BLK positively regulates TLR/IL-1R signaling by catalyzing TOLLIP phosphorylation.
TLR/IL-1R signaling plays a critical role in sensing various harmful foreign pathogens and mounting efficient innate and adaptive immune responses, and it is tightly controlled by intracellular regulators at multiple levels. In particular, TOLLIP forms a constitutive complex with IRAK1 and sequesters it in the cytosol to maintain the kinase in an inactive conformation under unstimulated conditions. However, the underlying mechanisms by which IRAK1 dissociates from TOLLIP to activate TLR/IL-1R signaling remain obscure. Herein, we show that BLK positively regulates TLR/IL-1R-mediated inflammatory response. BLK-deficient mice produce less inflammatory cytokines and are more resistant to death upon IL-1β challenge. Mechanistically, BLK is preassociated with IL1R1 and IL1RAcP in resting cells. IL-1β stimulation induces heterodimerization of IL1R1 and IL1RAcP, which further triggers BLK autophosphorylation at Y309. Activated BLK directly phosphorylates TOLLIP at Y76/86/152 and further promotes TOLLIP dissociation from IRAK1, thereby facilitating TLR/IL-1R-mediated signal transduction. Overall, these findings highlight the importance of BLK as an active regulatory component in TLR/IL-1R signaling.


Facile preparation and bifunctional imaging of Eu-doped GdPO4 nanorods with MRI and cellular luminescence.
The biocompatibility of multifunctional nanomaterials is very important for their clinical applications. Herein, the hexagonal crystal Eu-doped GdPO4 nanorods (NRs) in the template of silk fibroin (SF) peptides are successfully synthesized via a mineralization process. The sizes of the Eu-doped GdPO4 NRs with SF peptides (SF-NRs) are ∼150 nm in length and ∼10 nm in diameter. The Eu-doped SF-NRs have strong pink luminescence and a mass magnetic susceptibility value of 1.27 emu g(-1) in 20,000 G of magnetic field due to Eu ion doping. The cell test indicates that the Eu-doped SF-NRs obviously promote the viability of cells at an NR concentration of 25-200 μg mL(-1). A growth mechanism of Eu-doped GdPO4 SF-NRs is proposed to explain their strong cellular luminescence, magnetic resonance (MR) imaging and good cyto-compatibility. Compared to NRs without SF, the Eu-doped SF-NRs not only exhibit a higher effective positive signal-enhancement ability (the longitudinal relaxivity r1 value is 1.38 (Gd mM s)(-1)) and in vivo T1 weighted MR imaging enhancement under a 7.0 T MRI system, but also show the better luminescence imaging of living cells under the fluorescence microscope. This indicates that the Eu-doped SF-NRs have potential as T1 MRI contrast agents and optical imaging probes.


Development of mHealth system for supporting self-management and remote consultation of skincare.
Individuals with spina bifida (SB) are vulnerable to chronic skin complications such as wounds on the buttocks and lower extremities. Most of these complications can be prevented with adherence to self-care routines. We have developed a mobile health (mHealth) system for supporting self-care and management of skin problems called SkinCare as part of an mHealth suite called iMHere (interactive Mobile Health and Rehabilitation). The objective of this research is to develop an innovative mHealth system to support self-skincare tasks, skin condition monitoring, adherence to self-care regimens, skincare consultation, and secure two-way communications between patients and clinicians. In order to support self-skincare tasks, the SkinCare app requires three main functions: (1) self-care task schedule and reminders, (2) skin condition monitoring and communications that include imaging, information about the skin problem, and consultation with clinician, and (3) secure two-way messaging between the patient and clinician (wellness coordinator). The SkinCare system we have developed consists of the SkinCare app, a clinician portal, and a two-way communication protocol connecting the two. The SkinCare system is one component of a more comprehensive system to support a wellness program for individuals with SB. The SkinCare app has several features that include reminders to perform daily skin checks as well as the ability to report skin breakdown and injury, which uses a combination of skin images and descriptions. The SkinCare app provides reminders to visually inspect one's skin as a preventative measure, often termed a "skin check." The data is sent to the portal where clinicians can monitor patients' conditions. Using the two-way communication, clinicians can receive pictures of the skin conditions, track progress in healing over time, and provide instructions for how to best care for the wound. The system was capable of supporting self-care and adherence to regimen, monitoring adherence, and supporting clinician engagement with patients, as well as testing its feasibility in a long-term implementation. The study shows the feasibility of a long-term implementation of skincare mHealth systems to support self-care and two-way interactions between patients and clinicians.


Behçet's Disease and Nervous System Involvement.
Management of neuro-Behçet's disease can be divided into two stages: treatment of acute attacks and prevention of relapses. Treatment of acute attacks is accomplished by high-dose intravenous corticosteroids followed by maintenance treatment with oral steroids for 6-12 months depending on the type and severity of the neurological involvement. Relapses can be prevented by using immunosuppressants. Oral immunosuppressants such as azathioprine and mycophenolate are the most widely utilized agents for this purpose. Patients who are refractory or who cannot tolerate these medications can be managed by cyclophosphamide, interferon alpha, or anti-TNF-α monoclonal antibodies such as infliximab, etanercept, and adalimumab. Recent reports showed that newer agents such as tocilizumab, canakinumab, and anakinra, which exert their biological activity through IL-1 and IL-6 pathways, are also promising treatment alternatives for progressive or relapsing patients.


Real-World Data on Combined EGFR-TKI and Crizotinib Treatment for Acquired and De Novo MET Amplification in Patients with Metastatic EGFR-Mutated NSCLC.
Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2-8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3-19 months.


Sleep bruxism in children and adolescents-A scoping review.
This review paper focuses on sleep bruxism (SB) in children and adolescents. It aims to assess the landscape of knowledge published in the last 20 years. A total of 144 relevant publications from 386 previously identified through Medline were included, of which 83 were on possible SB, 37 on probable SB, 20 on definite SB and 4 were non-applicable. The review places emphasis on the recent evidence on prevalence, pathophysiology, diagnosis and management of SB in children and adolescents, with special focus on probable and definitive SB. The prevalence ranges from 5% to 50% depending on the age range and on the SB diagnosis (possible, probable or definitive). The pathophysiology is multifactorial, arousal associated and with behavioural problems and sleep disorders (obstructive sleep apnoea, snoring, nightmares) as risk factors, as well as respiratory conditions (allergies, oral breathing). Screening should include questionnaires and dental assessment. Instrumental recording is helpful to confirm diagnosis although more studies are needed to validate this approach in children. SB management includes controlling orofacial and dental consequences and assessing for any other comorbidity. Management options include occlusal splints, oral appliances (advancement mandibular), rapid maxillary expansion and some medications, although this last option is supported by limited evidences in children. Suggestions of future topics in research are delivered to better understand comorbidities, diagnosis and management with improved outcomes compared to what is currently available.


Salt handling and hypertension.
The kidney plays a central role in our ability to maintain appropriate sodium balance, which is critical to determination of blood pressure. In this review we outline current knowledge of renal salt handling at the molecular level, and, given that Westernized societies consume more salt than is required for normal physiology, we examine evidence that the lowering of salt intake can combat hypertension.


Experimental evaluation of antipyretic and analgesic activities of Amalakyadi Gana: An Ayurvedic formulation.
In Ayurvedic classics, the symptom fever is considered as a separate disease called Jwara. Acharya Sushruta has mentioned Amalakyadi Gana for treatment of all types of Jwara, which contains four drugs namely Amalaki (Emblica officinalis Gaertn.), Haritaki (Terminalia chebula Retz.), Pippali (Piper longum L.), and Chitraka (Plumbago zeylenica L.). To evaluate the antipyretic and analgesic activity of Amalakyadi Gana in experimental animals. Decoction and alcohol soluble extract of Amalakyadi Gana were used in the present study. Antipyretic activity of dosage forms were carried out against yeast-induced pyrexia in Wistar albino rats. Analgesic activity was evaluated using radiant heat model and formalin induced paw licking in Wistar albino rats. In yeast-induced pyrexia model, both dosage forms of test drug produced marked decrease in rectal temperature after 3 h, 6 h, and 9 h among which extract produced statistically significant decrease after 6 h compared to control group. In the tail flick method, both forms of test drug showed insignificant increase in tail flick response after 180 and 240 min compared to control group and in formalin induced paw liking model decoction form of test drug significantly increased the latency of onset of paw licking and decreased the paw licking in early phase while alcoholic extract produced insignificant effect compared to control group. Decoction and alcoholic extract of Amalakyadi Gana has moderate antipyretic activity in rats, which may be due to inhibition of the synthesis and/or release of local PGE2. Further, Amalakyadi Gana has mild analgesic effect through central and peripheral mechanism. The result of the present study provide further scope for development of new palatable dosage form and tested clinically for better efficacy.


[Role of the protein fraction of Bordetella pertussis in inducing experimental allergic encephalomyelitis].
B. pertussis protein fraction obtained by precipitation with trichloroacetic acid (TCA) stimulated the development of clinically and histologically pronounced experimental allergic encephalomyelitis (EAE) in guinea pigs when introduced together with a heterologous cerebral antigen, the two compounds forming an encephalitogenic mixture. The adjuvant activity of the TCA-precipitated fraction depended on its dose. The sera of the animals with EAE induced by the encephalitogenic mixture containing B. pertussis cells or TCA-precipitated fraction showed a cytopathogenic effect in the monolayer culture of newborn rat cerebellum cells. The cytopathogenic effect was more pronounced in the sera obtained at the period of the development of the clinical symptoms of the disease (days 14-18), while the cytotoxic effect of the sera obtained on day 30 after immunization decreased irrespective of the manifestations of EAE, this decrease being in correlation with the dose of the TCA-precipitated fraction in the encephalitogenic mixture.


