD). When applying SSVEP-based BCIs to real-life environments, the head must be moved to watch the stimuli displayed in an HMD, which generates muscular artifacts and significantly reduces BCI performance. In this study, we examined four-class SSVEP identification accuracies by using four artifact reduction methods in the situation of moving the head for both simulation and real datasets. In the simulation dataset, we found that artifact subspace reconstruction (ASR) and multi-scale dictionary learning (MSDL) showed better results especially at low signal-to-noise ratio. In the real dataset, we observed that reducing muscular artifacts resulted in performance degradation for independent component analysis-based methods, while ASR and MSDL showed relatively limited degradation and in some cases improved performance. Our future work is to improve ASR and MSDL for high performance with real data and to apply them to an online SSVEP-based BCI where the user moves his/her head.


Animal models of arthritis.
The criteria for selecting and establishing a animal model for arthritis were described. Rats are the most frequently used animals. Adjuvant and Myocobacterium induced arthritis provide a model of chronic joint inflammation, although significant differences exist when compared with human disease. A better model of arthritis in rats and mice can be induced by the injection of one strain of Mycoplasma arthritidis. An even better model is presented by rabbits first immunized against a protein such as heterologous fibrin or albumin, and then challenged by the same protein injected directly into a joint. This results in a localized chronic arthritis pathologically similar to that of man. Arithritis can also be induced in rabbits by the injection of polymers such as chitinor or Concanavalin A into the joint. Although there is no lack of arthritis animal models, there is no animal model which gives a true replication of rheumatoid arthritis.


Testicular cancer: the quest continues.
Treatment for testicular cancer has dramatically improved during the last 15 years. Much of this success has come about because of improved staging and operative techniques but, most importantly, through the introduction of successful systemic chemotherapy. Nonetheless, relevant issues still remain to be addressed in regard to the optimal therapy for patients with germ cell neoplasms. Included in these issues is delineating the most effective but minimally morbid treatment for patients with early-stage and low-volume metastatic disease while continuing to create innovative treatment approaches for poor-risk patients with metastatic disease. The unique association of primary mediastinal germ cell neoplasms with the development of non-germ cell cancers and Klinefelter's syndrome may provide some early clues for the determination of factors controlling differentiation. These observations issue a challenge to both clinical and preclinical researchers involved in the study of this neoplasm.


An assessment of transgenomics as a tool for identifying genes involved in the evolutionary differentiation of closely related plant species.
• Transgenomics is the process of introducing genomic clones from a donor species into a recipient species and then screening the resultant transgenic lines for phenotypes of interest. This method might allow us to find genes involved in the evolution of phenotypic differences between species as well as genes that have the potential to contribute to reproductive isolation: potential speciation genes. • More than 1100 20-kbp genomic clones from Leavenworthia alabamica were moved into Arabidopsis thaliana by transformation. After screening a single primary transformant for each line, clones associated with mutant phenotypes were tested for repeatability and co-segregation. • We found 84 clones with possible phenotypic effects, of which eight were repeatedly associated with the same phenotype. One clone, 11_11B, co-segregated with a short fruit phenotype. Further study showed that 11_11B affects seed development, with as much as one-third of the seeds aborted in some fruit. • Transgenomics is a viable strategy for discovering genes of evolutionary interest. We identify methods to reduce false positives and false negatives in the future. 11_11B can be viewed as a potential speciation gene, illustrating the value of transgenomics for studying the molecular basis of reproductive isolation.


