Metabolic and Transcriptional Changes in Cultured Muscle Stem Cells from Low Birth Weight Subjects.
Developmental programming of human muscle stem cells could in part explain why individuals born with low birth weight (LBW) have an increased risk of developing type 2 diabetes (T2D) later in life. We hypothesized that immature muscle stem cell functions including abnormal differentiation potential and metabolic function could link LBW with the risk of developing T2D. Design/Settings/Participants: We recruited 23 young men with LBW and 16 age-matched control subjects with normal birth weight. Biopsies were obtained from vastus lateralis, and muscle stem cells were isolated and cultured into fully differentiated myotubes. We studied glucose uptake, glucose transporters, insulin signaling, key transcriptional markers of myotube maturity, selected site-specific DNA methylation, and mitochondrial gene expression. We found reduced glucose uptake as well as decreased levels of glucose transporter-1 and -4 mRNA and of the Akt substrate of 160-kDa mRNA and protein in myotubes from LBW individuals compared with normal birth weight individuals. The myogenic differentiation markers, myogenin and myosin heavy chain 1 and 2, were decreased during late differentiation in LBW myotubes. Additionally, mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α and cytochrome c oxidase polypeptide 7A were reduced in LBW myotubes. Decreased gene expression was not explained by changes in DNA methylation levels. We demonstrate transcriptional and metabolic alterations in cultured primary satellite cells isolated from LBW individuals after several cell divisions, pointing toward a retained intrinsic defect conserved in these myotubes.


[Assessment of visual acuity evaluation performed by teachers of the "Eye in eye" program in Marília-SP, Brazil].
To assess quality and cut-off point (VA <0.7) of the examinations performed by teachers to detect reduced visual acuity (VA) in schoolchildren participants of the project called "Eye in eye " in Marilia-SP, Brazil. Visual acuity measurements were performed by trained teachers using Snellen's chart. The children with VA <0.7 in one of the eyes were referred to an ophthalmic examination. The ophthalmic examination was considered gold standard to assess quality and cut-off point of the examinations performed by teachers. VA test was performed in 604 schoolchildren of state public schools (1,208 eyes). Analyses were based on examined eyes. We calculated sensitivity (S), specificity (E), positive predictive value (PPV), negative predictive value (NPV) and likelihood rate (LR). We compared the means obtained by the teachers' examinations to means of the ophthalmologist's examinations. ROC curve was produced to evaluate whether VA lower than 0.7 is the best value for referral to an ophthalmic examination. VA means obtained by teachers and ophthalmologic examinations were 0.70 +/- 0.16 and 0.88 +/- 0.2 respectively. The difference between teachers' and ophthalmologists' examinations was 0.18 (p<0.0001). S, E, PPV, NPV and LR were: 82%, 40%, 27%, 89% and 1.37, respectively. False positive and negative rates were 59.5% and 18%. ROC curve evidenced that visual acuity of 0.7 was the best cut-off point to refer schoolchildren to an ophthalmic exam. We demonstrated the importance of the teachers' participation in improved schoolchildren ocular health. The examination performed by teachers obtained a satisfactory S with low E, NPV and high values of false positive results. The best cut-off point to refer schoolchildren to an ophthalmic examination was VA of 0.7.


Performance of an electrothermal swing adsorption system with postdesorption liquefaction for organic gas capture and recovery.
The use of adsorption on activated carbon fiber cloth (ACFC) followed by electrothermal swing adsorption (ESA) and postdesorption pressure and temperature control allows organic gases with boiling points below 0 °C to be captured from air streams and recovered as liquids. This technology has the potential to be a more sustainable abatement technique when compared to thermal oxidation. In this paper, we determine the process performance and energy requirements of a gas recovery system (GRS) using ACFC-ESA for three adsorbates with relative pressures between 8.3 × 10(-5) and 3.4 × 10(-3) and boiling points as low as -26.3 °C. The GRS is able to capture > 99% of the organic gas from the feed air stream, which is comparable to destruction efficiencies for thermal oxidizers. The energy used per liquid mole recovered ranges from 920 to 52,000 kJ/mol and is a function of relative pressure of the adsorbate in the feed gas. Quantifying the performance of the bench-scale gas recovery system in terms of its ability to remove organic gases from the adsorption stream and the energy required to liquefy the recovered organic gases is a critical step in developing new technologies to allow manufacturing to occur in a more sustainable manner. To our knowledge, this is the first time an ACFC-ESA system has been used to capture, recover, and liquefy organic compounds with vapor pressures as low as 8.3 × 10(-5) and the first time such a system has been analyzed for process performance and energy consumption.


Diabetes depresses synaptic transmission in sympathetic ganglia by inactivating nAChRs through a conserved intracellular cysteine residue.
Most people with diabetes develop severe complications of the autonomic nervous system; yet, the underlying causes of many diabetic-induced dysautonomias are poorly understood. Here we explore the idea that these dysautonomias results, in part, from a defect in synaptic transmission. To test this idea, we investigated cultured sympathetic neurons and show that hyperglycemia inactivates nAChRs through a mechanism involving an elevation in reactive oxygen species and an interaction with highly conserved cysteine residues located near the intracellular mouth of the nAChR channel. Consistent with this, we show that diabetic mice have depressed ganglionic transmission and reduced sympathetic reflexes, whereas diabetic mice expressing mutant postsynaptic nAChRs that lack the conserved cysteine residues on the alpha3 subunit have normal synaptic transmission in sympathetic ganglia and normal sympathetic reflexes. Our work suggests a new model for diabetic-induced dysautonomias and identifies ganglionic nAChRs as targets of hyperglycemia-induced downstream signals.


Recombination and the progression of meiosis in Saccharomyces cerevisiae.
Recombination is an essential part of meiosis: in almost all organisms, including Saccharomyces cerevisiae, proper chromosome segregation and the viability of meiotic products is dependent upon normal levels of recombination. In this article we examine the kinetics of the meiotic divisions in four mutants defective in the initiation of recombination. We find that mutations in any of three Early Exchange genes (REC104, REC114 or REC102) confer a phenotype in which the reductional division occurs earlier than in an isogenic wild-type diploid. We also present data confirming previous reports that strains with a mutation in the Early Exchange gene. MEI4 undergo the first division at about the same time as wild-type cells. The rec104 mutation is epistatic to the mei4 mutation for the timing of the first division. These observations suggest a possible relationship between the initiation of recombination and the timing of the reductional division. These data also allow these four Early Exchange genes examined to be distinguished in terms of their role in coordinating recombination with the reductional division.


"How can I not?": men's pathways to involvement in anti-violence against women work.
Despite growing male participation in ending violence against women, little is known about the factors that precipitate men's engagement as antiviolence "allies." This study presents findings from a qualitative analysis of interviews with 27 men who recently initiated involvement in an organization or event dedicated to ending sexual or domestic violence. Findings suggest that men's engagement is a process that occurs over time, that happens largely through existing social networks, and that is influenced by exposure to sensitizing experiences, tangible involvement opportunities and specific types of meaning making related to violence. Implications for models of ally development and for efforts to engage men in antiviolence work are discussed.


Identifying the safety profile of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in anticipation of a phase I clinical trial in patients with recurrent ovarian cancer.
The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma. Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects. Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD +/- GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time. These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.


High throughput approach to investigating ternary solvents of aqueous non-stoichiometric protic ionic liquids.
The use of ionic liquids (ILs) is limited for many applications due to their cost and/or viscosity. An efficient solution is to make mixtures of ILs with molecular solvents. However, it is well known that there are a large number of possible cation and anion combinations resulting in ILs, and this becomes a vast number when these are then combined with a molecular solvent. Therefore, we need structure-property relationships to design new IL-molecular solvent systems. In this work we have applied high throughput methods to investigate IL containing solutions to provide systematic data of a broad compositional space. We have principally focused on the surface tension, apparent pH and liquid nanostructure to identify potential self-assembly and protein stabilizing ability of solvent systems. Non-stoichiometric and aqueous IL-solvents were prepared in a high-throughput manner based on a deliberate experimental design approach such that 26 samples were prepared for each cation-anion-water combination. A selection of 8 protic ionic liquids (PILs) were used as starting materials, comprising ethanol-, ethyl-, butyl-, and pentylammonium cations combined with formate, acetate and nitrate anions. This resulted in a total of 208 different solvent systems. The measured solvent properties showed different trends in base-rich and acid-rich solvent combinations. Surface tensions of base-rich samples exhibited a relatively linear relationship with increasing excess amine, while acid-rich samples were more dominantly affected by the change in water content. Liquid nanostructure of acid-rich samples was retained upon water dilution, whereas a significant SAXS peak shift towards lower scattering angles was observed in the presence of excess amines, indicating larger nanosized aggregates were forming. The design of experiment approach used here is considered to be applicable to any multi-component solvent compositional space due to its suitability in using small data sets to cover large compositional spaces, and hence can be employed to decrease the time and sample quantities required.


[Experiences with a special vulvar clinic in Oslo].
Women with longstanding vulvar problems have difficulties finding medical care. In 2000, a first Norwegian vulvar clinic was opened at the Olafia centre for venereology in Oslo. The initiative was continued in 2003 by a multi-professional team in the dept. of gynaecology and obstetrics at Rikshospitalet University Hospital. Medical records from the two Vulva clinics have been reviewed in retrospect. During the period 2000 to 2003, a total of 217 patients had 470 visits to the Olafia clinic, mean age 31.4 years. Vulvodynia was diagnosed in 52% of all patients, 30% had a genital infection, 22% a genital dermatitis or dermatosis and 21% a primary sexual problem. At the multi-professional Rikshospitalet vulva clinic, run by specialists in gynaecology and dermato-venereology, 141 patients had 206 visits in 2003, mean age 42.5 years. Vulvodynia was diagnosed in 38%, 26% had a genital skin condition, 11% primary sexual problems, 10% a genital infection, and 10% a gynaecological problem. A few patients were healthy controls. The difference in diagnostic groups is related to the age of the patients. The options for vulvar patients have improved in Oslo. Multi-professional cooperation has been achieved in our department, which serves as a national referral centre.