Inhibition of beta-carotene and astaxanthin of NADPH-dependent microsomal phospholipid peroxidation.
To evaluate the antioxidant effects of beta-carotene and astaxanthin, rat liver microsomes were exposed to a mixture of chelated iron (Fe3+/ADP) and NADPH. The carotenoids (190 pmol/mg protein) were incorporated into some of these microsomal membranes, and phospholipid hydroperoxides (PLOOH), thiobarbituric acid reactive substances (TBARS) and endogenous alpha-tocopherol content were measured over time after the initiation of oxidant stress. In control microsomes, oxidant stress led to accumulation of 1,865 (+/- 371) pmol PLOOH/mg protein during the initial 10-min peroxidation reaction, followed by a more gradual decrease during the subsequent 20-min of reaction. PLOOH accumulation during the initial 10-min reaction period was reduced to 588 (+/- 169) pmol/mg protein with beta-carotene present and 800 (+/- 288) pmol/mg protein with astaxanthin present. During the following 20-min of incubation, PLOOH levels declined in the carotenoid-supplemented microsomes but continued to increase at a slower rate in control preparations. TBARS did not show such large accumulation as observed in PLOOH during the initial 10-min incubation in any microsomal sample. The presence of carotenoids in the microsomal membrane partially inhibited the loss of alpha-tocopherol, especially during the later phase of oxidant stress. When lipid peroxidation is generated by membrane-bound cyt-P450, the specific measurement of PLOOH clearly demonstrates that the presence of carotenoids provides antioxidant protection.


BENEFICIAL EFFECTS OF EXOGENOUS CROSSLINKING AGENTS ON SELF-ASSEMBLED TISSUE ENGINEERED CARTILAGE CONSTRUCT BIOMECHANICAL PROPERTIES.
As articular cartilage is unable to repair itself, there is a tremendous clinical need for a tissue engineered replacement tissue. Current tissue engineering efforts using the self-assembly process have demonstrated promising results, but the biomechanical properties remain at roughly 50% of native tissue. The objective of this study was to determine the feasibility of using exogenous crosslinking agents to enhance the biomechanical properties of a scaffoldless cartilage tissue engineering approach. Four crosslinking agents (glutaraldehyde, ribose, genipin, and methylglyoxal) were applied each at a single concentration and single application time. It was determined that ribose application resulted in a significant 69% increase in Young's modulus, a significant 47% increase in ultimate tensile strength, as well as a trend toward a significant increase in aggregate modulus. Additionally, methylglyoxal application resulted in a significant 58% increase in Young's modulus. No treatments altered the biochemical content of the tissue. To our knowledge, this is the first study to examine the use of exogenous crosslinking agents on any tissue formed using a scaffoldless tissue engineering approach. In particular, this study demonstrates that a one-time treatment with crosslinking agents can be employed effectively to enhance the biomechanical properties of tissue engineered articular cartilage. The results are exciting, as they demonstrate the feasibility of using exogenous crosslinking agents to enhance the biomechanical properties without the need for increased glycosaminoglycan (GAG) and collagen content.


Data-based analysis of winner-loser models of hierarchy formation in animals.
We review winner-loser models, the currently popular explanation for the occurrence of linear dominance hierarchies, via a three-part approach. (1) We isolate the two most significant components of the mathematical formulation of three of the most widely-cited models and rigorously evaluate the components' predictions against data collected on hierarchy formation in groups of hens. (2) We evaluate the experimental support in the literature for the basic assumptions contained in winner-loser models. (3) We apply new techniques to the hen data to uncover several behavioral dynamics of hierarchy formation not previously described. The mathematical formulations of these models do not show satisfactory agreement with the hen data, and key model assumptions have either little or no conclusive support from experimental findings in the literature. In agreement with the latest experimental results concerning social cognition, the new behavioral dynamics of hierarchy formation discovered in the hen data suggest that members of groups are intensely aware both of their own interactions as well as interactions occurring among other members of their group. We suggest that more adequate models of hierarchy formation should be based upon behavioral dynamics that reflect more sophisticated levels of social cognition.


First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Hemophilia Assessment and Resource Management System.
The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1,009,097,765 IU) and FIX (272,406,859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs.


Preliminary results from Brazil's first recovery housing program.
The recovery housing (RH) program was initiated in São Paulo with the objective of providing treatment for substance use disorders and addressing users' housing and employment problems. The purpose of this study was to describe the model based on its first 11 months of operation, it was launched in June 2016 in Brazil. We carried out a retrospective analysis of the records of all subjects treated in the RH of the Restart Program (Programa Recomeço) since its creation, from June 2016 to May 2017. Sixty-nine subjects were included. Thirty-five (51%) remained in the household until the end of treatment or were reinserted in society. Thirty-four (49%) presented recurrence during their stay, of which 16 (47%) volunteered for treatment in a therapeutic community or psychiatric hospital, 8 (23.5%) chose to continue with outpatient treatment only, 6 (17.7%) returned to their families and continued to receive outpatient treatment, and 4 (11.8%) discontinued the treatment. Of the 35 subjects who completed the RH program, 28 (80%) were in employment and 7 (20%) received governmental support for permanent disability on medical or psychiatric grounds. RH can be an important component of integrated care and is used in several countries. Although controversial, the use of urine tests to control relapse seems to have a positive impact on adherence to treatment and maintenance of abstinence. These preliminary findings corroborate, with clear limitations, the evidence available in the literature showing that RH programs are effective for the treatment of addictions.


Two-mechanism peak concentration model for cellular pharmacodynamics of Doxorubicin.
A mathematical model is presented for the cellular uptake and cytotoxicity of the anticancer drug doxorubicin. The model assumes sigmoidal, Hill-type dependence of cell survival on drug-induced damage. Experimental evidence indicates distinct intracellular and extracellular mechanisms of doxorubicin cytotoxicity. Drug-induced damage is therefore expressed as the sum of two terms, representing the peak values over time of concentrations of intracellular and extracellular drugs. Dependence of cell kill on peak values of concentration rather than on an integral over time is consistent with observations that dose-response curves for doxorubicin converge to a single curve as exposure time is increased. Drug uptake by cells is assumed to include both saturable and unsaturable components, consistent with experimental data. Overall, the model provides better fits to in vitro cytotoxicity data than previous models. It shows how saturation of cellular uptake or binding with concentration can result in plateaus in the dose-response curve at high concentrations and short exposure, as observed experimentally in some cases. The model provides a unified framework for analyzing doxorubicin cellular pharmacokinetic and pharmacodynamic data, and can be applied in mathematical models for tumor response and treatment optimization.


Dhh1p, a putative RNA helicase, associates with the general transcription factors Pop2p and Ccr4p from Saccharomyces cerevisiae.
The POP2 (Caf1) protein in Saccharomyces cerevisiae affects a variety of transcriptional processes and is a component of the Ccr4p complex. We have isolated five multicopy suppressor genes of a pop2 deletion mutation: CCR4, DHH1 (a putative RNA helicase), PKC1, STM1, and MPT5 (multicopy suppressor of pop two). Overexpression of either the CCR4 or DHH1 genes effectively suppressed phenotypes associated with pop2 mutant cells; overexpression of PKC1, STM1, or MPT5 genes produced only partial suppression. Disruption of the CCR4 or DHH1 genes resulted in phenotypes similar to those observed for pop2 cells. In addition, overexpression of the DHH1 gene also suppressed the ccr4 mutation, suggesting a close relationship between the POP2, CCR4, and DHH1 genes. Two-hybrid analysis and coimmunoprecipitation experiments revealed that Pop2p and Dhh1p interact physically, and these and other data suggest that Dhh1p is also a component of the Ccr4p complex. Finally, we investigated the genetic interaction between factors associated with POP2 and the PKC1 pathway. The temperature-sensitive growth defect of dhh1 or mpt5 cells was suppressed by overexpression of PKC1, and the defect of mpk1 cells was suppressed by overexpression of MPT5. These results and phenotypic analysis of double mutants from the POP2 and PKC1 pathways suggested that the POP2 and the PKC1 pathways are independent but have some overlapping functions.


Physiological aspects of visual perception. II. The subcortical visual direction of behavior.
The second part of the Bennett Lecture for 1975 by Denny-Brown examined the subcortical representation of the dissociation of function described by Denny-Brown and Chambers. Complete removal in the macaque monkey of the corticomesencephalic fibers where they pass from pulvinar to colliculus, and of the colliculus, resulted in the same loss of visual object identification, binocular fixation, and visuosocial behavior that followed removal of area 17. Vision for peripheral movement and spatial orientation ("panoramic vision") remained excellent, with release of catatonia. Conversely, unilateral electrolytic lesions of the mesencephalic tegmentum produced visuospatial distortion, asymmetry of optic righting, and directional difficulties in eye movement (Parinaud syndrome and skew deviation). When bilateral, tegmental lesions produced great constriction of visual field with release of convergence and fixation spasm. Suppression of peripheral attention resulted from perceptual rivalry.


Inorganic particulates associated with pulmonary alveolar proteinosis: SEM and X-ray microanalysis results.
Twenty-four cases of pulmonary alveolar proteinosis (PAP) were studied by light microscopy (LM) and scanning electron microscopy (SEM) to test the hypothesis that PAP was related to silica exposure. Increased numbers of birefringent particles (vs. controls) were found in 78% of PAP cases. SEM was used to locate inorganic particulates in situ, which were individually analyzed using energy dispersive X-ray analysis. When analyzed as an aggregate group of cases, no specific inorganic particulate was evidently associated with the PAP reaction. However, analysis of individual cases revealed more specific associations. The concentration of particles determined by SEM exceeded that found by LM by a factor ranging from 2.7 to 964. The concentration of inorganic particulates per cm3 in the areas of PAP ranged from 1.3 X 10(7) to 1.02 X 10(9). Controls all had less than 10(7) particles per cm3. Available environmental history correlated well with particulate analysis results, e.g., silica in a sandblaster, metal fumes in a welder, and cement particles in a cement finisher. Particulates with unique composition were also found in cases with unavailable histories, e.g. metal fumes suggestive of welding or soldering exposure, silicates suggestive of fine particle exposure (greater than 50% of particles less than 1 micron). Only 1 case (the sandblaster) showed greater than 50% of the particles to be silica. Of the 5 infants with PAP, 3 showed the major particulate to be talc, and 1 had evidence of toxic cadmium selenide fume exposure. These results are consistent with the hypothesis that PAP, at least in the majority of cases, is associated with exposure to small inorganic particulates of several types.