MOF-templated rough, ultrathin inorganic microcapsules for enzyme immobilization.
Ultrathin titania microcapsules with rough surfaces were prepared by using a metal-organic framework (ZIF-8) as one kind of hard template to mediate the structures of the microcapsule shell. Specifically, CaCO3 particles were first coated with tannic acid (TA) followed by the deposition of hydrophobic ZIF-8 and another TA layer, the obtained particles were then assembled with protamine/TiO2 bilayers through biomimetic mineralization. Finally, the microcapsules (Z-TiO2) were obtained after simultaneously removing CaCO3 and ZIF-8 templates using ethylenediaminetetraacetic acid (EDTA). The coordination interaction between TA and ZIF-8 ensured the robust templating which endowed the microcapsules with a rough surface and an ultrathin microcapsules shell (100 nm) with 4.4 nm pore size. Moreover, the surface roughness of microcapsules can be regulated by changing the size of ZIF-8 crystals. The microcapsules were then utilized to immobilize penicillin G acylase (PGA). And PGA@Z-TiO2 retained 69% activity of equivalent free PGA with a loading capacity of 160 mg g-1. The PGA@Z-TiO2 microcapsules exhibited superior reusability: after recycling 8 times, the conversion of the enzymatic reaction remained 36.0%, which was twice higher than that of PGA@TiO2 (14.7%). Moreover, compared with free PGA and PGA@TiO2 microcapsules, PGA@Z-TiO2 microcapsules exhibited higher thermal and storage stability. After storing for 60 days, the relative activity of PGA@Z-TiO2 remained 89.6%, which was higher than that of free PGA (34.5%) and PGA@TiO2 (73.6%). ZIF-8 can be envisioned to be a novel class of hard template for preparing a broad variety of microcapsules with different hierarchical structures.


Hydraulic performance of sewer pipes with deposited sediments.
This paper investigates in-sewer sediment deposit behaviour and its influence on the hydraulic performance of sewer pipes. This evaluation is based on experimental results regarding the mobility of non-cohesive and partly cohesive deposits in a partially full circular pipe. The focus of these tests is on the development of bed forms and friction characteristics. In particular, it is investigated to what extent the bed forms from the non-cohesive and (partly) cohesive sediments affect a sewer's discharge capacity. Based on the laboratory study results and on the existing criteria for sewer design, a generic assessment of a sewer's hydraulic performance is made. The relative discharge factor for a pipe with sediment deposit is analysed in terms of the thickness and roughness of the deposit.


Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes.
Restrictive cardiomyopathy (RCM) is rare in childhood, but has a grave prognosis. The cause of disease in most cases is unknown. To determine the prevalence of sarcomere protein gene mutations in children with idiopathic RCM. Twelve patients (9 female, mean age 5.1 years) with idiopathic RCM referred between 1991 and August 2006 underwent detailed clinical and genetic evaluation. Nine had received cardiac transplants at the time of the study. The entire coding sequences of the genes encoding eight cardiac sarcomere proteins and desmin were screened for mutations. Familial evaluation was performed on first-degree relatives. Four patients (33%) had a family history of cardiomyopathy: RCM (n = 2); dilated cardiomyopathy (n = 1) and left ventricular non-compaction (n = 1). Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and alpha-cardiac actin (ACTC) genes. Two were de novo mutations and 3 were new mutations. All mutations occurred in functionally important and conserved regions of the genes. Sarcomere protein gene mutations are an important cause of idiopathic RCM in childhood. We describe the first mutation in ACTC in familial RCM. The identification of RCM in a child should prompt consideration of sarcomere protein disease as a possible cause and warrants clinical evaluation of the family.


Assessing the Use of Data Systems to Estimate Return-on-Investment of Behavioral Healthcare Interventions: Opportunities and Barriers.
To improve access to and quality of affordable behavioral healthcare, there is a need for more research to identify which interventions can generate long-term, societal return-on-investment (ROI). Barriers to ROI studies in the behavioral health sector were explored by conducting semi-structured interviews with individuals from key stakeholder groups at state and national behavioral health-related organizations. Limited operating budgets, state-based payer systems, the lack of financial support, privacy laws, and other unique experiences of behavioral health providers and patients were identified as important factors that affect the collection and utilization of data. To comprehensively assess ROI of interventions, it is necessary to improve standardization and data infrastructure across multiple health and non-health systems and clarify or address legal, regulatory, and commercial conflicts.


