"She's a dog at the end of the day": Guide dog owners' perspectives on the behaviour of their guide dog.
A guide dog is a domestic dog (Canis familiaris) that is specifically educated to provide mobility support to a blind or visually impaired owner. Current dog suitability assessments focus on behavioural traits, including: trainability, reactivity or attention to environmental stimuli, low aggressiveness, fearfulness and stress behaviour, energy levels, and attachment behaviour. The aim of this study was to find out which aspects of guide dog behaviour are of key importance to guide dog owners themselves. Sixty-three semi-structured interview surveys were carried out with guide dog owners. Topics included the behaviour of their guide dog both within and outside their working role, and also focused on examples of behaviour which might be considered outside a guide dog owner's typical expectations. Both positive and negative examples and situations were covered. This allowed for the discovery of new perspectives and emerging themes on living and working with a guide dog. Thematic analysis of the results reveals that a dog's safe behaviour in the face of traffic was the most important positive aspect of a guide dog's behaviour and pulling or high tension on the lead and /or harness was the most discussed negative aspect. Other aspects of guide dog behaviour were highlighted as particularly pleasing or disappointing by owners including attentiveness to the task, work, environment and owner; confidence in work and decision making (with confident dogs resulting in confident owners) obedience and control; calmness and locating objectives. The results reveal important areas of behaviour that are not currently considered priorities in guide dog assessments; these key areas were consistency of behaviour, the dog's maturity and the dog's behaviour in relation to children. The survey revealed a large range in what owners considered problematic or pleasing behaviours and this highlights the heterogeneity in guide dog owners and the potential multifarious roles of the guide dog. This study contributes to the literature on which behaviour is considered appropriate or inappropriate in dogs and on the nature of human-animal interactions.


The safety of vasopressor-induced hypertension in subarachnoid hemorrhage patients with coexisting unruptured, unprotected intracranial aneurysms.
Vasopressor-induced hypertension (VIH) is an established treatment for patients with aneurysmal subarachnoid hemorrhage (SAH) who develop vasospasm and delayed cerebral ischemia (DCI). However, the safety of VIH in patients with coincident, unruptured, unprotected intracranial aneurysms is uncertain. This retrospective multiinstitutional study identified 1) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who required VIH therapy (VIH group), and 2) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who did not require VIH therapy (non-VIH group). All patients had previously undergone surgical or endovascular treatment for the presumed ruptured aneurysm. Comparisons between the VIH and non-VIH patients were made in terms of the patient characteristics, clinical and radiographic severity of SAH, total number of aneurysms, number of ruptured/unruptured aneurysms, aneurysm location/size, number of unruptured and unprotected aneurysms during VIH, severity of vasospasm, degree of hypervolemia, and degree and duration of VIH therapy. For the VIH group (n = 176), 484 aneurysms were diagnosed, 231 aneurysms were treated, and 253 unruptured aneurysms were left unprotected during 1293 total days of VIH therapy (5.12 total years of VIH therapy for unruptured, unprotected aneurysms). For the non-VIH group (n = 73), 207 aneurysms were diagnosed, 93 aneurysms were treated, and 114 unruptured aneurysms were left unprotected. For the VIH and non-VIH groups, the mean sizes of the ruptured (7.2 ± 0.3 vs 7.8 ± 0.6 mm, respectively; p = 0.27) and unruptured (3.4 ± 0.2 vs 3.2 ± 0.2 mm, respectively; p = 0.40) aneurysms did not differ. The authors observed 1 new SAH from a previously unruptured, unprotected aneurysm in each group (1 of 176 vs 1 of 73 patients; p = 0.50). Baseline patient characteristics and comorbidities were similar between groups. While the degree of hypervolemia was similar between the VIH and non-VIH patients (fluid balance over the first 10 days of therapy: 3146.2 ± 296.4 vs 2910.5 ± 450.7 ml, respectively; p = 0.67), VIH resulted in a significant increase in mean arterial pressure (mean increase over the first 10 days of therapy relative to baseline: 125.1% ± 1.0% vs 98.2% ± 1.2%, respectively; p < 0.01) and systolic blood pressure (125.6% ± 1.1% vs. 104.1% ± 5.2%, respectively; p < 0.01). For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during VIH therapy is rare. The authors do not recommend withholding VIH therapy from these patients.


Subacute bacterial endocarditis masquerading as type III essential mixed cryoglobulinemia.
An adult man presented severely ill with vasculitis of his lower extremities and with impaired kidney function. After detailed evaluation at a local hospital, a diagnosis of essential type III cryoglobulinemia was made. High-dose steroid and cyclophosphamide therapy was begun. The patient improved dramatically. However, 6 wk later when his steroid dose was reduced to 30 mg daily, vasculitis recurred. Intensifying his immunosuppressive therapy only worsened his condition. He was than transferred to the Ohio State University Medical Center for consideration for plasmapheresis for the presumed essential type III cryoglobulinemia. However, our evaluation showed that he had bacterial endocarditis causing his type III cryoglobulinemia. When immunosuppressive drugs were stopped and antibiotics were begun, his condition resolved completely. This case illustrates the difficulty of identifying infectious causes of cryoglobulinemia and emphasizes that an initial, highly favorable response of vasculitis to immunosuppressive therapy does not exclude an infectious cause for the vasculitis.


Identification of Subsets of Enteroaggregative Escherichia coli Associated with Diarrheal Disease among Under 5 Years of Age Children from Rural Gambia.
Enteroaggregative Escherichia coli (EAEC) cause acute and persistent diarrhea, mostly in children worldwide. Outbreaks of diarrhea caused by EAEC have been described, including a large outbreak caused by a Shiga toxin expressing strain. This study investigated the association of EAEC virulence factors with diarrhea in children less than 5 years. We characterized 428 EAEC strains isolated from stool samples obtained from moderate-to-severe diarrhea cases (157) and healthy controls (217) children aged 0-59 months recruited over 3 years as part of the Global Enteric Multicenter Study (GEMS) in The Gambia. Four sets of multiplex polymerase chain reaction were applied to detect 21 EAEC-virulence genes from confirmed EAEC strains that target pCVD432 (aatA) and AAIC (aaiC). In addition, Kirby-Bauer disc diffusion antimicrobial susceptibility testing was performed on 88 EAEC strains following Clinical Laboratory Standard Institute guidelines. We observed that the plasmid-encoded enterotoxin [odds ratio (OR): 6.9, 95% confidence interval (CI): 2.06-29.20, P < 0.001], aggregative adherence fimbriae/I fimbriae (aggA) [OR: 2.2, 95% CI: 1.16-4.29, P = 0.008], and hexosyltransferase (capU) [OR: 1.9, 95% CI 1.02-3.51, P = 0.028] were associated with moderate-to-severe diarrhea among children < 12 months old but not in the older age strata (> 12 months). Our data suggest that some EAEC-virulent factors have age-specific associations with moderate-to-severe diarrhea in infants. Furthermore, our study showed that 85% and 72% of EAEC strains tested were resistant to sulphamethoxazole-trimethoprim and ampicillin, respectively. Sulphamethoxazole-trimethoprim and ampicillin are among the first-line antibiotics used for the treatment of diarrhea in The Gambia.


Effects of pre-surgical administration of prostaglandin analogs on the outcome of trabeculectomy.
For primary open angle glaucoma (POAG), laser treatment or surgery is used when the target intraocular pressure (IOP) cannot be achieved by pharmacological agents, such as prostaglandin (PG) analogs; these drugs also have varied effects. We retrospectively reviewed the medical records of 74 POAG patients (74 eyes) whose IOP was inadequately controlled by PG analogs (bimatoprost [13 eyes], latanoprost [34 eyes], tafluprost [11 eyes], and travoprost [16 eyes]) and underwent primary trabeculectomy. The proportion of patients with no recurrent IOP elevation within 24 months post-trabeculectomy was significantly (P < 0.001) lower in the bimatoprost group (31.3%) than in the latanoprost (83.2%), tafluprost (45.5%), or travoprost groups (65.6%). Deepening of the upper eyelid sulcus (DUES) was observed before trabeculectomy in 18 of 74 eyes (24.3%) treated with bimatoprost (9 eyes; 50.0%), latanoprost (3 eyes; 16.7%), tafluprost (1 eye; 5.5%) and travoprost (5 eyes; 27.8%). The proportion of patients with no recurrent IOP elevation up to 24 months post-trabeculectomy was significantly (P < 0.0001) lower in the DUES(+) group (34.7%) than in the DUES(-) group (74.3%). Multivariate stepwise logistic regression analysis, with no recurrent IOP elevation used as dependent variable, and bimatoprost, latanoprost, travoprost, tafluprost, β-blocker, carbonic anhydrase inhibitor, brimonidine, gender, age, preoperative IOP, mean deviation, duration of PG analog use before surgery, and the number of ophthalmic solutions used as independent variables, identified only bimatoprost as a significant independent factor (P = 0.0368). Thus, the outcome of trabeculectomy varied depending on the PG analog used preoperatively, and bimatoprost use was associated with a high risk of recurrent IOP elevation up to 2 years post-trabeculectomy. This may indicate that the incidence of DUES differed with the PG analog used. Patients with glaucoma who are treated with bimatoprost should be monitored for DUES, and when these patients undergo trabeculectomy, the postoperative course of IOP should be followed carefully.


