Immunopathogenesis of recurrent vulvovaginal candidiasis.
Recurrent vulvovaginal candidiasis (RVVC) is a prevalent opportunistic mucosal infection, caused predominantly by Candida albicans, which affects a significant number of otherwise healthy women of childbearing age. Since there are no known exogenous predisposing factors to explain the incidence of symptomatic vaginitis in most women with idiopathic RVVC, it has been postulated that these particular women suffer from an immunological abnormality that prediposes them to RVVC. Because of the increased incidence of mucosal candidiasis in individuals with depressed cell-mediated immunity (CMI), defects in CMI are viewed as a possible explanation for RVVC. In this review, we attempt to place into perspective the accumulated information regarding the immunopathogenesis of RVVC, as well as to provide new immunological perspectives and hypotheses regarding potential immunological deficiencies that may predispose to RVVC and potentially other mucosal infections by the same organism. The results of both clinical studies and studies in an animal model of experimental vaginitis suggest that systemic CMI may not be the predominant host defense mechanism against C. albicans vaginal infections. Rather, locally acquired mucosal immunity, distinct from that in the peripheral circulation, is now under consideration as an important host defense at the vaginal mucosa, as well as the notion that changes in local CMI mechanism(s) may predispose to RVVC.


Interpretable correlation descriptors for quantitative structure-activity relationships.
The topological maximum cross correlation (TMACC) descriptors are alignment-independent 2D descriptors for the derivation of QSARs. TMACC descriptors are generated using atomic properties determined by molecular topology. Previous validation (J Chem Inf Model 2007, 47: 626-634) of the TMACC descriptor suggests it is competitive with the current state of the art. Here, we illustrate the interpretability of the TMACC descriptors, through the analysis of the QSARs of inhibitors of angiotensin converting enzyme (ACE) and dihydrofolate reductase (DHFR). In the case of the ACE inhibitors, the TMACC interpretation shows features specific to C-domain inhibition, which have not been explicitly identified in previous QSAR studies. The TMACC interpretation can provide new insight into the structure-activity relationships studied. Freely available, open source software for generating the TMACC descriptors can be downloaded from http://comp.chem.nottingham.ac.uk.


Experimental verification of proton beam monitoring in a human body by use of activity image of positron-emitting nuclei generated by nuclear fragmentation reaction.
Proton therapy is a form of radiotherapy that enables concentration of dose on a tumor by use of a scanned or modulated Bragg peak. Therefore, it is very important to evaluate the proton-irradiated volume accurately. The proton-irradiated volume can be confirmed by detection of pair-annihilation gamma rays from positron-emitting nuclei generated by the nuclear fragmentation reaction of the incident protons on target nuclei using a PET apparatus. The activity of the positron-emitting nuclei generated in a patient was measured with a PET-CT apparatus after proton beam irradiation of the patient. Activity measurement was performed in patients with tumors of the brain, head and neck, liver, lungs, and sacrum. The 3-D PET image obtained on the CT image showed the visual correspondence with the irradiation area of the proton beam. Moreover, it was confirmed that there were differences in the strength of activity from the PET-CT images obtained at each irradiation site. The values of activity obtained from both measurement and calculation based on the reaction cross section were compared, and it was confirmed that the intensity and the distribution of the activity changed with the start time of the PET imaging after proton beam irradiation. The clinical use of this information about the positron-emitting nuclei will be important for promoting proton treatment with higher accuracy in the future.


Outcome of cervical near-hanging injuries.
Cervical near-hangings are not rare, but have received little attention in the trauma literature. Increasing numbers of patients received from our local jail and detention centers prompted this study. Seventeen-year review of a level I Trauma Center Registry identified 67 patients with cervical strangulation for study. Data were analyzed using the Mann-Whitney test to evaluate continuous predictors, and Fisher's exact test for categorical predictors. Ten of 67 patients died (14.9% mortality). Patients having a lower Glasgow Coma Score (GCS) at the scene (3.5 +/- 1.3 vs. 8.3 +/- 5.0; p = 0.001) and lower GCS in the emergency department (ED) (3.0 +/- 0.0 vs. 9.0 +/- 5.3; p < 0.001) were more likely to die. Injuries consisted predominantly of neck abrasions and anoxic brain injuries (83% mortality). Laryngeal fractures and carotid arterial injuries were detected. No cervical spine fractures were seen, but subluxations were identified. Forty-two percent of the patients were in detention centers when the near-hanging incident occurred. Cervical near-hangings are referred to the Trauma Service for evaluation. Scene or ED GCS of 3 does not preclude neurologically intact survival, although mortality is high. In our study, the most useful prognostic factors were the need for airway control by intubation or cricothyrotomy, cardiopulmonary resuscitation, lower scene and ED GCS, and cerebral edema on CT Scan. Optimal evaluation includes head and neck CT and CT angiography of the neck. We plan to share these results with local authorities and encourage improvement in risk identification, with earlier involvement of mental health personnel.


An alternative pathway of T-cell activation: a functional role for the 50 kd T11 sheep erythrocyte receptor protein.
A series of seven monoclonal antibodies was produced against the T-lineage-specific 50 kd T11 sheep erythrocyte rosette (SRBC) receptor protein in order to define the function of the molecule. Three distinct epitopes were detected: T11(1), the SRBC binding site expressed on all T lymphocytes and thymocytes; T11(2), an epitope unrelated to the SRBC binding site but with a similar distribution; and T11(3), a neo-epitope expressed only upon T-cell activation. Simultaneous triggering of T11(2) and T11(3) epitopes by monoclonal antibodies induces T lymphocytes to proliferate and mediate their functional programs in the absence of antigen and/or antigen-presenting cells. This antigen-independent mode of triggering is distinct from that involving the T3-Ti antigen receptor complex and represents an alternate pathway of T-cell activation. Given that T11 is the earliest T-lineage surface glycoprotein to appear in thymic ontogeny and is thus expressed before T3-Ti, the former may be involved in clonal expansion and/or differentiation during early development.


Hand-held cell phone use while driving legislation and observed driver behavior among population sub-groups in the United States.
Cell phone use behaviors are known to vary across demographic sub-groups and geographic locations. This study examined whether universal hand-held calling while driving bans were associated with lower road-side observed hand-held cell phone conversations across drivers of different ages (16-24, 25-59, ≥60 years), sexes, races (White, African American, or other), ruralities (suburban, rural, or urban), and regions (Northeast, Midwest, South, and West). Data from the 2008-2013 National Occupant Protection Use Survey were merged with states' cell phone use while driving legislation. The exposure was presence of a universal hand-held cell phone ban at time of observation. Logistic regression was used to assess the odds of drivers having a hand-held cell phone conversation. Sub-groups differences were assessed using models with interaction terms. When universal hand-held cell phone bans were effective, hand-held cell phone conversations were lower across all driver demographic sub-groups and regions. Sub-group differences existed among the sexes (p-value, <0.0001) and regions (p-value, 0.0003). Compared to states without universal hand-held cell phone bans, the adjusted odds ratio (aOR) of a driver hand-held phone conversation was 0.34 [95% confidence interval (CI): 0.28, 0.41] for females versus 0.47 (CI 0.40, 0.55) for males and 0.31 (CI 0.25, 0.38) for drivers in Western states compared to 0.47 (CI 0.30, 0.72) in the Northeast and 0.50 (CI 0.38, 0.66) in the South. The presence of universal hand-held cell phone bans were associated lower hand-held cell phone conversations across all driver sub-groups and regions. Hand-held phone conversations were particularly lower among female drivers and those from Western states when these bans were in effect. Public health interventions concerning hand-held cell phone use while driving could reasonably target all drivers.


Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation.
Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis. We used small molecule inhibitors of Trx (PMX 464 and PX-12) to determine whether Trx activity influences platelet function, as well as an unbiased proteomics approach to identify potential Trx substrates on the surface of platelets that might contribute to platelet reactivity and function. Using LC-MS/MS we found that PMX 464 and PX-12 affected the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation were affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. To experimentally validate these findings we assessed platelet function in the presence of PMX 464, PX-12, and rutin (a selective inhibitor of the related protein disulphide isomerase). In agreement with the proteomics data, small molecule inhibitors of thioredoxin selectively inhibited GPVI-mediated platelet activation, and attenuated ristocetin-induced GPIb-vWF-mediated platelet agglutination, thus validating the findings of the proteomics study. These data reveal a novel role for thioredoxin in regulating platelet reactivity via proteins required for early platelet responses at sites of vessel injury (GPVI and GPIb). This work also highlights a potential opportunity for repurposing of PMX 464 and PX-12 as antiplatelet agents.


Farnesyltransferase inhibitor as anticancer agent.
Ras protein plays pivotal roles in control of normal and transformed cell growth. These ras genes are mutated in 30% of human cancer. For functioning of Ras protein its prenylation (farnesylation) is required. Therefore targeting Ras farnesylation is valuable approach for cancer treatment. Farnesyltransferase inhibitor (FTI) has been developed as anticancer drug and is currently evaluated in clinical trials. Different types of FTI have been identified that inhibit Ras farnesylation. FTI in combination with some cytotoxic antineoplastic drugs, exhibit additive effects.


An Unusual Case of Transorificial Abdomino-Thoracic Impalement Injury in a Child.
Impalement injuries are rare in the paediatric age group. Still rarer are injuries which traverse multiple body cavities. Such injuries require multispecialty management at a tertiary care centre. We describe a case of an accidental impalement injury in a 12-year-old boy after a fall from height. The rod was seen passing through the right lung in the paracardiac region, piercing the diaphragm and segment IV of the liver and then coursing anterior to the inferior vena cava in the midline. It was seen passing through the small bowel at multiple places and then coursing behind the bladder, entering the rectum and anal canal. Intra-operatively, right intercostal chest drain was inserted. At laparotomy, the liver was mobilized and a diaphragmatic tear of 2×1cm was visualized. The rod traversed through the right lobe of liver with no active bleeding. Both the entry and exit sites through the liver were visualized. The rod was also seen passing through the small bowel and its mesentery. The rod entered the pelvis posterior to the bladder below the peritoneal reflection. Moderate hemoperitoneum and fecal contamination was present. The rod was successfully removed and the patient was discharged with good condition and was well on follow up.