3'-18F-fluoro-3'-deoxy-L-thymidine: a new tracer for staging metastatic melanoma?
In this study, the feasibility of 3'-(18)F-fluoro-3'-deoxy-L-thymidine PET ((18)F-FLT PET) for staging patients with clinical stage III melanoma was investigated. Ten patients with melanoma and metastases to the locoregional draining lymph nodes, clinical stage III-based on physical examination, chest radiography, lactate dehydrogenase, and histopathologic confirmation-underwent a whole-body (18)F-FLT PET scan 1 h after injection of a median 400-MBq dose (range, 185-430 MBq) of (18)F-FLT. All (18)F-FLT PET lesions were verified using the American Joint Committee on Cancer Staging System, which includes physical examination, spiral CT, ultrasound, chest radiography, and histopathologic examinations. Size and mitotic rate of metastatic lymph nodes and skin metastases were determined. All histopathologic samples and (18)F-FLT PET lesions were categorized over anatomic regions and correlated. All locoregional metastases were correctly visualized by (18)F-FLT PET. Region-based sensitivity for detection of lymph node metastatic disease was 88%. There were 3 true-negative and 2 false-positive lesions. The detection limit for lymph node metastases appeared to be approximately 6 mm or a mitotic rate of 9 mitoses per 2 mm(2). Two patients were upstaged by (18)F-FLT PET, which was confirmed by CT. In 3 patients, (18)F-FLT PET detected a total of 3 additional lesions with therapeutic consequences, without influencing staging. These lesions were initially missed by clinical staging. (18)F-FLT PET seems promising for (re)staging purposes in clinical stage III melanoma. Further research is needed, in which (18)F-FLT PET should be compared with (18)F-FDG PET.


ADME evaluation in drug discovery. 9. Prediction of oral bioavailability in humans based on molecular properties and structural fingerprints.
Oral bioavailability is an essential parameter in drug screening cascades and a good indicator of the capability of the delivery of a given compound to the systemic circulation by oral administration. In the present work, we report a database of oral bioavailability of 1014 molecules determined in humans. A systematic examination of the relationships between various physicochemical properties and oral bioavailability were carried out to investigate the influence of these properties on oral bioavailability. A number of property-based rules for bioavailability classification were generated and evaluated. We found that no rule was an effective predictor for oral bioavailability because these simple rules cannot characterize the influence of important metabolic processes on bioavailability. Finally, the genetic function approximation (GFA) technique was employed to construct the multiple linear regression models for oral bioavailability using structural fingerprints as the basic parameters, together with several important molecular properties. The best model is able to predict human oral bioavailability with an r of 0.79, a q of 0.72, and a RMSE (root-mean-square error) of 22.30% of the compounds from the training set. The analysis of the descriptors chosen by GFA shows that the important structural fingerprints are primarily related to important intestinal absorption and well-known metabolic processes. The predictive power of the models was further evaluated using a separate test set of 80 compounds, and the consensus model can predict the oral bioavailability with r(test) = 0.71 and RMSE = 23.55% for the tested compounds. Since the necessary molecular properties and structural fingerprints can be calculated easily and quickly, the models we proposed here may help speed up the process of finding or designing compounds with improved oral bioavailability.


Embryonal rhabdomyosarcoma in a Rothschild's giraffe (Giraffa camelopardalis rothschildi).
Abstract: A 3-yr-old male Rothschild's giraffe (Giraffa camelopardalis rothschildi) presented for acute swelling caudomedial to the left parietal horn. Following initial diagnostics and supportive treatment, the mass was surgically resected and intralesional chemotherapy was administered. Despite treatment, the giraffe's condition worsened and euthanasia was performed. Gross necropsy revealed neoplastic invasion and destruction of underlying parietal bone, adjacent horn base, and sinuses, and metastases in the tracheobronchial and mandibular lymph nodes and lung. Histologically, the tumor was composed of packets of anaplastic round cells. Immunohistochemical studies further characterized the tumor as an embryonal rhabdomyosarcoma. This is the first reported case of rhabdomyosarcoma in a giraffe.


Advancing racial equity and social justice for Black communities in US tobacco control policy.
The US Food and Drug Administration (FDA) applies the Population Health Standard in tobacco product review processes by weighing anticipated health benefits against risks associated with a given commercial tobacco product at the population level. However, systemic racism (ie, discriminatory policies and practices) contributes to an inequitable distribution of tobacco-related health benefits and risks between white and Black/African Americans at the population level. Therefore, Black-centered, antiracist data standards for tobacco product review processes are needed to achieve racial equity and social justice in US tobacco control policy. Regardless of whether FDA implements such data standards, non-industry tobacco scientists should prioritise producing and disseminating Black-centred data relevant to FDA's regulatory authority. We describe how systemic racism contributes to disparities in tobacco-related outcomes and why these disparities are relevant for population-level risk assessments, then discuss four possible options for Black-centred data standards relevant to tobacco product review processes.