Upper Extremity Deep Venous Thrombosis: Etiologies, Diagnosis, and Updates in Therapeutic Strategies.
Upper extremity deep vein thrombosis (UEDVT) is responsible for 4 to 10% of all deep vein thrombosis (DVT). Untreated UEDVT can lead to significant disability secondary to the postthrombotic syndrome. To date, there are no randomized trials specifically comparing different therapeutic strategies. Ultimately, optimal management of UEDVT depends on the underlying etiology, patient symptoms, and degree of thrombosis, with supporting evidence primarily extrapolated from lower extremity DVT data. This article will review the classification, presentation, and diagnosis of both primary and secondary UEDVT. In addition, it will discuss updates in clinical guidelines, anticoagulation, endovascular and surgical treatment strategies.


The psychosexual and psychosocial impacts of polygamous marriages: a cross-sectional study among Somali women.
Polygamous marriages are common in many Africa countries. This study aimed to document psychosexual and psychosocial problems of Somali women engaged in monogamous or polygamous marriages. This cross-sectional study included 607 consecutive women who had presented between June 7 and October 1, 2022, to the Department of Gynaecology of Mogadishu Somali Turkey Training and Research Hospital in Mogadishu, the capital city of Somalia. Data included maternal age, type of marriage (polygamy, monogamy, and arranged marriage), wives' education, husbands' education, husband income, residence area (rural or urban), number of marriages, living in houses (same or different), number of co-wives, and age of marriage. The participants were asked to complete three questionnaires: The Female Sexual Function Index (FSFI), the Rosenberg Self-Esteem Scale (RSE), and the Brief Symptom Inventory-18 (BSI-18). Of 607 women, 435 (71.7%) had monogamous marriages and 172 (28.3%) had polygamous marriages. The mean age was 29.0 ± 7.2 years (range 16-46). In polygamous marriages, the mean number of wives a husband had was 2.4 ± 0.7 women (range 2- 4). The overall incidences of sexual dysfunction, low self-esteem and arranged marriage were 59.8%, 79.4% and 64.4%, respectively. Wives in polygamous marriages differed from those in monogamous marriages with significantly higher rate of illiterateness (41.9% vs. 27.4%, p = 0.004). Increases in husband income corresponded to higher rates of polygamous marriage. Women in polygamous marriages had significantly lower scores in the desire, arousal, orgasm, and satisfaction sub-domains. Sexual dysfunction, with a significantly increased rate among women in polygamous marriages. Polygamous marriages were associated with significantly higher levels of anxiety, and depression, and a significantly higher total BSI score (p = 0.010, p = 0.004, and p = 0.020, respectively). Women in both groups had similar levels of low self-esteem (p > 0.05). In univariate analysis, polygamous marriage was in significant inverse associations with the total FSFI score and subdomain scores of desire, arousal, orgasm, satisfaction, and sexual dysfunction and in significant associations with the BSI total score and subdomain scores of anxiety and depression (p < 0.05). Our findings suggest that women in polygamous marriages experience considerably higher psychosexual and psychosocial adverse effects as compared with their monogamous counterparts.


Preemptive analgesia and local anesthesia as a supplement to general anesthesia: a review.
General anesthesia (GA) and local anesthesia (LA) evolved on separate tracks. Procedures that could not be performed under LA were typically conducted under GA. Decoding of afferent linkage of peripheral noxious stimuli has provided important understanding that may change the way we traditionally treat surgical pain. In the 1980s, animal studies suggested that preemptive peripheral blocking of painful (nociceptive) stimuli to the central nervous system with regional anesthesia or LA and nonsteroidal analgesics could be beneficial in attenuating postoperative pain. Clinical studies based on this knowledge suggest combining LA with GA, and perhaps non-steroidal analgesics with or without narcotics, to reduce the severity of postoperative pain. General anesthetics can be given in lower minimal alveolar concentration when combined with LA, and recovery characteristics are superior. Increasing evidence suggests that the combined use of GA and LA may reduce the afferent barrage of surgery, and that preemptive analgesia may reduce postoperative pain and should be used in patient care. This article reviews the evidence supporting the combined use of LA or analgesics with GA or sedation to provide improved pain management after surgery.


[The effect of ecological and microbiological factors on the health status of pregnant women with pyelonephritis and on their newborn infants].
An analysis was performed of history, course of pregnancy, parturition, and condition of the newborn babies in female patients with pyelonephritis depending on the microbiological factor and environmental situation in the zone of residence. The pregnant women living under adverse environmental conditions display high levels of endocrine, cardiovascular, gastrointestinal disorders, and of tonsillitis. In the majority of cases, pregnancy is noted to be complicated by anemia (76.7%) and fetoplacental incompetence (62.9%), with infants being born in asphyxia presenting with signs of hypotrophy, congenital infection. Of the above infants, 37% develop postnatal inflammatory conditions. Two variants were shown to play a part in the etiology of pyelonephritis: monoetiological one marked by predominance of Staphylococcus aureus and Escherichia coli and polyetiological variant characterized by predominance of Candida fungi, Staphylococcus aureus, and mycoplasma. Irrespective of the microbiological factor, the female patients with pyelonephritis demonstrated high levels of premature birth, had a history of infertility, and were presenting with genital and extragenital pathologies.


Cloning and sequence analysis of 14 DRB alleles of the bovine major histocompatibility complex by using the polymerase chain reaction.
The genetic diversity in the first domain exon of a bovine class II DRB gene was investigated by PCR amplification and DNA sequencing. Genomic DNA samples representing 14 different class II haplotypes, defined by RFLP analysis, were used. The analysis revealed an extensive polymorphism and 14 alleles at a single locus, designated DRB3, were identified. Multiple amino acid substitutions were found in all pairwise comparisons of alleles; 5 to 21 substitutions in the 83 positions compared. The genetic diversity at the amino acid level found in cattle matches the one previously found in the DRB1 locus in man. The significantly higher frequency of replacement substitutions compared with the frequency of silent substitutions provides strong evidence that there is selection for genetic diversity in the bovine DRB3 first domain exon. A comparison of the DRB polymorphism in man and cattle reveals a striking similarity as regards the location of polymorphic positions in the DRB molecule and the degree of polymorphism at polymorphic positions. The majority of polymorphic positions in both species are found in the proposed antigen recognition site of the class II molecule. In addition, there are eight positions which are polymorphic in both species but have not been assigned to the antigen recognition site. The possible functional significance of the polymorphism of these latter positions is discussed.


ASHP Statement on the pharmacist's role in substance abuse prevention, education, and assistance.
The American Society of Health- System Pharmacists (ASHP) believes that pharmacists have the unique knowledge, skills, and responsibilities for assuming an important role in substance abuse prevention, education, and assistance. Pharmacists, as health care providers, should be actively involved in reducing the negative effects that substance abuse has on society, health systems, and the pharmacy profession. Further, ASHP supports efforts to rehabilitate pharmacists and other health-system employees whose mental or physical impairments are caused by substance abuse.


Climate anomalies and competition reduce establishment success during island colonization.
Understanding the factors that facilitate or constrain establishment of populations in novel environments is crucial for conservation biology and the study of adaptive radiation. Important questions include: (1) Does the timing of colonization relative to stochastic events, such as climatic perturbations, impact the probability of successful establishment? (2) To what extent does community context (e.g., the presence of competitors) change the probability of establishment? (3) How do sources of intrapopulation variance, such as sex differences, affect success at an individual level during the process of establishment? Answers to these questions are rarely pursued in a field-experimental context or on the same time scales (months to years) as the processes of colonization and establishment. We introduced slender anole lizards (Anolis apletophallus) to eight islands in the Panama Canal and tracked them over multiple generations to investigate the factors that mediate establishment success. All islands were warmer than the mainland (ancestral) environment, and some islands had a native competitor. We transplanted half of these populations only 4 months before the onset of a severe regional drought and the other half 2 years (two generations) before the drought. We found that successful establishment depended on both the intensity of interspecific competition and the timing of colonization relative to the drought. The islands that were colonized shortly before the drought went functionally extinct by the second generation, and regardless of time before the drought, the populations on islands with interspecific competition declined continuously over the study period. Furthermore, the effect of the competitor interacted with sex, with males suffering, and females benefitting, from the presence of a native competitor. Our results reveal that community context and the timing of colonization relative to climactic events can combine to determine establishment success and that these factors can generate opposite effects on males and females.