Electrodiffusion: a continuum modeling framework for biomolecular systems with realistic spatiotemporal resolution.
A computational framework is presented for the continuum modeling of cellular biomolecular diffusion influenced by electrostatic driving forces. This framework is developed from a combination of state-of-the-art numerical methods, geometric meshing, and computer visualization tools. In particular, a hybrid of (adaptive) finite element and boundary element methods is adopted to solve the Smoluchowski equation (SE), the Poisson equation (PE), and the Poisson-Nernst-Planck equation (PNPE) in order to describe electrodiffusion processes. The finite element method is used because of its flexibility in modeling irregular geometries and complex boundary conditions. The boundary element method is used due to the convenience of treating the singularities in the source charge distribution and its accurate solution to electrostatic problems on molecular boundaries. Nonsteady-state diffusion can be studied using this framework, with the electric field computed using the densities of charged small molecules and mobile ions in the solvent. A solution for mesh generation for biomolecular systems is supplied, which is an essential component for the finite element and boundary element computations. The uncoupled Smoluchowski equation and Poisson-Boltzmann equation are considered as special cases of the PNPE in the numerical algorithm, and therefore can be solved in this framework as well. Two types of computations are reported in the results: stationary PNPE and time-dependent SE or Nernst-Planck equations solutions. A biological application of the first type is the ionic density distribution around a fragment of DNA determined by the equilibrium PNPE. The stationary PNPE with nonzero flux is also studied for a simple model system, and leads to an observation that the interference on electrostatic field of the substrate charges strongly affects the reaction rate coefficient. The second is a time-dependent diffusion process: the consumption of the neurotransmitter acetylcholine by acetylcholinesterase, determined by the SE and a single uncoupled solution of the Poisson-Boltzmann equation. The electrostatic effects, counterion compensation, spatiotemporal distribution, and diffusion-controlled reaction kinetics are analyzed and different methods are compared.


Influence of spontaneous otoacoustic emissions on distortion product otoacoustic emission amplitudes.
Although the influence of the levels and ratios of the primary stimulus on the amplitude of distortion product otoacoustic emissions (DPOAEs) has been studied intensely, the influence of the presence of spontaneous otoacoustic emissions (SOAEs) has been investigated less thoroughly. The present investigation analysed whether the unilateral presence of 58 SOAEs in 43 normal-hearing adults was related to larger DPOAEs in the ear with SOAEs compared to the contralateral ear having no SOAEs. The study was designed such that the only factor that could influence the amplitude of DPOAEs was the presence of SOAEs. Input/output (I/O) functions were collected in response to primary tones that were presented in 5-dB steps from 70 to 40 dB SPL at the frequency of the unilaterally recorded SOAE of each subject. The primary outcome was the demonstration of statistically significant (P < 0.05) larger DPOAEs in ears exhibiting SOAEs than in ears without measurable SOAEs, except at the highest stimulus level of 70 dB SPL. These results suggest that SOAEs play an additive role in the measurement of DPOAEs. The enhancing effect of the unilateral presence of SOAEs on DPOAEs was statistically significant for 65 dB SPL and lower levels of primary tones. The authors speculate that passive cochlear properties begin to participate in the generation of DPOAEs at primary-stimulus levels greater than 65 dB SPL.


Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment
Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumors. Despite advances in treatment modalities it remains largely incurable. The objective of our review is to provide a holistic picture of GBM epidemiology, etiology, pathogenesis, clinical findings and treatment. A literature search was conducted for GBM at PubMed and Google Scholar, with relevant key words like glioblastoma multiforme, pathogenesis, signs and symptoms, treatment etc., and papers published until 2015 were reviewed. It was found that radiation and certain genetic syndromes are the only risk factors identified to date for GBM. Depending on the tumor site patients may present to the clinic with varying symptoms. To confirm the presence and the extent of tumor, various invasive and non-invasive imaging techniques require employment. The literature survey revealed the pathogenesis to involve aberrations of multiple signaling pathways through multiple genetic mutations and altered gene expression. Although several treatment options are available, including surgery, along with adjuvant chemo- and radio-therapy, the disease has a poor prognosis and patients generally succumb within 14 months of diagnosis.


Atraumatic brachial plexopathy following intravenous heroin use.
A 32-year-old man presented to the accident & emergency (A&E) department complaining of an inability to use his left arm and shoulder. The previous day he had injected heroin intravenously into his left antecubital vein. Examination revealed signs of a left-sided brachial plexus lesion. There was no history or sign of trauma. Neurological investigation revealed motor and sensory loss compatible with a complete brachial plexus lesion. He exhibited a very rare condition, asymmetrical atraumatic brachial plexopathy, thought to result from an inflammatory cause, which not only affects the brachial, but also other plexi or individual nerves in the body and thought to be related to repeated intravenous use of heroin. This is a condition for which there is no specific treatment but which usually resolves spontaneously in the absence of continuing heroin misuse.


Catechol-o-methyltransferase and methoxyestradiols participate in the intraoviductal nongenomic pathway through which estradiol accelerates egg transport in cycling rats.
Estradiol (E(2)) accelerates oviductal egg transport through intraoviductal nongenomic pathways in cyclic rats and through genomic pathways in pregnant rats. This shift in pathways, which we have provisionally designated as intracellular path shifting (IPS), is caused by mating-associated signals and represents a novel and hitherto unrecognized phenomenon. The mechanism underlying IPS is currently under investigation. Using microarray analysis, we identified several genes the expression levels of which changed in the rat oviduct within 6 hours of mating. Among these genes, the mRNA level for the enzyme catechol-O-methyltransferase (COMT), which produces methoxyestradiols from hydroxyestradiols, decreased 6-fold, as confirmed by real-time PCR. O-methylation of 2-hydroxyestradiol was up to 4-fold higher in oviductal protein extracts from cyclic rats than from pregnant rats and was blocked by OR486, which is a selective inhibitor of COMT. The levels in the rat oviduct of mRNA and protein for cytochrome P450 isoforms 1A1 and 1B1, which form hydroxyestradiols, were detected by RT-PCR and Western blotting. We explored whether methoxyestradiols participate in the pathways involved in E(2)-accelerated egg transport. Intrabursal application of OR486 prevented E(2) from accelerating egg transport in cyclic rats but not in pregnant rats, whereas 2-methoxyestradiol (2ME) and 4-methoxyestradiol mimicked the effect of E(2) on egg transport in cyclic rats but not in pregnant rats. The effect of 2ME on egg transport was blocked by intrabursal administration of the protein kinase inhibitor H-89 or the antiestrogen ICI 182780, but not by actinomycin D or OR486. We conclude that in the absence of mating, COMT-mediated formation of methoxyestradiols in the oviduct is essential for the nongenomic pathway through which E(2) accelerates egg transport in the rat oviduct. Yet unidentified mating-associated signals, which act directly on oviductal cells, shut down the E(2) nongenomic signaling pathway upstream and downstream of methoxyestradiols. These findings highlight a physiological role for methoxyestradiols in the female genital tract, thereby confirming the occurrence of and providing a partial explanation for the mechanism underlying IPS.


Socioeconomic status is significantly associated with dietary salt intakes and blood pressure in Japanese workers (J-HOPE Study).
The association of socioeconomic status (SES) with nutrients intakes attracts public attention worldwide. In the current study, we examined the associations of SES with dietary salt intake and health outcomes in general Japanese workers (2,266) who participated in this Japanese occupational cohort. SES was assessed by a self-administered questionnaire. Dietary intakes were assessed with a validated, brief, self-administered diet history questionnaire (BDHQ). Multiple linear regression and stratified analysis were used to evaluate the associations of salt intake with the confounding factors. Education levels and household incomes were significantly associated with salt intake, as well as blood pressures (P < 0.05). After adjusting for age, sex and total energy intake, both years of education and household income significantly affect the salt intake (for education, β = -0.031, P = 0.040; for household income, β = -0.046, P = 0.003). SES factors also affect the risk of hypertension, those subjects with higher levels of education or income had lower risk to become hypertensive (ORs for education was 0.904, P < 0.001; ORs for income was 0.956, P = 0.032). Our results show that SES is an independent determinant of salt intake and blood pressure, in order to lower the risk of hypertension, the efforts to narrow the social status gaps should be considered by the health policy-makers.


Medulloepithelioma: invasive versus noninvasive diagnostic methods and their impacts on outcome.
The purpose of this study was to report a case of a 34-month-old patient who presented with leukoria and underwent a vitrectomy and vitreous biopsy at an outside hospital followed by definitive enucleation for a nonteratoid medulloepithelioma and to review the literature regarding metastatic rates for this tumor after intraocular surgery. The authors reviewed the clinical, histopathologic, and neuroimaging records in the unusual case of a child with medulloepithelioma who had previously undergone pars plana vitrectomy and vitreous biopsy. An in-depth literature search was performed for patients with medulloepithelioma with prior biopsy or surgery. Clinical examination showed a subluxed cataractous lens and neovascular glaucoma. Ultrasonography showed a large, cystic lesion with high reflectivity. Enucleation was performed, and histopathologic analysis showed a diffuse nonteratoid medulloepithelioma. Metastasis in medulloepithelioma is very rare. A systematic review of cases of patients with medulloepithelioma undergoing invasive intervention indicated that some patients subsequently developed metastases. Such procedures should be avoided to prevent orbital seeding or creating tracts for tumor migration and ultimate extraocular relapse.