The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death.
The aim of the present investigation was to characterize the role of the MAPK kinase kinase-1 (MEKK-1) in stress-induced cell death of insulin producing cells. We observed that transient overexpression of the wild type MEKK-1 protein in the insulin-producing cell lines RIN-5AH and betaTC-6 increased c-Jun N-terminal kinase (JNK) phosphorylation and augmented cell death induced by diethylenetriamine/nitroso-1-propylhydrazino)-1-propanamine (DETA/NO), streptozotocin (STZ), and hydrogen peroxide (H2O2). Furthermore, DETA/NO or STZ induced a rapid threonine phosphorylation of MEKK-1. Silencing of MEKK-1 gene expression in betaTC-6 and human dispersed islet cells, using in vitro-generated diced small interfering RNA, resulted in protection from DETA/NO, STZ, H2O2, and tunicamycin induced cell death. Moreover, in DETA/NO-treated cells diced small interfering RNA-mediated down-regulation of MEKK-1 resulted in decreased activation of JNK but not p38 and ERK. Inhibition of JNK by treatment with SP600125 partially protected against DETA/NO- or STZ-induced cell death. In summary, our results support an essential role for MEKK-1 in JNK activation and stress-induced beta-cell death. Increased understanding of the signaling pathways that augment or diminish beta-cell MEKK-1 activity may aid in the generation of novel therapeutic strategies in the treatment of type 1 diabetes.


The effect of DentalVibe on pain and discomfort during local anesthesia in children: a randomized clinical trial.
Objective: To evaluate the effectiveness of using DentalVibe during injection in comparison with the traditional injection technique, regarding pain and discomfort associated with buccal infiltration anesthesia (BIA) in pediatric patients. Method and materials: This randomized clinical trial included 6- to 12-year-old healthy children currently receiving nonurgent dental treatment on the maxillary arch that required BIA. In the control group, subjects received traditional BIA. In the test group, they received BIA with the aid of DentalVibe. A sample of 30 subjects per group was included. The mean ± SD age of the subjects was 9.18 ± 1.66 years. All the subjects were videotaped, and two trained and calibrated evaluators assessed the children's behaviors during the injection using the face, legs, activity, cry, consolability (FLACC) scale independently. Immediately after anesthesia administration, the subjects were administered the validated Arabic version of the Wong-Baker FACES scale ranging from 0 to 10. Results: Female subjects showed significantly higher mean FLACC and Wong-Baker FACES scale scores (2.20 ± 1.82 and 2.93 ± 3.05) compared with males (1.08 ± 1.37 and 1.12 ± 2.09) (P = .008 and P = .006, respectively). Multiple regression analysis showed that regardless of age and treatment group, females had significantly higher mean scores on the FLACC (β = 1.63, P = .002) and the Wong-Baker FACES scales (OR = 4.44, P = .004) than males. Conclusion: The use of DentalVibe did not significantly affect pain, discomfort, or time during BIA among pediatric patients compared with the traditional technique. Female children were more likely to report higher pain and discomfort scores during BIA administration regardless of age and anesthesia administration technique.


Thrombospondin-1 in vascular development, vascular function, and vascular disease.
Angiogenesis is vital to developmental, regenerative and repair processes. It is normally regulated by a balanced production of pro- and anti-angiogenic factors. Alterations in this balance under pathological conditions are generally mediated through up-regulation of pro-angiogenic and/or downregulation of anti-angiogenic factors, leading to growth of new and abnormal blood vessels. The pathological manifestation of many diseases including cancer, ocular and vascular diseases are dependent on the growth of these new and abnormal blood vessels. Thrompospondin-1 (TSP1) was the first endogenous angiogenesis inhibitor identified and its anti-angiogenic and anti-inflammatory activities have been the subject of many studies. Studies examining the role TSP1 plays in pathogenesis of various ocular diseases and vascular dysfunctions are limited. Here we will discuss the recent studies focused on delineating the role TSP1 plays in ocular vascular development and homeostasis, and pathophysiology of various ocular and vascular diseases with a significant clinical relevance to human health.


Neurod1 Is Essential for the Primary Tonotopic Organization and Related Auditory Information Processing in the Midbrain.
Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.


α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1.
This review describes the recent discoveries about a powerful electroneutral NaCl reabsorption mechanism in intercalated cells, and its regulation by an intrarenal metabolite paracrine, α-ketoglutartate, and the G-protein coupled receptor, Oxgr1. The distal nephron fine-tunes sodium, chloride, potassium, hydrogen, bicarbonate and water transport to maintain electrolyte homeostasis and blood pressure. Intercalated cells have been traditionally viewed as the professional regulators of acid-base balance, but recent studies reveal that a specific population of intercalated cells, identified by the pendrin-transporter, have a surprising role in the regulation of salt balance. The pendrin-positive intercalated cells (PP-ICs) facilitate electroneutral NaCl reabsorption through the cooperative activation of multitransport protein network. α-Ketoglutartate is synthesized and secreted into the proximal tubule lumen in the combined state of metabolic alkalosis and intravascular volume contraction to activate Oxgr1 in PP-IC, which in turn activates the multitransport protein network to drive salt reabsorption and bicarbonate secretion by these cells. Recent studies identify a novel salt transport pathway in intercalated cells that is activated by an intrarenal paracrine system, α-ketoglutartate/Oxgr1. Activation of the paracrine system and transport pathway, particularly during alkalosis and volume contraction, mitigates deleterious salt wasting while restoring acid-base balance.


How culture affects validity: understanding Japanese residents' sense-making of evaluating clinical teachers.
Traditionally, evaluation is considered a measurement process that can be performed independently of the cultural context. However, more recently the importance of considering raters' sense-making, that is, the process by which raters assign meaning to their collective experiences, is being recognised. Thus far, the majority of the discussion on this topic has originated from Western perspectives. Little is known about the potential influence of an Asian culture on raters' sense-making. This study explored residents' sense-making associated with evaluating their clinical teachers within an Asian setting to better understand contextual dependency of validity. A qualitative study using constructivist grounded theory. The Japanese Ministry of Health, Labour and Welfare has implemented a system to monitor the quality of clinical teaching within its 2-year postgraduate training programme. An evaluation instrument was developed specifically for the Japanese setting through which residents can evaluate their clinical teachers. 30 residents from 10 Japanese teaching hospitals with experience in evaluating their clinical teachers were sampled purposively and theoretically. We conducted in-depth semistructured individual interviews. Sensitising concepts derived from Confucianism and principles of response process informed open, axial and selective coding. Two themes and four subthemes were constructed. Japanese residents emphasised the awareness of their relationship with their clinical teachers (1). This awareness was fuelled by their sense of hierarchy (1a) and being part of the collective society (1b). Residents described how the meaning of evaluation (2) was coloured by their perceived role as senior (2a) and their experienced responsibility for future generations (2b). Japanese residents' sense-making while evaluating their clinical teachers appears to be situated and affected by Japanese cultural values. These findings contribute to a better understanding of a culture's influence on residents' sense-making of evaluation instruments and the validity argument of evaluation.


The Role of AOPP in Age-Related Bone Loss and the Potential Benefits of Berry Anthocyanins.
Age-related bone loss is a major factor in osteoporosis and osteoporotic fractures among the elderly. Because bone homeostasis involves a balance between bone formation and resorption, multiple mechanisms may induce age-dependent changes in bone. Oxidative stress is one such factor that contributes to the pathology of aging-associated osteoporosis (AAO). Advanced oxidation protein products (AOPP) are a biomarker of oxidant-mediated protein damage, and can also act to increase the production of reactive oxygen species (ROS), thereby perpetuating oxidative damage. AOPP is a relatively novel marker of oxidative stress, and its role in bone aging has not been fully elucidated. Furthermore, it has been theorized that dietary antioxidants may decrease AOPP levels, thereby reducing AAO risk, but a limited number of studies have been specifically targeted at addressing this hypothesis. Therefore, the objective of this review is to examine the findings of existing research on the role of AOPP in age-related bone loss, and the potential use of dietary antioxidants to mitigate the effects of AAOP on age-related bone loss. Cross-sectional studies have delivered mixed results, showing that AOPP levels are inconsistently associated with bone loss and aging. However, in vitro studies have documented multiple mechanisms by which AOPP may lead to bone loss, including upregulation of the JNK/p38 MAPK signaling pathways as well as increasing expression of sclerostin and of receptor activator of NFκB ligand (RANKL). Studies also indicate that antioxidants-especially berry anthocyanins-may be an effective dietary agent to prevent aging-associated bone deterioration by inhibiting the formation of AOPP and ROS. However, the understanding of these pathways in AAO has largely been based on in vitro studies, and should be examined in further animal and human studies in order to inform recommendations regarding dietary anthocyanin use for the prevention of AAO.


Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats.
The pharmacokinetics of orally administered pefloxacin were studied to evaluate the bio-enhancing effect of the herbal bio-enhancer, trikatu, in mountain Gaddi goats (n = 6). The findings of the study revealed a decreased plasma concentration (p > 0.05) of pefloxacin following trikatu administration during the absorption phase (10, 15, 20 min post pefloxacin administration). In contrast, the plasma concentrations of pefloxacin were significantly higher at 4, 6, 8 and 12 h (during the elimination phase) of the pefloxacin administration. The findings of the investigation revealed higher values for the area under the curve, the area under the first moment of the plasma drug concentration time curve, the mean residential time, the total duration of pharmacological action and bioavailability. Trikatu treatment, however, significantly reduced the elimination half life (t 1/2 beta) and zero time intercept of the elimination phase. The apparent volume of distribution based on the total area under the plasma drug concentration curve [(Vd(area)] and the apparent volume of distribution based on the zero time plasma concentration intercept of the elimination phase [Vd(B)] were significantly higher in trikatu treated animals indicating a better penetration of the drug. Based on the MIC of 0.8 microg/ml of pefloxacin, a priming dose of 6.0 mg/kg and a maintenance dose of 2.21 mg/kg is required to be administered at 8 h intervals. For practical purposes in goats this would mean a priming dose of 6 mg/kg and a maintenance dose of 2 mg/kg given by the oral route, to be repeated at 8 h intervals.