Sensitivity to direction and velocity of fast frequency chirps in the inferior colliculus of awake rabbit.
Neurons in the mammalian inferior colliculus (IC) are sensitive to the velocity (speed and direction) of fast frequency chirps contained in Schroeder-phase harmonic complexes (SCHR). However, IC neurons are also sensitive to stimulus periodicity, a prominent feature of SCHR stimuli. Here, to disentangle velocity sensitivity from periodicity tuning, we introduced a novel stimulus consisting of aperiodic random chirps. Extracellular, single-unit recordings were made in the IC of Dutch-belted rabbits in response to both SCHR and aperiodic chirps. Rate-velocity functions were constructed from aperiodic-chirp responses and compared to SCHR rate profiles, revealing interactions between stimulus periodicity and neural velocity sensitivity. A generalized linear model analysis demonstrated that periodicity tuning influences SCHR response rates more strongly than velocity sensitivity. Principal component analysis of rate-velocity functions revealed that neurons were more often sensitive to the direction of lower-velocity chirps and were less often sensitive to the direction of higher-velocity chirps. Overall, these results demonstrate that sensitivity to chirp velocity is common in the IC. Harmonic sounds with complex phase spectra, such as speech and music, contain chirps, and velocity sensitivity would shape IC responses to these sounds.


Host-controlled cell-to-cell movement of a hybrid barley stripe mosaic virus expressing a dianthovirus movement protein.
The triple gene block (TGB) of barley stripe mosaic virus (BSMV), coding for viral movement proteins (MPs), was replaced by the single MP gene of red clover necrotic mosaic virus (RCNMV). Accumulation of the hybrid virus in barley plants (the selective host for BSMV) was reduced compared to BSMV. The hybrid virus induced small necrotic local lesions on Chenopodium amaranticolor leaves and did not infect Nicotiana clevelandii (the selective host for RCNMV). The hybrid virus accumulated in the inoculated leaves of Nicotiana benthamiana, but not in the upper noninoculated leaves. Thus the RCNMV MP gene substituted for the BSMV TGB in cell-to-cell movement, but not in systemic spread. Hybrid virus movement was efficient only in N. benthamiana, the common host for BSMV and RCNMV. These data point to the involvement of host-specific factors in the function of virus-coded transport determinants.


Intervention of cardiomyocyte death based on the impedance-sensing technique of monitoring cell adhesion.
Cardiomyocyte death is a critical risk factor in a variety of cardiovascular diseases [1, 2]. At the level of individual cardiomyocytes, cell adhesion alters at the early phase of ongoing death. It suggested the possibility of detecting the early sign of cell death through cell detachment and so that we could intervene in the cell response before cell fell into step with the irreversible death processes. In this work, we demonstrated the application of our impedance-sensing technique [3] in the intervention of cell responses to chemical stimuli. The results showed that the cell detachment could be detected with our impedance-sensing technique earlier than conventional biochemical staining techniques, and it could be used to guide the precautionary removal of TNF-alpha from the cell culture to intervene in the cell responses and prevent cardiomyocytes from cell death.


Deficient gamma-interferon production in patients with systemic lupus erythematosus.
We examined the ability of peripheral mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE) to produce gamma-interferon (gamma-IFN) in vitro. MNC from patients with SLE produced varying amounts of gamma-IFN upon mitogenic stimulation. However, they produced distinctly decreased amounts of gamma-IFN upon in vitro stimulation with interleukin-2 (IL-2). Deficient production seemed to be primary, rather than secondary to either excessive monocytic suppression or failure of IL-2 to bind to the MNC surface membranes. gamma-IFN-specific RNA transcription, as determined by slot-blot analysis, was severely decreased in MNC that had been stimulated with phytohemagglutinin or IL-2. These findings suggest that MNC of patients with SLE have defects in the IL-2 signal transduction which is required for production of gamma-IFN.


Persistence of Helicobacter pylori in heterotrophic drinking-water biofilms.
Although the route of transmission of Helicobacter pylori remains unknown, drinking water has been considered a possible transmission vector. It has been shown previously that, in water, biofilms are a protective niche for several pathogens, protecting them from stressful conditions, such as low carbon concentration, shear stress, and less-than-optimal temperatures. In this work, the influence of these three parameters on the persistence and cultivability of H. pylori in drinking-water biofilms was studied. Autochthonous biofilm consortia were formed in a two-stage chemostat system and then inoculated with the pathogen. Total numbers of H. pylori cells were determined by microscopy using a specific H. pylori 16S rRNA peptide nucleic acid probe, whereas cultivable cells were assessed by standard plating onto selective H. pylori medium. Cultivable H. pylori could not be detected at any time point, but the ability of H. pylori cells to incorporate, undergo morphological transformations, persist, and even agglomerate in biofilms for at least 31 days without a noticeable decrease in the total cell number (on average, the concentration was between 1.54 x 10(6) and 2.25 x 10(6) cells cm(-2)) or in the intracellular rRNA content may indicate that the loss of cultivability was due to entry into a viable but noncultivable state. Unlike previous results obtained for pure-culture H. pylori biofilms, shear stress did not negatively influence the numbers of H. pylori cells attached, suggesting that the autochthonous aquatic bacteria have an important role in retaining this pathogen in the sessile state, possibly by providing suitable microaerophilic environments or linking biomolecules to which the pathogen adheres. Therefore, biofilms appear to provide not only a safe haven for H. pylori but also a concentration mechanism so that subsequent sloughing releases a concentrated bolus of cells that might be infectious and that could escape routine grab sample microbiological analyses and be a cause of concern for public health.


Multi-level model of missed nursing care in the context of hospital merger.
The aim of this study was to delineate the multi-level relationships of individual registered nurse (RN) and nursing unit factors on missed nursing care. This was a quantitative model-building study using a descriptive, cross-sectional design. Surveys (N = 553) and administrative unit records from nurses in one hospital system undergoing merger were included. The results showed that 36% of the variation in missed nursing care is due to the unit context, with a corresponding 64% due to individual nurse differences. At the unit level, workload, skill mix, and critical unit type affected the amount of missed nursing care. At the individual nurse level, more experience, supplies problems, communication problems, and involvement in errors of commission all increased the perception of the amount of missed nursing care. Education level was not related to the amount of missed nursing care. The findings highlight the importance of unit- and individual-level interventions to redesign hospital nursing care.


International classification of functioning, disability, and health core sets for hearing loss: a discussion paper and invitation.
The World Health Organization's International Classification of Functioning, Disability and Health (ICF) has adopted a multifactorial understanding of functioning and disability, merging a biomedical paradigm with a social paradigm into a wider understanding of human functioning. Altogether there are more than 1400 ICF-categories describing different aspects of human functioning and there is a need to developing short lists of ICF categories to facilitate use of the classification scheme in clinical practice. To our knowledge, there is currently no such standard measuring instrument to facilitate a common validated way of assessing the effects of hearing loss on the lives of adults. The aim of the project is the development of an internationally accepted, evidence-based, reliable, comprehensive and valid ICF Core Sets for Hearing Loss. The processes involved in this project are described in detail and the authors invite stakeholders, clinical experts and persons with hearing loss to actively participate in the development process.


The Neurosciences of Health Communication: An fNIRS Analysis of Prefrontal Cortex and Porn Consumption in Young Women for the Development of Prevention Health Programs.
This work explores the use of fNIRS neuroimaging technique using young female college students with different levels of consumption of pornography, and the activation of the prefrontal cortex (cue reactivity) when viewing a pornographic clip (cue exposure) versus a control clip. The results indicate that the viewing of the pornographic clip (vs. control clip) causes an activation of Brodmann's area 45 of the right hemisphere (BA 45, pars triangularis) (p < 0.01). An effect also appears between the level of self-reported consumption and the activation of right BA 45: the higher the level of self-reported consumption, the greater the activation (p < 0.01). On the other hand, those participants who have never consumed pornographic material do not show activity of the right BA 45 compared to the control clip (p < 0.01) indicating a qualitative difference between non-consumers and consumers. These results are consistent with other research made in the field of addictions. It is hypothesized that the mirror neuron system may be involved, through the mechanism of empathy, which could provoke vicarious eroticism. Finally, we suggest the applications that these results may have for primary and secondary prevention programs in the field of problematic consumption of pornography.


Seasonal dietary intakes and socioeconomic status among women in the Terai of Nepal.
Despite widespread nutritional deficiencies, investigations of usual diet in rural South Asia remain sparse. The present study characterizes year-round and seasonal dietary patterns of women in the Terai of Nepal by sociodemographic status, using a novel, weekly single-visit and usual food frequency questionnaire that links recall to the agricultural season. The study was conducted across seasons in 2006-2008 among 15,899 women of reproductive age in Sarlahi district. Intakes were tabulated for all foods, overall and by socioeconomic status (SES), and in and out of season, as appropriate. Foods consumed regularly [median (interquartile range) weekly frequency] were rice [13 (7-13)], potatoes [10 (5-13)], legumes [6 (2-9)], and vegetable oil [13 (13-13)]. Animal products were infrequently consumed [1 (0-2) time per week] as were fruits and vegetables, most with a median weekly intake frequency of 0. Higher SES was associated with more frequent consumption of most food-groups, including in-season fruits and vegetables. Diets of women in the Terai of Nepal lack diversity and, likely, nutrient adequacy, which may pose health risks.


Amniotic Membrane Transplant with a Special Technique (Motowa's Sandwich Technique) in Mooren's Ulcer.
To illustrate amniotic membrane transplant (AMT) with a novel surgical technique ("sandwich technique") for treating patients with malignant Mooren's ulcer. A case report of a patient with bilateral, malignant Mooren's ulcer who had undergone systemic steroid therapy and topical immunosuppresive therapy to stabilize his condition. However, perforation of cornea occurred in one eye. AMT with a new surgical technique ("Motowa's sandwich technique") was performed to treat this case. On the 1(st) day postoperatively, there was no pain, no photophobia, and visual acuity was same as preoperatively. At 4 weeks postoperatively, visual acuity improved in the right eye to 20/160 with pinhole, and there was no fluorescein staining. The right eye was quiet. Amniotic membrane transplant with "Motowa's sandwich technique" resulted in the preservation of the anatomical integrity and progression of disease was halted along with an improved vision. This technique is a novel surgical modality in treating Mooren's ulcer. Further study on a large cohort of patients is required for evidence-based data to verify the outcome of this initial case report.