Electromyographic activity to keep a lower limb in a raised position in healthy subjects and subjects with multiple sclerosis.
The objective of this work was to assess the activation of the stabilization muscles used to keep one lower limb raised from a supine position, in healthy subjects and in subjects with multiple sclerosis (MS) in two different conditions. The test required subjects to keep the right lower limb at 45 degrees from the supine position on a horizontal bed plane, with the knee extended. The position was reached in two ways: by raising the right limb (A), and by resting the left lower limb on the bed after both limbs had been raised (B). During the test, pelvis and hip kinematics and the surface electromyographic (sEMG) activity were acquired. Fourteen healthy subjects and 14 subjects with multiple sclerosis were included in the study. showed that in the A condition, healthy subjects had a greater activation of the biceps femoris than the abdominal muscles, while in the B condition the difference between the two muscles decreased. In the MS group there was no difference in muscular activation for the two conditions. The data show that in the MS subjects there is an alteration of the stabilization muscles with regard the quality of the activation. Starting from these data new exercises of motor rehabilitation in subjects with multiple sclerosis could be recommended.


Proteomic analysis of mantle-cell lymphoma by protein microarray.
Mantle-cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma (NHL) that behaves aggressively and remains incurable. In order to understand the pathogenesis of MCL and design new therapies, it is important to accurately analyze molecular changes in pathways dysregulated in MCL. We used antibody microarrays to compare patterns of protein expression between CD19(+) purified B lymphocytes from normal tonsil and 7 cases of histologically confirmed MCL. Protein overexpression was defined as a higher than 1.3-fold or 2-fold increase in at least 67% of tumor samples compared with normal B-cell control. Of the polypeptides, 77 were overexpressed using the higher than 1.3-fold cutoff, and 13 were overexpressed using the 2-fold cutoff. These included cell cycle regulators (regulator of chromosome condensation 1 [RCC1], murine double minute 2 [MDM2]), a kinase (citron Rho-interacting kinase [CRIK]), chaperone proteins (heat shock 90-kDa protein [Hsp90], Hsp10), and phosphatase regulators (A-kinase anchor protein 1 [AKAP149], protein phosphatase 5 [PP5], and inhibitor 2). The elevated expression of some of these polypeptides was confirmed by immunoblotting and immunohistochemistry, whereas elevated expression of others could not be confirmed, illustrating the importance of confirmatory studies. This study describes a novel technique that identifies proteins dysregulated in MCL.


Efficacy of cartilage conduction hearing aids in children.
Cartilage conduction hearing aids (CC-HAs) are novel hearing aids that use the third hearing pathway of cartilage conduction. We assessed the efficacy of CC-HAs and the hearing effects and safety of additional tape compression over the transducer in children with hearing loss. The patients (n = 42) underwent a one-month free trial of CC-HAs. Forty of them were patients with auditory canal atresia or stenosis. CC-HA-aided and unaided hearing thresholds (48 fitted ears) were determined using standard audiograms, after which participants could choose to purchase the device or not. We calculated the purchase rates and compared the patient characteristics between the purchase and non-purchase groups along with the purchase reason (or not). We applied additional tape compression over the CC-HA transducer and assessed the hearing effects and side effects. CC-HA led to hearing improvements at all frequencies. Overall, 72.92% of participants purchased a CC-HA after the trial. By applying additional tape compression over the CC-HA transducer, the stability and hearing gains were improved mainly at low frequencies, and no side effects such as dermatitis were observed. CC-HAs are efficacious in producing hearing improvements in children, especially in patients with atresia or canal stenosis who cannot use air conduction hearing aids. Furthermore, we found that the additional tape compression over the transducer was an easy and a safe method for improving the hearing effects and stability of the CC-HA.


Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer.
Elevated mammographic density (MD) is one of the strongest risk factors for sporadic breast cancer. Epidemiologic evidence suggests that MD is, in part, genetically determined; however, the relationship between MD and BRCA1/2 mutation status is equivocal. We compared MD in unaffected BRCA1/2 mutation carriers enrolled in the U.S. National Cancer Institute's Clinical Genetics Branch's Breast Imaging Study (n = 143) with women at low-to-average breast cancer risk enrolled in the same study (n = 29) or the NCI/National Naval Medical Center's Susceptibility to Breast Cancer Study (n = 90). The latter were BRCA mutation-negative members of mutation-positive families or women with no prior breast cancer, a Pedigree Assessment Tool score <8 (i.e., low risk of a hereditary breast cancer syndrome) and a Gail score <1.67. A single experienced mammographer measured MD using a computer-assisted thresholding method. We collected standard breast cancer risk factor information in both studies. Unadjusted mean percent MD was higher in women with BRCA1/2 mutations compared with women at low-to-average breast cancer risk (37.3% vs. 33.4%; P = 0.04), but these differences disappeared after adjusting for age and body mass index (34.9% vs. 36.3%; P = 0.43). We explored age at menarche, nulliparity, age at first birth, menopausal status, number of breast biopsies, and exposure to exogenous hormonal agents as potential confounders of the MD and BRCA1/2 association. Taking these factors into account did not significantly alter the results of the age/body mass index-adjusted analysis. Our results do not provide support for an independent effect of BRCA1/2 mutation status on mammographic density.


Amiodarone for refractory atrial fibrillation.
Atrial fibrillation (AF) is a difficult arrhythmia to manage with antiarrhythmic agents. Amiodarone is highly effective in restoring and maintaining normal sinus rhythm in patients with AF. However, the mechanism and predictors of efficacy for amiodarone in treating AF have not been adequately addressed. Various measures of success or failure of amiodarone therapy were examined in 68 patients who had paroxysmal or chronic, established AF refractory to conventional antiarrhythmic agents. The patients were 25 to 75 years old (mean 59) and mean follow-up was 21 months (range 3 to 56). Maintenance amiodarone dosages were 200 to 400 mg/day. Overall, amiodarone therapy was effective long term in 54 of the 68 patients (79%). Left atrial diameter, age, gender and origin of AF were not helpful in predicting success or failure of amiodarone therapy. The presence of chronic AF for longer than 1 year was an adverse factor in maintaining normal sinus rhythm (p = 0.007), although the success rate even in this group was relatively high (57%). Thirty-five percent of the patients had adverse effects, which precluded long-term therapy with amiodarone in 10%.


Quantifying innervation facilitated by deep learning in wound healing.
The peripheral nerves (PNs) innervate the dermis and epidermis, which have been suggested to play an important role in wound healing. Several methods to quantify skin innervation during wound healing have been reported. Those usually require multiple observers, are complex and labor-intensive, and noise/background associated with the Immunohistochemistry (IHC) images could cause quantification errors/user bias. In this study, we employed the state-of-the-art deep neural network, DnCNN, to perform pre-processing and effectively reduce the noise in the IHC images. Additionally, we utilized an automated image analysis tool, assisted by Matlab, to accurately determine the extent of skin innervation during various stages of wound healing. The 8mm wound is generated using a circular biopsy punch in the wild-type mouse. Skin samples were collected on days 3,7,10 and 15, and sections from paraffin-embedded tissues were stained against pan-neuronal marker- protein-gene-product 9.5 (PGP 9.5) antibody. On day 3 and day 7, negligible nerve fibers were present throughout the wound with few only on the lateral boundaries of the wound. On day 10, a slight increase in nerve fiber density appeared, which significantly increased on day 15. Importantly we found a positive correlation (R 2 = 0.933) between nerve fiber density and re-epithelization, suggesting an association between re-innervation and re-epithelization. These results established a quantitative time course of re-innervation in wound healing, and the automated image analysis method offers a novel and useful tool to facilitate the quantification of innervation in the skin and other tissues.


Congenital central hypoventilation syndrome and the PHOX2B gene: a model of respiratory and autonomic dysregulation.
The paired-like homeobox 2B gene (PHOX2B) is the disease-defining gene for congenital central hypoventilation syndrome (CCHS). Individuals with CCHS typically present in the newborn period with alveolar hypoventilation during sleep and often during wakefulness, altered respiratory control including reduced or absent ventilatory responses to hypercarbia and hypoxemia, and autonomic nervous system (ANS) dysregulation; however, a subset of individuals present well into adulthood. Thermoregulation is altered and perception of shortness of breath is absent, but voluntary breathing is retained. Structural and functional magnetic resonance imaging (MRI) and limited post-mortem studies in subjects with CCHS reveal abnormalities in both forebrain and brainstem. MRI changes appear in the hypothalamus (responsible for thermal drive to breathing), posterior thalamus and midbrain (mediating O(2) and oscillatory motor patterns), caudal raphé and locus coeruleus (regulating serotonergic and noradrenergic systems), the lateral medulla, parabrachial pons, and cerebellum (coordinating chemoreceptor and somatic afferent activity with breathing), and insular and cingulate cortices (mediating shortness of breath perception). Structural and functional alterations in these sites may result from PHOX2B mutations or be secondary to hypoxia/perfusion alterations from suboptimal management/compliance. The study of CCHS, with collaboration between physician-scientists and basic scientists, offers a rare opportunity to investigate control of breathing within the complex physiological network of the ANS.


Evaluation of skin viability in nipple sparing mastectomy (NSM).
Nipple sparing mastectomy (NSM) is quickly becoming the standard of care due to earlier stage of breast cancer diagnosis, increased prevalence of prophylactic mastectomies, improved surgical techniques, and the desire of women to keep their nipples. However, the procedure is plagued with problems of nipple and skin necrosis due to the inherent ischemic nature of mastectomy. Indocyanine green (ICG) technologies offer surgeons new information that is helpful in the battle to reduce these devastating complications.