Respiratory symptoms, spirometry and chronic occupational paraquat exposure.
A cross-sectional study was conducted to evaluate the relationship between respiratory health and paraquat exposure. The study population was selected from among workers at 15 Nicaraguan banana plantations which relied on paraquat for the control of weeds. All the workers were interviewed after they received their job assignment for the day of the survey, and all who reported never having applied paraquat and all who reported more than 2 years of cumulative exposure as applicators of paraquat with knapsack sprayers were invited for medical evaluation. One hundred and thirty-four exposed workers and 152 unexposed workers were administered a questionnaire interview asking about exposure and respiratory symptoms, and they underwent spirometric testing of forced expiratory volume in 1 s (FEV1.0) and forced vital capacity (FVC). In the exposed group 53% reported having experienced a skin rash or burn resulting from paraquat exposure, 25% reported epistaxis, 58% nail damage, and 42% paraquat splashed in the eyes. There was a consistent dose-response relationship between intensity of exposure (as indicated by a history of skin rash or burn) and the prevalence of dyspnea. This relationship was more marked for more severe dyspnea. There was a 3-fold increase in episodic wheezing accompanied by shortness of breath among the more intensely exposed workers. There was no relationship between exposure and FEV1.0 or FVC. The high prevalence of respiratory symptoms associated with exposure, in the absence of spirometric abnormalities associated with exposure, could be a result of unmeasured gas exchange abnormalities among workers with long-term exposure to paraquat.


Minimal intensity conditioning strategies for bone marrow failure: is it time for "preventative" transplants?
Hematopoietic cell transplantation (HCT) can cure blood dyscrasias and reduce the risk of hematologic cancers in patients with inherited bone marrow failure syndromes (IBMFS). However, because of its high mortality rate, HCT is generally reserved until patients with IBMFS manifest life-threatening cytopenias or myeloid malignancy, at which point outcomes are poor. Screening tests that accurately predict transformation and enable timely intervention are lacking. These unknowns and risks limit the use of HCT in patients with IBMFS, sometimes until significant disease-related sequelae have occurred. A major goal for IBMFS is to reduce cellular therapy-related complications to the point that earlier intervention can be considered before significant transfusion exposure, occurrence of comorbidities, or malignant transformation. In recent decades, disease-specific allogeneic HCT trials have yielded significant improvements in outcomes in IBMFS conditions, including Fanconi anemia and dyskeratosis congenita. This is in large part due to marked reductions in conditioning intensity to address the increased sensitivity of these patients to cytotoxic chemotherapy and radiation. The success of these approaches may also indicate an ability to leverage intrinsic fitness defects of hematopoietic stem and progenitor cells across IBMFS disorders. Now with advances in tracking somatic genetic evolution in hematopoiesis and tailored minimal intensity conditioning regimens, this question arises: is it time for preventative HCT for IBMFS?


Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.
The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.


The significance of spleen size in children with sickle cell anemia.
It is well established that splenic dysfunction occurs in early childhood in sickle cell anemia (SCA), although the determinants and consequences of splenic injury are not fully understood. In this study, we examined spleen size and splenic function in 100 children with SCA aged 0-16 years at King's College Hospital in London. Spleen size was assessed by abdominal ultrasound (US) and splenic function by pitted red blood cells (PIT counts). In our cohort, 5.6% of children aged 6-10 years and 19.4% of children aged 11-16 years had no visible spleen on US (autosplenectomy). Splenomegaly was common in all age groups, with 28% of children overall having larger spleens than the average for their age. Only one child had a PIT count suggesting preserved splenic function. We found no correlation between hemoglobin F levels and spleen size, nor was there any difference in spleen size between children treated with or without hydroxyurea. Although there was a trend toward increased spleen length in children with co-inherited α-thalassemia, this did not reach statistical significance. Finally, we found a strong association between erythrocyte deformability measured with oxygen gradient ektacytometry, spleen size, and PIT counts. In conclusion, our results do not agree with the general perception that most children with SCA undergo autosplenectomy within the first decade of life and indicate that loss of erythrocyte deformability contributes to loss of splenic filtration capacity in SCA, as well as phenotypical variations in spleen size.


Epidemiology of HIV infection in large urban areas in the United States.
While the U.S. HIV epidemic continues to be primarily concentrated in urban area, local epidemiologic profiles may differ and require different approaches in prevention and treatment efforts. We describe the epidemiology of HIV in large urban areas with the highest HIV burden. We used data from national HIV surveillance for 12 metropolitan statistical areas (MSAs) to determine disparities in HIV diagnoses and prevalence and changes over time. Overall, 0.3% to 1% of the MSA populations were living with HIV at the end of 2007. In each MSA, prevalence was >1% among blacks; prevalence was >2% in Miami, New York, and Baltimore. Among Hispanics, prevalence was >1% in New York and Philadelphia. The relative percentage differences in 2007 HIV diagnosis rates, compared to whites, ranged from 239 (San Francisco) to 1239 (Baltimore) for blacks and from 15 (Miami) to 413 (Philadelphia) for Hispanics. The epidemic remains concentrated, with more than 50% of HIV diagnoses in 2007 attributed to male-to-male sexual contact in 7 of the 12 MSAs; heterosexual transmission surpassed or equaled male-to-male sexual transmission in Baltimore, Philadelphia, and Washington, DC. Yet in several MSAs, including Baltimore and Washington, DC, AIDS diagnoses increased among men-who-have sex with men in recent years. These data are useful to identify local drivers of the epidemic and to tailor public health efforts for treatment and prevention services for people living with HIV.


Genetic Evidence for a Long-Range Activity That Directs Pollen Tube Guidance in Arabidopsis.
The fertilization process of plants is governed by different kinds of cell-cell interactions. In higher plants, these interactions are required both for recognition of the pollen grain by the female reproductive system and to direct the growth of the pollen tube inside the ovary. Despite many years of study, the signaling mechanisms that guide the pollen tube toward its target, the ovule, are largely unknown. Two distinct types of principles, mechanical and chemotropic, have been suggested to account for the directed growth of the pollen tube. The first of these two types of models implies that the guidance of the pollen tube depends on the architecture and chemical properties of the female reproductive tissues, whereas the latter suggests that the ovule provides a signal for the target-directed growth of the pollen tube. To examine such a role for the ovules, we analyzed the growth path of pollen tubes in mutants defective in ovule development in Arabidopsis. The results presented here provide unique in vivo evidence for an ovule-derived, long-range activity controlling pollen tube guidance. A morphological comparison of the ovule mutants used in this study indicates that within the ovule, the haploid embryo sac plays an important role in this long-range signaling process.


Use of flow-diverting stents as salvage treatment following failed stent-assisted embolization of intracranial aneurysms.
Flow-diverting stents, including the Pipeline embolization device (PED) and Silk, have been beneficial in the treatment of aneurysms previously unable to be approached via endovascular techniques. Recurrent aneurysms for which stent-assisted embolization has failed are a therapeutic challenge, given the existing intraluminal construct with continued blood flow into the aneurysm. We report our experience using flow-diverting stents in the repair of 25 aneurysms for which stent-assisted embolization had failed. Nineteen (76%) of these aneurysms at the 12-month follow-up showed improved Raymond class occlusion, with 38% being completely occluded, and all aneurysms demonstrated decreased filling. One patient developed a moderate permanent neurologic deficit. Appropriate stent sizing, proximal and distal construct coverage, and preventing flow diverter deployment between the previously deployed stent struts are important considerations to ensure wall apposition and prevention of endoleak. Flow diverters are shown to be a reasonable option for treating previously stented recurrent cerebral aneurysms.


Purification and characterization of protocatechuate 2,3-dioxygenase from Bacillus macerans: a new extradiol catecholic dioxygenase.
Protocatechuate 2,3-dioxygenase (2,3-PCD) from Bacillus macerans JJ1b has been purified to homogeneity for the first time. The enzyme catalyzes proximal extradiol ring cleavage of protocatechuate (PCA) with the attendant incorporation of both atoms of oxygen from O2. The holoenzyme has a mass of 143 +/- 7 kDa as determined by ultracentrifugation and other techniques. It is composed of four apparently identical subunits with M(r)s of 35,500, each containing one iron atom. Mössbauer spectroscopy of 57Fe-enriched enzyme showed that the irons are indistinguishable and are high spin (S = 2) Fe2+ in both the uncomplexed and substrate-bound enzyme. However, the quadrupole splitting, delta EQ, and isomer shift, delta, of the Mössbauer spectrum changed from delta EQ = 2.57 mm/s and delta = 1.29 mm/s to delta EQ = 2.73 mm/s and delta = 1.19 mm/s upon PCA binding to the enzyme, showing that the iron environment is altered when substrate is present. The enzyme was also found to bind variable and substoichiometric amounts of Mn2+, but this metal could be removed without loss of activity or stability. The inherently electron paramagnetic resonance (EPR)-silent Fe2+ of the enzyme reversibly bound nitric oxide to produce an EPR-active species (g = 4.11, 3.95; S = 3/2). The specific activity of the enzyme was found to be correlated with the amount of the S = 3/2 species formed, showing that activity is dependent on Fe2+. Anaerobic addition of substrates to the enzyme-nitric oxide complex significantly altered the EPR spectrum, suggesting that substrates bind to or near the iron. The enzyme was inactivated by reagents that oxidize the Fe2+, such as H2O2 and K3FE(CN)6; full activity was restored after reduction of the iron by ascorbate. Steady-state kinetic data were found to be consistent with an ordered bi-uni mechanism in which the organic substrate must add to 2,3-PCD before O2. The enzyme has the broadest substrate range of any of the well-studied catecholic dioxygenases. All substrates have vicinal hydroxyl groups on the aromatic ring except 4-NH2-3-hydroxybenzoate. This is the first substrate lacking vicinal hydroxyl groups reported for catecholic extradiol dioxygenases. 2,3-PCD is the final member of the PCA dioxygenase family to be purified. It is compared with other members of this family as well as other catecholic dioxygenases.


Orientational ordering of water in extended hydration shells of cations is ion-specific and is correlated directly with viscosity and hydration free energy.
Specific ion effects in aqueous solutions are investigated at the molecular, nanoscopic and macroscopic levels. Femtosecond elastic second harmonic scattering (fs-ESHS) is used here to assess the chemical effects of ions on molecular and nanoscopic length scales of water, probing changes in the charge distribution around ions as well as structural orientational order of water molecules in extended hydration shells. We measured >0.05 M electrolyte solutions with a series of chloride salts (LiCl, NaCl, KCl, CsCl, RbCl, NH4Cl, MgCl2, CaCl2, and SrCl2). Ion specificity is observed in both the local electronic anisotropy and the nanoscopic orientational ordering of water. Both observables are influenced more by cations with larger valencies and smaller sizes and follow a direct Hofmeister trend. These ion-induced structural changes in the hydrogen-bond network of water are strongly correlated with the viscosity B-coefficient and the Gibbs free energy of hydration of ions. Such a connection between the nanoscopic and macroscopic changes provides a possibility to construct a molecular model for specific ion effects in aqueous solutions.