Cell surface receptors for gammaretroviruses.
Evidence obtained during the last few years has greatly extended our understanding of the cell surface receptors that mediate infections of retroviruses and has provided many surprising insights. In contrast to other cell surface components such as lectins or proteoglycans that influence infections indirectly by enhancing virus adsorption onto specific cells, the true receptors induce conformational changes in the viral envelope glycoproteins that are essential for infection. One surprise is that all of the cell surface receptors for gamma-retroviruses are proteins that have multiple transmembrane (TM) sequences, compatible with their identification in known instances as transporters for important solutes. In striking contrast, almost all other animal viruses use receptors that exclusively have single TM sequences, with the sole proven exception we know of being the coreceptors used by lentiviruses. This evidence strongly suggests that virus genera have been prevented because of their previous evolutionary adaptations from switching their specificities between single-TM and multi-TM receptors. This evidence also implies that gamma-retroviruses formed by divergent evolution from a common origin millions of years ago and that individual viruses have occasionally jumped between species (zoonoses) while retaining their commitment to using the orthologous receptor of the new host. Another surprise is that many gamma-retroviruses use not just one receptor but pairs of closely related receptors as alternatives. This appears to have enhanced viral survival by severely limiting the likelihood of host escape mutations. All of the receptors used by gamma-retroviruses contain hypervariable regions that are often heavily glycosylated and that control the viral host range properties, consistent with the idea that these sequences are battlegrounds of virus-host coevolution. However, in contrast to previous assumptions, we propose that gamma-retroviruses have become adapted to recognize conserved sites that are important for the receptor's natural function and that the hypervariable sequences have been elaborated by the hosts as defense bulwarks that surround the conserved viral attachment sites. Previously, it was believed that binding to receptors directly triggers a series of conformational changes in the viral envelope glycoproteins that culminate in fusion of the viral and cellular membranes. However, new evidence suggests that gamma-retroviral association with receptors triggers an obligatory interaction or cross-talk between envelope glycoproteins on the viral surface. If this intermediate step is prevented, infection fails. Conversely, in several circumstances this cross-talk can be induced in the absence of a cell surface receptor for the virus, in which case infection can proceed efficiently. This new evidence strongly implies that the role of cell surface receptors in infections of gamma-retroviruses (and perhaps of other enveloped animal viruses) is more complex and interesting than was previously imagined. Recently, another gammaretroviral receptor with multiple transmembrane sequences was cloned. See Prassolov, Y., Zhang, D., Ivanov, D., Lohler, J., Ross, S.R., and Stocking, C. Sodium-dependent myo-inositol transporter 1 is a receptor for Mus cervicolor M813 murine leukemia virus.


A computationally efficient and reliable bond order measure.
Bond order indexes are useful measures that connect quantum mechanical results with chemical understanding. One of these measures, the natural bond order index, based on the natural resonance theory procedure and part of the natural bond orbital analysis tools, has been proved to yield reliable results for many systems. The procedure's computational requirements, nevertheless, scales so highly with the number of functions in the basis set and the delocalization of the system, that the calculation of this bond order is limited to small or medium size molecules. We present in this work a bond order index, the first order perturbation theory bond order (fopBO), which is based on and strongly connected to the natural bond orbital analysis tools. We present the methodology for the calculation of the fopBO index and a number of test calculations that shows that it is as reliable as the natural bond orbital index, with the same weak sensitivity to variations among commonly used basis sets and, as opposed to the natural bond order index, suitable for the study of large systems, such as most of those of biological interest.


Fast deterministic ptychographic imaging using X-rays.
We present a deterministic approach to the ptychographic retrieval of the wave at the exit surface of a specimen of condensed matter illuminated by X-rays. The method is based on the solution of an overdetermined set of linear equations, and is robust to measurement noise. The set of linear equations is efficiently solved using the conjugate gradient least-squares method implemented using fast Fourier transforms. The method is demonstrated using a data set obtained from a gold-chromium nanostructured test object. It is shown that the transmission function retrieved by this linear method is quantitatively comparable with established methods of ptychography, with a large decrease in computational time, and is thus a good candidate for real-time reconstruction.


An In Vitro-In Vivo Simulation Approach for the Prediction of Bioequivalence.
The aim of this study was to develop a new in vitro-in vivo simulation (IVIVS) approach in order to predict the outcome of a bioequivalence study. The predictability of the IVIVS procedure was evaluated through its application in the development process of a new generic product of amlodipine/irbesartan/hydrochlorothiazide. The developed IVIVS methodology is composed of three parts: (a) mathematical description of in vitro dissolution profiles, (b) mathematical description of in vivo kinetics, and (c) development of joint in vitro-in vivo simulations. The entire programming was done in MATLAB® and all created scripts were validated through other software. The IVIVS approach can be implemented for any number of subjects, clinical design, variability and can be repeated for thousands of times using Monte Carlo techniques. The probability of success of each scenario is recorded and finally, an overall assessment is made in order to select the most suitable batch. Alternatively, if the IVIVS shows reduced probability of BE success, the R&D department is advised to reformulate the product. In this study, the IVIVS approach predicted successfully the BE outcome of the three drugs. During the development of generics, the IVIVS approach can save time and expenses.


Modern concepts in crown preparation.
The preparation of teeth for full coverage is one of the most abused procedures in fixed prostheses. It is fallacious to discard precision preparations on the grounds that they will not be visible once the crown is constructed. In truth, what takes place in the preparation phase of crown and bridge construction determines the quality of the final restoration.


ED overcrowding spurs interest in quality and credentialing issues.
Quality in emergency medicine is not a new concept. But applying quality principles to emergency department operations is another thing altogether. While the JCAHO and the American College of Emergency Physicians are examining quality issues in emergency medicine, individual hospitals are looking for solutions to the quality question. And they are accepting the reality that hiring and retaining high-quality physicians remains a key element.


Scaling, selection, and evolutionary dynamics of the mitotic spindle.
Cellular structures such as the nucleus, Golgi, centrioles, and spindle show remarkable diversity between species, but the mechanisms that produce these variations in cell biology are not known. Here we investigate the mechanisms that contribute to variations in morphology and dynamics of the mitotic spindle, which orchestrates chromosome segregation in all Eukaryotes and positions the division plane in many organisms. We use high-throughput imaging of the first division in nematodes to demonstrate that the measured effects of spontaneous mutations, combined with stabilizing selection on cell size, are sufficient to quantitatively explain both the levels of within-species variation in the spindle and its diversity over ∼100 million years of evolution. Furthermore, our finding of extensive within-species variation for the spindle demonstrates that there is not just one "wild-type" form, rather that cellular structures can exhibit a surprisingly broad diversity of naturally occurring behaviors. Our results argue that natural selection acts predominantly on cell size and indirectly influences the spindle through the scaling of the spindle with cell size. Previous studies have shown that the spindle also scales with cell size during early development. Thus, the scaling of the spindle with cell size controls its variation over both ontogeny and phylogeny.


Metabolic imaging: a link between lactate dehydrogenase A, lactate, and tumor phenotype.
We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. LDH-A expression, lactate concentration, glucose utilization, and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels [measured by magnetic resonance spectroscopic imaging (MRSI)] and tumor glucose utilization [measured by [(18)F]2-deoxy-2-fluoro-D-glucose positron emission tomography ([(18)F]FDG-PET)] was assessed in orthotopic breast tumors derived from these cell lines. We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate 10-fold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less-intense hypoxia staining was observed in the larger 67NR tumors and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Lactate-MRSI has a greater dynamic range than [(18)F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors.


Quantum versus classical foundation of statistical mechanics under experimentally realistic conditions.
Focusing on isolated macroscopic systems, described in terms of either a quantum mechanical or a classical model, our two key questions are how far does an initial ensemble (usually far from equilibrium and largely unknown in detail) evolve towards a stationary long-time behavior (equilibration) and how far is this steady state in agreement with the microcanonical ensemble as predicted by statistical mechanics (thermalization). A recently developed quantum mechanical treatment of the problem is briefly summarized, putting particular emphasis on the realistic modeling of experimental measurements and nonequilibrium initial conditions. Within this framework, equilibration can be proven under very weak assumptions about those measurements and initial conditions, while thermalization still requires quite strong additional hypotheses. An analogous approach within the framework of classical mechanics is developed and compared with the quantum case. In particular, the assumptions to guarantee classical equilibration are now rather strong, while thermalization then follows under relatively weak additional conditions.


Total (fumarolic + diffuse soil) CO2 output from Furnas volcano.
Furnas volcano, in São Miguel island (Azores), being the surface expression of rising hydrothermal steam, is the site of intense carbon dioxide (CO2) release by diffuse degassing and fumaroles. While the diffusive CO2 output has long (since the early 1990s) been characterized by soil CO2 surveys, no information is presently available on the fumarolic CO2 output. Here, we performed (in August 2014) a study in which soil CO2 degassing survey was combined for the first time with the measurement of the fumarolic CO2 flux. The results were achieved by using a GasFinder 2.0 tunable diode laser. Our measurements were performed in two degassing sites at Furnas volcano (Furnas Lake and Furnas Village), with the aim of quantifying the total (fumarolic + soil diffuse) CO2 output. We show that, within the main degassing (fumarolic) areas, the soil CO2 flux contribution (9.2 t day-1) represents a minor (~15 %) fraction of the total CO2 output (59 t day-1), which is dominated by the fumaroles (~50 t day-1). The same fumaroles contribute to ~0.25 t day-1 of H2S, based on a fumarole CO2/H2S ratio of 150 to 353 (measured with a portable Multi-GAS). However, we also find that the soil CO2 contribution from a more distal wider degassing structure dominates the total Furnas volcano CO2 budget, which we evaluate (summing up the CO2 flux contributions for degassing soils, fumarolic emissions and springs) at ~1030 t day-1.