Olfactory Network Differences in Master Sommeliers: Connectivity Analysis Using Granger Causality and Graph Theoretical Approach.
Previous studies investigating the differences in olfactory processing and judgments between trained sommeliers and controls have shown increased activations in brain regions involving higher level cognitive processes in sommeliers. However, there is little information about the influence of expertise on causal connectivity and topological properties of the connectivity networks between these regions. Therefore, the current study focuses on addressing these questions in a functional magnetic resonance imaging (fMRI) study of olfactory perception in Master Sommeliers. fMRI data were acquired from Master Sommeliers and control participants during different olfactory and nonolfactory tasks. Mean time series were extracted from 90 different regions of interest (ROIs; based on Automated Anatomical Labeling atlas). The underlying neuronal variables were extracted using blind hemodynamic deconvolution and then input into a dynamic multivariate autoregressive model to obtain connectivity between every pair of ROIs as a function of time. These connectivity values were then statistically compared to obtain paths that were significantly different between the two groups. The obtained connectivity matrices were further studied using graph theoretical methods. In sommeliers, significantly greater connectivity was observed in connections involving the precuneus, caudate, putamen, and several frontal and temporal regions. The controls showed increased connectivity from the left hippocampus to the frontal regions. Furthermore, the sommeliers exhibited significantly higher small-world topology than the controls. These findings are significant, given that learning about neuroplasticity in adulthood in these regions may then have added clinical importance in diseases such as Alzheimer's and Parkinson's where early neurodegeneration is isolated to regions important in smell.


Evaluation of the effects of Neptune Krill Oil on the management of premenstrual syndrome and dysmenorrhea.
To evaluate the effectiveness of Neptune Krill Oil (NKO) for the management of premenstrual syndrome and dysmenorrhea. To compare the effectiveness of NKO for the management of premenstrual syndrome and dysmenorrhea with that of omega-3 fish oil. Double-blind, randomized clinical trial. Outpatient clinic. Seventy patients of reproductive age diagnosed with premenstrual syndrome according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R). Treatment period of three months with either NKO or omega-3 fish oil. Self-Assessment Questionnaire based on the American College of Obstetricians and Gynecologists (ACOG) diagnostic criteria for premenstrual syndrome and dysmenorrhea and number of analgesics used for dysmenorrhea. In 70 patients with complete data, a statistically significant improvement was demonstrated among baseline, interim, and final evaluations in the self assessment questionnaire (P < 0.001) within the NKO group as well as between-group comparison to fish oil, after three cycles or 45 and 90 days of treatment. Data analysis showed a significant reduction of the number of analgesics used for dysmenorrhea within the NKO group (comparing baseline vs. 45- vs. 90-day visit). The between-groups analysis illustrated that women taking NKO consumed significantly fewer analgesics during the 10-day treatment period than women receiving omega-3 fish oil (P < 0.03). Neptune Krill Oil can significantly reduce dysmenorrhea and the emotional symptoms of premenstrual syndrome and is shown to be significantly more effective for the complete management of premenstrual symptoms compared to omega-3 fish oil.


Association of Subway Driver's Depressive Symptoms and Experience of Work-Related Problems.
Subway drivers experience various types of work-related problems during their driving, and those experiences can act as risk factors for depressive symptoms. This study was conducted to investigate the association between work-related problems and subway driver's depressive symptoms. We recruited all of the 961 current subway drivers of a subway company located in Seoul, South Korea and conducted a survey of their socio-demographic and vocational characteristics, hospital visits as an outpatient or inpatient, and work-related problem experiences during the last year. Work-related problems included an accident resulting in death or injury, a conflict with a customer, a sudden stop from an emergency bell, or a near accident. Depressive symptoms were measured with the Center for Epidemiologic Studies-Depression (CES-D) instrument. The survey was performed using a self-report questionnaire from April 16 to July 13, 2007. The data of 827 drivers (86.2%) were analyzed. Experience of a conflict with a passenger (p=0.011), a sudden stop from an emergency bell (p=0.001), or a near accident (p=0.001) increased the prevalence of depressive symptoms among subway drivers. A multiple logistic regression analysis revealed that a sudden stop from an emergency bell increased the risk of depressive symptoms significantly (OR=2.59, p=0.026). Near accidents were marginally associated with a higher risk for depressive symptoms (OR=1.62, p=0.062). The experience of a sudden stop from an emergency bell increased subway driver's depressive symptoms, and near accidents may increase the risk of depressive symptoms. Therefore, interventions for the drivers who had experienced these work-related problems are needed.


Preventing opportunistic infections among human immunodeficiency virus-infected adults in African countries.
The burden of human immunodeficiency virus (HIV)-related disease in sub-Saharan Africa continues to increase; providing adequate care for the huge number of people affected is a daunting task, especially given the limited resources available. Recent studies have shown that low-cost regimens can prevent some of the most important causes of HIV-related disease in African countries. Isoniazid preventive therapy can reduce the incidence of tuberculosis; priorities are to seek opportunities for implementation, to assess effectiveness under operational conditions, and to monitor its effect on resistance patterns. Cotrimoxazole was shown to be highly effective in reducing morbidity and mortality among individuals with symptomatic HIV disease in Côte d'Ivoire, and should be implemented where it is likely to be of benefit. Pneumococcal polysaccharide vaccine was disappointingly ineffective among HIV-infected Ugandan adults, but newer conjugate vaccines are becoming available that should be investigated. The benefit of these preventive regimens to the individual may be modest when compared with the effect of antiretroviral therapy. However, simple preventive therapies could reach a much wider population than is immediately feasible for expensive and complex antiretroviral regimens, and thus have the potential for substantial benefit at the population level. The availability of effective and affordable regimens to prevent HIV-related disease may also encourage people to seek HIV testing, combat denial, and help overcome the sense of powerlessness in countries where the HIV epidemic has hit hardest.


Ontogeny of the behavioral effects of lysergic acid diethylamide in cats.
The ontogeny of the behavioral effects of lysergic acid diethylamide (LSD) was examined in cats between the ages of 4 and 112 days postpartum. The kittens showed little LSD-induced behavioral change prior to 14 days of age. By the age of 21 days, however, the kittens exhibited many of the behavioral signs characteristic of LSD-induced behaviors in adult cats. These behaviors include limb-flicking, abortive grooming, head-shakes, grooming, and investigatory responses. In general, these behaviors began at a low frequency of occurrence, then increased rapidly with advancing age, reaching adult values by approximately 35-40 days of age, and remained relatively constant through 112 days postpartum. The time course for the behavioral effects following an acute injection of LSD showed the adult pattern, i.e., persisting for approximately 8 hr post-injection, from their earliest appearance during ontogeny. Young kittens (21-42 days of age) were resistant to the development of tolerance following repeated administration of the drug. LSD was capable of eliciting certain behaviors, such as head-shakes and grooming, well in advance of the age at which they normally appear spontaneously. This indicates that the neuronal and musculature substrata are developed for the performance of these behaviors long before the kitten naturally employs them.


Neurological complications of chronic myeloid leukaemia: any cure?
To attempt to explain the non-reversal, contrary to the widely held view, of the neurological deficits complicating chronic myeloid leukaemia. Using patients' case folders and haematological malignancy register all cases of chronic myeloid leukaemia seen in Jos University Teaching Hospital between July 1995 and June 2005 were retrospectively studied. All the available literature on the subject was also reviewed. Thirty-three cases of chronic myeloid leukaemia were seen within the study period. Five (15.15%) of them had one or more sensori-neural defects. Of the five, two (40%) patients presented with bilateral hearing impairment, each beginning with the left ear; one (20%) presented with left ear hearing loss; one (20%) came with severe left ear tinnitus; one (20%) presented with complete bilateral hearing and bilateral visual losses. Fundoscopy showed leukaemic deposits on the retina. Other causes of blindness and deafness, e.g. trauma and foreign body in the ear respectively, were excluded. While the complications due to hyperleucocytosis-induced stasis recover following the conventional treatment, those due to other pathogenetic mechanisms such as leukaemic deposits do not return to their pre-morbid states following disease control despite the use of the currently available treatment protocols. For future research, more still needs to be done to elicit other uncommon pathogenetic mechanisms underlying these complications with a view to finding specific treatment measures for worrisome chronic myeloid leukaemia-related sensori-neural deficits.


[Do psychomotor symptoms predict the treatment response of patients with depressive disorders?].
Patients with depressive disorders may present with typical psychomotor symptoms such as retardation and/or agitation. So far, however,the prognostic significance of these symptoms is unclear. To present an overview in which we assess to what extent psychomotor symptoms can predict the effect of the type of treatment that patients with depressive disorders receive. We searched the literature using Medline. Psychomotor symptoms might predict that the patient will respond more favourably to treatment with dopaminergic antidepressants and broad-spectrum antidepressants (TCAs) and particularly to electroconvulsive therapy than to 'single-acting serotonergic antidepressants' - but, so far, the scientific evidence for the foregoing is limited. In our view psychomotor symptoms do have a predictive value with regard to treatment response, but further research is needed.


The malaria testing and treatment market in Kinshasa, Democratic Republic of the Congo, 2013.
The Democratic Republic of Congo (DRC) is one of the two most leading contributors to the global burden of disease due to malaria. This paper describes the malaria testing and treatment market in the nation's capital province of Kinshasa, including availability of malaria testing and treatment and relative anti-malarial market share for the public and private sector. A malaria medicine outlet survey was conducted in Kinshasa province in 2013. Stratified multi-staged sampling was used to select areas for the survey. Within sampled areas, all outlets with the potential to sell or distribute anti-malarials in the public and private sector were screened for eligibility. Among outlets with anti-malarials or malaria rapid diagnostic tests (RDT) in stock, a full audit of all available products was conducted. Information collected included product information (e.g. active ingredients, brand name), amount reportedly distributed to patients in the past week, and retail price. In total, 3364 outlets were screened for inclusion across Kinshasa and 1118 outlets were eligible for the study. Among all screened outlets in the private sector only about one in ten (12.1%) were stocking quality-assured Artemisinin-based Combination Therapy (ACT) medicines. Among all screened public sector facilities, 24.5% had both confirmatory testing and quality-assured ACT available, and 20.2% had sulfadoxine-pyrimethamine (SP) available for intermittent preventive therapy during pregnancy (IPTp). The private sector distributed the majority of anti-malarials in Kinshasa (96.7%), typically through drug stores (89.1% of the total anti-malarial market). Non-artemisinin therapies were the most commonly distributed anti-malarial (50.1% of the total market), followed by non quality-assured ACT medicines (38.5%). The median price of an adult quality-assured ACT was $6.59, and more expensive than non quality-assured ACT ($3.71) and SP ($0.44). Confirmatory testing was largely not available in the private sector (1.1%). While the vast majority of anti-malarial medicines distributed to patients in Kinshasa province are sold within the private sector, availability of malaria testing and appropriate treatment for malaria is alarmingly low. There is a critical need to improve access to confirmatory testing and quality-assured ACT in the private sector. Widespread availability and distribution of non quality-assured ACT and non-artemisinin therapies must be addressed to ensure effective malaria case management.