Analysis of silencing escape of tomato leaf curl virus: an evaluation of the role of DNA methylation.
RNA silencing is a sequence-specific mechanism regulating gene expression and has been used successfully for antiviral defense against RNA viruses. Similar strategies to develop resistance against DNA containing Tomato leaf curl virus (TLCV) and some other geminiviruses have been unsuccessful. To analyze this silencing escape, we transformed tomato plants with a hairpin construct from the TLCV C2 open reading frame (ORF). The transgenic plants showed a strong RNA silencing response, and following TLCV inoculation, their infection was delayed. However, the viral infection was not prevented and TLCV DNA accumulated to the levels found in nontransgenic plants. To determine the fate of a transgene carrying homology to the virus, we used transgenic plants carrying the TLCV C4 gene, which induces a distinct phenotype. Upon TLCV infection, the phenotype was abolished and C4 transcript disappeared. Concurrently, TLCV-specific small interfering RNAs were produced. In situ hybridization showed abundant levels of TLCV DNA in phloem cells of TLCV-infected C4 transgenic plants. However, the C4 transcripts were no longer detectable in nonvascular cells. Analysis of the transgene by methylation sequencing revealed a high level of de novo methylation of asymmetric cytosines in both the C4 ORF and its 35S promoter. A high level of methylation also was found at both symmetric and asymmetric cytosines of the complementary-sense strand of TLCV double-stranded DNA. Given the previous finding that methylated geminiviral DNA is not competent for replication, we provide a model whereby TLCV evades host defense through a population of de novo synthesized unmethylated DNA.


Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature.
Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 °C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels.


[Insulin analogues: searching for a physiological replacement].
Insulin analogues, developed by molecular engineering, have structural changes in the A and B insulin chains. These modifications change their action profile, rendering insulin replacement closer to physiology. Rapid acting analogues like lispro, aspart and glulisine, are absorbed rapidly from the subcutaneous tissue to the circulation. In addition, two long acting insulin analogues have been developed: glargine and detemir. The combination of a long acting insulin, to maintain baseline levels, and multiple daily doses of a rapid acting analogue are the mainstay of basal-bolus therapy. Multiples studies have compared human insulin (NPH and regular) with insulin analogues in patients with type 1 or 2 diabetes mellitus, showing an improvement in the metabolic control, fewer hypoglycemic events and better quality of life. In summary, insulin analogues offer new therapeutic options and allow an individualized intensive treatment.


Acceleration-Based Kalman Tracking for Super-Resolution Ultrasound Imaging In Vivo.
Super-resolution ultrasound (SRUS) can image microvascular structure and flow at subwave-diffraction resolution based on localizing and tracking microbubbles (MBs). Currently, tracking MBs accurately under limited imaging frame rates and high MB concentrations remains a challenge, especially under the effect of cardiac pulsatility and in highly curved vessels. In this study, an acceleration-incorporated MB motion model is introduced into a Kalman tracking framework. The tracking performance was evaluated using simulated microvasculature with different MB motion parameters, concentrations, and acquisition frame rates, and in vivo human breast tumor US datasets. The simulation results show that the acceleration-based method outperformed the nonacceleration-based method at different levels of acceleration and acquisition frame rates and achieved significant improvement in true positive rate (TPR; up to 11.3%) and false negative rate (FNR; up to 13.2%). The proposed method can also reduce errors in vasculature reconstruction via the acceleration-based nonlinear interpolation, compared with linear interpolation (up to [Formula: see text]). The tracking results from temporally downsampled low frame rate in vivo datasets from human breast tumors show that the proposed method has better MB tracking performance than the baseline method, if using results from the initial high frame data as a reference. Finally, the acceleration estimated from tracking results also provides a spatial speed gradient map that may contain extra valuable diagnostic information.


Mortality in male alcoholics after ten to fourteen years.
Alcoholics frequently die prematurely. The purpose of this study was to determine: (1) whether subjects in a sample of 360 male alcoholics, followed over a period of 10-14 years, died prematurely: (2) if so, from what causes; and (3) whether such deaths are predictable from characteristics present at initial assessment. Subjects were male veterans (N = 360) with a diagnosis of alcoholism admitted to an inpatient substance abuse treatment program at the Kansas City Veterans Affairs (VA) Medical Center during 1980-1984 who consented to participate in intake evaluations and subsequent follow-ups at 1 year and 10-14 years later. Of the 357 (99.2%) men located at the 10-14 year follow-up, 96 (26.6%) were confirmed as deceased, 255 survivors agreed to be reassessed and 6 subjects refused reassessment. Information regarding cause of death was obtained from death certificates, VA records and other sources. At intake, the subsequently deceased men were older, had less education, lower psychosocial functioning, more medical problems and greater psychiatric severity. Their overall death rate was 2.5 times greater than that of a reference group of men. Men in the 35-44 year age group were 5.5 times as likely to die. A statistical model utilizing measures of alcohol dependence to predict mortality from intake to 10-14 year follow-up indicated that alcoholics who limited drinking were half as likely to die whereas those who engaged in morning drinking were 2.5 times more likely to die. Alcoholic men, especially those in the group aged 35 to 44 years, have a significantly higher risk of premature death than a reference group of men. Men who engaged in morning drinking and could not limit drinking appeared to be at higher risk of mortality 10 years later.


Serum cholesterol trajectories in the 10 years prior to lymphoma diagnosis.
Many studies suggest a role for cholesterol in cancer development. Serum cholesterol levels have been observed to be low in newly diagnosed lymphoma cases. The objective of these analyses was to examine the time-varying relationship of cholesterol with lymphomagenesis in the 10 years prior to diagnosis by lymphoma subtype. Participants were selected from the combined membership of six National Cancer Institute-funded Cancer Research Network health plans from 1998 to 2008, excluding members with human immunodeficiency virus, cancer (except lymphoma), or organ transplants. Incident lymphoma cases within this population were ascertained and matched with up to five controls. Total serum cholesterol, high-density lipoprotein, and low-density lipoprotein were collected from plan databases. Multilevel, multivariable longitudinal models were fit after choosing the best polynomial order by deviance statistics for selected lymphoma histotypes to examine pre-diagnosis cholesterol trajectories: Hodgkin lymphoma (n = 519) and all non-Hodgkin lymphomas combined (n = 12,635) as well as six subtypes of the latter. For all categories, lymphoma cases had statistically significantly lower estimated total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels than controls in the years prior to diagnosis/index date. Between-group differences were most pronounced 3-4 years prior to diagnosis, when cases' cholesterol levels declined steeply. This analysis is the first to examine changes in serum cholesterol for a decade prior to lymphoma diagnosis. A drop in cholesterol levels was evident several years before diagnosis. Our results suggest that cholesterol-related pathways have an important relationship with lymphomagenesis and low cholesterol could be a preclinical lymphoma marker.


Differential pollinator effectiveness and importance in a milkweed (Asclepias, Apocynaceae) hybrid zone.
Exceptions to the ideal of complete reproductive isolation between species are commonly encountered in diverse plant, animal, and fungal groups, but often the causative ecological processes are poorly understood. In flowering plants, the outcome of hybridization depends in part on the effectiveness of pollinators in interspecific pollen transport. In the Asclepias exaltata and A. syriaca (Apocynaceae) hybrid zone in Shenandoah National Park, Virginia, extensive introgression has been documented. The objectives of this study were to (1) determine the extent of pollinator overlap among A. exaltata, A. syriaca, and their hybrids and (2) identify the insect taxa responsible for hybridization and introgression. We observed focal plants of parental species and hybrids to measure visitation rate, visit duration, and per-visit pollinia removal and deposition, and we calculated pollinator effectiveness and importance. Visitation rates varied significantly between the 2 yr of the study. Overall, Apis mellifera, Bombus sp., and Epargyreus clarus were the most important pollinators. However, Bombus sp. was the only visitor that was observed to both remove and insert pollinia for both parent species as well as hybrids. We conclude that Bombus may be a key agent of hybridization and introgression in these sympatric milkweed populations, and hybrids are neither preferred nor selected against by pollinators. Thus, we have identified a potential mechanism for how hybrids act as bridges to gene flow between A. exaltata and A. syriaca. These results provide insights into the breakdown of prezygotic isolating mechanisms.


Geranylgeranylation but not GTP-loading of Rho GTPases determines T cell function.
Rho guanosine triphosphatases (GTPases) orchestrate signaling pathways leading to cell migration. They are typically responsible for the organization of actin filaments that support actomyosin contractility and cell-body translocation. The function of Rho GTPases depends on GTP-loading and isoprenylation by geranylgeranyl pyrophosphate (GGpp). The latter posttranslational modification may be manipulated by agents such as 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMGCRIs) that prevent de novo synthesis of isoprenoids such as GGpp. HMGCRIs have anti-inflammatory properties and substantially reduce infiltration of inflammatory immune cells into target tissues, including the central nervous system (CNS) during neuroinflammation. The depletion of the cellular isoprenoid pool is believed to result in the regulation of antigen-specific T cells outside the target organ and also to prevent migration of these cells into target organs, such as the CNS. In vivo treatment with HMGCRI in the experimental autoimmune encephalitis (EAE) rodent model of multiple sclerosis reduces the capacity of activated T cells to traffic to and within the brain. This presentation shows that geranylgeranylation is fundamental for RhoA-mediated downstream events such as influencing cytoskeletal organization and the migration of T cells. Tethering of RhoA to the membrane by GGpp is necessary for T cell migration and provides a mechanism by which HMGCRI may prevent T cell infiltration into inflamed compartments.