Clinical Profiles in Renal Patients with COVID-19.
The COVID-19 pandemic has led to frequent referrals to the emergency department on suspicion of this infection in maintenance hemodialysis (MHD) and kidney transplant (KT) patients. We aimed to describe their clinical features comparing confirmed and suspected non-confirmed COVID-19 cases during the Spanish epidemic peak. Confirmed COVID-19 ((+)COVID-19) corresponds to patient with positive RT-PCR SARS-CoV-2 assay. Non-confirmed COVID-19 ((-)COVID-19) corresponds to patients with negative RT-PCR. COVID-19 was suspected in 61 patients (40/803 KT (4.9%), 21/220 MHD (9.5%)). Prevalence of (+)COVID-19 was 3.2% in KT and 3.6% in MHD patients. Thirty-four (26 KT and 8 MHD) were (+)COVID-19 and 27 (14 KT and 13 MHD) (-)COVID-19. In comparison with (-)COVID-19 patients, (+)COVID-19 showed higher frequency of typical viral symptoms (cough, dyspnea, asthenia and myalgias), pneumonia (88.2% vs. 14.3%) and LDH and CRP while lower phosphate levels, need of hospital admission (100% vs. 63%), use of non-invasive mechanical ventilation (36% vs. 11%) and mortality (38% vs. 0%) (p < 0.001). Time from symptoms onset to admission was longer in patients who finally died than in survivors (8.5 vs. 3.8, p = 0.007). In KT and MHD patients, (+)COVID-19 shows more clinical severity than suspected non-confirmed cases. Prompt RT-PCR is mandatory to confirm COVID-19 diagnosis.


Behavioral changes in response to sound exposure and no spatial avoidance of noisy conditions in captive zebrafish.
Auditory sensitivity in fish serves various important functions, but also makes fish susceptible to noise pollution. Human-generated sounds may affect behavioral patterns of fish, both in natural conditions and in captivity. Fish are often kept for consumption in aquaculture, on display in zoos and hobby aquaria, and for medical sciences in research facilities, but little is known about the impact of ambient sounds in fish tanks. In this study, we conducted two indoor exposure experiments with zebrafish (Danio rerio). The first experiment demonstrated that exposure to moderate sound levels (112 dB re 1 μPa) can affect the swimming behavior of fish by changing group cohesion, swimming speed and swimming height. Effects were brief for both continuous and intermittent noise treatments. In the second experiment, fish could influence exposure to higher sound levels by swimming freely between an artificially noisy fish tank (120-140 dB re 1 μPa) and another with ambient noise levels (89 dB re 1 μPa). Despite initial startle responses, and a brief period in which many individuals in the noisy tank dived down to the bottom, there was no spatial avoidance or noise-dependent tank preference at all. The frequent exchange rate of about 60 fish passages per hour between tanks was not affected by continuous or intermittent exposures. In conclusion, small groups of captive zebrafish were able to detect sounds already at relatively low sound levels and adjust their behavior to it. Relatively high sound levels were at least at the on-set disturbing, but did not lead to spatial avoidance. Further research is needed to show whether zebrafish are not able to avoid noisy areas or just not bothered. Quantitatively, these data are not directly applicable to other fish species or other fish tanks, but they do indicate that sound exposure may affect fish behavior in any captive condition.


Long-term function after Charnley total hip arthroplasty.
The purpose of this study was to report the functional results and mortality rates of a consecutive series of patients younger than 50 years after Charnley total hip arthroplasty. The original group of 69 patients (93 hips) was followed up until death or a minimum of 25 years after surgery. Of the original 93 hips, 29 had been revised at some point. Functional outcomes included the Short Form-36, Western Ontario and McMaster University University Osteoarthritis Index (WOMAC), 6-minute walk distance, Noyes activity scale, and Harris hip scores and included followup in 42 of 43 living patients. The functional outcome of patients was good, with comparable Short Form-36 scores compared with normative values of healthy age-matched subjects. The 6-minute walk distances and WOMAC scores were slightly lower than healthy normatives but were thought to be influenced by medical comorbidities. Although comorbid medical and musculoskeletal conditions significantly hindered most measures of function, revision surgery or radiographic loosening of components had no significant influence on function. The mortality rates of this cohort of patients were similar to normative values at both 10 and 25 years after surgery.


5-Hydroxytryptamine-induced calcium-channel gating in rainbow trout (Oncorhynchus mykiss) peripheral blood lymphocytes.
The present study was conducted on peripheral blood lympho-cytes of rainbow trout (Oncorhynchus mykiss) to assess the role of 5-hydroxytryptamine (5-HT; 'serotonin') in calcium signalling. 5-HT-induced increases in intracellular free calcium concentrations, [Ca2+]i, and its action was mediated by 5-HT receptor subtype 3 (5-HT3), but not by 5-HT receptor subtype 1A (5-HT1A) or subtype 2 (5-HT2) in these cells. In Ca2+-containing medium (1 mM CaCl2), 5-HT and 2-methyl-5-HT (5-HT3 receptor agonist) induced increases in [Ca2+]i, whereas in Ca2+-free medium (0 Ca2+, 1 mM EGTA), these two agents failed to evoke increases in [Ca2+]i in these cells, demonstrating that 5-HT mobilizes Ca2+ from the extracellular environment. Furthermore, 5-HT-induced increases in [Ca2+]i are not contributed to by the intracellular endoplasmic reticulum (ER) pool, as thapsigargin, an agent that recruits Ca2+ from ER stores, had additive effects on 5-HT-induced [Ca2+]i responses in fish peripheral lymphocytes. 5-HT-induced increases in [Ca2+]i were mediated by 5-HT3 receptors via gating the calcium through L-type, but not N-type, calcium channels in trout lymphocytes.


The premenstrual syndrome.
The recognition of the relationship between premenstrual syndrome and cyclical ovarian activity has enabled the rationalization of treatment. Placebo-controlled studies have established the efficacy of treatments that alter ovarian function, therefore it should no longer be necessary to rely on the placebo effect of unproven treatments such as progesterone.


The relationships between loneliness and mental and physical health are moderated by the tendency for interpersonal victimhood: A study of young adult cancer patients.
To assess whether loneliness is inversely related to young adult cancer patients' subjective reports of mental and physical health, and to explore whether such inverse relationships are moderated by young adult cancer patients' tendency for interpersonal victimhood. Young adult cancer patients (N = 140) ranging in age from 19-39 years completed two questionnaires distributed three months apart. Patients reported loneliness, their tendency for interpersonal victimhood, and mental and physical health. Hypotheses were tested using the PROCESS macro for SPSS, which tests for main effects and moderation effects. Loneliness was inversely related to mental health, but there was no main effect of loneliness on physical health. Tendency for interpersonal victimhood significantly moderated the relationships between loneliness and both mental and physical health, such that a greater tendency for interpersonal victimhood strengthened the inverse relationships between loneliness and both mental and physical health. Loneliness continues to be an important predictor of mental health for young adult cancer patients, and this relationship is strengthened when a patient has a greater tendency for interpersonal victimhood. Health care providers, family members, and other supporters should monitor the quantity and quality of patients' relationships with others and also facilitate conversations that can address aspects of the tendency for interpersonal victimhood, such as rumination or the need for recognition.


Distribution and current infection status of Biomphalaria straminea in Hong Kong.
Schistosomiasis, also generally known as snail fever, is a parasitic disease caused by trematode flatworms of the genus Schistosoma. In Hong Kong and mainland China, the freshwater snail Biomphalaria straminea has been introduced and has the potential to transmit intestinal schistosomiasis caused by S. mansoni, a parasite of man which has a wide distribution in Africa and parts of the New World, especially Brazil. The first identification of B. straminea in Hong Kong dates back to the 1970s, and its geographical distribution, phylogenetic relationships, and infection status have not been updated for more than 30 years. Thus, this study aims to reveal the distribution and current infection status of B. straminea in contemporary Hong Kong. Snails were collected from different parts of Hong Kong from July 2016 to January 2017. Both anatomical and molecular methods were applied to identify B. straminea. Cytochrome c oxidase subunit 1 (cox1), internal transcribed spacer 1 (ITS1), 5.8S rDNA, internal transcribed spacer 2 (ITS2), and 16S ribosomal DNA (rDNA) were sequenced from individual snails and analyzed. To detect the presence of S. mansoni, both biopsy and PCR analyses were carried out. Using both anatomical and molecular analyses, this study demonstrated the existence of black- and red-coloured shell B. straminea in different districts in the New Territories in Hong Kong, including places close to the mainland China border. None of the B. straminea (n = 87) investigated were found to be infected with S. mansoni when tested by biopsy and PCR. The Hong Kong B. straminea are genetically indistinguishable, based on the chosen molecular markers (cox1, ITS1-5.8S-ITS2, and 16S rDNA), and are similar to those obtained in mainland China and South America. Biomphalaria straminea is now well established in freshwater habitats in Hong Kong. No evidence of infection with S. mansoni has been found. Surveillance should be continued to monitor and better understand this schistosomiasis intermediate host in mainland China and Hong Kong.


Association between social class and food consumption in the Italian EPIC population.
The objectives of the present study were to validate the social stratification variables adopted by the European Prospective Investigation into Cancer and Nutrition (EPIC) by comparing them with data from another independent source and to evaluate the geographic and social distribution of eating habits in the Italian EPIC population. The validation of the socioeconomic data collected by the EPIC study was performed with the Turin Longitudinal Study as gold standard and using Cohen's kappa statistics to evaluate the concordance between the studies. We then analyzed food groups based on the consumption of meat and fats, carbohydrates, sweets and alcohol, and on an index of the Mediterranean diet. The standardized scores for each food group were subdivided into quartiles, which were used to compare persons in the extreme quartiles. Analysis of the differences in eating habits by center and by educational level was conducted separately for men and women, calculating the prevalence rate ratios and controlling for age, area of birth and body mass index. Concordance between the two data sources was high for educational level and low for the social-class index based on occupation. Most of the eating habits considered to be potentially harmful (high consumption of meat or fats and alcohol and low consumption of olive oil and fish) were more frequent in Northern than in Southern Italy. These habits were inversely correlated with educational level, especially in the South. A significant improvement in health could be obtained in the Italian population if culturally and socioeconomically disadvantaged individuals were to abandon their diet rich in meat and fats, as done by more advantaged persons. In the absence of preventive interventions specifically addressed to disadvantaged groups, it is likely that social inequalities in mortality and morbidity will increase.