[The experience of family caregivers of older people with depression].
The objective of the study was to understand how family caregivers experience the depression of older people in their care, within their cultural context. This is a qualitative study of ethnographic trajectory, performed using Spradley as the framework. The cultural universe consisted of relatives who performed the role of caregivers, who provided informed consent. Caregivers perceived the disease as a deep limitation on their way of living, involving loneliness, sadness and pity. The feelings of the depressed patients extend to the caregiver, who also faces the risk of suffering from depression. The responsibilities of caring also generate feelings of guilt that produce more suffering. Relatives recognize the onset of the disease, their attributes, the forms of treatment, and the social stigma associated with this mental disease and that they have a fundamental role in providing support and care in the recovery process.


Assessing the Potential for Error in Investigating Intraneural Vascularity: A Need for a Standardized Imaging Protocol.
This study examined the implementation of a Doppler sonography imaging protocol to assess intraneural blood flow, within the median nerve, in healthy individuals. A total of 176 participants were examined, and this involved 717 retrospective observations of the images collected. The implemented imaging protocol was assessed, and the data that were collected were cleaned and checked for fidelity and validity. A large percentage of missing evidence (11%-35%) across proximal, mid, and distal carpal tunnel locations. Only a quarter of cases with evidence of intraneural blood flow had the strongest evidence of a power Doppler video clip, of which only three-quarters were valid. The study identified potential areas for improving the imaging protocol to reduce missing data and improve data quality. This study demonstrates the significance of a standardized imaging protocol to guide the sonographic acquisition of Doppler images and provides important insights into potential issues with data quality. The recommendations have the potential to help future studies assess intraneural blood flow in healthy populations in a more rigorous and reliable way. Incorporating the study's recommendations into a standardized protocol, there is potential to enhance the diagnostic accuracy of carpal tunnel syndrome and improve diagnosis and treatment.


Screening for celiac disease in Danish adults.
The prevalence of celiac disease (CD) as recorded in the Danish National Patient Registry is ∼50/100,000 persons. This is much lower than the reported prevalence of CD in other Nordic countries and underdiagnosis is suspected. Our aim was to estimate the prevalence of CD in a population-based study of Danish adults. A total of 2297 adults aged 24-76 years living in the southwestern part of Copenhagen were screened for CD by immunoglobulin (Ig)A and IgG antibodies to transglutaminases and deamidated gliadin. IgA/IgG-positive participants were invited to a clinical evaluation, including biopsies, by a gastroenterologist. Of the invited 56 participants, 40 underwent a full clinical evaluation and 8 persons were diagnosed with CD; 2 of the 16 persons, who did not complete the clinical evaluation, were considered by experts to have probable CD. None of the above 56 participants had a known history of CD or a recorded diagnosis of CD in National Patient Registry. By combining cases of biopsy-proven CD (n = 8), probable CD (n = 2), and registry-recorded CD (n = 1), the prevalence of CD was estimated to be 479/100,000 (11/2297) persons (95% CI: 197-761). In this general adult population, the prevalence of CD as estimated by screening and clinical evaluation was 10 times higher than the registry-based prevalence of CD. Of 11 participants diagnosed with CD in our screening study, 10 were unaware of the diagnosis prior to the study. Thus, our study suggests that CD is markedly underdiagnosed in Danish adults.


Chemistry and biology of vitamin E.
Our understanding of the role of vitamin E in human nutrition, health, and disease has broadened and changed over the past two decades. Viewed initially as nature's most potent lipid-soluble antioxidant (and discovered for its crucial role in mammalian reproduction) we have now come to realize that vitamin E action has many more facets, depending on the physiological context. Although mainly acting as an antioxidant, vitamin E can also be a pro-oxidant; it can even have nonantioxidant functions: as a signaling molecule, as a regulator of gene expression, and, possibly, in the prevention of cancer and atherosclerosis. Since the term vitamin E encompasses a group of eight structurally related tocopherols and tocotrienols, individual isomers have different propensities with respect to these novel, nontraditional roles. The particular beneficial effects of the individual isomers have to be considered when dissecting the physiological impact of dietary vitamin E or supplements (mainly containing only the alpha-tocopherol isomer) in clinical trials. These considerations are also relevant for the design of transgenic crop plants with the goal of enhancing vitamin E content because an engineered biosynthetic pathway may be biased toward formation of one isomer. In contrast to the tremendous recent advances in knowledge of vitamin E chemistry and biology, there is little hard evidence from clinical and epidemiologic studies on the beneficial effects of supplementation with vitamin E beyond the essential requirement.