HIV-1 Tat-mediated apoptosis in human brain microvascular endothelial cells.
The integrity of the blood-brain barrier (BBB) is critical for normal brain function. Neuropathological abnormalities in AIDS patients have been associated with perivascular HIV-infected macrophages, gliosis, and abnormalities in the permeability of the BBB. The processes by which HIV causes these pathological conditions are not well understood. To characterize the mechanism by which HIV-1 Tat protein modulates human brain microvascular endothelial cell (HBMEC) functions, we studied the effects of HIV-1 Tat in modulating HBMEC apoptosis and permeability. Treatment of HBMEC with HIV-1 Tat led to Flk-1/KDR and Flt-4 receptor activation and the release of NO. The protein levels of endothelial NO synthase (NOS) and inducible NOS were increased by HIV-1 Tat stimulation. Importantly, HIV-1 Tat caused apoptosis of HBMEC, as evidenced by changes in the cleavage of poly(A)DP-ribose polymerase, DNA laddering, and incorporation of fluorescein into the nicked chromosomal DNA (TUNEL assay). HIV-1 Tat-mediated apoptosis in HBMEC was significantly inhibited in the presence of N-nitro-L-arginine methyl ester (an inhibitor of NOS) and wortmannin (a phosphoinositol 3-kinase inhibitor). Furthermore, HIV-1 Tat treatment significantly increased HBMEC permeability, and pretreatment with both N-nitro-L-arginine methyl ester and wortmannin inhibited the Tat-induced permeability. Taken together, these results indicate that dysregulated production of NO by HIV-1 Tat plays a pivotal role in brain endothelial injury, resulting in the irreversible loss of BBB integrity, which may lead to enhanced infiltration of virus-carrying cells across the BBB.


Life-cycle assessment of greenhouse gas emissions from dairy production in Eastern Canada: a case study.
The objective of this study was to conduct a life-cycle assessment (LCA) of greenhouse gas (GHG) emissions from a typical nongrazing dairy production system in Eastern Canada. Additionally, as dairying generates both milk and meat, this study assessed several methods of allocating emissions between these coproducts. An LCA was carried out for a simulated farm based on a typical nongrazing dairy production system in Quebec. The LCA was conducted over 6 yr, the typical lifespan of dairy cows in this province. The assessment considered 65 female Holstein calves, of which 60 heifers survived to first calving at 27 mo of age. These animals were subsequently retained for an average of 2.75 lactations. Progeny were also included in the analysis, with bulls and heifers in excess of replacement requirements finished as grain-fed veal (270 kg) at 6.5 mo of age. All cattle were housed indoors and fed forages and grains produced on the same farm. Pre-farm gate GHG emissions and removals were quantified using Holos, a whole-farm software model developed by Agriculture and Agri-Food Canada and based on the Intergovernmental Panel for Climate Change Tier 2 and 3methodologies with modifications for Canadian conditions. The LCA yielded a GHG intensity of 0.92 kg of CO(2) Eq/kg of fat- and protein-corrected milk yield. Methane (CH(4)) accounted for 56% of total emissions, with 86% originating from enteric fermentation. Nitrous oxide accounted for 40% of total GHG emissions. Lactating cows contributed 64% of total GHG emissions, whereas calves under 12 mo contributed 10% and veal calves only 3%. Allocation of GHG emissions between meat and milk were assessed as (1) 100% allocation to milk, (2) economics, (3) dairy versus veal animals, and (4) International Dairy Federation equation using feed energy demand for meat and milk production. Comparing emissions from dairy versus veal calves resulted in 97% of the emissions allocated to milk. The lowest allocation of emissions to milk (78%) was associated with the International Dairy Federation equation. This LCA showed that greatest reductions in GHG emissions would be achieved by applying mitigation strategies to reduce enteric CH(4) from the lactating cow, with minimal reductions being achievable in young stock. Choice of coproduct allocation method can also significantly affect the relative allocation of GHG emissions to milk and meat.


Intervention mapping as a guide for the development of a diabetes peer support intervention in rural Alabama.
Peer support is a promising strategy for the reduction of diabetes-related health disparities; however, few studies describe the development of such strategies in enough detail to allow for replication. The objective of this article is to describe the development of a 1-year peer support intervention to improve diabetes self-management among African American adults with diabetes in Alabama's Black Belt. We used principles of intervention mapping, including literature review, interviews with key informants, and a discussion group with community health workers, to guide intervention development. Qualitative data were combined with behavioral constructs and principles of diabetes self-management to create a peer support intervention to be delivered by trained peer advisors. Feedback from a 1-month pilot was used to modify the training and intervention. The resulting intervention includes a 2-day training for peer advisors, who were each paired with 3 to 6 clients. A one-on-one in-person needs assessment begins an intensive intervention phase conducted via telephone for 8 to 12 weeks, followed by a maintenance phase of at least once monthly contacts for the remainder of the intervention period. A peer support network and process measures collected monthly throughout the study supplement formal data collection points at baseline, 6 months, and 12 months. Intervention mapping provided a useful framework for the development of culturally relevant diabetes peer support intervention for African Americans living in Alabama's Black Belt. The process described could be implemented by others in public health to develop or adapt programs suitable for their particular community or context.


Structure of CD84 provides insight into SLAM family function.
The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. These receptors share a common ectodomain organization: a membrane-proximal immunoglobulin constant domain and a membrane-distal immunoglobulin variable domain that is responsible for ligand recognition. CD84 is a homophilic family member that enhances IFN-gamma secretion in activated T cells. Our solution studies revealed that CD84 strongly self-associates with a K(d) in the submicromolar range. These data, in combination with previous reports, demonstrate that the SLAM family homophilic affinities span at least three orders of magnitude and suggest that differences in the affinities may contribute to the distinct signaling behavior exhibited by the individual family members. The 2.0 A crystal structure of the human CD84 immunoglobulin variable domain revealed an orthogonal homophilic dimer with high similarity to the recently reported homophilic dimer of the SLAM family member NTB-A. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent the formation of undesired heterodimers among the SLAM family homophilic receptors. These structural data also suggest that, like NTB-A, all SLAM family homophilic dimers adopt a highly kinked organization spanning an end-to-end distance of approximately 140 A. This common molecular dimension provides an opportunity for all two-domain SLAM family receptors to colocalize within the immunological synapse and bridge the T cell and antigen-presenting cell.


Histone methyltransferase NSD2 mediates the survival and invasion of triple-negative breast cancer cells via stimulating ADAM9-EGFR-AKT signaling.
Triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis due to the lack of an effective targeted therapy. Histone lysine methyltransferases (KMTs) have emerged as attractive drug targets for cancer therapy. However, the function of the majority of KMTs in TNBC has remained largely unknown. In the current study, we found that KMT nuclear receptor binding SET domain protein 2 (NSD2) is overexpressed in TNBC tumors and that its overexpression is associated with poor survival of TNBC patients. NSD2 regulates TNBC cell survival and invasion and is required for tumorigenesis and tumor growth. Mechanistically, NSD2 directly controls the expression of EGFR and ADAM9, a member of the ADAM (a disintegrin and metalloproteinase) family that mediates the release of growth factors, such as HB-EGF. Through its methylase activity, NSD2 overexpression stimulates EGFR-AKT signaling and promotes TNBC cell resistance to the EGFR inhibitor gefitinib. Together, our results identify NSD2 as a major epigenetic regulator in TNBC and provide a rationale for targeting NSD2 alone or in combination with EGFR inhibitors as a targeted therapy for TNBC.


Characteristics and outcomes of patients with carcinoma in situ only at radical cystectomy.
To describe the cancer-specific outcomes of patients with pathologic carcinoma in situ (CIS) only at radical cystectomy. The records of 812 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder transitional cell carcinoma at three U.S. academic centers were reviewed. Of the 812 patients, 99 (12%) had CIS only at radical cystectomy. The distribution of clinical stage for the 99 patients with CIS only at radical cystectomy was as follows: 47% of patients had CIS only, 8% had cT1, 15% had cT1 plus CIS, 10% had cT2, 13% had cT2 plus CIS, 6% had cTa, and 1% had Ta plus CIS. Two patients had lymphovascular invasion in the radical cystectomy specimen, and three had metastases to the lymph nodes. The actuarial recurrence-free survival estimates were 89.8% (95% confidence interval [CI] 83.0% to 96.6%) at 3 years and 83.0% (95% CI 73.2% to 92.8%) at 5 and 7 years after radical cystectomy. Six patients (6%) had died of bladder cancer at analysis and 13 (13%) had died of other causes without evidence of disease recurrence. The actuarial disease-specific survival estimates were 95.8% (95% CI 91.2% to 99.9%) at 3 years, 90.7% (95% CI 82.4% to 98.9%) at 5 years, and 87.2% (95% CI 76.8% to 97.5%) at 7 years after surgery. On univariate Cox regression analyses, only metastasis to lymph nodes was associated with bladder cancer recurrence and death (P <0.001). Disease control seemed durable for patients with pathologic CIS only at radical cystectomy in the absence of metastases to the lymph nodes, even in the case of failure after intravesical therapy.


'Placement budgets' for supported employment--improving competitive employment for people with mental illness: study protocol of a multicentre randomized controlled trial.
Vocational integration of people with mental illness is poor despite their willingness to work. The 'Individual Placement and Support' (IPS) model which emphasises rapid and direct job placement and continuing support to patient and employer has proven to be the most effective vocational intervention programme. Various studies have shown that every second patient with severe mental illness was able to find competitive employment within 18 months. However, the goal of taking up employment within two months was rarely achieved. Thus, we aim to test whether the new concept of limited placement budgets increases the effectiveness of IPS. Six job coaches in six out-patients psychiatric clinics in the Canton of Zurich support unemployed patients of their clinic who seek competitive employment. Between June 2010 and May 2011 patients (N=100) are randomly assigned to three different placement budgets of 25h, 40h, or 55h working hours of job coaches. Support lasts two years for those who find a job. The intervention ends for those who fail to find competitive employment when the respective placement budgets run out. The primary outcome measure is the time between study inclusion and first competitive employment that lasted three months or longer. Over a period of three years interviews are carried out every six months to measure changes in motivation, stigmatization, social network and social support, quality of life, job satisfaction, financial situation, and health conditions. Cognitive and social-cognitive tests are conducted at baseline to control for confounding variables. This study will show whether the effectiveness of IPS can be increased by the new concept of limited placement budgets. It will also be examined whether competitive employment leads in the long term to an improvement of mental illness, to a transfer of the psychiatric support system to private and vocational networks, to an increase in financial independence, to a reduction of perceived and internalized stigma, and to an increase in quality of life and job satisfaction of the patient. In addition, factors connected with fast competitive employment and holding that job down in the long term are being examined (motivation, stigmatization, social and financial situation). ISRCTN89670872.