Cell-matrix mechanobiology: applications to brain tumors and design of tissue engineering scaffolds.
It is becoming increasingly clear that mechanical and other biophysical signals from the extracellular matrix (ECM) can powerfully influence a wide variety of fundamental cell behaviors, including proliferation, differentiation, death, and motility. This concept has significant implications both for understanding the pathophysiology of disease and the design of biointerfaces found in cellular microdevices and tissue engineering platforms. Here we briefly review recent progress from our laboratory in investigating the role of ECM-derived mechanical signals in the specific context of two systems: The growth and spread of malignant brain tumors and the design of microscale cardiac tissue engineering systems. In both cases, mechanical signals encoded in the ECM govern motility, mechanics, and/or proliferation in profound and unexpected ways and rely upon the cell's reciprocal ability to generate contractile force through myosin and its molecular regulators.


Prediction of visual outcomes after open globe injury in children: a 17-year Canadian experience.
To analyze the predictive value of ocular trauma scoring systems for open globe injury in children, to determine risk factors for poor visual outcome, and to assess circumstances under which trauma occurs. The medical records of patients <18 years of age who presented with open globe injuries from January 1992 to December 2009 were examined retrospectively. Information recorded included demographic profile; date, time, and place of injury; cause and extent of injury; complications; and final best-corrected visual acuity. Injuries were classified by Ocular Trauma Classification Group guidelines. A total of 131 patients were included. Final best-corrected visual acuity was ≥20/40 in 74 patients (56.5%) after mean follow-up of 24.8 months. Injuries occurred more commonly in boys (98/131), and 45% of injuries occurred in children aged ≤5 years (P = 0.001). Injuries were more common indoors (P = 0.003), in the afternoon (P < 0.001), and on Saturdays and Mondays (P = 0.004). Multiple regression analysis identified risk factors for final best-corrected visual acuity <20/40: age <5 years, injuries with retrolimbal involvement, wound length >5 mm, globe rupture, vitreous hemorrhage, and retinal detachment (P < 0.05). Visual outcomes after pediatric open globe injury in this study compare favorably to results reported previously. Knowledge of weekly fluctuations in occurrence may help guide development of prevention strategies. Age <5 years is an independent risk factor for a poorer outcome. The ocular trauma score is useful in assessing prognosis after pediatric open globe injury.


Moral Distress Among Operating Room Personnel During the COVID-19 Pandemic: A Qualitative Study.
The ongoing COVID-19 pandemic has necessitated the reallocation of healthcare resources, and a minimization of elective activities. Healthcare personnel involved in COVID-19 care have been negatively affected by the associated excess stress. The existing COVID-19 research has focused on the experiences among healthcare personnel in general, and not particularly on the operating room team members, who have often been relocated to overburdened workplaces. Therefore, we aimed to explore the experiences in this particular group. This study has a qualitative inductive design based on interviews with a strategic sample of 12 operating room team members: surgeons, anesthesiologist, specialist nurses, and nurse assistants. The interviews were analyzed using content analysis. Three themes were identified: "Feeling safe in the familiar and anxiety in the unknown", "To be the ones left behind", and "The possibility for recuperation in a seemingly everlasting situation". The participants described working hard, although their efforts were experienced as not enough according to their moral ideals. We interpreted this as feelings and signs of moral distress, a commonly described concept in previous studies during the COVID-19 pandemic, and a risk for burn out. The operating room team members emphasized the negative stress of being in the unknown, performing work tasks in an unfamiliar place and situation, and experiencing conflicting feelings of relief and guilt. Organizational strategies toward a functional leadership and support should be emphasized. Such strategies might reduce the risk of psychological consequences such as burn out.


Italian validation of the "Constructed Meaning Scale": preliminary results.
The sense or meaning (constructed meaning) that a person attributes to their own illness is one of the factors involved in the process of adaptation. The Constructed Meaning Scale (CMS), originally developed in the United States by Fife in 1995, is a brief 8-item survey investigating the subjective meaning that patients associate with their disease. The purpose of this study was to validate an Italian version of the CMS in a sample of patients with chronic disabling disease. The validation process consisted of 4 steps: (1) creation of an Italian version (translation and back translation); (2) administration of the translated version to a small sample of patients affected by different types of disease to verify its comprehensibility; (3) administration of the final version to a sample of 122 patients affected by chronic disabling conditions; (4) statistical analysis. The Italian version of the CMS was found to have the following psychometric properties: range of total-item correlation = .30 to .64; Cronbach's Alpha = .79; correlation with CBA 2.0 Depression Scale = -.44. We isolated two factors through VARIMAX factor analysis, which we defined as "disease as permanent damage" and "process of adaptation". The Italian version of the CMS is easy to understand and minimizes possible cultural biases. The psychometric properties of the scale are satisfactory.


A Randomized Trial Comparing Effect of Yoga and Exercises on Quality of Life in among nursing population with Chronic Low Back Pain.
Chronic low back pain (CLBP) adversely affects quality of life (QOL) in nursing professionals. Integrated yoga has a positive impact on CLBP. Studies assessing the effects of yoga on CLBP in nursing population are lacking. Aim: This study was conducted to evaluate the effects of integrated yoga and physical exercises on QOL in nurses with CLBP. A total of 88 women nurses from a tertiary care hospital of South India were randomized into yoga group (n = 44; age - 31.45 ± 3.47 years) and physical exercise group (n = 44; age - 32.75 ± 3.71 years). Yoga group was intervened with integrated yoga therapy module practices, 1 h/day and 5 days a week for 6 weeks. Physical exercise group practiced a set of physical exercises for the same duration. All participants were assessed at baseline and after 6 weeks with the World Health Organization Quality of Life-brief (WHOQOL-BREF) questionnaire. Data were analyzed by Paired-samples t-test and Independent-samples t-test for within- and between-group comparisons, respectively, using the Statistical Package for the Social Sciences (SPSS). Within-group analysis for QOL revealed a significant improvement in physical, psychological, and social domains (except environmental domain) in both groups. Between-group analysis showed a higher percentage of improvement in yoga as compared to exercise group except environmental domain. Integrated yoga was showed improvements in physical, psychological, and social health domains of QOL better than physical exercises among nursing professionals with CLBP. There is a need to incorporate yoga as lifestyle intervention for nursing professionals.


CHOROIDAL NEOVASCULAR AREA AND VESSEL DENSITY COMPARISON BETWEEN TWO SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY DEVICES.
To compare choroidal neovascularization (CNV) area and vessel density (VD) measurements between two different swept-source optical coherence tomography angiography (SS-OCTA) devices. En face optical coherence tomography angiography (OCTA) images of patients affected by neovascular age-related macular degeneration were collected prospectively from two devices: Zeiss PLEX Elite 9000 (Carl Zeiss Meditec, Dublin, CA) and Topcon DRI OCT Triton SS-OCTA (Topcon, Tokyo, Japan). Choroidal neovascularization area and VD of images were measured and analyzed with ImageJ software by two readers to evaluate the agreement between two devices, with respect to different image size (3 × 3 and 6 × 6 mm) and different image segmentation (automatic vs. manual), and a Topcon equivalent Zeiss segmentation as control (i.e., the equivalent anatomical slab given by Topcon device on the Zeiss device). A total of 30 eyes (30 patients) were analyzed. There was an excellent agreement between the two readers in CNV area measurements intraclass correlation coefficient >0.9 in all analyses. We found excellent agreement in CNV area measurements (manual and automatic segmentations) when comparing 3 × 3-mm or 6 × 6-mm images both for each single device and between the two devices (overall intraclass correlation coefficient > 0.9). Vessel density measurements between manual to automatic segmentation within the same device and same image size had a high intraclass correlation coefficient value, but there was a poor agreement in VD between different image sizes (3 × 3 mm vs. 6 × 6 mm) in the same device and also comparing the two devices (3 × 3 Topcon vs. 3 × 3 Zeiss; 6 × 6 Topcon vs. 6 × 6 Zeiss). There was a poor agreement between the Topcon equivalent Zeiss segmentation and all other segmentations. There was an excellent agreement in CNV area measurements for both swept-source optical coherence tomography angiography devices in automatic and manual segmentations. However, the Topcon equivalent Zeiss segmentation was not comparable with any of the preset segmentations of Topcon and Zeiss devices. There was a poor agreement in CNV VD between different image size and different devices. For these reasons, it seems that, for accurate longitudinal analysis of VD, it is better to use the same device for each individual, even if both devices can be used interchangeably for CNV area measurements using automatic or manual segmentations.


Inhibition of early response genes prevents changes in global joint metabolomic profiles in mouse post-traumatic osteoarthritis.
Although joint injury itself damages joint tissues, a substantial amount of secondary damage is mediated by the cellular responses to the injury. Cellular responses include the production and activation of proteases (MMPs, ADAMTSs, Cathepsins), and the production of inflammatory cytokines. The trajectory of cellular responses is driven by the transcriptional activation of early response genes, which requires Cdk9-dependent RNA Polymerase II phosphorylation. Our objective was to determine whether inhibition of cdk9-dependent early response gene activation affects changes in the joint metabolome. To model post-traumatic osteoarthritis, we subjected mice to non-invasive Anterior Cruciate Ligament (ACL)-rupture joint injury. Following injury, mice were treated with flavopiridol - a potent and selective inhibitor of Cdk9 kinase activity - to inhibit Cdk9-dependent transcriptional activation, or vehicle control. Global joint metabolomics were analyzed 1 h after injury. We found that injury induced metabolomic changes, including increases in Vitamin D3 metabolism, anandamide, and others. Inhibition of primary response gene activation immediately after injury largely prevented the global changes in the metabolomics profiles. Cluster analysis of joint metabolomes identified groups of injury-induced and drug-responsive metabolites. Metabolomic profiling provides an instantaneous snapshot of biochemical activity representing cellular responses. We identified two sets of metabolites that change acutely after joint injury: those that require transcription of primary response genes, and those that do not. These data demonstrate the potential for inhibition of early response genes to alter the trajectory of cell-mediated degenerative changes following joint injury, which may offer novel targets for cell-mediated secondary joint damage.