Enhanced Spatial Mapping of Histone Proteoforms in Human Kidney Through MALDI-MSI by High-Field UHMR-Orbitrap Detection.
Core histones including H2A, H2B, H3, and H4 are key modulators of cellular repair, transcription, and replication within eukaryotic cells, playing vital roles in the pathogenesis of disease and cellular responses to environmental stimuli. Traditional mass spectrometry (MS)-based bottom-up and top-down proteomics allows for the comprehensive identification of proteins and of post-translational modification (PTM) harboring proteoforms. However, these methodologies have difficulties preserving near-cellular spatial distributions because they typically require laser capture microdissection (LCM) and advanced sample preparation techniques. Herein, we coupled a matrix-assisted laser desorption/ionization (MALDI) source with a Thermo Scientific Q Exactive HF Orbitrap MS upgraded with ultrahigh mass range (UHMR) boards for the first demonstration of complementary high-resolution accurate mass (HR/AM) measurements of proteoforms up to 16.5 kDa directly from tissues using this benchtop mass spectrometer. The platform achieved isotopic resolution throughout the detected mass range, providing confident assignments of proteoforms with low ppm mass error and a considerable increase in duty cycle over other Fourier transform mass analyzers. Proteoform mapping of core histones was demonstrated on sections of human kidney at near-cellular spatial resolution, with several key distributions of histone and other proteoforms noted within both healthy biopsy and a section from a renal cell carcinoma (RCC) containing nephrectomy. The use of MALDI-MS imaging (MSI) for proteoform mapping demonstrates several steps toward high-throughput accurate identification of proteoforms and provides a new tool for mapping biomolecule distributions throughout tissue sections in extended mass ranges.


Sexuality and schizophrenia: a review.
Sexual functioning has received little attention as an important aspect of patient care for those suffering from severe mental disorders such as schizophrenia. Yet, it has been implicated as one of the major factors contributing to noncompliance with antipsychotic medications and is documented by people with schizophrenia to be one of the areas of treatment with the most unmet needs. A stronger focus on sexuality and preventing sexual dysfunction in schizophrenia would likely be a major benefit for improving treatment. This review will describe possible mechanisms for sexual dysfunction, describe sexual disturbances that have been documented in the literature of people who have schizophrenia, and summarize and discuss assessment measures available. Moreover, a focus on second-generation antipsychotics (SGA) and their association with sexual functioning is described. Each SGA (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) will be described for its prolactin effects, documented sexual disturbances associated with use, and product labeling regarding sexual function. Treatment options and psychosocial issues pertaining to sexuality also are presented.


The weight of evidence: a method for assessing the strength of evidence on the effectiveness of HIV prevention interventions among young people.
To design a method for assessing the strength of evidence on the effectiveness of different interventions to prevent the spread of HIV that will be the basis for the reviews in this series. The literature on the evaluation of public health interventions was reviewed, and a method was developed in consultation with colleagues involved in this series of reviews and others. The method involves the following steps. First, define the key types of intervention that policy-makers need to choose between in the population setting under consideration. Second, define the strength of evidence that would be needed to justify widespread implementation of the intervention. Third, develop explicit inclusion and exclusion criteria for the studies under review. Fourth, critically review all eligible studies and their findings, by intervention type. Fifth, summarize the strength of the evidence on the effectiveness of each type of intervention. Sixth, compare the strength of the evidence provided by the studies against the threshold of evidence that would be needed to recommend widespread implementation. Seventh, from this comparison, derive evidence-based recommendations related to the implementation of each type of intervention in the setting or population group. The method proposed here provides a systematic, rigorous and transparent approach to reviewing evidence on the effectiveness of interventions of different types and in different population settings in order to generate recommendations for policy-makers.


A network of HSPG core proteins and HS modifying enzymes regulates netrin-dependent guidance of D-type motor neurons in Caenorhabditis elegans.
Heparan sulfate proteoglycans (HSPGs) are proteins with long covalently attached sugar side chains of the heparan sulfate (HS) type. Depending on the cellular context HS chains carry multiple structural modifications such as sulfate residues or epimerized sugars allowing them to bind to a wide range of molecules. HSPGs have been found to play extremely diverse roles in animal development and were shown to interact with certain axon guidance molecules. In this study we describe the role of the Caenorhabditis elegans HSPG core proteins Syndecan (SDN-1) and Glypican (LON-2) and the HS modifying enzymes in the dorsal guidance of D-type motor axons, a process controlled mainly by the conserved axon guidance molecule UNC-6/Netrin. Our genetic analysis established the specific HS code relevant for this axon guidance event. Using two sensitized genetic backgrounds, we isolated novel components influencing D-type motor axon guidance with a link to HSPGs, as well as new alleles of several previously characterized axon guidance genes. Interestingly, the dorsal axon guidance defects induced by mutations in zfp-1 or lin-35 depended on the transgene oxIs12 used to visualize the D-type motor neurons. oxIs12 is a large multi-copy transgene that enlarges the X chromosome by approximately 20%. In a search for genes with a comparable phenotype we found that a mutation in the known dosage compensation gene dpy-21 showed similar axon guidance defects as zfp-1 or lin-35 mutants. Thus, derepression of genes on X, where many genes relevant for HS dependent axon guidance are located, might also influence axon guidance of D-type motor neurons.


Dosimetric feasibility of brain stereotactic radiosurgery with a 0.35 T MRI-guided linac and comparison vs a C-arm-mounted linac.
MRI is the gold-standard imaging modality for brain tumor diagnosis and delineation. The purpose of this work was to investigate the feasibility of performing brain stereotactic radiosurgery (SRS) with a 0.35 T MRI-guided linear accelerator (MRL) equipped with a double-focused multileaf collimator (MLC). Dosimetric comparisons were made vs a conventional C-arm-mounted linac with a high-definition MLC. The quality of MRL single-isocenter brain SRS treatment plans was evaluated as a function of target size for a series of spherical targets with diameters from 0.6 cm to 2.5 cm in an anthropomorphic head phantom and six brain metastases (max linear dimension = 0.7-1.9 cm) previously treated at our clinic on a conventional linac. Each target was prescribed 20 Gy to 99% of the target volume. Step-and-shoot IMRT plans were generated for the MRL using 11 static coplanar beams equally spaced over 360° about an isocenter placed at the center of the target. Couch and collimator angles are fixed for the MRL. Two MRL planning strategies (VR1 and VR2) were investigated. VR1 minimized the 12 Gy isodose volume while constraining the maximum point dose to be within ±1 Gy of 25 Gy which corresponded to normalization to an 80% isodose volume. VR2 minimized the 12 Gy isodose volume without the maximum dose constraint. For the conventional linac, the TB1 method followed the same strategy as VR1 while TB2 used five noncoplanar dynamic conformal arcs. Plan quality was evaluated in terms of conformity index (CI), conformity/gradient index (CGI), homogeneity index (HI), and volume of normal brain receiving ≥12 Gy (V12Gy ). Quality assurance measurements were performed with Gafchromic EBT-XD film following an absolute dose calibration protocol. For the phantom study, the CI of MRL plans was not significantly different compared to a conventional linac (P > 0.05). The use of dynamic conformal arcs and noncoplanar beams with a conventional linac spared significantly more normal brain (P = 0.027) and maximized the CGI, as expected. The mean CGI was 95.9 ± 4.5 for TB2 vs 86.6 ± 3.7 (VR1), 88.2 ± 4.8 (VR2), and 88.5 ± 5.9 (TB1). Each method satisfied a normal brain V12Gy ≤ 10.0 cm3 planning goal for targets with diameter ≤2.25 cm. The mean V12Gy was 3.1 cm3 for TB2 vs 5.5 cm3 , 5.0 cm3 and 4.3 cm3 , for VR1, VR2, and TB1, respectively. For a 2.5-cm diameter target, only TB2 met the V12Gy planning objective. The MRL clinical brain plans were deemed acceptable for patient treatment. The normal brain V12Gy was ≤6.0 cm3 for all clinical targets (maximum target volume = 3.51 cm3 ). CI and CGI ranged from 1.12-1.65 and 81.2-88.3, respectively. Gamma analysis pass rates (3%/1mm criteria) exceeded 97.6% for six clinical targets planned and delivered on the MRL. The mean measured vs computed absolute dose difference was -0.1%. The MRL system can produce clinically acceptable brain SRS plans for spherical lesions with diameter ≤2.25 cm. Large lesions (>2.25 cm) should be treated with a linac capable of delivering noncoplanar beams.