Streptomyces kalpinensis sp. nov., an actinomycete isolated from a salt water beach.
A novel actinobacterium designated TRM 46509T was isolated from a salt water beach at Kalpin, Xinjiang, north-west China. The strain was aerobic and Gram-stain-positive, with an optimum NaCl concentration for growth of 1 % (w/v). The isolate formed sparse aerial mycelium and produced spiral spores at the end of the aerial mycelium on Gauze's No. 1 medium. The isolate contained ll-diaminopimelic acid as the diagnostic diamino acid and ribose as the major whole-cell sugar. The polar lipids included diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylinositol mannosides and an unidentified phospholipid. The predominant menaquinones were MK-9(H2), MK-9(H6) and MK-9(H8). The major fatty acids were C16:0, iso-C16 : 0, anteiso-C15 : 0, iso-C15 : 0 and iso-C14 : 0. The G+C content of the DNA was 69.3 mol%. Phylogenetic analysis showed that strain TRM 46509T shared 16S rRNA gene sequence similarity of 97.6 % with the closest described species Streptomyces tacrolimicus ATCC 55098T. On the basis of evidence from this polyphasic study, strain TRM 46509T should be designated as representing a novel species of the genus Streptomyces, for which the name Streptomyces kalpinensis sp. nov. is proposed. The type strain is TRM 46509T (=CCTCC AA 2015028T=KCTC 39667T).


Microdissection of zebrafish embryonic eye tissues.
Zebrafish is a popular animal model for research on eye development because of its rapid ex utero development and good fecundity. By 3 days post fertilization (dpf), the larvae will show the first visual response. Many genes have been identified to control a proper eye development, but we are far from a complete understanding of the underlying genetic architecture. Whole genome gene expression profiling is a useful tool to elucidate genetic regulatory network for eye development. However, the small size of the embryonic eye in zebrafish makes it challenging to obtain intact and pure eye tissues for expression analysis. For example, the anterior-posterior length of the eye between day 2 and 3 is only approximately 200-300 microm, while the diameter of the lens is less 100 microm. Also, the retinal pigment epithelium (RPE) underlying the retina is just a single-layer epithelium. While gene expression profiles can be obtained from the whole embryo, they do not accurately represent the expression of these tissues. Therefore pure tissue must be obtained for a successful gene expression profiling of eye development. To address this issue, we have developed an approach to microdissect intact retina and retina with RPE attached from 1-3 dpf, which cover major stages of eye morphogenesis. All procedures can be done with fine forceps and general laboratory supplies under standard stereomicroscopes. For retinal dissection, the single-layer RPE is removed and peeled off by brushing action and the preferential adherence of the RPE remnants to the surface of the culture plate for dissection. For RPE-attached retinal dissection, the adherence of RPE to the dissection plate is removed before the dissection so that the RPE can be completely preserved with the retina. A careful lifting action of this tissue can efficiently separate the presumptive choroid and sclera. The lens can be removed in both cases by a chemically etched tungsten needle. In short, our approach can obtain intact eye tissues and has been successfully utilized to study tissue-specific expression profiles of zebrafish retina and retinal pigment epithelium.


Role of magnetic resonance spectroscopy in differential diagnosis of solitary pulmonary lesions.
The aim of our study was to evaluate the availability of magnetic resonance spectroscopy (MRS) for the differentiation of benign or malignant pulmonary nodules and masses. A total of 59 patients (45 male, 14 female) with pulmonary nodules and masses were included in this prospective study. MRS was applied to the pulmonary lesions of the patients and choline levels were determined. Afterwards CT-guided percutaneous needle biopsy was performed. According to the biopsy results, pulmonary lesions were benign in 25 patients and malignant in 34 patients. Choline levels were significantly higher in malignant lesions compared with benign lesions (p < 0.001). When the other conditions were kept constant, the probability of malignancy significantly increased by 17.38-fold (95% CI, 3.78-79.93) in those with choline levels >1.65 µmol/g compared to those with choline levels ≤1.65 µmol/g (p < 0.001). MRS is a noninvasive method that can be used in the differential diagnosis of pulmonary nodules and masses.


The value of choice as a reinforcer for typically developing children.
Previous research has shown that providing choices may result in an increase in appropriate behavior and a decrease in inappropriate behavior; however, the process by which choice results in a behavior change is unknown. In the current study, we replicated and extended previous research by determining the prevalence of preference for choice in a large number of children and evaluating whether a history of differential outcomes associated with choice and no choice resulted in changes in preference for those conditions. Results from Study 1 showed that the majority of participants preferred choice contexts when child choice and experimenter choice resulted in identical outcomes. In Study 2, participants' preferences were altered when child choice and experimenter choice resulted in differential outcomes, but a history with differential outcomes did not produce a reliable and durable effect on selections.


DDI-CPI, a server that predicts drug-drug interactions through implementing the chemical-protein interactome.
Drug-drug interactions (DDIs) may cause serious side-effects that draw great attention from both academia and industry. Since some DDIs are mediated by unexpected drug-human protein interactions, it is reasonable to analyze the chemical-protein interactome (CPI) profiles of the drugs to predict their DDIs. Here we introduce the DDI-CPI server, which can make real-time DDI predictions based only on molecular structure. When the user submits a molecule, the server will dock user's molecule across 611 human proteins, generating a CPI profile that can be used as a feature vector for the pre-constructed prediction model. It can suggest potential DDIs between the user's molecule and our library of 2515 drug molecules. In cross-validation and independent validation, the server achieved an AUC greater than 0.85. Additionally, by investigating the CPI profiles of predicted DDI, users can explore the PK/PD proteins that might be involved in a particular DDI. A 3D visualization of the drug-protein interaction will be provided as well. The DDI-CPI is freely accessible at http://cpi.bio-x.cn/ddi/.


Response of focal refractory status epilepticus to lacosamide in an infant.
Status epilepticus (SE) is a life-threatening medical emergency which is frequently encountered in the critical care setting and can be refractory to treatment. Refractory status epilepticus (RSE) is defined as SE that has failed to respond to adequately used first-line and second-line antiepileptic medications. Super refractory status epilepticus is defined as SE that persists for 24 hours or more after the use of an anaesthetic agent or recurs after its withdrawal.If SE persists beyond a period of 7 days it is referred to as prolonged, refractory status epilepticus (PRSE). There are limited data guiding treatment of RSE in the paediatric population.Lacosamide (LCM) is licensed as an adjunctive treatment for partial-onset seizures. Evidence for the efficacy of LCM in paediatric SE is scarce. This case report may suggest a synergistic effect of LCM on slow-activation sodium channels in conjunction with medications such as phenytoin that causes fast inactivation of sodium channels. The dual fast and slow inactivation of sodium channels may enhance the effectiveness in treatment of RSE. This is the first case report of PRSE in an infant, successfully treated with LCM. A brief review of literature is also a part of this report.


Does the 1-year Decline in Walking Speed Predict Mortality Risk Beyond Current Walking Speed in Adults With Knee Osteoarthritis?
To investigate whether walking speed at 1 timepoint, decline over the past 12 months, or both predict mortality risk over 11 years in adults with, or at risk of, knee osteoarthritis (OA). Using the data from the Osteoarthritis Initiative, we defined slow versus adequate walking speed as walking < 1.22 versus ≥ 1.22 m/s on a 20m walk test during the 12-month follow-up visit. We defined meaningful decline (yes/no) as slowing ≥ 0.08 m/s over the past year. At the 12-month visit, we classified adequate sustainers as those with adequate walking speed and no meaningful decline, slow sustainers as slow walking speed and no meaningful decline, adequate decliners as adequate walking speed and meaningful decline, and slow decliners as slow walking speed and meaningful decline. Mortality was recorded over 11 years. To examine the association of walking speed with mortality, HR and 95% CI were calculated using Cox regression, adjusted for potential confounders. Of 4229 participants in the analytic sample (58% female, age 62 ± 9 yrs, BMI 29 ± 5 kg/m2), 6% (n = 270) died over 11 years. Slow sustainers and slow decliners had 2-times increased mortality risk compared to adequate sustainers (HR 1.96, 95% CI 1.44-2.66 for slow sustainers, and HR 2.08, 95% CI 1.46-2.96 for slow decliners). Adequate decliners had 0.43 times the mortality risk compared with adequate sustainers (HR 0.57, 95% CI 0.32-1.01). In adults with, or at risk of, knee OA, walking slower than 1.22 m/s in the present increased mortality risk, regardless of decline over the previous year.


Dental management in renal failure: patients on dialysis.
Chronic renal failure is an important health care problem throughout the world, with an incidence of 337, 90, 107 and 95 new cases per million inhabitants/year in the United States, Australia, New Zealand and the United Kingdom, respectively. These figures moreover invariably tend to increase. During the progression of renal damage, clinical manifestations are noted in practically all body organs and systems, and 90% of all affected patients experience oral symptoms. The existing management options range from simple measures based on changes in diet and life style, to different forms of dialysis (hemodialysis and peritoneal dialysis), and also kidney transplantation. Given the multiple oral manifestations of chronic renal failure, and the different repercussions of its treatment upon the oral cavity, these patients require special considerations and precautions in the face of dental treatment. Consultation with the nephrologist is essential before any dental treatment is carried out, in order to determine the condition of the patient, define the best moment for dental treatment, introduce the necessary pharmacological adjustments, or to establish other important aspects for preventing complications in the dental clinic. The present study reviews the characteristics of the disease, the existing therapeutic options, and the considerations of relevance for the dental professional.


[Osteoporosis and climacteric].
The climacteric period, menopause, constitutes a physiological process in a woman's life which can modify her health and increase the occurrence of some diseases which are related to estrogen deprivation; among these, osteoporosis stands out. After analyzing its etiology and risk factors, the author provides a detailed description of various preventive measures against this disease: nutrition, physical exercise, healthy living habits, etc.