Expression of CD38 with intracellular enzymatic activity: a possible explanation for the insulin release induced by intracellular cADPR.
CD38 is a transmembrane glycoprotein expressed in multiple cell types, including pancreatic β cells. It can serve as an enzyme that catalyzes the metabolism of two different Ca(2+)-mobilizing compounds, cyclic adenosine diphosphoribose (cADPR) and nicotinic acid adenine dinucleotide phosphate. One of these metabolites, cADPR, is known to be involved in glucose-induced insulin secretion from pancreatic β cells. Although the essential role of CD38 for endogenous cADPR synthesis has been established, the relationship between the proposed extracellular enzymatic activity of CD38 and the intracellular Ca(2+) modulation caused by the intracellular cADPR accumulation has not yet been fully explained. For a better understanding of the role of CD38 in the insulin secretion machinery, analysis of the intracellular localization of this molecule in pancreatic β cells is essential. In an attempt to provide a method to probe the N-terminal and C-terminal of CD38 separately, we generated an insulin-secreting MIN6 murine pancreatic β cell line expressing a human CD38 bearing an N-terminal FLAG epitope tag. We found a weak but consistent expression of the FLAG epitope outside of the cells, indicating the presence of a small amount of CD38 with cytoplasmic enzymatic activity. MIN6 cells transfected with human CD38 exhibited increased glucose-induced insulin release. In addition, anti-FLAG cross-linking further enhanced the insulin release, suggesting that the N-terminal of CD38 expressed on the cell surface functions as a receptor for an unknown ligand and triggers positive signals for insulin secretion.


[Pantogam active in the complex treatment of dystonic hyperkineses].
Efficacy of pantogam active in the complex treatment of facial and cervical dystonic hyperkineses was studied in 37 patients (25 women, 12 men) with dystonic torticollis, blepharospasm, oromandibular dystonia with illness duration more than 6 months. In these patients, the previous treatment had no positive effect. Pantogam active was prescribed in dose 900-1800 mg/day during 12 weeks. Efficacy was assessed with the TWSTRS, the HADS and the CGI-I. Pantogam active as add-on to basic treatment led to the reduction of severity in dystonic hyperkineses on the average 2-2,5 months from baseline. The best effect was seen in patients with short disease duration. The prescription of this drug allowed to increase the dose of drugs traditionally used in treatment of dystonia (clonazepam, cyclodole, tiapridal, baclofen) due to the decrease of their side-effects.


The value of prolactin in predicting prolactinοma in hyperprolactinaemic polycystic ovarian syndrome.
To identify a serum prolactin (PRL) cut-off value indicative of a PRL-producing adenoma in women with polycystic ovarian syndrome (PCOS) and hyperprolactinaemia and characterize such patients. In the present retrospective case-control study, the medical records of 528 PCOS women were reviewed. Pituitary magnetic resonance imaging (MRI) was performed in PCOS patients with PRL levels ≥94.0 ng/mL and/or symptoms suspicious of a pituitary adenoma (PA). Prolactinoma diagnosis was made in the presence of an MRI-identifiable PA with biochemical and radiological response to dopamine agonists. Receiver operating characteristic (ROC) curve analysis was performed to determine a serum PRL threshold that could identify hyperprolactinaemic PCOS subjects with prolactinomas. Clinical, metabolic and endocrine parameters were also analysed. Among 528 patients with PCOS, 60 (11.4%) had elevated PRL levels. Of 44 (73.3%) patients who had pituitary imaging, 19 had PAs, 18 normal MRI and 7 other abnormalities. Patients harbouring prolactinomas had significantly higher PRL levels compared to patients without adenomas (median PRL 95.4 vs 49.2 ng/mL, P < .0001). A PRL threshold of 85.2 ng/mL could distinguish patients with prolactinomas with 77% sensitivity and 100% specificity [Area Under the curve (AUC) (95%) 0.91(0.8-1.018), P = .0001]. PCOS women with prolactinomas were younger and had lower LH levels compared to women without prolactinomas. In women with PCOS, PRL levels exceeding 85.2 ng/mL are highly suggestive of a prolactinoma warranting pituitary imaging. Pituitary MRI could also be considered in young PCOS patients with milder PRL elevation and low LH levels.


Hand washing practice among health care workers in a teaching hospital.
Health care associated infection has been identified as one of the major challenges of modern medicine and remains as a major health concern around the globe. Hands of the health-care workers are potential vehicle for transmission of pathogenic organisms within the healthcare environment. Hand washing is widely accepted as one of the most effective measures in prevention of health care associated infections. A descriptive cross-sectional study was conducted to assess the hand washing practice among the doctors, intern doctors, nurses, medical students and nursing students in a multi specialty, non government tertiary care teaching hospital in Kathmandu. Summary statistics and chi-square tests were performed and the type I error was set at 0.05 for analysis. Out of the total 336 participants of the study, there was significant difference in hand washing practice among the participants (P<0.001). Hand washing practice both before and after the patient examination was found to be highest among the nursing students followed by the nurses. The frequency of hand washing after exposure to hospital instruments, blood or other body fluids among the participants was remarkably high (more than 90%) in all groups. Nearly 99% of the participants agreed upon the fact that hand washing could be an effective measure in preventing health care associated infections. The healthcare workers understand the importance of hand washing but tend to wash their hands selectively depending upon the indications. The majority of the health care workers wash their hands after the patient care than before.


LeFort III internal distraction in syndromic craniosynostosis.
Distraction osteogenesis of the mid-face alleviates the requirements of substantial autogenous bone grafts and donor site morbidity and alleviates the restriction of the soft-tissue envelope in gaining advancement of the mid-face. A prospective study, over a 14-month period, was initiated to evaluate the results of seven consecutive patients undergoing mid-facial advancement who were treated with Le Fort III internal distraction using the MID device. All patients had syndromic craniosynostoses and six patients had previously undergone fronto-orbital advancement. Four patients had symptoms of airway obstruction and one patient was tracheostomy dependent. Six of the patients completed the distraction as planned. Lateral cephalograms were analyzed and the mean linear distraction was 18 mm with a range of 8 mm to 23 mm. Complications included infection (one patient), mechanical failure (one patient), intraoperative fragment dysjunction (three patients), velopharyngeal insufficiency (one patient), conjunctivitis (two patients), trismus (six patients), and bony irregularities. It was concluded that in our Unit's future protocol for managing infant syndromic synostoses, synostectomies and cranial vault remodeling will be undertaken in infants as before, but that in early childhood, patients with severe mid-facial hypoplasia and/or respiratory compromise will be offered distraction osteogenesis as a substitute for the traditional Le Fort III advancement and bone grafting.


Protective immunity induced with malaria vaccine, RTS,S, is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ T cells producing IFN-gamma.
The Plasmodium falciparum circumsporozoite (CS) protein-based pre-erythrocytic stage vaccine, RTS,S, induces a high level of protection against experimental sporozoite challenge. The immune mechanisms that constitute protection are only partially understood, but are presumed to rely on Abs and T cell responses. In the present study we compared CS protein peptide-recalled IFN-gamma reactivity of pre- and RTS,S-immune lymphocytes from 20 subjects vaccinated with RTS,S. We observed elevated IFN-gamma in subjects protected by RTS,S; moreover, both CD4(+) and CD8(+) T cells produced IFN-gamma in response to CS protein peptides. Significantly, protracted protection, albeit observed only in two of seven subjects, was associated with sustained IFN-gamma response. This is the first study demonstrating correlation in a controlled Plasmodia sporozoite challenge study between protection induced by a recombinant malaria vaccine and Ag-specific T cell responses. Field-based malaria vaccine studies are in progress to validate the establishment of this cellular response as a possible in vitro correlate of protective immunity to exo-erythrocytic stage malaria vaccines.


The effects of toe direction on three-dimensional knee kinematics during closed kinetic chain exercise in patients with anterior cruciate ligament deficient knee.
Closed Kinetic Chain Exercise (CKC Ex) is a safe rehabilitation method for anterior cruciate ligament deficient (ACLD) and reconstructed knees. However, CKC Ex can be risky based on abnormal toe directions. The purpose was to investigate knee kinematics during CKC Ex under three toe directions in ACLD. Twenty patients with unilateral ACL injury participated. The subjects performed five weight-bearing-static lunge tests on each limb under three toe directions, including 0 degrees (TN), 20 degrees (TI), and -20 degrees (TO). Three-dimensional knee kinematics were calculated using three-dimensional motion analysis system and were compared among three different toe directions. Among three different toe directions, peak values of knee valgus and external rotation on ACLD side were significantly larger in TO than in TN and TI. In addition, the total excursion in the coronal plane on ACLD side was significantly larger in TO than in TN and TI. Regarding the differences between ACLD and ACLI, peak values of internal rotation angle was significantly smaller in ACLD than in ACLI. From the present results, tibial rotation and knee abduction were strongly affected by toe direction. When considering a safe rehabilitation, it would be better to avoid TI and TO in CKC Ex in patients with unilateral ACL injury.