Society of Anesthesia and Sleep Medicine Guideline on Intraoperative Management of Adult Patients With Obstructive Sleep Apnea.
The purpose of the Society of Anesthesia and Sleep Medicine Guideline on Intraoperative Management of Adult Patients With Obstructive Sleep Apnea (OSA) is to present recommendations based on current scientific evidence. This guideline seeks to address questions regarding the intraoperative care of patients with OSA, including airway management, anesthetic drug and agent effects, and choice of anesthesia type. Given the paucity of high-quality studies with regard to study design and execution in this perioperative field, recommendations were to a large part developed by subject-matter experts through consensus processes, taking into account the current scientific knowledge base and quality of evidence. This guideline may not be suitable for all clinical settings and patients and is not intended to define standards of care or absolute requirements for patient care; thus, assessment of appropriateness should be made on an individualized basis. Adherence to this guideline cannot guarantee successful outcomes, but recommendations should rather aid health care professionals and institutions to formulate plans and develop protocols for the improvement of the perioperative care of patients with OSA, considering patient-related factors, interventions, and resource availability. Given the groundwork of a comprehensive systematic literature review, these recommendations reflect the current state of knowledge and its interpretation by a group of experts at the time of publication. While periodic reevaluations of literature are needed, novel scientific evidence between updates should be taken into account. Deviations in practice from the guideline may be justifiable and should not be interpreted as a basis for claims of negligence.


Tumor-Induced Osteomalacia and the Importance of Plasma Fibroblast Growth Factor 23 as an Indicator: Diagnostic Delay Leads to a Suicide Attempt.
Tumor-induced osteomalacia is a rare hypophosphatemic disease caused by unregulated production of fibroblast growth factor 23 by a tumor, thereby inducing renal phosphate wasting and inhibiting appropriate increase of calcitriol production. Symptoms of tumor-induced osteomalacia, including muscle weakness, bone pain, and pathologic fractures, are nonspecific and warrant further workup. We report the case of a 50-year-old African American female with no known psychiatric illness who was admitted after a failed suicide attempt provoked by severe bone pain. She had been treated for fibromyalgia and hypophosphatemic rickets at other facilities with no improvement. The findings of profound renal phosphate wasting initiated further evaluation, which revealed an elevated fibroblast growth factor 23 level and a right proximal fibular mesenchymal tumor on octreotide scintigraphy. Magnetic resonance imaging confirmed the findings of a solid intramuscular tumor corresponding to the octreotide avid lesion. After wide excision of the tumor, serum phosphate and parathyroid hormone levels began to normalize. This case highlights the importance of extensively investigating the cause of bone pain, weakness, and fatigue in patients without a family history of hypophosphatemia or bone disorders. The aforementioned symptoms may precede recurrent pathological fractures, and a thorough workup ensures that a diagnosis of tumor is not delayed or overlooked, as tumor resection confers a favorable prognosis and dramatic increase in the quality of life for patients.


The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory.
Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with the development of anxiety, depression and cognitive function linked to mechanisms of emotional learning and memory. In rodents fear conditioning and passive avoidance (PA) are associative learning paradigms to study emotional memory. This review assesses the role of 5-HT1AR and 5-HT7R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT1ARs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT1AR facilitates memory retention possibly via 5-HT7R activation and evidence is provided that 5HT7R can facilitate emotional memory upon reduced 5-HT1AR transmission. These findings highlight the differential role of these 5-HTRs in cognitive/emotional domains of behavior. Moreover, the results indicate that tonic and phasic 5-HT release can exert different and potentially opposing effects on emotional memory, depending on the states of 5-HT1ARs and 5-HT7Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role for the responsiveness to drug treatment, e.g., by SSRIs which increase intrasynaptic 5-HT levels thereby activating multiple pre- and postsynaptic 5-HTR subtypes.


Activation of lysosomal cathepsins in pregnant bovine leukocytes.
In ruminants, interferon-tau (IFNT)-mediated expression of interferon-stimulated genes in peripheral blood leukocytes (PBLs) can indicate pregnancy. Recently, type 1 IFN-mediated activation of lysosomes and lysosomal cathepsins (CTSs) was observed in immune cells. This study investigated the status of lysosomal CTSs and lysosomes in PBLs collected from pregnant (P) and non-pregnant (NP) dairy cows, and conducted in vitro IFNT stimulation of NP blood leukocytes. Blood samples were collected 0, 7, 14 and 18 days post-artificial insemination, and the peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs) separated. The fluorescent activity of CTSB and CTSK in PMNs significantly increased with the progress of pregnancy, especially on day 18. In vitro supplementation of IFNT significantly increased the activities of CTSB and CTSK in NP PBMCs and PMNs. CTSB expression was significantly higher in PBMCs and PMNs collected from P day-18 cows than from NP cows, whereas there was no difference in CTSK expression. IFNT increased CTSB expression but did not affect CTSK expression. Immunodetection showed an increase of CTSB in P day-18 PBMCs and PMNs. In vitro stimulation of IFNT increased CTSB in NP PBMCs and PMNs. Lysosomal acidification showed a significant increase in P day-18 PBMCs and PMNs. IFNT also stimulated lysosomal acidification. Expressions of lysosome-associated membrane protein (LAMP) 1 and LAMP2 were significantly higher in P day-18 PBMCs and PMNs. The results suggest that pregnancy-specific activation of lysosomal functions by CTS activation in blood leukocytes is highly associated with IFNT during maternal and fetal recognition of pregnancy.


A well-connected and conserved nucleoplasmic helicase is required for production of box C/D and H/ACA snoRNAs and localization of snoRNP proteins.
Biogenesis of small nucleolar RNA-protein complexes (snoRNPs) consists of synthesis of the snoRNA and protein components, snoRNP assembly, and localization to the nucleolus. Recently, two nucleoplasmic proteins from mice were observed to bind to a model box C/D snoRNA in vitro, suggesting that they function at an early stage in snoRNP biogenesis. Both proteins have been described in other contexts. The proteins, called p50 and p55 in the snoRNA binding study, are highly conserved and related to each other. Both have Walker A and B motifs characteristic of ATP- and GTP-binding and nucleoside triphosphate-hydrolyzing domains, and the mammalian orthologs have DNA helicase activity in vitro. Here, we report that the Saccharomyces cerevisiae ortholog of p50 (Rvb2, Tih2p, and other names) is required for production of C/D snoRNAs in vivo and, surprisingly, H/ACA snoRNAs as well. Point mutations in the Walker A and B motifs cause temperature-sensitive or lethal growth phenotypes and severe defects in snoRNA accumulation. Notably, depletion of p50 (called Rvb2 in this study) also impairs localization of C/D and H/ACA core snoRNP proteins Nop1p and Gar1p, suggesting a defect(s) in snoRNP assembly or trafficking to the nucleolus. Findings from other studies link Rvb2 orthologs with chromatin remodeling and transcription. Taken together, the present results indicate that Rvb2 is involved in an early stage of snoRNP biogenesis and may play a role in coupling snoRNA synthesis with snoRNP assembly and localization.


#MedEd: exploring the relationship between altmetrics and traditional measures of dissemination in health professions education.
Researchers, funders, and institutions are interested in understanding and quantifying research dissemination and impact, particularly related to communicating with the public. Traditionally, citations have been a primary impact measure; however, citations can be slow to accrue and focus on academic use. Recently altmetrics, which track alternate dissemination forms (e. g., social media), have been suggested as a complement to citation-based metrics. This study examines the relationship between altmetrics and traditional measures: journal article citations and access counts. The researchers queried Web of Science and Altmetric Explorer for articles published in HPE journals between 2013-2015. They identified 2,486 articles with altmetrics. Data were analyzed using negative binomial and linear regression models. Blogging was associated with the greatest increase in citations (13% increase), whereas Tweets (1.2%) and Mendeley (1%) were associated with smaller increases. Journal impact factor (JIF) was associated with a 21% increase in citations. Publicly accessible articles were associated with a 19% decrease, but the interactive effect between accessible articles and JIF was associated with a 12% increase. When examining access counts, publicly accessible articles had an increase of 170 access counts whereas blogging was associated with a decrease of 87 accesses. This study suggests that several altmetrics outlets are positively associated with citations, and that public accessibility, holding all other independent variables constant, is positively related to article access. Given the scientific community's evolving focus on dissemination these findings have implications for stakeholders, providing insight into the factors that may improve citations and access of articles.


Antibacterial activity of berry juices, an in vitro study.
The aim of the present study was to evaluate in vitro antibacterial activities of blackcurrant and sea buckthorn juices on bacteria associated with gingival inflammation. The growth of selected bacteria (Streptococcus mitis, Streptococcus mutans, Streptococcus sanguinis, Streptococcus gordonii, Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa) was studied in vitro on agar plates. The content of phenols in the different extracts was measured with HPLC-ESI-MS. The spectrometric analysis identified that the highest level of the single phenols studied was found for ferulic acid (113 μg/ml) in blackcurrant juice. Sea buckthorn contained low levels of selected phenols. Total bacterial inhibition for all bacterial species studied was found at 20% berry juice concentration with pH varying between 4.1-5.4. The present study identified that in vitro bacterial growth on agar plates was inhibited by blackcurrant and sea buckthorn juices and that low juice pH explains bacterial in vitro growth. This may have clinical implications in biofilm development, reducing the risks for both tooth decay and gingivitis.


Testing of a new one-stage bone-transport surgical procedure exploiting the periosteum for the repair of long-bone defects.
A recently proposed one-stage bone-transport surgical procedure exploits the intrinsic osteogenic potential of the periosteum while providing mechanical stability through intramedullary nailing. The objective of this study was to assess the efficacy of this technique to bridge massive long-bone defects in a single stage. With use of an ovine femoral model, an in situ periosteal sleeve was elevated circumferentially from healthy diaphyseal bone, which was osteotomized and transported over an intramedullary nail into a 2.54-cm (1-in) critical-sized diaphyseal defect. The defect-bridging and bone-regenerating capacity of the procedure were tested in five groups of seven animals each, which were defined by the absence (Group 1; control) or presence of the periosteal sleeve alone (Group 2), bone graft within the periosteal sleeve (Groups 3 and 5), as well as retention of adherent, vascularized cortical bone chips on the periosteal sleeve with or without bone graft (Groups 4 and 5). The efficacy of the procedure was assessed qualitatively and quantitatively. At sixteen weeks, osseous bridging of the defect was observed in all twenty-eight experimental sheep in which the periosteal sleeve was retained; the defect persisted in the remaining seven control sheep. Among the experimental groups 2 through 5, significant differences were observed in the density of the regenerated bone tissue; the two groups in which vascularized bone chips adhered to the inner surface of the periosteal sleeve (Groups 4 and 5) showed a higher mean bone density in the defect zone (p < 0.02) than did the other groups. In these two groups with the highest bone density, the addition of bone graft was associated with a significantly lower callus density than that observed without bone graft (p < 0.05). The volume of regenerate bone (p < 0.02) was significantly greater in the groups in which the periosteal sleeve was retained than it was in the control group. Among the experimental groups (groups 2 through 5), however, with the numbers studied, no significant differences in the volume of regenerate bone could be attributed to the inclusion of bone graft within the sleeve or to vascularized bone chips remaining adherent to the periosteum. The novel surgical procedure was shown to be effective in bridging a critical-sized defect in an ovine femoral model. Vascularized bone chips adherent to the inner surface of the periosteal sleeve, without the addition of morselized cancellous bone graft within the sleeve, provide not only a comparable volume of regenerate bone and composite tissue (callus and bone) but also a superior density of regenerate bone compared with that after the addition of bone graft.