Robust optical flow estimation based on a sparse motion trajectory set.
This paper presents an approach to the problem of estimating a dense optical flow field. The approach is based on a multiframe, irregularly spaced motion trajectory set, where each trajectory describes the motion of a given point as a function of time. From this motion trajectory set a dense flow field is estimated using a process of interpolation. A set of localized motion models are estimated, with each pixel labeled as belonging to one of the motion models. A Markov random field framework is adopted, allowing the incorporation of contextual constraints to encourage region-like structures. The approach is compared with a number of conventional optical flow estimation algorithms taken over a number of real and synthetic sequences. Results indicate that the method produces more accurate results for sequences with known ground truth flow. Also, applying the method to real sequences with unknown flow results in lower DFD, for all of the sequences tested.


[Differential diagnosis of a red nose].
A red nose is a semiological sign shared in common by a series of diseases. The differential diagnosis is important to establish. A careful clinical examination often allows to reach the precise diagnosis. A skin biopsy is required when erythema is accompanied by a cutaneous infiltration suggesting some granulomatous and tumoral processes.


Formation and persistence of O6-ethylguanine in genomic and transgene DNA in liver and brain of lambda(lacZ) transgenic mice treated with N-ethyl-N-nitrosourea.
LacZ transgenic mice are suitable for short-term mutagenicity studies in vivo. Mutagenicity in these mice is determined in the lacZ transgene. Since the lacZ gene is of bacterial origin the question has been raised whether DNA-adduct formation and repair in the transgene are comparable to those in total genomic DNA. Mice were treated with N-ethyl-N-nitrosourea (ENU) and killed at several time points following treatment. Some mice were pretreated with O6-benzylguanine to inactivate the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). O6-ethylguanine (O6-EtG) was determined in lacZ in liver and brain by means of a monoclonal antibody-based immunoaffinity assay. In addition, O6-EtG and N7-ethylguanine (N7-EtG) were assayed in total genomic DNA of liver and brain with an immunoslotblot procedure. In liver, the initial O6-EtG level in total genomic DNA was 1.6 times that in lacZ. The extent of repair of O6-EtG during the first 1.5 h after treatment was 2.1 times that in lacZ. At later time points, O6-EtG repair was the same. N7-EtG repair in genomic DNA was evident. In contrast to the liver, little repair of O6-EtG in total genomic and lacZ DNA occurred in the brain while N7-EtG was repaired. No initial difference in O6-EtG levels were found in lacZ and genomic brain DNA. These findings indicate that in the liver, total genomic DNA is more accessible than lacZ to ENU and/or the AGT protein, during the first 1.5 h following treatment. Because the difference in O6-EtG levels in the transgene and genomic DNA in the liver is restricted to the first 1.5 h after treatment, while the fixation of mutations occurs at later time points, O6-EtG-induced mutagenesis most likely is also very similar in both types of DNA.


Capitation and risk adjustment in health care financing: an international progress report.
In every system of health care, capitation payments have become the accepted tool used by health care purchasers in much of the developed world to determine prospective budgets. The policy prescription of capitation is perceived to address both equity objectives (of great importance in publicly funded systems of health care) and efficiency objectives (the dominant concern in competitive insurance markets). An examination of the current state of the art in 20 countries outside the United States in which health care capitation has been implemented confirms that capitation has assumed central importance within diverse systems of health care. In practice, however, the setting of capitation payments has been heavily constrained to date by poor data availability and unsatisfactory analytic methodology.


Autophagy regulates DUOX1 localization and superoxide production in airway epithelial cells during chronic IL-13 stimulation.
The airway epithelium is a broad interface with the environment, mandating well-orchestrated responses to properly modulate inflammation. Classically, autophagy is a homeostatic pathway triggered in response to external cellular stresses, and is elevated in chronic airway diseases. Recent findings highlight the additional role of autophagy in vesicle trafficking and protein secretion, implicating autophagy pathways in complex cellular responses in disease. Th2 cytokines, IL-13 and IL-4, are increased in asthma and other airway diseases contributing to chronic inflammation. Previously, we observed that IL-13 increases reactive oxygen species (ROS) in airway epithelial cells in an autophagy-dependent fashion. Here, we tested our hypothesis that autophagy is required for IL-13-mediated superoxide production via the NADPH oxidase DUOX1. Using a mouse model of Th2-mediated inflammation induced by OVA-allergen, we observed elevated lung amounts of IL-13 and IL-4 accompanied by increased autophagosome levels, determined by LC3BII protein levels and immunostaining. ROS levels were elevated and DUOX1 expression was increased 70-fold in OVA-challenged lungs. To address the role of autophagy and ROS in the airway epithelium, we treated primary human tracheobronchial epithelial cells with IL-13 or IL-4. Prolonged, 7-day treatment increased autophagosome formation and degradation, while brief activation had no effect. Under parallel culture conditions, IL-13 and IL-4 increased intracellular superoxide levels as determined by electron paramagnetic resonance (EPR) spectroscopy. Prolonged IL-13 activation increased DUOX1, localized at the apical membrane. Silencing DUOX1 by siRNA attenuated IL-13-mediated increases in superoxide, but did not reduce autophagy activities. Notably, depletion of autophagy regulatory protein ATG5 significantly reduced superoxide without diminishing total DUOX1 levels. Depletion of ATG5, however, diminished DUOX1 localization at the apical membrane. The findings suggest non-canonical autophagy activity regulates DUOX1-dependent localization required for intracellular superoxide production during Th2 inflammation. Thus, in chronic Th2 inflammatory airway disease, autophagy proteins may be responsible for persistent intracellular superoxide production.


Capillary affinity gel electrophoresis. New tool for detection of the mutation on DNA.
Capillary affinity gel electrophoresis is a new technique for the recognition of the specific DNA base and/or sequence. This technology is also applicable to the characterization of binding properties of DNA-based drugs, chiral separation, and the selective separation of antibody mimetics using imprinted polymers. This article reviews the present state of studies on the capillary affinity gel electrophoresis, including the principle, theory, methods, and applications of this technology. The great potential of capillary affinity gel electrophoresis for the detection of the mutation onDNA is illustrated.


Pre-existing musculoskeletal pain and its association with mortality in newly diagnosed co-morbid conditions: an electronic health record cohort study.
Musculoskeletal pain is a common risk factor for co-morbid conditions and might increase the risk of poor outcomes. The objective was to determine whether patients with pre-existing musculoskeletal pain have an increased risk for mortality following a new diagnosis of a co-morbid condition. Patients aged ≥45 years with a new diagnosis of acute coronary syndrome (ACS), stroke, cancer, dementia or pneumonia recorded in a UK electronic primary care database linked to hospital and mortality records were examined. The association of mortality with musculoskeletal pain (inflammatory conditions, OA and regional pain) was determined. The sample size varied from 128 649 (stroke) to 406 289 (cancer) by cohort, with 22-31% having pre-existing musculoskeletal conditions. In the ACS cohort, there was a higher rate of mortality for all musculoskeletal types. There were also higher unadjusted mortality rates in patients with inflammatory arthritis compared with those without musculoskeletal pain in the stroke, cancer and dementia cohorts and for patients with OA in the stroke and cancer cohorts. After adjustment for the number of prescribed medications and age, the increased risk of mortality remained only for patients with inflammatory arthritis in the ACS cohort (adjusted hazard ratio = 1.07; 95% CI 1.03, 1.10). Older adults with inflammatory arthritis and OA have increased risk of mortality when they develop a new condition, which seems to be related to the prescription of multiple medicines. Pre-existing musculoskeletal pain is an indicator of a complex patient who is at risk of poorer outcomes at the onset of new illnesses.


Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects.
We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.


Pelvic Tuberculosis Diagnosed during Operative Laparoscopy for Suspected Ovarian Cancer.
While the combination of a pelvic mass, very high serum level of CA-125, chest adenopathy, and ascites is concerning for advanced-stage ovarian cancer, the etiology of such a presentation can be due to disseminated pelvic tuberculosis. A 67-year-old para 2 African-American woman presented with abdominal pain and shortness of breath. Subsequent CT and MR imaging demonstrated chest adenopathy, a pelvic mass, omental caking, and ascites. The patient underwent diagnostic laparoscopy with biopsy revealing noncaseating granulomas and subsequent tissue culture revealed Mycobacterium tuberculosis. The patient was diagnosed with disseminated pelvic tuberculosis and multidrug therapy was initiated. Pelvic tuberculosis can mimic advanced-stage ovarian cancer; thus obtaining a tissue sample may be beneficial to more appropriately direct treatment and planning for neoadjuvant therapies given the ineffectiveness of extensive surgical procedures in treating pelvic tuberculosis commonly employed in the treatment of advanced-stage ovarian cancer.


Prognosis of six-month functioning after moderate to severe traumatic brain injury: a systematic review of prospective cohort studies.
To systematically review which determinants, assessed within the first month after a moderate to severe traumatic brain injury, predict 6-month functional outcome. Databases were searched for relevant publications between 1995 and August 2008. Selection criteria were: prospective cohort studies; determinants associated with functional outcome 6 months after moderate to severe traumatic brain injury in adult patients; determinants assessed within the first month post-injury. Two reviewers independently performed the selection and quality assessment. A best- evidence synthesis was performed for prognostic factors assessed in 2 or more studies. Twenty-eight studies were included, 27 of which were high quality. Most studies used the Glasgow Outcome Score at 6 months post-injury as outcome measure, sometimes in combination with other outcome measures. Strong evidence for predicting outcome at 6 months was found for the Glasgow Coma Scale (GCS), GCS admission, motor score, midline shift on computed tomography scan, subdural haematoma and pulsatility index. Strong evidence of no association was found for gender and intraventricular haemorrhage. For other determinants, inconclusive or no evidence was found. GCS, GCS on admission, motor score, midline shift, subdural haematoma and pulsatility index predicted outcome 6 months after traumatic brain injury. Gender and intraventricular haemorrhage did not have predictive value.


Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment.
NSCLC (non-small cell lung cancer) is a leading cause of cancer-related deaths worldwide. Clinical trials showed that Hiltonol, a stable dsRNA representing an advanced form of polyI:C (polyinosinic-polycytidilic acid), is an adjuvant cancer-immunomodulator. However, its mechanisms of action and effect on lung cancer have not been explored pre-clinically. Here, we examined, for the first time, how a novel Hiltonol cocktail kills NSCLC cells. By retrospective analysis of NSCLC patient tissues obtained from the tumor biobank; pre-clinical studies with Hiltonol alone or Hiltonol+++ cocktail [Hiltonol+anti-IL6+AG490 (JAK2 inhibitor)+Stattic (STAT3 inhibitor)]; cytokine analysis; gene knockdown and gain/loss-of-function studies, we uncovered the mechanisms of action of Hiltonol+++. We demonstrated that Hiltonol+++ kills the cancer cells and suppresses the metastatic potential of NSCLC through: (i) upregulation of pro-apoptotic Caspase-9 and Caspase-3, (ii) induction of cytosolic cytochrome c, (iii) modulation of pro-inflammatory cytokines (GRO, MCP-1, IL-8, and IL-6) and anticancer IL-24 in NSCLC subtypes, and (iv) upregulation of tumor suppressors, PKR (protein kinase R) and OAS (2'5' oligoadenylate synthetase). In silico analysis showed that Lys296 of PKR and Lys66 of OAS interact with Hiltonol. These Lys residues are purportedly involved in the catalytic/signaling activity of the tumor suppressors. Furthermore, knockdown of PKR/OAS abrogated the anticancer action of Hiltonol, provoking survival of cancer cells. Ex vivo analysis of NSCLC patient tissues corroborated that loss of PKR and OAS is associated with cancer advancement. Altogether, our findings unraveled the significance of studying tumor biobank tissues, which suggests PKR and OAS as precision oncological suppressor candidates to be targeted by this novel Hiltonol+++ cocktail which represents a prospective drug for development into a potent and tailored therapy for NSCLC subtypes.


Neglect of the complex: why psychotherapy for post-traumatic clinical presentations is often ineffective.
Evidence of efficacy in studies of post-traumatic conditions is largely derived from studies in which variables are kept to a minimum. Extrapolation of treatments from uncomplicated disorders to complex conditions may therefore be called evidence-based without being evidenced. Complex conditions with polysymptomatic presentations and extensive comorbidity are being denied proper evaluation, and patients most severely traumatised from the early stages of their development are not provided with rigorously evaluated psychotherapies because they are more difficult to study in the manner approved by research protocols. Such evidence as there is suggests that the simple extension of treatments for uncomplicated disorders is seriously inadequate. This has significant implications for health services responsible for the provision of the most efficacious treatments to those whose disorders arise from severe trauma, often very early in their life.


Detecting the Dark Matter of Unpublished Clinical Cancer Studies: An Analysis of Phase 3 Randomized Controlled Trials.
Unpublished randomized controlled trial (RCT) frequency, correlates, and financial impact are not well understood. We sought to characterize the nonpublication of peer-reviewed manuscripts among interventional, therapeutic, multi-arm, phase 3 oncology RCTs. Trials were identified by searching ClinicalTrials.gov, while publications and abstracts were identified through PubMed and Google Scholar. Trial data were extracted from ClinicalTrials.gov and individual publications. Publication was defined as a peer-reviewed manuscript addressing the primary endpoint. Patient accrual cost was extrapolated from experimental data; investigators/sponsors were contacted to determine nonpublication reasons. Six hundred eighty-four completed RCTs met inclusion criteria, which accrued 434,610 patients from 1994 to 2015; 638 were published (93.3%) and 46 were unpublished (6.7%). Among the unpublished trials, the time difference from primary endpoint maturity to data abstraction was a median of 6 years (interquartile range, 4 to 8 years). On multiple binary logistic regression analysis, factors associated with unpublished trials included lack of cooperative group sponsorship (odds ratio, 5.91, 95% CI, 1.35 to 25.97; P=.019) and supportive care investigation (odds ratio, 2.90; 95% CI, 1.13 to 7.41; P=.027). The estimated inflation-adjusted average cost of patient accrual for all unpublished trials was $113,937,849 (range, $41,136,883 to $320,201,063). Direct contact with sponsors/investigators led to a 50.0% response rate (n=23 of 46); manuscript in preparation and/or in submission (n=10 of 23) was the most commonly cited reason for nonpublication. In conclusion, approximately 1 in 15 clinical oncology RCTs are unpublished and this has a profound impact on the research enterprise. The cooperative group infrastructure may serve as a blueprint to reduce nonpublication.


The effect of supraclavicular lymph node irradiation upon the thyroid gland in the post-operative breast carcinoma patients.
To identify the effect of post-operative irradiation to the thyroid gland in patients with breast carcinoma. Seventy seven patients with partial or total mastectomized breast carcinoma who received routine irradiation therapy (Hockey stick method: supraclavicular, internal mammary lymph nodes, and chest wall irradiation with 5,040 rads, divided into 30 treatments) were reviewed in terms of their ipsilateral thyroid gland response. All patients had the bilateral thyroid sizes measured annually by ultrasonography before and after radiation therapy. In the one-year follow-up group (n=77), 32 patients (41.5%) demonstrated decreased ipsilateral thyroid gland size after Hockey Stick irradiation therapy (p=0.428), in the two-year follow-up group (n=37), 26 patients (70.3%) demonstrated decreased gland size after Hockey Stick irradiation (p=0.001), and in the three-year follow-up group (n=21), 15 patients (71.4%) showed a decreased thyroid gland size (p=0.005). Most the patients with breast carcinoma (32/77 at the one-year follow-up, 26/37 at the two-year follow-up, and 15/21 at the three-year follow-up) after post-operative Hockey Stick irradiation therapy showed reduced ipsilateral thyroid gland size. Routine en face treatment of the supraclavicular lymph nodes, using the Hockey Stick method, should be reconsidered.


Urban forest fragments as unexpected sanctuaries for the rare endemic ghost butterfly from the Atlantic forest.
Anthropogenic land expansion, particularly urbanization, is pervasive, dramatically modifies the environment and is a major threat to wildlife with its associated environmental stressors. Urban remnant vegetation can help mitigate these impacts and could be vital for species unable to survive in harsh urban environments. Although resembling nonurban habitats, urban vegetation remnants are subject to additional environmental stresses. Here, we evaluate the occurrence and density of the endemic ghost butterfly (Morpho epistrophus nikolajewna) that was once common, in the highly fragmented Atlantic forest of NE Brazil. We tested whether this butterfly would be found at lower densities in urban forest fragments of contrasting sizes as opposed to rural ones, given the number of environmental stressors found in urban areas. We surveyed 14 forest fragments (range 2.8 to over 3,000 ha) of semideciduous Atlantic forest in rural and urban locations using transect based distance sampling. The ghost butterflies showed strong seasonality; flying only from April to June. They were only identified in an urban fragment (515 ha), with an estimate of 720 individuals and a density 1.4 ind/ha. All forest fragments had experienced some level of logging in the past, which might have had an effect in the butterfly population. Nevertheless, rural forest fragments were subject to increased particulate matter concentrations, associated to biomass burning that we suggest might have had a more influential role driving the collapse of rural populations. Our findings show the importance of urban forest remnants to sustain population of this endangered species.


Guar gum and glycemic control of pregnant insulin-dependent diabetic patients.
The effect of guar gum preparation on the glycemic control of 12 pregnant insulin-dependent diabetic patients was investigated. The study was performed on inpatients and lasted 3 wk (from week 32 of pregnancy and onward). Weeks 32 and 34 were control periods during which time the patients had their normal diet only. During week 33, the diet was supplemented with guar. The mean blood glucose level of week 33 was 14% lower than that of week 32 (P less than 0.01) but equal to that of week 34. Mean fluctuations of blood glucose during individual days of the 3 wk were similar. The M-value declined significantly from week 32 to week 33, but the M-value of week 33 was not different from that of week 34. The average 24-h glycosuria declined by 63% from week 32 to week 33 (P less than 0.05), whereas the values of weeks 33 and 34 were not significantly different. The mean daily insulin doses of weeks 32, 33, and 34 were similar. The results show that whereas admission of pregnant insulin-dependent diabetic women to a diabetes ward exerts a favorable influence on diabetes control, no further improvement is obtainable if the diet is supplemented with guar.