Information-Theoretic Approaches in EEG Correlates of Auditory Perceptual Awareness under Informational Masking.
In informational masking paradigms, the successful segregation between the target and masker creates auditory perceptual awareness. The dynamics of the build-up of auditory perception is based on a set of interactions between bottom-up and top-down processes that generate neuronal modifications within the brain network activity. These neural changes are studied here using event-related potentials (ERPs), entropy, and integrated information, leading to several measures applied to electroencephalogram signals. The main findings show that the auditory perceptual awareness stimulated functional activation in the fronto-temporo-parietal brain network through (i) negative temporal and positive centro-parietal ERP components; (ii) an enhanced processing of multi-information in the temporal cortex; and (iii) an increase in informational content in the fronto-central cortex. These different results provide information-based experimental evidence about the functional activation of the fronto-temporo-parietal brain network during auditory perceptual awareness.


Phase I study of cisplatin, hyperthermia, and lapatinib in patients with recurrent carcinoma of the uterine cervix in a previously irradiated area.
Patients with recurrent cervical cancer in a previously irradiated area might benefit from cisplatin combined with hyperthermia. Lapatinib inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and HER2. Overexpression of EGFR and HER2 is frequently seen in patients with cervical cancer and is potentially involved in chemotherapy resistance. In addition, preclinical data suggest a synergistic effect of combining cisplatin and lapatinib. Consequently, this phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of lapatinib added to fixed doses of cisplatin and hyperthermia. Eight patients with previously irradiated recurrent cervical carcinoma were enrolled and scheduled for 6 weekly administrations of 70 mg/m(2) cisplatin combined with locoregional hyperthermia. Hyperthermia consisted of the achievement of intraluminal temperatures of 40-43°C as homogeneously as possible over 60 minutes. Daily lapatinib was added on days 1-56, starting with a dose level of 1,000 mg. The MTD was defined as the highest dose at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT). DLT was defined as grade 4 neutropenia lasting >7 days, febrile neutropenia grade ≥3, grade 4 thrombocytopenia, grade ≥2 renal toxicity, postponement of cisplatin and hyperthermia for ≥2 weeks, or grade ≥3 nonhematologic adverse events except for nausea or vomiting, diarrhea, or skin toxicity, for which the following DLT definitions were applied: grade ≥3 persistent nausea or vomiting or diarrhea despite optimal medical treatment or grade 4 skin toxicity. Safety, pharmacodynamics, and response were assessed. The first two patients of both the 1,000- and 750-mg dose level experienced DLTs. Of the four patients treated at dose level -2 (500 mg), only one patient was able to complete the treatment as planned, two patients experienced a DLT, and one patient was not evaluable because of early progressive disease. In the evaluable patients, one patient with progressive disease, four patients with stable disease, and two patients with partial response were observed. One patient with a partial response had a resection of the local recurrence. Pathological analysis showed a complete pathological response. Enumeration of circulating endothelial cells measured at baseline and during therapy did not show consistent results. The same applied for the pharmacodynamic effects on Ki-67, p27Kip1, and EGFR in pretreatment and on-therapy skin biopsies. It is not feasible to combine lapatinib with fixed doses of cisplatin and hyperthermia in patients with recurrent cervical carcinoma in a previously irradiated area mainly because of increased cisplatin-related toxicity. The observed complete pathological response is intriguing and warrants further investigation of combinations consisting of HER2 blockade and cisplatin plus hyperthermia.


New Insights into Phylogenetic Relationship of Hydrocotyle (Araliaceae) Based on Plastid Genomes.
Hydrocotyle, belonging to the Hydrocotyloideae of Araliaceae, consists of 95 perennial and 35 annual species. Due to the lack of stable diagnostic morphological characteristics and high-resolution molecular markers, the phylogenetic relationships of Hydrocotyle need to be further investigated. In this study, we newly sequenced and assembled 13 whole plastid genomes of Hydrocotyle and performed comparative plastid genomic analyses with four previously published Hydrocotyle plastomes and phylogenomic analyses within Araliaceae. The plastid genomes of Hydrocotyle exhibited typical quadripartite structures with lengths from 152,659 bp to 153,669 bp, comprising a large single-copy (LSC) region (83,958-84,792 bp), a small single-copy (SSC) region (18,585-18,768 bp), and a pair of inverted repeats (IRs) (25,058-25,145 bp). Each plastome encoded 113 unique genes, containing 79 protein-coding genes, 30 tRNA genes, and four rRNA genes. Comparative analyses showed that the IR boundaries of Hydrocotyle plastomes were highly similar, and the coding and IR regions exhibited more conserved than non-coding and single-copy (SC) regions. A total of 2932 simple sequence repeats and 520 long sequence repeats were identified, with specificity in the number and distribution of repeat sequences. Six hypervariable regions were screened from the SC region, including four intergenic spacers (IGS) (ycf3-trnS, trnS-rps4, petA-psbJ, and ndhF-rpl32) and two coding genes (rpl16 and ycf1). Three protein-coding genes (atpE, rpl16, and ycf2) were subjected to positive selection only in a few species, implying that most protein-coding genes were relatively conserved during the plastid evolutionary process. Plastid phylogenomic analyses supported the treatment of Hydrocotyle from Apiaceae to Araliaceae, and topologies with a high resolution indicated that plastome data can be further used in the comprehensive phylogenetic research of Hydrocotyle. The diagnostic characteristics currently used in Hydrocotyle may not accurately reflect the phylogenetic relationships of this genus, and new taxonomic characteristics may need to be evaluated and selected in combination with more comprehensive molecular phylogenetic results.


Mode of oral iron administration and the amount of iron habitually consumed do not affect iron absorption, systemic iron utilisation or zinc absorption in iron-sufficient infants: a randomised trial.
Different metabolic pathways of supplemental and fortification Fe, or inhibition of Zn absorption by Fe, may explain adverse effects of supplemental Fe in Fe-sufficient infants. We determined whether the mode of oral Fe administration or the amount habitually consumed affects Fe absorption and systemic Fe utilisation in infants, and assessed the effects of these interventions on Zn absorption, Fe and Zn status, and growth. Fe-sufficient 6-month-old infants (n 72) were randomly assigned to receive 6·6 mg Fe/d from a high-Fe formula, 1·3 mg Fe/d from a low-Fe formula or 6·6 mg Fe/d from Fe drops and a formula with no added Fe for 45 d. Fractional Fe absorption, Fe utilisation and fractional Zn absorption were measured with oral (57Fe and 67Zn) and intravenous (58Fe and 70Zn) isotopes. Fe and Zn status, infection and growth were measured. At 45 d, Hb was 6·3 g/l higher in the high-Fe formula group compared with the Fe drops group, whereas serum ferritin was 34 and 35 % higher, respectively, and serum transferrin 0·1 g/l lower in the high-Fe formula and Fe drops groups compared with the low-Fe formula group (all P<0·05). No intervention effects were observed on Fe absorption, Fe utilisation, Zn absorption, other Fe status indices, plasma Zn or growth. We concluded that neither supplemental or fortification Fe nor the amount of Fe habitually consumed altered Fe absorption, Fe utilisation, Zn absorption, Zn status or growth in Fe-sufficient infants. Consumption of low-Fe formula as the only source of Fe was insufficient to maintain Fe stores.


Quinolones, theophylline, and diclofenac interactions with the gamma-aminobutyric acid receptor.
Epileptic seizures and hallucinations, which are rare in patients receiving quinolones, have been observed more frequently in patients receiving both quinolones and either theophylline or nonsteroidal anti-inflammatory drugs. Inhibition of gamma-aminobutyric acid (GABA) binding to the GABA receptor, resulting in general excitation of the central nervous system, may be the underlying mechanism of these adverse phenomena. We demonstrate here that ciprofloxacin displaced a GABA-like substance (muscimol) from the GABA receptor when administered in concentrations of greater than 10(-4) M. These concentrations were lower than those needed by pefloxacin, ofloxacin, and nalidixic acid to reach a concentration that inhibits 50% of binding. The combination of ciprofloxacin and theophylline was additive in reducing the level of muscimol binding to the GABA receptor, whereas a diclofenac-ciprofloxacin combination had no effect. The concentrations of both ciprofloxacin and the other quinolones used were much higher than those observed in human serum and cerebrospinal fluid in a clinical setting; however, different human GABA receptor affinities, preexisting GABA excitation, or underlying central nervous system disease may amplify the excitatory side effects observed by the co-administration of quinolones and theophylline. Attention should be paid to the possible epileptogenic activity of the simultaneous administration of quinolones with aminophylline, nonsteroidal anti-inflammatory drugs, or other unpredictable drugs.


A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii.
Interferon-γ (IFN-γ) is essential for host defense against intracellular pathogens. Stimulation of innate immune cells by IFN-γ upregulates ∼2,000 effector genes such as immunity-related GTPases including p65 guanylate-binding protein (Gbp) family genes. We show that a cluster of Gbp genes was required for host cellular immunity against the intracellular parasite Toxoplasma gondii. We generated mice deficient for all six Gbp genes located on chromosome 3 (Gbp(chr3)) by targeted chromosome engineering. Mice lacking Gbp(chr3) were highly susceptible to T. gondii infection, resulting in increased parasite burden in immune organs. Furthermore, Gbp(chr3)-deleted macrophages were defective in IFN-γ-mediated suppression of T. gondii intracellular growth and recruitment of IFN-γ-inducible p47 GTPase Irgb6 to the parasitophorous vacuole. In addition, some members of Gbp(chr3) restored the protective response against T. gondii in Gbp(chr3)-deleted cells. Our results suggest that Gbp(chr3) play a pivotal role in anti-T. gondii host defense by controlling IFN-γ-mediated Irgb6-dependent cellular innate immunity.