Experimental study on calcium carbonate precipitation using electromagnetic field treatment.
The present study investigated the effectiveness of electromagnetic fields in preventing calcium carbonate (CaCO₃) fouling in cooling water. Four different frequencies and two different voltages were adopted to induce electromagnetic fields directly in water with constant water temperature and constant flow velocity. Artificial hard water was used. The solution conductivities decreased by 17-25% from their initial values in the electromagnetic anti-fouling treatment (EAT) cases, depending on different frequencies of electric pulses, whereas the untreated case dropped by 31%. The particle size became small and the crystal structure changed into loose style after EAT. The EAT device independently developed by the State Key Laboratory had been validated as an effective apparatus in preventing CaCO₃ fouling in cooling water.


Masculinity and sexual practices in the military: a South African study.
The military's organisational culture tends to condone or encourage risk-taking behaviour. Willingness to accept and engage in risk-taking behaviour is central to good soldiering and is strongly associated with readiness for combat. This core attribute of military culture might predispose soldiers to engage in other higher-risk behaviours, such as unprotected sex. Soldiers' working and living conditions, such as the high level of work-related stress in combat and deployment situations, and being away from home and particularly from partners for long periods, are reported as contributing to high levels of HIV in military groups. This article explores the underlying value system in the military context as a strong enabler of higher-risk sexual practices among male soldiers. This not only obstructs gender equality in the military organisation but also impacts on the prevalence of HIV. The article derives from a qualitative study of a diverse sample of 23-33-year-old male South African soldiers. Semi-structured interviews were conducted with 14 fulltime soldiers and the interview transcripts were analysed through interpretive discourse analysis. The findings highlight that when soldiers are on deployment or attending military courses they are often tempted to engage in higher-risk sexual behaviours. Underlying this narrative are patriarchal notions that men 'need' sex and cannot endure being without it, and that they have the right therefore to demand it from their partner or to seek it from multiple partners. Male soldiers' sexual practices appear to be rationalised predominantly on the basis of the 'male sexual drive' discourse. The research found an association between work in the military and higher-risk sexual activity. Therefore, we argue that tackling HIV in the military demands critical examination of the constructions of masculinity.


Peptide leukotriene receptor antagonism in myocardial ischaemia and reperfusion.
The aim was to investigate the role of peptide leukotrienes in the pathophysiology of myocardial injury during reperfusion of previously ischaemic myocardium. Adult male cats (2.9-5.4 kg) were subjected to left anterior descending coronary artery occlusion for 3 h followed by 3 h of reperfusion. The peptide leukotriene receptor antagonist, LY-171883, was given intravenously only during the reperfusion period (3 mg.kg-1 bolus; 3 mg.kg-1 x h-1 infusion). Ischaemic injury was assessed by nitroblue tetrazolium staining and tissue creatine kinase activity; neutrophil infiltration was determined by myeloperoxidase activity of myocardial homogenates. There was no significant difference at any time point in the experimental protocol between mean arterial blood pressure or pressure-rate index in cats given LY-171883 (3 mg.kg-1) and cats given vehicle. The area at risk of infarction (AAR) was 24(SEM 2)% for vehicle treated cats and 22(2)% for the drug treated cats. The necrotic area was 48(5)% of the AAR for the vehicle group but only 29(5)% of the AAR for the group given LY-171883 (p < 0.02). Left ventricular maximum +dP/dt tended to be higher with drug treatment compared to vehicle at the end of the reperfusion period. Tissue from the area at risk was assayed for creatine kinase activity and neutrophil specific myeloperoxidase activity as an index of the accumulation of neutrophils in this region. Creatine kinase activity was significantly higher (p < 0.05) in the AAR for drug nu vehicle treated cats following reperfusion, confirming the histochemical analysis. Myeloperoxidase activity increased approximately 12-fold in the AAR of cats receiving vehicle. LY-171883 did not reduce the myeloperoxidase activity significantly in the area at risk. LY-171883 has a protective effect in ischaemia-reperfusion injury to the myocardium. These findings suggest a role for peptide leukotrienes both in the extension of ischaemic damage and in post-ischaemic ventricular dysfunction during reperfusion.


New diagnostic criteria of adrenal subclinical Cushing's syndrome: opinion from the Japan Endocrine Society.
New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 μg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 μg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 μg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 μg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 μg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 μg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging.


Human EML4, a novel member of the EMAP family, is essential for microtubule formation.
Human EML4 (EMAP-like protein 4) is a novel microtubule-associated WD-repeat protein of 120 kDa molecular weight, which is classified as belonging to the conserved family of EMAP-like proteins. Cosedimentation assays demonstrated that EML4 associates with in vitro polymerized microtubules. Correspondingly, immunofluorescence stainings and transient expression of EGFP-labeled EML4 revealed a complete colocalization of EML4 with the interphase microtubule array of HeLa cells. We present evidence that the amino-terminal portion of EML4 (amino acids 1-249) is essential for the association with microtubules. Immunoprecipitation experiments revealed that EML4 is hyperphosphorylated on serine/threonine residues during mitosis. In addition, immunofluorescence stainings demonstrated that hyperphosphorylated EML4 is associated with the mitotic spindle, suggesting that the function of EML4 is regulated by phosphorylation. siRNA-mediated knockdown of EML4 in HeLa cells led to a significant decrease in the number of cells. In no case mitotic figures could be observed in EML4 negative HeLa cells. Additionally, we observed a significant reduction of the proliferation rate and the uptake of radioactive [3H]-thymidine as a result of EML4 silencing. Most importantly, EML4 negative cells showed a completely modified microtubule network, indicating that EML4 is necessary for correct microtubule formation.


Hypothalamic--pituitary-- adrenal axis dysregulation in women with irritable bowel syndrome in response to acute physical stress.
Irritable bowel syndrome (IBS) supports the concept of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. This study investigates the neuroendocrine and psychological responses to the acute physical stress of a lumbar puncture (LP) in women with diarrhea-predominant IBS by assessing central and peripheral HPA activity and affective measures. Blood samples have been collected at baseline and immediately post- and 1 hr following LP from 13 women with IBS and 13 controls. Plasma adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine levels are analyzed. A single measure of cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF(CSF)) and norepinephrine(CSF) is noted. Affective assessments are used to rate anxiety and depression with the Hospital Anxiety and Depression Scale (HADS) and acute mood state is rated using the Stress Symptom Rating questionnaire (stress, anxiety, anger, arousal). The women with IBS display blunted ACTH and cortisol responses to the LP along with a profile of affective responsiveness suggestive of chronic psychosocial stress, although no CRF(CSF) differences between groups are observed.


Smooth muscle cell proliferation and restenosis after stand alone coronary excimer laser angioplasty.
It has been shown that coronary excimer laser angioplasty can remove atherosclerotic intracoronary tissue. Stand alone coronary excimer laser angioplasty was successfully performed in a 53 year old white man with 90% stenosis of the left anterior descending coronary artery and exertional angina (Canadian Cardiovascular Society class III). The lesion was reduced to a 30% residual stenosis with use of a 1.2 mm and subsequently a 1.8 mm diameter laser catheter. Early follow-up angiography 24 h later revealed persistent patency and unchanged lesion diameter of the target vessel. The patient was free of symptoms during the 2 month follow-up period, but died suddenly while playing in a tennis tournament 63 days after the procedure. Postmortem histologic examination revealed 80% restenosis at the lesion site without plaque disruption or thrombosis. Specific staining of the histologic specimen for smooth muscle cells using alpha-actin revealed significant smooth muscle cell proliferation at the site of coronary excimer laser angioplasty. However, most of the vessel narrowing appeared to be due to underlying fibrotic plaque as a result of insufficient tissue ablation. This was probably related to the size of the currently available catheters, which are too small to create a large channel.


Financing equitable access to antiretroviral treatment in South Africa.
While South Africa spends approximately 7.4% of GDP on healthcare, only 43% of these funds are spent in the public system, which is tasked with the provision of care to the majority of the population including a large proportion of those in need of antiretroviral treatment (ART). South Africa is currently debating the introduction of a National Health Insurance (NHI) system. Because such a universal health system could mean increased public healthcare funding and improved access to human resources, it could improve the sustainability of ART provision. This paper considers the minimum resources that would be required to achieve the proposed universal health system and contrasts these with the costs of scaled up access to ART between 2010 and 2020. The costs of ART and universal coverage (UC) are assessed through multiplying unit costs, utilization and estimates of the population in need during each year of the planning cycle. Costs are from the provider's perspective reflected in real 2007 prices. The annual costs of providing ART increase from US$1 billion in 2010 to US$3.6 billion in 2020. If increases in funding to public healthcare only keep pace with projected real GDP growth, then close to 30% of these resources would be required for ART by 2020. However, an increase in the public healthcare resource envelope from 3.2% to 5%-6% of GDP would be sufficient to finance both ART and other services under a universal system (if based on a largely public sector model) and the annual costs of ART would not exceed 15% of the universal health system budget. Responding to the HIV-epidemic is one of the many challenges currently facing South Africa. Whether this response becomes a "resource for democracy" or whether it undermines social cohesiveness within poor communities and between rich and poor communities will be partially determined by the steps that are taken during the next ten years. While the introduction of a universal system will be complex, it could generate a health system responsive to the needs of all South Africans.