Notch signaling in stem cell systems.
The Notch signaling pathway is among the most commonly used communication channels in animal cells. Recent studies have demonstrated that this pathway is indispensable for cells in various stages of maturation, including terminal differentiation. One main focus in mammalian studies is the role of Notch in embryonic and postembryonic stem cell systems. In this review, the roles of Notch signaling in various mammalian stem and early progenitor cells are summarized.


Understanding Interfacial Alignment in Solution Coated Conjugated Polymer Thin Films.
Domain alignment in conjugated polymer thin films can significantly enhance charge carrier mobility. However, the alignment mechanism during meniscus-guided solution coating remains unclear. Furthermore, interfacial alignment has been rarely studied despite its direct relevance and critical importance to charge transport. In this study, we uncover a significantly higher degree of alignment at the top interface of solution coated thin films, using a donor-acceptor conjugated polymer, poly(diketopyrrolopyrrole-co-thiophene-co-thieno[3,2-b]thiophene-co-thiophene) (DPP2T-TT), as the model system. At the molecular level, we observe in-plane π-π stacking anisotropy of up to 4.8 near the top interface with the polymer backbone aligned parallel to the coating direction. The bulk of the film is only weakly aligned with the backbone oriented transverse to coating. At the mesoscale, we observe a well-defined fibril-like morphology at the top interface with the fibril long axis pointing toward the coating direction. Significantly smaller fibrils with poor orientational order are found on the bottom interface, weakly aligned orthogonal to the fibrils on the top interface. The high degree of alignment at the top interface leads to a charge transport anisotropy of up to 5.4 compared to an anisotropy close to 1 on the bottom interface. We attribute the formation of distinct interfacial morphology to the skin-layer formation associated with high Peclet number, which promotes crystallization on the top interface while suppressing it in the bulk. We further infer that the interfacial fibril alignment is driven by the extensional flow on the top interface arisen from increasing solvent evaporation rate closer to the meniscus front.


Detection of measles virus genome in bronchoalveolar lavage cells in a patient with measles pneumonia.
Measles is frequently complicated with pneumonia that could be fatal in numerous occasions. However, a prompt and precise diagnosis of measles is not easily made particularly in the early stage of the disease, or in immunocompromised individuals because of the lack of typical clinical features or the defect in antigen-specific antibody production. In the present paper, we describe a 27-yr-old male who developed fever, skin rash typical of measles, and diffuse pulmonary infiltrates associated with respiratory failure. Infection of lung cells with measles virus was proved by detection of viral genome ribonucleic acid within alveolar macrophages and lymphocytes recovered by bronchoalveolar lavage using reverse transcription-polymerase chain reaction amplification. These techniques may offer a useful tool to make the swift and precise diagnosis of measles pneumonia, thus allowing appropriate therapeutic approaches to the disease.


[Electron spin resonance of electron transport in photosynthetic systems. IX. Temperature dependence of the kinetics of P700 redox transients in bean chloroplasts induced by flashes of different duration].
The temperature dependence of the kinetics of P700 redox transients in bean chloroplasts was studied. The flashes of white light with different duration (7 microseconds, 0.5 and 0.75 ms) were fired simultaneously with the background continuous far red light (lambda max = 707 nm). It was shown that the rate of P700+ reduction was temperature dependent and increased with the rise of the concentration of the reductants in the electron transport chain between photosystems. Photosystem 2 donates electrons to P700+ at temperatures from -5 to 45 degrees C under various modes of flash illumination. Experiments with spin labels showed that there were correlation between the physical state of lipids in the chloroplasts membrane and the rates of different steps of electron transport from photosystem 2 to photosystem 1--plastoquinone reduction by photosystem 2 and plastoquinol oxidation by photosystem 1. We assume that the rates of electron transport reaction of the plastoquinone shuttle are controlled by diffusion of plastoquinone and plastoquinole in the hydrophobic part of the thylakoid membrane. Additional evidence in support of that proposal was obtained from the temperature dependence of light induced spin label reduction which occurred due to its interaction with the plastoquinol of plastosemiquinone.