Ephrin A1 promotes proliferation of bovine endometrial cells with abundant expression of proliferating cell nuclear antigen and cyclin D1 changing the cell population at each stage of the cell cycle.
Ephrin A1 has a role in a variety of biological events, including cell proliferation, differentiation, migration, and angiogenesis. Ephrin A1 expression is abundant in trophoblasts and endometrial cells during the implantation period; however, its intracellular activities have not yet been reported in bovine endometrial (BEND) epithelial cells. The aim of this study was to identify the functional role of ephrin A1 in BEND cells, which have served as a good model system for investigating the regulation of signal transduction following treatment with interferon-τ (IFNT) in vitro. Supplementation of ephrin A1 to BEND cells increased cell proliferation and increased levels of proliferating cell nuclear antigen and cyclin D1 protein in BEND cell nuclei. To investigate intracellular mechanisms regulated by ephrin A1, we performed Western blot analysis focused on mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling, which are significantly involved in the successful maintenance of pregnancy. Ephrin A1 dose-dependently increased phosphorylation of extracellular signal-regulated kinases (ERK)1/2, c-Jun N-terminal kinases (JNK), P38, protein kinase B (AKT), P70S6K, S6, and cyclin D1, and the activated proteins were suppressed by pharmacological inhibitors including wortmannin (a PI3K inhibitor), U0126 (an ERK1/2 inhibitor), and SP600125 (a JNK inhibitor). Among ephrin A1 receptors, abundant expression of EPHA2 and EPHA4 messenger RNA was detected in BEND cells by reverse transcription polymerase chain reaction analysis. Furthermore, tunicamycin-induced endoplasmic reticulum (ER) stress was inactivated by ephrin A1 treatment of BEND cells. Our findings suggest that ephrin A1 promotes the development of BEND cells and likely enhances uterine capacity and maintenance of pregnancy by activating MAPK and PI3K signaling cascades and by restoring ER stress.


[The monitoring of immunological indices in odontogenic abscesses and phlegmons and their differential diagnostic meaning].
The immune homeostasis parameters have been monitored in 31 patients with odontogenic abscesses and phlegmons. Immunological values possessing differential diagnostic significance have been detected. Activation of phagocytosis, spontaneous and stimulated activity of phagocytes in parallel with a moderate decrease in the cellular functional reserve, increased immunoregulatory index, and moderate shifts in the concentrations of IgG and IgM are characteristic of odontogenic abscesses, while odontogenic phlegmons are characterized by deep depression of the phagocyte function and failure of cellular and humoral immunity. The disorders in the immune functions of patients with odontogenic phlegmons normalized 2 weeks later than in those with odontogenic abscesses. Both diseases run a wave-like course and are characterized by phasic changes in immunological parameters, which is significant for determining pathogenesis and choosing appropriate immunocorrective therapy.


Is there an increase of postpartum hemorrhage, and is severe hemorrhage associated with more frequent use of obstetric interventions?
To analyze changes in postpartum hemorrhage over a 10-year period from 1998 to 2007, and to explore factors associated with severe hemorrhage. Retrospective cohort study, prospectively collected information. Stavanger University Hospital, a secondary referral center, Norway. An unselected population of 41,365 women giving birth at the hospital. We analyzed changes over time in mean postpartum hemorrhage, severe postpartum hemorrhage and associated factors. Estimated blood loss >1,000 ml was defined as severe hemorrhage. Data were collected from the hospital's database. Severe postpartum hemorrhage and obstetric interventions. We observed an increase in severe hemorrhage during the study period. After cesarean sections, the risk of severe hemorrhage was twice the risk of severe hemorrhage after vaginal deliveries (5.9%; 95% CI 5.3-6.6 vs. 2.8%; 95% CI 2.6-2.9). The most important factors associated with severe hemorrhage following vaginal deliveries were twin deliveries (OR 6.8), retained placenta (OR 3.9) and inductions of labor (OR 2.2). For cesarean sections, twin deliveries had the strongest association with severe hemorrhage (OR 3.7) followed by general anesthesia (OR 3.0). Obstetric interventions became more frequent; elective cesarean sections increased from 2.4 to 4.9%, acute cesarean sections from 5.5 to 8.9%, operative vaginal deliveries from 9.3 to 12.5%, inductions of labor from 14.3 to 15.8% and augmentations of labor from 5.8 to 29.3%. The incidence of severe postpartum hemorrhage increased, and this may be related to more frequent use of obstetric interventions.


Acute effect of calcitonin on rat renal electrolyte transport.
Renal clearance studies were performed on parathyroid-intact and acutely thyroparathyroidectomized (TPTX) rats to clarify calcitonin (CT) action on renal electrolyte transport. Although CT (0.15 U x 100 g body wt-1 x h-1) reduced fractional excretion of calcium and magnesium by 72 and 46%, respectively, in TPTX rats without altering sodium and phosphate excretion, a 10-fold increase in CT (1.5 U) caused a smaller reduction in calcium and magnesium excretion and significantly increased sodium and phosphate excretion. A higher CT dose (15 U) did not alter calcium excretion, increased magnesium excretion, and caused an even greater increase in sodium and phosphate excretion. Results in parathyroid-intact animals were similar. Despite the fall in plasma calcium following CT administration, the filtered calcium load was unaltered due to a concomitant increase in glomerular filtration rate. Calcium infusion prior to CT (0.15 U) prevented a detectable fall in plasma calcium concentration. However, a 45% fall in fractional calcium excretion occurred despite the significant increase in filtered calcium. These data suggest that the physiological role of calcitonin on the nephron is to conserve calcium. Reports of increased electrolyte excretion presumably reflect a depressant effect of pharmacological doses of CT on nephron function.


Sex Work as an Emerging Risk Factor for Human Immunodeficiency Virus Seroconversion Among People who Inject Drugs in the SurvUDI Network.
Recent analyses have shown an emerging positive association between sex work and human immunodeficiency virus (HIV) incidence among people who inject drugs (PWIDs) in the SurvUDI network. Participants who had injected in the past 6 months were recruited across the Province of Quebec and in the city of Ottawa, mainly in harm reduction programs. They completed a questionnaire and provided gingival exudate for HIV antibody testing. The associations with HIV seroconversion were tested with a Cox proportional hazard model using time-dependent covariables including the main variable of interest, sexual activity (sex work; no sex work; sexually inactive). The final model included significant variables and confounders of the associations with sexual activity. Seventy-two HIV seroconversions were observed during 5239.2 person-years (py) of follow-up (incidence rates: total = 1.4/100 py; 95% confidence interval [CI], 1.1-1.7; sex work = 2.5/100 py; 95% CI, 1.5-3.6; no sex work = 0.8/100 py; 95% CI, 0.5-1.2; sexually inactive = 1.8/100 py; 95% CI, 1.1-2.5). In the final multivariate model, HIV incidence was significantly associated with sexual activity (sex work: adjusted hazard ratio [AHR], 2.19; 95% CI, 1.13-4.25; sexually inactive: AHR, 1.62; 95% CI, 0.92-2.88), and injection with a needle/syringe used by someone else (AHR, 2.84; 95% CI, 1.73-4.66). Sex work is independently associated with HIV incidence among PWIDs. At the other end of the spectrum of sexual activity, sexually inactive PWIDs have a higher HIV incidence rate, likely due to more profound dependence leading to increased vulnerabilities, which may include mental illness, poverty, and social exclusion. Further studies are needed to understand whether the association between sex work and HIV is related to sexual transmission or other vulnerability factors.


Immunization with Clinical HIV-1 Env Proteins Induces Broad Antibody Dependent Cellular Cytotoxicity-Mediating Antibodies in a Rabbit Vaccination Model.
The induction of both neutralizing antibodies and non-neutralizing antibodies with effector functions, for example, antibody-dependent cellular cytotoxicity (ADCC), is desired in the search for effective vaccines against HIV-1. In the pursuit of novel immunogens capable of inducing an efficient antibody response, rabbits were immunized with selected antigens using different prime-boost strategies. We immunized 35 different groups of rabbits with Env antigens from clinical HIV-1 subtypes A and B, including immunization with DNA alone, protein alone, and DNA prime with protein boost. The rabbit sera were screened for ADCC activity using a GranToxiLux-based assay with human peripheral blood mononuclear cells as effector cells and CEM.NKRCCR5 cells coated with HIV-1 envelope as target cells. The groups with the highest ADCC activity were further characterized for cross-reactivity between HIV-1 subtypes. The immunogen inducing the most potent and broadest ADCC response was a trimeric gp140. The ADCC activity was highest against the HIV-1 subtype corresponding to the immunogen. The ADCC activity did not necessarily reflect neutralizing activity in the pseudovirus-TZMbl assay, but there was an overall correlation between the two antiviral activities. We present a rabbit vaccination model and an assay suitable for screening HIV-1 vaccine candidates for the induction of ADCC-mediating antibodies in addition to neutralizing antibodies. The antigens and/or immunization strategies capable of inducing antibodies with ADCC activity did not necessarily induce neutralizing activity and vice versa. Nevertheless, we identified vaccine candidates that were able to concurrently induce both types of responses and that had ADCC activity that was cross-reactive between different subtypes. When searching for an effective vaccine candidate, it is important to evaluate the antibody response using a model and an assay measuring the desired function.


Spatial navigation measured by the Floor Maze Test in patients with subjective cognitive impairment, mild cognitive impairment, and mild Alzheimer's disease.
Impaired spatial navigation is an early sign of Alzheimer's disease (AD), but this can be difficult to assess in clinical practice. We examined how the performance on the Floor Maze Test (FMT), which combines navigation with walking, differed between patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and mild AD. We also explored if there was a significant relationship between the FMT and the cognitive tests or sociodemographic factors. The study included 128 patients from a memory clinic classified as having SCI (n = 19), MCI (n = 20), and mild AD (n = 89). Spatial navigation was assessed by having the patients walk through the FMT, a two-dimensional maze. Both timed measures and number of errors were recorded. Cognitive function was assessed by the Word List Memory test, the Clock Drawing test, the Trail Making tests (TMT) A and B, and the Mini Mental Status Examination (MMSE). The patients with MCI were slower than those with SCI, while the patients with mild AD more frequently completed the FMT with errors or gave up than the patients with MCI. Performance on the FMT was significantly associated with executive function (measured by TMT-B). The performances on the FMT worsened with increasing severity of cognitive impairment, and the FMT was primarily associated with executive function. The explained variance was relatively low, which may indicate that the standard cognitive test battery does not capture impairments of spatial navigation.