The diagnosis of dementia with single photon emission computed tomography.
Single photon emission computed tomography is a practical modality for the study of physiologic cerebral activity in vivo. We utilized single photon emission computed tomography and N-isopropyl-p-iodoamphetamine iodine 123 to evaluate regional cerebral blood flow in nine patients with Alzheimer's disease (AD), five healthy elderly control subjects, and two patients with multi-infarct dementia. We found that all subjects with AD demonstrated flow deficits in temporoparietal cortex bilaterally, and that the ratio of activity in bilateral temporoparietal cortex to activity in the whole slice allowed the differentiation of all patients with AD from both the controls and from the patients with multi-infarct dementia. Furthermore, this ratio showed a strong correlation with disease severity in the AD group. Single photon emission computed tomography appears to be useful in the differential diagnosis of dementia and reflects clinical features of the disease.


Personal utility in genomic testing: a systematic literature review.
Researchers and clinicians refer to outcomes of genomic testing that extend beyond clinical utility as 'personal utility'. No systematic delineation of personal utility exists, making it challenging to appreciate its scope. Identifying empirical elements of personal utility reported in the literature offers an inventory that can be subsequently ranked for its relative value by those who have undergone genomic testing. A systematic review was conducted of the peer-reviewed literature reporting non-health-related outcomes of genomic testing from 1 January 2003 to 5 August 2016. Inclusion criteria specified English language, date of publication, and presence of empirical evidence. Identified outcomes were iteratively coded into unique domains. The search returned 551 abstracts from which 31 studies met the inclusion criteria. Study populations and type of genomic testing varied. Coding resulted in 15 distinct elements of personal utility, organized into three domains related to personal outcomes: affective, cognitive, and behavioral; and one domain related to social outcomes. The domains of personal utility may inform pre-test counseling by helping patients anticipate potential value of test results beyond clinical utility. Identified elements may also inform investigations into the prevalence and importance of personal utility to future test users.


Self-Reported Eczema in Relation with Mortality from Cardiovascular Disease in Japanese: the Japan Collaborative Cohort Study.
Previous studies suggested a positive association between eczema and cardiovascular disease (CVD), probably through enhanced systemic inflammation. However, several studies reported null findings about eczema and CVD, so the evidence is still controversial. We asked 85,099 participants (35,489 men and 49,610 women), aged 40 to 79 years, without a history of CVD or cancer at baseline between 1988 and 1990, to complete a lifestyle questionnaire, including information eczema frequency (seldom, sometimes or often). During the 6,389,818 person-years of follow-up, there were 1,174 deaths from coronary heart disease (CHD), 979 from heart failure, 366 from cardiac arrhythmia, 2,454 from total stroke, 1,357 from ischemic stroke, 1,013 from hemorrhagic stroke, and 201 from aortic aneurysm or dissection. The multivariable-adjusted model showed that individuals who "sometimes" or "often" had eczema had 0.82 (95%confidence interval (CI): 0.69-0.97) or 1.26 (95%CI: 1.01-1.56) times the risk of mortality from CHD, respectively, compared to those who "seldom" did. Individuals who "often" had 1.30 (95%CI: 1.05-1.61) times the risk of mortality from CHD, compared to those who "seldom or sometimes" did. There was no association of eczema with mortality from other CVD, or no interaction between eczema and sex or age, in relation to any CVD mortality risk. Self-reported frequent eczema was associated with increased risk of mortality from CHD, but not other major CVD, in a Japanese general population. Since steroid usage was not considered, future studies should include it as a potential confounding factor.


Understanding the benefits of musical training: effects on oscillatory brain activity.
A number of studies suggest that musical training has benefits for other cognitive domains, such as language and mathematics, and studies of children and adults indicate structural as well as functional differences between the brains of musicians and nonmusicians. The induced gamma-band response has been associated with attentional, expectation, memory retrieval, and integration of top-down, bottom-up, and multisensory processes. Here we report data indicating that the induced gamma-band response to musical sounds is larger in adult musicians than in nonmusicians and that it develops in children after 1 year of musical training beginning at age 4.5 years, but not in children of this age who are not engaged in musical lessons. We conclude that musical training affects oscillatory networks in the brain associated with executive functions, and that superior executive functioning could enhance learning and performance in many cognitive domains.


Nosocomial Acinetobacter baumannii infections: microbiological and clinical epidemiology.
Acinetobacter baumannii is an important opportunistic pathogen that is rapidly evolving toward multidrug resistance and is involved in various nosocomial infections that are often severe. It is difficult to prevent A. baumannii infection because A. baumannii is ubiquitous and the epidemiology of the infections it causes is complex. To study the epidemiology of A. baumannii infections and assess the relation between fluoroquinolone use and the persistence of multidrug-resistant clones. Three case-control studies and a retrospective cohort study. A 20-bed medical and surgical intensive care unit. Acinetobacter baumannii was isolated from 45 patients in urine (31%), the lower respiratory tract (26.7%), wounds (17.8%), blood (11.1%), skin (6.7%), cerebrospinal fluid (4.4%), and sinus specimens (2.2%). One death was due to A. baumannii infection. Antimicrobial resistance pattern and molecular typing were used to characterize isolates. The incidence of A. baumannii infection and the use of fluoroquinolones were calculated annually. Initially, 28 patients developed A. baumannii infection. Eleven isolates had the same antimicrobial susceptibility profile, genotypic profile, or both (epidemic cases), and 17 were heterogeneous (endemic cases). A surgical procedure done in an emergency operating room was the main risk factor for epidemic cases, whereas previous receipt of a fluoroquinolone was the only risk factor for endemic cases. The opening of a new operating room combined with the restriction of fluoroquinolone use contributed to a transitory reduction in the incidence of infection. When a third epidemiologic study was done, previous receipt of a fluoroquinolone was again an independent risk factor and a parallel was seen between the amount of intravenous fluoroquinolones prescribed and the incidence of endemic infection. Epidemic infections coexisted with endemic infections favored by the selection pressure of intravenous fluoroquinolones.


Effects of pravastatin with niacin or magnesium on lipid levels and postprandial lipemia.
This study was designed to evaluate the therapeutic effectiveness of 3 different pharmacologic lipid-lowering regimens in the treatment of patients with clustered lipid risk factors. Sixty-five patients with low high-density lipoprotein (HDL) levels and hypertriglyceridemia were randomized to 1 of 3 treatment arms: pravastatin/niacin, pravastatin/magnesium, or pravastatin/placebo. After 18 weeks, patients in the pravastatin/niacin group had a -41% change in the total cholesterol/HDL ratio compared with -13% in the pravastatin/magnesium arm and -16% in the pravastatin/placebo group. The HDL2 and HDL3 subfractions, as well as the apolipoprotein A-I levels, were increased significantly only in the pravastatin/niacin arm. The levels of small dense low-density lipoprotein (LDL) cholesterol (LDL3) were decreased to a greater extent in the pravastatin/niacin arm (-43%) than in either the pravastatin/magnesium (-13%) or the pravastatin/placebo (-20%) arm. Only the pravastatin/niacin regimen significantly diminished postprandial lipemia (-32% change in the remnant particle triglyceride concentration and decreased very-low-density lipoprotein remnant levels). Thus, in this group of patients with clustered risk factors, the combination of pravastatin and niacin resulted in significant improvements in HDL and triglyceride levels, total cholesterol to HDL ratio, small dense LDL levels, and postprandial lipemia. Pravastatin alone or in combination with magnesium resulted in less significant changes that were largely limited to LDL cholesterol reduction.


Sirtuins in cognitive ageing and Alzheimer's disease.
Sirtuins are a family of enzymes highly conserved in evolution and involved in mechanisms known to promote healthy ageing and longevity. This review aims to discuss recent advances in understanding the role of sirtuins, in particular mammalian SIRT1, in promoting longevity and its potential molecular basis for neuroprotection against cognitive ageing and Alzheimer's disease pathology. Accumulative increase in oxidative stress during ageing has been shown to decrease SIRT1 activity in catabolic tissue, possibly by direct inactivation by reactive oxygen. SIRT1 overexpression prevents oxidative stress-induced apoptosis and increases resistance to oxidative stress through regulation of the FOXO family of forkhead transcription factors. In addition, resveratrol strongly stimulates SIRT1 deacetylase activity in a dose-dependent manner by increasing its binding affinity to both the acetylated substrate and NAD(+). Recently, SIRT1 has been shown to affect amyloid production through its influence over the ADAM10 gene. Upregulation of SIRT1 can also induce the Notch pathway and inhibit mTOR signalling. Recent studies have revealed some of the mechanisms and pathways that are associated with the neuroprotective effects of SIRT1.


Feeding and behavioral activation in infant rats.
Three-day-old rats that were separated from their mothers and deprived of food were found to be capable of feeding either from small puddles of milk or when milk was infused into the front of their mouths. Such feeding was accompanied by a dramatic increase in behavioral activity and only occurred in a warm environment. These data demonstrate that neural systems for ingestive behavior are present at birth and suggest the existence of feeding-related arousal or motivational systems.