Novel insights into the pervasive role of RNA structure in post-transcriptional regulation of gene expression in plants.
RNA folding is an intrinsic property of RNA that serves a key role in every step of post-transcriptional regulation of gene expression, from RNA maturation to translation in plants. Recent developments of genome-wide RNA structure profiling methods have transformed research in this area enabling focus to shift from individual molecules to the study of tens of thousands of RNAs. Here, we provide a comprehensive review of recent advances in the field. We discuss these new insights of RNA structure functionality within the context of post-transcriptional regulation including mRNA maturation, translation, and RNA degradation in plants. Notably, we also provide an overview of how plants exhibit different RNA structures in response to environmental changes.


Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation.
Ultraviolet (UV) light induces DNA-damage checkpoints and mutagenesis, which are involved in cancer protection and tumorigenesis, respectively. How cells identify DNA lesions and convert them to checkpoint-activating structures is a major question. We show that during repair of UV lesions in noncycling cells, Exo1-mediated processing of nucleotide excision repair (NER) intermediates competes with repair DNA synthesis. Impediments of the refilling reaction allow Exo1 to generate extended ssDNA gaps, detectable by electron microscopy, which drive Mec1 kinase activation and will be refilled by long-patch repair synthesis, as shown by DNA combing. We provide evidence that this mechanism may be stimulated by closely opposing UV lesions, represents a strategy to redirect problematic repair intermediates to alternative repair pathways, and may also be extended to physically different DNA damages. Our work has significant implications for understanding the coordination between repair of DNA lesions and checkpoint pathways to preserve genome stability.


Using institutional theory to analyse hospital responses to external demands for finance and quality in five European countries.
Given the impact of the global economic crisis, delivering better health care with limited finance grows more challenging. Through the lens of institutional theory, this paper explores pressures experienced by hospital leaders to improve quality and constrain spending, focusing on how they respond to these often competing demands. An in-depth, multilevel analysis of health care quality policies and practices in five European countries including longitudinal case studies in a purposive sample of ten hospitals. How hospitals responded to the financial and quality challenges was dependent upon three factors: the coherence of demands from external institutions; managerial competence to align external demands with an overall quality improvement strategy, and managerial stability. Hospital leaders used diverse strategies and practices to manage conflicting external pressures. The development of hospital leaders' skills in translating external requirements into implementation plans with internal support is a complex, but crucial, task, if quality is to remain a priority during times of austerity. Increasing quality improvement skills within a hospital, developing a culture where quality improvement becomes embedded and linking cost reduction measures to improving care are all required.


Genomic imprinting mediates dosage compensation in a young plant XY system.
Sex chromosomes have repeatedly evolved from a pair of autosomes. Consequently, X and Y chromosomes initially have similar gene content, but ongoing Y degeneration leads to reduced expression and eventual loss of Y genes1. The resulting imbalance in gene expression between Y genes and the rest of the genome is expected to reduce male fitness, especially when protein networks have components from both autosomes and sex chromosomes. A diverse set of dosage compensating mechanisms that alleviates these negative effects has been described in animals2-4. However, the early steps in the evolution of dosage compensation remain unknown, and dosage compensation is poorly understood in plants5. Here, we describe a dosage compensation mechanism in the evolutionarily young XY sex determination system of the plant Silene latifolia. Genomic imprinting results in higher expression from the maternal X chromosome in both males and females. This compensates for reduced Y expression in males, but results in X overexpression in females and may be detrimental. It could represent a transient early stage in the evolution of dosage compensation. Our finding has striking resemblance to the first stage proposed by Ohno6 for the evolution of X inactivation in mammals.


Growth-dependent podocyte failure causes glomerulosclerosis.
Podocyte depletion leads to glomerulosclerosis, but whether an impaired capacity of podocytes to respond to hypertrophic stress also causes glomerulosclerosis is unknown. We generated transgenic Fischer 344 rats that express a dominant negative AA-4E-BP1 transgene driven by the podocin promoter; a member of the mammalian target of rapamycin complex 1 (mTORC1) pathway, 4E-BP1 modulates cap-dependent translation, which is a key determinant of a cell's hypertrophic response to nutrients and growth factors. AA-4E-BP1 rat podocytes expressed the transgene and had normal kidney histology and protein excretion at 100 g of body weight but developed ESRD by 12 months. Proteinuria and glomerulosclerosis were linearly related to both increasing body weight and transgene dose. Uni-nephrectomy reduced the body weight at which proteinuria first developed by 40%-50%. The initial histologic manifestation of disease was the appearance of bare areas of glomerular basement membrane from the pulling apart of podocyte foot processes, followed by adhesions to the Bowman capsule. Morphometric analysis confirmed the mismatch between glomerular tuft volume and total podocyte volume (number × size) per tuft in relation to weight gain and nephrectomy. Proteinuria and glomerulosclerosis did not develop if dietary calorie restriction prevented weight gain and glomerular enlargement. In summary, failure of podocytes to match glomerular tuft growth in response to growth signaling through the mTORC1 pathway can trigger proteinuria, glomerulosclerosis, and progression to ESRD. Reducing body weight and glomerular growth may be useful adjunctive therapies to slow or prevent progression to ESRD.


Immunosuppressive therapy for pemphigus vulgaris complicated by malakoplakia of the bladder.
Pemphigus vulgaris is an uncommon auto-immune disease which responds well to treatment with corticosteroids and azathioprine. Malakoplakia is a rare granulomatous disease associated with coliform infections and an altered cellular immune response. We report a 68-year-old female patient with pemphigus vulgaris who, after 2 years on maintenance prednisone and azathioprine immunotherapy, developed malakoplakia of the bladder associated with chronic E. coli urinary-tract infection. The malakoplakia responded well to treatment with cotrimoxazole, bethanechol chloride and ascorbic acid, combined with tapering of the corticosteroid dosage. Our patient presents an uncommon but interesting complication of long-term immunosuppressive therapy for pemphigus vulgaris.


New antiepileptic drugs: comparison of key clinical trials.
Data accrued from clinical trials of five new antiepileptic drugs (AEDs) are compared for efficacy in reducing seizures and self-reported adverse events as a basis of selection among new AEDs. Drawbacks to use of these data also are demonstrated. A review of double-blind, placebo-controlled clinical trials of a new AED or placebo added to a standard AED provided data on reduction of complex partial seizures (CPSs). Success is > or =50% fewer CPSs with a new AED or placebo; Overall Improvement is the success rate with drug minus the success rate with placebo. Adverse events were tabulated from product-labeling lists of COSTART items (incidence, > or =5%). The Summary Complaint score is the total number of reports of individual events for each AED. Efficacy data demonstrate differences in Overall Improvement rates among five new AEDs and placebos (p = 0.001). However, rates of response to placebo also differed significantly among trials (p = 0.01). Adverse events predominantly affect central nervous system, psychiatric, and general body systems. However, patients in the placebo control groups did not consistently report adverse effects. Summary Complaint scores differ among the five new AEDs, but variability in use of COSTART terms nullifies comparisons. Comparisons of data for five new AEDs provide information for selection among treatments when a second drug is needed to improve control of CPSs. However, significant differences among the control groups and other problems make comparisons between trials problematic. The final choice should be based on the need of the individual patient for superior seizure control versus minimal adverse effects.


Increase of adipose tissue lipoprotein lipase activity with weight loss.
Obese subjects have elevated adipose tissue lipoprotein lipase activity per fat cell when compared with lean control subjects. This enzyme, which is rate limiting for the uptake and storage of lipoprotein triglyceride in adipose tissue, has been shown to be further elevated in a group of previously obese subjects who had been weight stable at a reduced weight for 4-28 mo. In the present prospective study of eight obese subjects, adipose tissue lipoprotein lipase activity was demonstrated to increase after weight stabilization at a reduced weight (0.33 mU/10(6) cells). In three subjects who lost weight and subsequently regained their lost weight, the enzyme activity increased after weight loss and then returned toward the original basal level with weight gain. One subject who maintained his weight loss for 10 mo. continued to have an elevated level of enzyme activity. Because adipose tissue lipoprotein lipase activity does not "normalize" after weight loss, we hypothesize that this enzyme may play a counterregulatory role in resisting deviation from a "set point" for fat mass or fat cell size and thereby predispose to reattainment of the original obese state.


Bioactive Lipid Mediators in the Initiation and Resolution of Inflammation after Spinal Cord Injury.
Neuroinflammation is a prominent feature of the response to CNS trauma. It is also an important hallmark of various neurodegenerative diseases in which inflammation contributes to the progression of pathology. Inflammation in the CNS can contribute to secondary damage and is therefore an excellent therapeutic target for a range of neurological conditions. Inflammation in the nervous system is complex and varies in its fine details in different conditions. It involves a wide variety of secreted factors such as chemokines and cytokines, cell adhesion molecules, and different cell types that include resident cell of the CNS, as well as immune cells recruited from the peripheral circulation. Added to this complexity is the fact that some aspects of inflammation are beneficial, while other aspects can induce secondary damage in the acute, subacute and chronic phases. Understanding these aspects of the inflammatory profile is essential for developing effective therapies. Bioactive lipids constitute a large group of molecules that modulate the initiation and the resolution of inflammation. Dysregulation of these bioactive lipid pathways can lead to excessive acute inflammation, and failure to resolve this by specialized pro-resolution lipid mediators can lead to the development of chronic inflammation. The focus of this review is to discuss the effects of bioactive lipids in spinal cord trauma and their potential for therapies.