[Comparative study on three algorithms of the ICD-10 Charlson comorbidity index with myocardial infarction patients].
To compare the performance of three International Statistical Classification of Diseases, 10th Revision translations of the Charlson comorbidities when predicting in-hospital among patients with myocardial infarction (MI). MI patients > or =20 years of age with the first admission during 2006 were identified(n=20,280). Charlson comorbidities were drawn from Heath Insurance Claims Data managed by Health Insurance Review and Assessment Service in Korea. Comparisions for various conditions included (a) three algorithms (Halfon, Sundararajan, and Quan algorithms), (b) lookback periods (1-, 3- and 5-years), (c) data range (admission data, admission and ambulatory data), and (d) diagnosis range (primary diagnosis and first secondary diagnoses, all diagnoses). The performance of each procedure was measured with the c-statistic derived from multiple logistic regression adjusted for age, sex, admission type and Charlson comorbidity index. A bootstrapping procedure was done to determine the approximate 95% confidence interval. Among the 20,280 patients, the mean age was 63.3 years, 67.8% were men and 7.1% died while hospitalized. The Quan and Sundararajan algorithms produced higher prevalences than the Halfon algorithm. The c-statistic of the Quan algorithm was slightly higher, but not significantly different, than that of other two algorithms under all conditions. There was no evidence that on longer lookback periods, additional data, and diagnoses improved the predictive ability. In health services study of MI patients using Health Insurance Claims Data, the present results suggest that the Quan Algorithm using a 1-year lookback involving primary diagnosis and the first secondary diagnosis is adequate in predicting in-hospital mortality.


Performance of ancestry-informative SNP and microhaplotype markers.
The use of microhaplotypes (MHs) for ancestry inference has added to an increasing number of ancestry-informative markers (AIMs) for forensic application that includes autosomal single nucleotide polymorphisms (SNPs) and insertions/deletions (indels). This study compares bi-allelic and tri-allelic SNPs as well as MH markers for their ability to differentiate African, European, South Asian, East Asian, and American population groups from the 1000 Genomes Phase 3 database. A range of well-established metrics were applied to rank each marker according to the population differentiation potential they measured. These comprised: absolute allele frequency differences (δ); Rosenberg's informativeness for (ancestry) assignment (In); the fixation index (FST); and the effective number of alleles (Ae). A panel consisting of all three marker types resulted in the lowest mean divergence per population per individual (MDPI = 2.16%) when selected by In. However, when marker types were not mixed, MHs were the highest performing markers by most metrics (MDPI < 4%) for differentiation between the five continental populations.


Automated identification of Fos expression.
The concentration of Fos, a protein encoded by the immediate-early gene c-fos, provides a measure of synaptic activity that may not parallel the electrical activity of neurons. Such a measure is important for the difficult problem of identifying dynamic properties of neuronal circuitries activated by a variety of stimuli and behaviours. We employ two-stage statistical pattern recognition to identify cellular nuclei that express Fos in two-dimensional sections of rat forebrain after administration of antipsychotic drugs. In stage one, we distinguish dark-stained candidate nuclei from image background by a thresholding algorithm and record size and shape measurements of these objects. In stage two, we compare performance of linear and quadratic discriminants, nearest-neighbour and artificial neural network classifiers that employ functions of these measurements to label candidate objects as either Fos nuclei, two touching Fos nuclei or irrelevant background material. New images of neighbouring brain tissue serve as test sets to assess generalizability of the best derived classification rule, as determined by lowest cross-validation misclassification rate. Three experts, two internal and one external, compare manual and automated results for accuracy assessment. Analyses of a subset of images on two separate occasions provide quantitative measures of inter- and intra-expert consistency. We conclude that our automated procedure yields results that compare favourably with those of the experts and thus has potential to remove much of the tedium, subjectivity and irreproducibility of current Fos identification methods in digital microscopy.