Pectin methyl esterase inhibits intrusive and symplastic cell growth in developing wood cells of Populus.
Wood cells, unlike most other cells in plants, grow by a unique combination of intrusive and symplastic growth. Fibers grow in diameter by diffuse symplastic growth, but they elongate solely by intrusive apical growth penetrating the pectin-rich middle lamella that cements neighboring cells together. In contrast, vessel elements grow in diameter by a combination of intrusive and symplastic growth. We demonstrate that an abundant pectin methyl esterase (PME; EC 184.108.40.206) from wood-forming tissues of hybrid aspen (Populus tremula x tremuloides) acts as a negative regulator of both symplastic and intrusive growth of developing wood cells. When PttPME1 expression was up- and down-regulated in transgenic aspen trees, the PME activity in wood-forming tissues was correspondingly altered. PME removes methyl ester groups from homogalacturonan (HG) and transgenic trees had modified HG methylesterification patterns, as demonstrated by two-dimensional nuclear magnetic resonance and immunostaining using PAM1 and LM7 antibodies. In situ distributions of PAM1 and LM7 epitopes revealed changes in pectin methylesterification in transgenic trees that were specifically localized in expanding wood cells. The results show that en block deesterification of HG by PttPME1 inhibits both symplastic growth and intrusive growth. PttPME1 is therefore involved in mechanisms determining fiber width and length in the wood of aspen trees.


Carbon and nitrogen metabolism in Rhizobium.
One of the paradigms of symbiotic nitrogen fixation has been that bacteroids reduce N2 to ammonium and secrete it without assimilation into amino acids. This has recently been challenged by work with soybeans showing that only alanine is excreted in 15N2 labelling experiments. Work with peas shows that the bacteroid nitrogen secretion products during in vitro experiments depend on the experimental conditions. There is a mixed secretion of both ammonium and alanine depending critically on the concentration of bacteroids and ammonium concentration. The pathway of alanine synthesis has been shown to be via alanine dehydrogenase, and mutation of this enzyme indicates that in planta there is likely to be mixed secretion of ammonium and alanine. Alanine synthesis directly links carbon catabolism and nitrogen assimilation in the bacteroid. There is now overwhelming evidence that the principal carbon sources of bacteroids are the C4-dicarboxylic acids. This is based on labelling and bacteroid respiration data, and mutation of both the dicarboxylic acid transport system (dct) and malic enzyme. L-malate is at a key bifurcation point in bacteroid metabolism, being oxidized to oxaloacetate and oxidatively decarboxylated to pyruvate. Pyruvate can be aminated to alanine or converted to acetyl-CoA where it either enters the TCA cycle by condensation with oxaloacetate or forms polyhydroxybutyrate (PHB). Thus regulation of carbon and nitrogen metabolism are strongly connected. Efficient catabolism of C4-dicarboxylates requires the balanced input and removal of intermediates from the TCA cycle. The TCA cycle in bacteroids may be limited by the redox state of NADH/NAD+ at the 2-ketoglutarate dehydrogenase complex, and a number of pathways may be involved in bypassing this block. These pathways include PHB synthesis, glutamate synthesis, glycogen synthesis, GABA shunt and glutamine cycling. Their operation may be critical in maintaining the optimum redox poise and carbon balance of the TCA cycle. They can also be considered to be overflow pathways since they act to remove or add electrons and carbon into the TCA cycle. Optimum operation of the TCA cycle has a major impact on nitrogen fixation.


Glycosylation of simian immunodeficiency virus influences immune-tissue targeting during primary infection, leading to immunodeficiency or viral control.
Glycans of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) play pivotal roles in modulating virus-target cell interactions. We have previously reported that, whereas SIVmac239 is pathogenic, its deglycosylated essentially nonpathogenic mutant (Δ5G) serves as a live-attenuated vaccine, although both replicate similarly during primary infection. These findings prompted us to determine whether such a polarized clinical outcome was due to differences in the immune tissues targeted by these viruses, where functionally and phenotypically different memory CD4(+) T cells reside. The results showed that Δ5G replicates in secondary lymphoid tissue (SLT) at 1- to 2-log-lower levels than SIVmac239, whereas SIVmac239-infected but not Δ5G-infected animals deplete CXCR3(+) CCR5(+) transitional memory (TrM) CD4(+) T cells. An early robust Δ5G replication was localized to small intestinal tissue, especially the lamina propria (effector site) rather than isolated lymphoid follicles (inductive site) and was associated with the induction and depletion of CCR6(+) CXCR3(-) CCR5(+) effector memory CD4(+) T cells. These results suggest that differential glycosylation of Env dictates the type of tissue-resident CD4(+) T cells that are targeted, which leads to pathogenic infection of TrM-Th1 cells in SLT and nonpathogenic infection of Th17 cells in the small intestine, respectively.


Evaluation of zebrafish as a model to study the pathogenesis of the opportunistic pathogen Cronobacter turicensis.
Bacteria belonging to the genus Cronobacter spp. have been recognized as causative agents of life-threatening systemic infections, primarily in premature, low-birth weight and/or immune-compromised neonates. Knowledge remains scarce regarding the underlying molecular mechanisms of disease development. In this study, we evaluated the use of a zebrafish model to study the pathogenesis of Cronobacter turicensis LMG 23827(T), a clinical isolate responsible for two fatal sepsis cases in neonates. Here, the microinjection of approximately 50 colony forming units (CFUs) into the yolk sac resulted in the rapid multiplication of bacteria and dissemination into the blood stream at 24 h post infection (hpi), followed by the development of a severe bacteremia and larval death within 3 days. In contrast, the innate immune response of the embryos was sufficiently developed to control infection after the intravenous injection of up to 10(4) CFUs of bacteria. Infection studies using an isogenic mutant devoid of surviving and replicating in human macrophages (ΔfkpA) showed that this strain was highly attenuated in its ability to kill the larvae. In addition, the suitability of the zebrafish model system to study the effectiveness of antibiotics to treat Cronobacter infections in zebrafish embryos was examined. Our data indicate that the zebrafish model represents an excellent vertebrate model to study virulence-related aspects of this opportunistic pathogen in vivo.


Association of Periodontitis With Urinary Albumin Excretion in Korean Adults With Diabetes: The 2012 Korea National Health and Nutrition Examination Survey.
Albuminuria and periodontitis are both commonly associated with systemic inflammation. However, the association between urinary albumin excretion (UAE) and periodontitis in patients with type 2 diabetes has not been fully investigated. This study aimed to investigate the association between UAE and periodontitis in Korean adults with type 2 diabetes.This study performed a cross-sectional analysis and used hierarchical multivariable logistic regression analysis models. Data from the 2012 Korean National Health and Nutrition Examination Survey were analyzed. A total of 547 patients, with type 2 diabetes without renal impairment, were included in this study. UAE was assessed using the urinary albumin to creatinine ratio (UACR). A community periodontal index greater than or equal to code 3 was used to define periodontitis.The risk of periodontitis tended to increase as UACR increased even after adjustment for potential confounders (P for trend in the odds ratios = 0.05 in model 1; 0.02 in model 2; and 0.01 in model 3). In a subgroup analysis, the prevalence of periodontitis was significantly higher in the patients with albuminuria (UACR >30 mg/g) than in those without albuminuria among patients younger than 65 years (P = 0.03), those with newly diagnosed diabetes (P = 0.04), or those without obesity (P = .04).UAE was positively associated with the risk of periodontitis in Korean adults with type 2 diabetes. In the patients who were younger, were newly diagnosed with diabetes, or had normal body mass index, individuals with albuminuria were more likely to have a higher prevalence of periodontitis. Early identification of periodontitis may be helpful in Korean diabetic adults with increased UAE.


A full Bayesian model to handle structural ones and missingness in economic evaluations from individual-level data.
Economic evaluations from individual-level data are an important component of the process of technology appraisal, with a view to informing resource allocation decisions. A critical problem in these analyses is that both effectiveness and cost data typically present some complexity (eg, nonnormality, spikes, and missingness) that should be addressed using appropriate methods. However, in routine analyses, standardised approaches are typically used, possibly leading to biassed inferences. We present a general Bayesian framework that can handle the complexity. We show the benefits of using our approach with a motivating example, the MenSS trial, for which there are spikes at one in the effectiveness and missingness in both outcomes. We contrast a set of increasingly complex models and perform sensitivity analysis to assess the robustness of the conclusions to a range of plausible missingness assumptions. We demonstrate the flexibility of our approach with a second example, the PBS trial, and extend the framework to accommodate the characteristics of the data in this study. This paper highlights the importance of adopting a comprehensive modelling approach to economic evaluations and the strategic advantages of building these complex models within a Bayesian framework.


Estimated HIV trends and program effects in Botswana.
This study uses surveillance, survey and program data to estimate past trends and current levels of HIV in Botswana and the effects of treatment and prevention programs. Data from sentinel surveillance at antenatal clinics and a national population survey were used to estimate the trend of adult HIV prevalence from 1980 to 2007. Using the prevalence trend we estimated the number of new adult infections, the transmission from mothers to children, the need for treatment and the effects of antiretroviral therapy (ART) and adult and child deaths. Prevalence has declined slowly in urban areas since 2000 and has remained stable in rural areas. National prevalence is estimated at 26% (25-27%) in 2007. About 330,000 (318,000-335,000) people are infected with HIV including 20,000 children. The number of new adult infections has been stable for several years at about 20,000 annually (12,000-26,000). The number of new child infections has declined from 4600 in 1999 to about 890 (810-980) today due to nearly complete coverage of an effective program to prevent mother-to-child transmission (PMTCT). The annual number of adult deaths has declined from a peak of over 15,500 in 2003 to under 7400 (5000-11,000) today due to coverage of ART that reaches over 80% in need. The need for ART will increase by 60% by 2016. Botswana's PMTCT and treatment programs have achieved significant results in preventing new child infections and deaths among adults and children. The number of new adult infections continues at a high level. More effective prevention efforts are urgently needed.