Lack of association between gene polymorphisms of Angiotensin converting enzyme, Nod-like receptor 1, Toll-like receptor 4, FAS/FASL and the presence of Helicobacter pylori-induced premalignant gastric lesions and gastric cancer in Caucasians.
Several polymorphisms of genes involved in the immunological recognition of Helicobacter pylori and regulating apoptosis and proliferation have been linked to gastric carcinogenesis, however reported data are partially conflicting. The aim of our study was to evaluate potential associations between the presence of gastric cancer (GC) and high risk atrophic gastritis (HRAG) and polymorphisms of genes encoding Angiotensin converting enzyme (ACE), Nod-like receptor 1 (NOD1), Toll-like receptor 4 (TLR4) and FAS/FASL. Gene polymorphisms were analyzed in 574 subjects (GC: n = 114; HRAG: n = 222, controls: n = 238) of Caucasian origin. ACE I/D (rs4646994), NOD1 796G>A (rs5743336), TLR4 3725G>C (rs11536889), FAS 1377G>A (rs2234767), FAS 670A>G (rs1800682) and FASL 844T>C (rs763110) were genotyped by different PCR approaches and restriction fragment length polymorphism analysis. Frequencies of genotypes in our study are similar to the data reported on subjects of Caucasian ethnicity. There was a tendency for NOD1 796G/G genotype to be associated with increased risk of HRAG (62.4% vs. 54.5% in controls, p = 0.082). FAS 670G/G genotype was more frequent in HRAG when compared to controls, 23.9% and 17.2% respectively, however it failed to reach significance level (p = 0.077). We did not find any significant associations for all polymorphisms in relation to GC or HRAG. NOD1 796G>A and TLR4 3725G>C gene polymorphisms were also not associated with Helicobacter pylori infection. ACE, NOD1, TRL4 and FAS/FASL gene polymorphisms are not linked with gastric carcinogenesis in Caucasians, and therefore they should not be considered as potential biomarkers for identifying individuals with higher risk for GC.


Mycophenolate Mofetil-induced Diffuse Large B-cell Lymphoma in Which a Solitary Lung Nodule Remitted Spontaneously.
A 76-year-old woman with dermatomyositis was being treated with prednisolone, tacrolimus, and mycophenolate mofetil. There was a solitary lung nodule in the right middle lobe on chest computed tomography at a routine follow-up examination. A transbronchial lung biopsy was performed, and the histopathologic findings indicated diffuse large B-cell lymphoma. An immunodeficiency-associated lymphoproliferative disorder was suspected, and mycophenolate mofetil was stopped without adding any other therapy. Nine months later, the pulmonary nodule had disappeared on chest computed tomography.


Management trends. Resting energy expenditure in the HAART era.
HIV infection in the HAART era is often accompanied by nutritional complications, including rapid weight loss and weight gain. Changes in weight are directly related to shifts in energy balance. Understanding the interplay between dietary intake and energy utilization is important for investigating the factors contributing to a person's weight shifts. Total energy use includes resting metabolic rate, or resting energy expenditure (REE), and voluntary activity, both of which are commonly abnormal in persons with HIV infection. There is now evidence that both the level of viral load and the use of HAART affect REE. The role of energy expenditure in lipodystrophy is unknown but is an area of research interest. The current understanding of energy balance in persons with HIV infection is explained here for the health care provider.


A Restricted Role for FcγR in the Regulation of Adaptive Immunity.
By their interaction with IgG immune complexes, FcγR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcγR-knockout mice, it has been concluded that FcγRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcγRs (FcγRI/II/III/IV-/- mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcγRIIb-deficient mice, FcγRI/II/III/IV-/- mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcγRs in the modulation of the adaptive immune response in vivo. We conclude that FcγRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.


Depth from automatic defocusing.
This paper presents a depth recovery method that gives the depth of any scene from its defocused images. The method combines depth from defocusing and depth from automatic focusing techniques. Blur information in defocused images is utilised to measure depth in a way similar to determining depth from automatic focusing but without searching for sharp images of objects. The proposed method does not need special scene illumination and involves only a single camera. Therefore, there are no correspondence, occlusion and intrusive emissions problems. The paper gives experimental results which demonstrate the accuracy of the method.


Using genetic admixture to explain racial differences in insulin-related phenotypes.
Documented differences in measures of insulin secretion and action between African Americans and European Americans may be due to either genetic or environmental factors. This study used genetic admixture (ADM), determined from approximately 20 ancestry informative markers, and a questionnaire designed to assess socioeconomic status (SES) to examine potential genetic and environmental contributions to minimal model-derived measures of insulin sensitivity (S(I)), fasting insulin, and the acute insulin response to glucose (AIR(g)) in 125 children residing in Birmingham, Alabama. The study was longitudinal in design and yielded multiple outcome measures on each subject. Mixed models analysis was used to determine if ADM and SES were independently related to S(I), fasting insulin, and AIR(g) after adjusting for confounding factors (pubertal status, adiposity, age) and for repeated testing of individuals. In this cohort, African ADM ranged from 0% (individuals with no markers reflecting African ancestry) to 100% (individuals with all 20 markers reflecting African ancestry). Results indicated that ADM was independently related to S(I) (P < 0.001) and fasting insulin (P < 0.01), with individuals having greater African ADM having a lower S(I) and a higher fasting insulin concentration. Both ADM (P < 0.001) and SES (P < 0.05) were independently related to AIR(g); children with greater African ADM or lower SES had a higher AIR(g), even after adjusting for S(I). These observations suggest that use of ADM can replace assignment of individuals to categorical racial groups; that lower S(I) and higher fasting insulin among African Americans compared with European Americans may have a genetic basis; and that higher AIR(g) among African Americans may be due to both genetic factors and to environmental factors that remain to be identified.


Cognition and social-physiological factors associated with malnutrition in hospitalized older adults in Taiwan.
Malnutrition is prevalent among hospitalized geriatric patients. The aim of this study was to explore the impact of cognitive status and its associated factors on the nutritional status of hospitalized geriatric patients. A descriptive and cross-sectional study design was conducted. Two instruments, the Mini Nutritional Assessment and the Mini-Mental State Examination (MMSE), were administered to 401 geriatric participants. Linear regression was used to examine the contribution of cognitive status and its associated factors to the nutritional status of participants. Participants had a mean age of 85 years, and three quarters (73.6%) were men. Participants earned a mean MMSE score of 19.1 ± 8.0 and a mean Mini Nutritional Assessment score of 20.2 ± 5.2. Two thirds (67.1%) were at risk for malnutrition, and 22.7% experienced malnutrition. One third (33.1%) had mild-to-moderate cognitive impairment, and 32.2% had severe cognitive impairment. The MMSE scores accounted for 21% of the total variability in nutritional status. In addition, the Charlson Comorbidity Index score and care status were also significant predictors of malnutrition and, together with the MMSE scores, accounted for 53% of the variability in the nutritional status of participants in the regression model. Findings indicate that cognitive status, concomitant comorbidities, and care status are significant predictors of malnutrition. The results of this study provide information to help clinicians identify at-risk populations for malnutrition and develop appropriate nutrition programs based on individual needs.


Studying cell cycle checkpoints using Drosophila cultured cells.
Drosophila cell lines are valuable tools to study a number of cellular processes, including DNA damage responses and cell cycle checkpoint control. Using an in vitro system instead of a whole organism has two main advantages: it saves time and simple and effective molecular techniques are available. It has been shown that Drosophila cells, similarly to mammalian cells, display cell cycle checkpoint pathways required to survive DNA damaging events (de Vries et al. 2005, Journal of Cell Science 118, 1833-1842; Bae et al. 1995, Experimental Cell Research 217, 541-545). Moreover, a number of proteins involved in checkpoint and cell cycle control in mammals are highly conserved among different species, including Drosophila (de Vries et al. 2005, Journal of Cell Science 118, 1833-1842; Bae et al. 1995, Experimental Cell Research 217, 541-545; LaRocque et al. 2007, Genetics 175, 1023-1033; Sibon et al. 1999, Current Biology 9, 302-312; Purdy et al. 2005, Journal of Cell Science 118, 3305-3315). Because of straightforward and highly efficient methods to downregulate specific transcripts in Drosophila cells, these cells are an excellent system for genome-wide RNA interference (RNAi) screens. Thus, the following methods, assays and techniques: Drosophila cell culture, RNAi, introducing DNA damaging events, determination of cell cycle arrest, and determination of cell cycle distributions described here may well be applied to identifying new players in checkpoint mechanisms and will be helpful to investigate the function of these new players in detail. Results obtained with studies using in vitro systems can subsequently be extended to studies in the complete organism as described in the chapters provided by the Su laboratory and the Takada laboratory.


Prednisolone in early pregnancy inhibits regulatory T cell generation and alters fetal and placental development in mice.
Corticosteroids have been utilised in the assisted reproduction setting with the expectation of suppressing aberrant immune activation and improving fertility in women. However, the effects of corticosteroids on fertility, and on pregnancy and offspring outcomes, are unclear. In this study, mice were administered prednisolone (1 mg/kg) or PBS daily in the pre-implantation phase, and effects on the adaptive immune response, the implantation rate, fetal development and postnatal outcomes were investigated. Prednisolone disrupted the expected expansion of CD4+ T cells in early pregnancy, inhibiting generation of both regulatory T cells (Treg cells) and effector T cells and suppressing IFNG required for T cell functional competence. Prednisolone caused an 8-20% increase in the embryo implantation rate and increased the number of viable pups per litter. In late gestation, fetal and placental weights were reduced in a litter size-dependent manner, and the canonical inverse relationship between litter size and fetal weight was lost. The duration of pregnancy was extended by ~ 0.5 day and birth weight was reduced by ~ 5% after prednisolone treatment. Viability of prednisolone-exposed offspring was comparable to controls, but body weight was altered in adulthood, particularly in male offspring. Thus, while prednisolone given in the pre-implantation phase in mice increases maternal receptivity to implantation and resource investment in fetal growth, there is a trade-off in long-term consequences for fetal development, birth weight and offspring health. These effects are associated with, and likely caused by, prednisolone suppression of the adaptive immune response at the outset of pregnancy.


Upper extremity surgery in children with cerebral palsy.
Pediatric patients with cerebral palsy present unique challenges. Any treatment regimen must take into account potential growth, possible sequelae of surgery, and, in some cases, significant behavioral issues. Careful evaluation of motor and sensory function of the extremity and of use patterns is imperative because these findings play a critical role in determining the ultimate success of any intervention. Every patient is addressed independently and treatment individualized. The patient and parents must understand that surgery can address only the function or position of the anatomic area. Surgery will not correct the underlying problem.