Learners' Perception of the Applicability of Pre-clinical Subjects to Clinical Training and Experience in Obafemi Awolowo University, Ile-Ife.
This article was migrated. The article was marked as recommended. Introduction: This study investigated how Final Year Students and Newly qualified Doctors of Obafemi Awolowo University (OAU) Medical School perceive the applicability of the three pre-clinical subjects (Anatomy, Biochemistry and Physiology) to clinical studies and medical practice with the aim of ascertaining whether or not the students are able to establish a real connect between knowledge acquired in the pre-clinical years and their experience during clinical exposure. Methods: A cross sectional study involving 106 final year medical students and 81 interns was conducted using convenience sampling method. Data was collected using a structured self-administered questionnaire consisting of demographic characteristics and 10 items regarding perception of the relevance of basic medical courses to clinical training experience. Responses were rated using a 5 point Likert scale, which ranged from "strongly disagree" to "strongly agree". Data analysis was carried out using descriptive and inferential statistics and values expressed as mean of scores. Results: Overall mean scores for anatomy, biochemistry and physiology were 26.4 ± 0.32, 25.7 ± 0.29 and 28.1 ± 0.31 respectively. Thus, physiology was rated as having the highest applicability with the highest score in 4 out of 10 items. Biochemistry had the lowest score for the item "I remember most of the content of the course even now". Newly qualified Doctors were found to have a more positive perception of anatomy and biochemistry than final year medical students. All Subjects were scored high (average of 3-0/4.0) on items having to do with introduction of curriculum integration and clinical studies to teaching. Conclusion: Findings from the study suggest that the responses of the subjects were based more on their ability to understand and recall content, rather than how relevant the subjects are to their clinical experience. The study concludes that there is an urgent need to embrace integration of the curriculum and introduce more learner-centered teaching methods.


The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia.
The use of opioid agonists acting outside the central nervous system (CNS) is a promising therapeutic strategy for pain control that avoids deleterious central side effects such as apnea and addiction. In human clinical trials and rat models of inflammatory pain, peripherally restricted opioids have repeatedly shown powerful analgesic effects; in some mouse models however, their actions remain unclear. Here, we investigated opioid receptor coupling to K(+) channels as a mechanism to explain such discrepancies. We found that GIRK channels, major effectors for opioid signalling in the CNS, are absent from mouse peripheral sensory neurons but present in human and rat. In vivo transgenic expression of GIRK channels in mouse nociceptors established peripheral opioid signalling and local analgesia. We further identified a regulatory element in the rat GIRK2 gene that accounts for differential expression in rodents. Thus, GIRK channels are indispensable for peripheral opioid analgesia, and their absence in mice has profound consequences for GPCR signalling in peripheral sensory neurons.


Mechanochemical Drug Conjugation via pH-Responsive Imine Linkage for Polyether Prodrug Micelles.
Prodrug-type polymer-drug conjugates based on highly biocompatible functional polyethers are developed through mechanochemical post-polymerization modification. Herein, we design functional epoxide monomers of ethoxyethyl glycidyl ether (EEGE) and azidohexyl glycidyl ether (AHGE) and synthesize diblock copolyethers of PEEGE-b-PAHGE via sequential anionic ring-opening polymerization. Subsequent conversion of the functional monomers to the corresponding hydroxyl and amine groups allows for the preparation of double hydrophilic block copolyethers. Most notably, mechanochemical modification allows for the conjugation of these polymers with a highly hydrophobic and potent anticancer agent, cinnamaldehyde, through an imine linkage. The self-assembly of the resulting polymer-drug conjugates into polymeric micelles is characterized by dynamic light scattering and atomic force microscopy. The pH-responsive cleavage of the imine linkages under acidic conditions leads to the release of cinnamaldehyde with a concomitant disassembly of the polymeric micelles. The superior biocompatibility coupled with the solvent-less mechanochemical conjugation approach provides a convenient means to introduce various therapeutics for smart drug delivery.