Rituximab in dermatology.
Rituximab was introduced into clinical practice as a medication with considerable potential. Its use in patients with B-cell lymphoma and rheumatoid arthritis revealed numerous indications in autoimmune diseases, many of which involve the skin, thus requiring dermatologists to become familiar with both the characteristics of anti-CD20 antibodies and the role of B cells in multiple skin diseases. Thanks to these developments, we will be able to use rituximab more frequently and appropriately in our patients and draw up consensus guidelines based on large case series. In other words, establishing the indications for rituximab will make it possible to shorten disease course and reduce morbidity due to more specific drugs.


Rickets and soil strontium.
The subjects of this study were children aged 6-60 months living in villages in the Ulas Health Region, Sivas. The villages were divided into two groups according to the amount of strontium in the soil: region 1, > 350 ppm, 650 children; region 2, < 350 ppm, 1596 children. Overall, the prevalence of one or more clinical signs of rickets was 22.9%. The prevalence in region 1 was 31.5% and that in region 2, 19.5%. These values were significantly different (p < 0.001). When other variables which may be relevant to the occurrence of rickets were taken into account, the difference in prevalence persisted. The results suggest that in villages where nutrition is mainly based on grain cereals the presence of strontium in the soil will increase the prevalence of rickets significantly. As a preventive measure, a greater proportion of the foods given to children in these villages should be derived from animal origin, and cereals and drinking water supplies should be obtained from villages with a low soil strontium content, or calcium supplements should be given.


Capacity of octacalcium phosphate to promote osteoblastic differentiation toward osteocytes in vitro.
Octacalcium phosphate (OCP) has been shown to act as a nucleus for initial bone deposition and enhancing the early stages of osteoblastic differentiation. However, the effect on differentiation at the late stage into osteocytes has not been elucidated. The present study was designed to investigate whether OCP can promote the differentiation lineage from osteoblasts to late osteocytes using a clonal cell line IDG-SW3 compared to commercially available sintered β-tricalcium phosphate (β-TCP) and hydroxyapatite (HA) in a transwell cell culture. Special attention was paid to detect the progress of OCP hydrolysis associated with ionic dissolution products from this material. OCP induced the appearance of an alkaline phosphatase (ALP) peak in the IDG-SW3 cells compared to β-TCP and HA and increased SOST/sclerostin and FGF23 gene expression after 35 days of incubation. Analyses by X-ray diffraction, curve fitting of Fourier transform infrared spectra, and acid phosphate inclusion of the materials showed that OCP tended to hydrolyze to an apatitic structure during the incubation. Since the hydrolysis enhanced inorganic phosphate ion (Pi) release from OCP in the media, IDG-SW3 cells were further incubated in the conditioned media with an increased concentration of Pi in the presence or absence of phosphonoformic acid (PFA), which is an inhibitor of Pi transport within the cells. An increase in Pi concentration up to 1.5 mM raised ALP activity, while its positive effect was eliminated in the presence of 0.1 to 0.5 mM PFA. Calcium ions did not show such an effect. These results indicate the stimulatory capacity of OCP on osteoblastic differentiation toward osteocytes. Octacalcium phosphate (OCP) has been shown to have a superior osteoconductivity due to its capacity to enhance initial stage of osteoblast differentiation. However, the effect of OCP on the late osteoblastic differentiation into osteocyte is unknown. This study showed the capacity associated with the structural change of OCP. The data show that OCP released inorganic phosphate (Pi) ions while the hydrolysis advanced if soaked in the media, determined by chemical and physical analyses, and enhanced osteocytes differentiation of IDG-SW3 cells more than hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP). Conditioned elevated Pi-containing media in the absence of OCP enhanced the osteocyte differentiation in the range of the concentration induced by OCP, the effect of which was cancelled by the inhibitor of Pi-transporters.


Medical Oncologists' Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study.
Background Although almost every state medical marijuana (MM) law identifies cancer as a qualifying condition, little research supports MM's use in oncology. We hypothesized that the discrepancy between these laws and the scientific evidence base poses clinical challenges for oncologists. Oncologists' beliefs, knowledge, and practices regarding MM were examined in this study. Methods In November 2016, we mailed a survey on MM to a nationally-representative, random sample of 400 medical oncologists. Main outcome measures included whether oncologists reported discussing MM with patients, recommended MM clinically in the past year, or felt sufficiently informed to make such recommendations. The survey also queried oncologists' views on MM's comparative effectiveness for several conditions (including its use as an adjunct to standard pain management strategies) and its risks compared with prescription opioids. Bivariate and multivariate analyses were performed using standard statistical techniques. Results The overall response rate was 63%. Whereas only 30% of oncologists felt sufficiently informed to make recommendations regarding MM, 80% conducted discussions about MM with patients, and 46% recommended MM clinically. Sixty-seven percent viewed it as a helpful adjunct to standard pain management strategies, and 65% thought MM is equally or more effective than standard treatments for anorexia and cachexia. Conclusion Our findings identify a concerning discrepancy between oncologists' self-reported knowledge base and their beliefs and practices regarding MM. Although 70% of oncologists do not feel equipped to make clinical recommendations regarding MM, the vast majority conduct discussions with patients about MM and nearly one-half do, in fact, recommend it clinically. A majority believes MM is useful for certain indications. These findings are clinically important and suggest critical gaps in research, medical education, and policy regarding MM.


Smoking on hospital grounds and the impact of outdoor smoke-free zones.
To describe the type and location of smokers on the grounds of smoke-free public hospitals and to observe the impact of introducing smoke-free signs in outdoor areas of the hospital grounds. Observation study of outdoor smoking behaviour before and after the introduction of outdoor smoke-free signs at one hospital (H1) and at the same two time periods at a nearby control hospital (H2), which already had some outdoor smoke-free signs at Time 1. The John Hunter Hospital (H1) in Newcastle, Australia and a nearby control hospital, Maitland Hospital (H2) in 1991. All people in defined outdoor sites of the two hospitals on seven randomly selected days over two weeks before and after the policy change were coded as either "smoker" or "non-smoker" and as either "staff", "patient", or "visitor". The number of smokers observed in each site was measured as a proportion of all smokers observed on the grounds of that hospital. Introduction of outdoor smoke-free zones and signs at H1. Less than 10% of observed outdoor smokers in both hospitals were patients, 40% were visitors, and more than 50% were staff. Of outdoor smokers, 82% were observed less than 10 m from entrances to the hospital building at time 1. After the introduction of signs in H1, a 4-percentage point decrease (P < 0.05) occurred in the percentage of smokers observed in smoke-free zones at time 2 (from 32% to 28%), compared with a 2-percentage point decrease (P > 0.05 at time 2 in H2 (from 48% to 46%). This observation study of smoking behaviour in hospital grounds highlights the need to reduce smoking among staff and visitors near hospital entrances. Specific strategies are discussed, which are likely to enhance compliance and hence enable the effective introduction of smoke-free policies on hospital grounds.


The sufR gene (sll0088 in Synechocystis sp. strain PCC 6803) functions as a repressor of the sufBCDS operon in iron-sulfur cluster biogenesis in cyanobacteria.
The suf operon is composed of four genes (sufB, sufC, sufD, and sufS) and is highly conserved in the genomes of cyanobacteria. Open reading frame sll0088 in Synechocystis sp. strain PCC 6803 is located near the 5' end of the suf operon but is transcribed in the direction opposite that of the suf operon. We previously reported the isolation of two independent suppressor strains of C14S(PsaC) that mapped to sll0088 and restored photoautotrophic growth. The protein encoded by sll0088 has two significant features: (i) a DNA-binding domain near the N terminus and (ii) four highly conserved cysteine residues near the C terminus. The protein has high sequence similarity to transcription regulatory proteins with a conserved DNA-binding domain and can be classified in the DeoR family of helix-loop-helix proteins. The protein falls into a further subclass that contains a C-X(12)-C-X(13)-C-X(14)-C motif near the C terminus, which may represent a metal-binding site. The expressed Sll0088 protein harbored an iron-sulfur cluster as shown by optical and electron paramagnetic resonance spectroscopy. Compared to the wild type, expression levels of the sufBCDS genes were elevated when cells were grown under conditions of oxidative and iron stress and were even higher in a null mutant of Synechococcus sp. strain PCC 7002 in which the sll0088 homolog was insertionally inactivated. In agreement with the proposed role of the sufBCDS genes in iron metabolism, the growth rate of the null mutant was significantly higher than that of the wild type under iron-limiting conditions. We propose that the protein encoded by sll0088 is a transcriptional repressor of the suf operon, and we name the gene sufR.


Effectiveness of and User Experience With Web-Based Interventions in Increasing Physical Activity Levels in People With Multiple Sclerosis: A Systematic Review.
Supporting people with multiple sclerosis (MS) to achieve and maintain recommended levels of physical activity is important but challenging. Web-based interventions are increasingly being used to deliver targeted exercise programs and promote physical activity. The purpose of this study was to systematically review current evidence regarding the effectiveness and user experience of web-based interventions in increasing physical activity in people with MS. MEDLINE, EMBASE, CINAHL, AMED, PEDro, PsychInfo, Web of Sciences, The Cochrane Library, and gray literature were searched from 1990 to September 2016. English language articles reporting the use of web-based interventions to increase physical activity in adults with MS were included. Eligible quantitative studies were of any design and reported a measure of physical activity. Qualitative studies exploring users' experiences in any context were included. Of the 881 articles identified, 9 met the inclusion criteria. Two reviewers independently assessed methodological quality and extracted data using standardized critical appraisal and data extraction tools from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). Meta-analysis of self-reported physical activity questionnaire data from 4 studies demonstrated a standardized mean difference of 0.67 (95% CI = 0.43-0.92), indicating a positive effect in favor of the web-based interventions. Narrative review of accelerometry data from 3 studies indicated increases in objectively measured physical activity. No qualitative studies met the inclusion criteria. In the 9 included articles, only 2 different interventions (used with people who were ambulant) were reported. Web-based interventions had a short-term positive effect on self-reported physical activity in people who had MS and were ambulant. Evidence is not currently available to support or refute their use in the long-term or with people who are not ambulant.


Systematic review of the effect of training interventions on the skills of health professionals in promoting health behaviour, with meta-analysis of subsequent effects on patient health behaviours.
We aimed to identify, synthesise and evaluate randomised control trial evidence on the effects of healthcare professional training on the delivery quality of health behaviour change interventions and, subsequently, on patient health behaviours. Systematic review with narrative synthesis of effects on delivery quality and meta-analysis of health behaviour outcomes. We searched: Medline, EMBASE, PsychInfo, AMED, CINAHL Plus and the Cochrane Central Register of Control Trials up to March 2019. Studies were included if they were in English and included intervention delivery quality as an outcome. The systematic review was registered on PROSPERO (registration: CRD42019124502). Twelve-studies were identified as suitable for inclusion. All studies were judged as being high risk of bias with respect to training quality outcomes. However with respect to behavioural outcomes, only two of the six studies included in the meta-analysis had a high risk and four had some concerns. Educational elements (e.g. presentations) were used in all studies and nine included additional practical learning tasks. In eight studies reporting delivery quality, 54% of healthcare professional communication outcomes and 55% of content delivery outcomes improved in the intervention arm compared to controls. Training that included both educational and practical elements tended to be more effective. Meta-analysis of patient health behavioural outcomes in six-studies found significant improvements (Standardised mean difference (SMD): 0.20, 95% confidence interval: 0.11 to 0.28, P < 0.0001, I2 = 0%). No significant difference was found between short (≤6-months) and long-term (> 6-months) outcomes (SMD: 0.25 vs 0.15; P = 0.31). Delivery quality of health behaviour change interventions appears to improve following training and consequently to improve health behaviours. Future studies should develop more concise /integrated measures of delivery quality and develop optimal methods of training delivery.


The determinants of change in patella cartilage volume in osteoarthritic knees.
The rate of change in patella articular cartilage and factors influencing it, in subjects with osteoarthritis (OA), is unknown. We performed a cohort study to determine this. One hundred ten subjects with OA had baseline skyline and lateral radiographs and magnetic resonance imaging (MRI) on their knee. They were followed 2 years later with a repeat MRI of the same knee. Patella and tibial cartilage volume was measured at baseline and followup. Risk factors assessed at baseline were tested for their association with change in patella cartilage volume over time. The annual percentage loss of patella cartilage was 4.5 +/- 4.3%. Sex, body mass index (BMI), and pain score at baseline were associated with an increase in cartilage loss. The rate of patella cartilage loss was greater in women than men, 5.3% versus 3.5% (p < 0.03), independent of age, BMI, and pain score. No association was seen between change in patellar cartilage volume and change in either medial or lateral tibial cartilage volume (r = 0.02, p = 0.86 and r = 0.08, p = 0.43, respectively). In OA, patella cartilage volume is lost at 4.5 +/- 4.3% per year. The main factors affecting this are sex, BMI, and baseline pain score. The poor correlation between patella cartilage loss and cartilage loss in the tibial compartment suggests that the pathogenetic mechanisms for OA in the patellofemoral and tibiofemoral joint may differ. Further work will be required to determine whether the rate of patella cartilage loss in OA is steady or phasic, and to determine which factors can be modified to reduce cartilage loss.


Bone mineral density during 3 years of growth hormone in previously GH-treated young adults with PWS.
In children with Prader-Willi syndrome (PWS), growth hormone (GH) treatment has positive effects on bone mineral density (BMD). Two 1-year studies did not show a difference between GH or placebo on BMD in young adults with PWS. However, there are no studies investigating BMD during longer-term GH treatment in young adults with PWS. Open-label, a prospective study in 43 young adults with PWS. BMD of the total body (BMDTBSDS) and lumbar spine (BMADLSSDS) measured by DXA. In the total group, estimated mean (95% CI) of BMDTB remained similar during 3 years of GH, being -0.76 (-1.11 to -0.41) SDS at start and -0.90 (-1.27 to -0.54) SDS after 3 years (P = 0.11), as did BMADLS, being -0.36 (-0.72 to 0.01) SDS and -0.46 (-0.77 to -0.16) SDS, respectively (P = 0.16). In men, there was a significant decrease in BMDTBSDS during 3 years of GH, while BMADLSSDS remained similar. In women, both BMDTBSDS and BMADLSSDS remained similar. BMDTBSDS was associated with female sex, lean body mass and age. The majority of patients received sex steroid replacement therapy (SSRT). During 3 years of combined GH and SSRT treatment, BMD remained stable in the normal range in young adults with PWS. However, men showed a decline in BMDTBSDS, probably due to insufficient SSRT. We recommended to continue GH treatment in young adults with PWS and to start SSRT during adolescence unless puberty progresses normally.


Risk factors for unfavorable clinical outcome in patients with documented heparin-induced thrombocytopenia.
Prognostic factors for unfavorable clinical outcome in patients with heparin-induced thrombocytopenia (HIT) are largely unknown. In this multicenter, retrospective, case-control study, all HIT patients were treated with danaparoid. Study cases were HIT patients with an unfavorable clinical outcome. Controls were HIT patients who were not study cases. Unfavorable clinical outcome was defined as the occurrence of at least one of the following clinical events: death within 60 days after HIT start date, or venous or arterial thromboembolism, amputation, major bleeding, or disseminated intra-vascular coagulation between 48 hours and 60 days after HIT start date. Compared with controls (n=65), thrombotic episodes within 48 hours of HIT start date were more frequent (59.2% versus 32.3%; p=0.004), the median time between HIT start date and initiation of danaparoid infusion was longer (3.0 versus 1.0 days; p=0.001), and this treatment was more frequently underdosed (43.8% versus 18.8%; p=0.004) in study cases (n=49). Upon multivariate analysis, all these three parameters were significant predictive factors for unfavorable clinical outcome. The adjusted odds ratios [95% confidence interval] were 6.6 [2.5-17.3] for time between HIT start date and danaparoid initiation over 48 hours, 4.3 [1.5-12.0] for danaparoid underdosing, and 3.2 [1.3-8.0] for presence of a thromboembolic episode at HIT start date. This study supports the recommendations concerning the management of HIT patients, namely discontinuation of all heparin administration once the diagnosis is suspected and prompt initiation of an alternative anticoagulant drug with a strict adherence to doses specifically recommended for these patients.


[Identification of a new mutation of the NPHP1 gene].
Kidney cystic diseases are inherited disorders causing chronic renal failure. According to the genetic defect they are classified as diseases of the primary ciliary complex and uromodulin-associated diseases. Mutations in genes coding for ciliary proteins are the basis of a broad category of genetic diseases, called ciliopathies. To date, three important ciliopathies are known: the autosomal dominant form and the recessive shape of the polycystic kidney and the nephronophthisis (NPHP). Juvenile Nephronophthisis (NPHP) is a progressive renal tubulo-interstitial disorder with a form of autosomal recessive inheritance that progresses inexorably towards terminal renal failure. Three different forms have been distinguished: juvenile (NPH1), infantile (NPH2) and adolescent (NPH3). Juvenile Nephronophthisis or nephronophthisis type 1 (NPH1), is the most frequent form. In most patients with a suspected diagnosis of NPHP, based primarily on clinical and radiological data, the deletion in homozygous NPHP1 is present in 20-40% of cases. Heterozygous deletions are found in 6% of patients, with concomitant mutation of the NPHP1 gene on the second allele. In this study we subjected to genetic screening 6 patients with suspected NPHP causing chronic renal failure, belonging to 6 families. The genetic screening identified in 2/6 patients a deletion of exons 5-7-20 and in 4/6 patients an heterozygous deletion of exon 20 and an heterozygous deletion on exon 17 not yet described in literature. Our results suggest that genetic screening should be included in the diagnostic procedure of patients with suspected nephronophthisis and that it may be used alternatively to renal biopsy.


Pediatric Acute Severe Neurologic Illness and Injury in an Urban and a Rural Hospital in the Democratic Republic of the Congo.
Empirical knowledge suggests that acute neurologic disorders are common in sub-Saharan Africa, but studies examining the true burden of these diseases in children are scarce. We performed this prospective, observational study to evaluate the prevalence, clinical characteristics, treatment approaches, and outcomes of children suffering acute neurologic illness or injury (ANI) in an urban and rural site in the Democratic Republic of the Congo. Over 12 months, 471 out of 6,563 children admitted met diagnostic criteria for ANI, giving a hospital-based prevalence of 72/1,000 admissions. Two hundred and seventy-two children had clinical findings consistent with central nervous system infection but lacked complete diagnostic evaluation for definitive classification. Another 151 children were confirmed to have cerebral malaria (N = 109, 23% of admissions), bacterial meningitis (N = 38, 8% of admissions), tuberculous meningitis (N = 3, 0.6% of admissions), or herpes encephalitis (N = 1, 0.21% of admissions). Febrile convulsions, traumatic brain injury, and epilepsy contributed less significantly to overall hospital prevalence of ANI (3.19/1,000, 1.37/1,000, and 1.06/1,000, respectively). Overall mortality for the cohort was 21% (97/471). Neurologic sequelae were seen in another 31% of participants, with only 45% completing the study with a normal neurologic examination. This type of data is imperative to help plan effective strategies for illness and injury prevention and control, and to allow optimal use of limited resources in terms of provision of acute care and rehabilitation for these children.


Isolation of flavonoids from apple peel using novel graphene oxide cotton fiber.
A novel graphene oxide cotton fibre (GOF) was used to adsorb flavonoids from crude ethanol extracts derived from apple peels. Ultra-high pressure liquid chromatography-mass spectrometry was used to analyse polyphenol content, and the resulting data demonstrated that GOF-based flash chromatography can be used to efficiently separate polyphenols from sugars and can facilitate the removal of 95% of the sugar content. Flavonoids can be easily separated from phenolic acids. Chalcones and flavonols were eluted with 100% methanol and subsequently flavan-3-ols can be eluted with 0.04 M sodium hydroxide. The novel GOF has the potential to be used in the isolation of flavonoids.