Evaluation of collagen-based membranes for guided bone regeneration, by three-dimensional computerized microtomography.
The aim of this study was to evaluate the use of a collagen-based membrane compared with no treatment on guided bone regeneration by 3-dimensional computerized microtomography (μCT). Defects were created between the mesial and distal premolar roots of the second and third premolars (beagle dogs; n = 8). A collagen-based membrane (Vitala; Osteogenics Biomedical Inc., TX, USA) was placed in one of the defects (membrane group; n = 16), and the other was left untreated (no-membrane group; n = 16). Left and right sides provided healing samples for 2 and 16 weeks. Three-dimensional bone architecture was acquired by μCT and categorized as fully regenerated (F, bone height and width) or nonregenerated (N). Chi-square tests (95% level of significance) showed that tooth did not have an effect on outcome (P = .5). Significantly higher F outcomes were observed at 16 weeks than 2 weeks (P = .008) and in membrane group than in no-membrane group (P = .008). The collagen-based membrane influenced bone regeneration at the furcation.


A rare complication with a single dose of alendronate.
The authors present a case of an 84-year-old patient who presented to the emergency department with sudden onset abdominal pain radiating to the neck. The patient's medication included warfarin, and alendronate, which was started by the general practitioner 2 days prior to presentation. Initial systemic examination and investigations, including chest x-ray, were unremarkable. Within 24 h of presentation the patient developed bilateral pneumonia with effusions. Due to continued clinical deterioration over the next 48 h, a CT thorax was performed that showed evidence of large oesophageal perforation with mediastinitis and gas in the mediastinum. The patient was treated with an expandable metal stent, bilateral chest drains, broad spectrum antibiotics, antifungals and total parenteral nutrition. Over a period of 8 weeks the patient made an excellent recovery. This rare case illustrates the importance of vigilance for the life-threatening complication of oesophageal perforation with alendronate treatment.


Biosimilars: how similar or dissimilar are they?
The imminent expiry of patents on biological medicinal products, such as epoetin alfa in 2006, has significant implications for nephrology in Australia. The purpose of this review is to examine the differences between biosimilars (similar biological medicinal products) and generic low molecular weight (chemical) drugs. The approach that regulatory agencies, including the European Medicines Agency (EMEA) and the Therapeutic Goods Administration (TGA), are taking towards biosimilars is also discussed. Biosimilars differ from generic chemical drugs in many important ways, including the size and complexity of the active substance, the nature of the starting materials (cell banks, tissues and other biological products), and the complexity of the manufacturing processes. Therefore, it has been acknowledged by the EMEA that established legal and regulatory principles of 'essential similarity' that are applied to standard chemical generics cannot be readily applied to biosimilars. One of the key areas of concern with the introduction of biosimilars into the field of nephrology will be guaranteeing the safety and efficacy of biosimilars. New manufacturers will need to ensure that their biopharmaceutical has a similar efficacy and safety profile to the innovator product through more extensive clinical trials than the limited testing done for generic versions of low molecular weight chemical medicines.


A survey of trace metal burdens in increment cores from eastern cottonwood (Populus deltoides) across a childhood cancer cluster, Sandusky County, OH, USA.
A dendrochemical study of cottonwood trees (Populus deltoides) was conducted across a childhood cancer cluster in eastern Sandusky County (Ohio, USA). The justification for this study was that no satisfactory explanation has yet been put forward, despite extensive local surveys of aerosols, groundwater, and soil. Concentrations of eight trace metals were measured by ICP-MS in microwave-digested 5-year sections of increment cores, collected during 2012 and 2013. To determine whether the onset of the first cancer cases could be connected to an emergence of any of these contaminants, cores spanning the period 1970-2009 were taken from 51 trees of similar age, inside the cluster and in a control area to the west. The abundance of metals in cottonwood tree annual rings served as a proxy for their long-term, low-level accumulation from the same sources whereby exposure of the children may have occurred. A spatial analysis of cumulative metal burdens (lifetime accumulation in the tree) was performed to search for significant 'hotspots', employing a scan statistic with a mask of variable radius and center. For Cd, Cr, and Ni, circular hotspots were found that nearly coincide with the cancer cluster and are similar in size. No hotspots were found for Co, Cu, and Pb, while As and V were largely below method detection limits. Whereas our results do not implicate exposure to metals as a causative factor, we conclude that, after 1970, cottonwood trees have accumulated more Cd, Cr, and Ni, inside the childhood cancer cluster than elsewhere in Sandusky County.