Effects of biotic and abiotic factors on resistance versus resilience of Douglas fir to drought.
Significant increases in tree mortality due to drought-induced physiological stress have been documented worldwide. This trend is likely to continue with increased frequency and severity of extreme drought events in the future. Therefore, understanding the factors that influence variability in drought responses among trees will be critical to predicting ecosystem responses to climate change and developing effective management actions. In this study, we used hierarchical mixed-effects models to analyze drought responses of Pseudotsuga menziesii in 20 unmanaged forests stands across a broad range of environmental conditions in northeastern Washington, USA. We aimed to 1) identify the biotic and abiotic attributes most closely associated with the responses of individual trees to drought and 2) quantify the variability in drought responses at different spatial scales. We found that growth rates and competition for resources significantly affected resistance to a severe drought event in 2001: slow-growing trees and trees growing in subordinate canopy positions and/or with more neighbors suffered greater declines in radial growth during the drought event. In contrast, the ability of a tree to return to normal growth when climatic conditions improved (resilience) was unaffected by competition or relative growth rates. Drought responses were significantly influenced by tree age: older trees were more resistant but less resilient than younger trees. Finally, we found differences between resistance and resilience in spatial scale: a significant proportion (approximately 50%) of the variability in drought resistance across the study area was at broad spatial scales (i.e. among different forest types), most likely due to differences in the total amount of precipitation received at different elevations; in contrast, variation in resilience was overwhelmingly (82%) at the level of individual trees within stands and there was no difference in drought resilience among forest types. Our results suggest that for Pseudotsuga menziesii resistance and resilience to drought are driven by different factors and vary at different spatial scales.


Telephone psychotherapy and telephone care management for primary care patients starting antidepressant treatment: a randomized controlled trial.
Both antidepressant medication and structured psychotherapy have been proven efficacious, but less than one third of people with depressive disorders receive effective levels of either treatment. To compare usual primary care for depression with 2 intervention programs: telephone care management and telephone care management plus telephone psychotherapy. Three-group randomized controlled trial with allocation concealment and blinded outcome assessment conducted between November 2000 and May 2002. A total of 600 patients beginning antidepressant treatment for depression were systematically sampled from 7 group-model primary care clinics; patients already receiving psychotherapy were excluded. Usual primary care; usual care plus a telephone care management program including at least 3 outreach calls, feedback to the treating physician, and care coordination; usual care plus care management integrated with a structured 8-session cognitive-behavioral psychotherapy program delivered by telephone. Blinded telephone interviews at 6 weeks, 3 months, and 6 months assessed depression severity (Hopkins Symptom Checklist Depression Scale and the Patient Health Questionnaire), patient-rated improvement, and satisfaction with treatment. Computerized administrative data examined use of antidepressant medication and outpatient visits. Treatment participation rates were 97% for telephone care management and 93% for telephone care management plus psychotherapy. Compared with usual care, the telephone psychotherapy intervention led to lower mean Hopkins Symptom Checklist Depression Scale depression scores (P =.02), a higher proportion of patients reporting that depression was "much improved" (80% vs 55%, P<.001), and a higher proportion of patients "very satisfied" with depression treatment (59% vs 29%, P<.001). The telephone care management program had smaller effects on patient-rated improvement (66% vs 55%, P =.04) and satisfaction (47% vs 29%, P =.001); effects on mean depression scores were not statistically significant. For primary care patients beginning antidepressant treatment, a telephone program integrating care management and structured cognitive-behavioral psychotherapy can significantly improve satisfaction and clinical outcomes. These findings suggest a new public health model of psychotherapy for depression including active outreach and vigorous efforts to improve access to and motivation for treatment.


Post-Intravitreal injection pain reduction using topical NSAIDS: A comparative study.
To compare the efficacy of two different topical non-steroidal anti-inflammatory drugs (NSAIDs) drops with versus without conservatives after intravitreal injections (IVIs). Prospective, randomized, placebo-controlled, single-blinded comparative study. A total of 308 eyes of 252 patients receiving an IVI of anti-vascular endothelial growth factor (anti-VEGF) were randomly assigned to receive either a single drop of nepafenac 0.1%, preservative-free diclofenac 0.1%, or artificial tears (control group) immediately after IVI. Primary outcome measure was pain scores immediately, six hours and twenty-four hours post- injection. 166 patients received one topical drop of NSAIDS, of which 90 in the diclofenac group and 76 in the nepafenac group. Additional 86 patients were included in the control group. Mean reported pain score was significantly lower at six hours after IVI in the preservative-free diclofenac group (17.1 ± 23.0) than in the nepafenac group (26.2 ± 31.9) and the control group (27.5 ± 29.2) (p = 0.03). At twenty-four hours post-injection there was no statistically significant difference between the groups. Patients reported less pain compared to previous IVIs and none referred to urgent health care, but these findings were not statistically significant. The use of topical preservative-free NSAIDs may be superior to preservative- containing NSAIDs in pain relief after IVIs and may be considered as part of the treatment protocol of this population.


How to approach hypercalcaemia.
The management of patients with hypercalcaemia should be informed by the patient's symptoms and signs, by the degree of elevation of calcium, by the underlying mechanism by which calcium has been elevated and by the disease process underlying the presentation. Regardless of diagnosis, all significantly hypercalcaemic patients should be rendered euvolaemic before any further and more specific treatment is considered. Highly symptomatic patients and those with a calcium level of > 3.5 mmol represent a medical emergency that requires inpatient treatment.


A Quality Improvement Approach to Reducing the Caesarean section Surgical Site Infection Rate in a Regional Hospital.
Surgical site infection (SSI) rates are used extensively by hospitals as a basis for quality improvement. A 30-day post-discharge SSI programme for Caesarean section operations has been implemented in Our Lady of Lourdes Hospital since 2011. It has been shown that skin antisepsis and antibiotic prophylaxis are key factors in the prevention of SSI. Using quality improvement methodology, an infection prevention bundle was introduced to address these two factors. Skin antisepsis was changed from povidone-iodine to chlorhexidine-alcohol. Compliance with choice of antibiotic prophylaxis increased from 89.6% in 2014 to 98.5% in 2015. Compliance with timing also improved. The SSI rate of 7.5% was the lowest recorded to date, with the majority of SSIs (64%) diagnosed after hospital discharge. The level of variation was also reduced. However, the continued presence of variation and possibility of lower infection rates from the literature imply that further improvements are required.


Does your patient accounting process pass the systems test?
There have been many changes to the patient accounting management process in recent years, the introduction of electronic data interchange (EDI) among them. The future, however, holds considerably more opportunities--and some potential threats. This article examines the issues and provides a series of practical suggestions for meeting the future challenges of the patient accounting process.


Enhancement of fcgamma receptor-mediated phagocytosis by transforming mutants of Cbl.
Phagocytosis mediated by FcgammaR plays an important role in host defense. The molecular events involved in this process have not been completely defined. The adapter protein Cbl has been implicated in FcgammaR signaling, but the function of Cbl in phagocytosis is unknown. Here we show that overexpression of the transforming mutants of Cbl, Cbl-70Z, and v-Cbl, but not wild-type (wt) Cbl, enhance phagocytosis mediated by FcgammaR in COS cells. Cbl-70Z, but not Cbl-wt, also enhanced FcgammaR-mediated phagocytosis in P388D1 murine macrophage cells. Cbl-70Z did not affect tyrosine phosphorylation or in vitro kinase activity of Syk, indicating that Syk may not be the direct target of Cbl-70Z in the enhancement of phagocytosis. A point mutation (G306E) in the phosphotyrosine domain of Cbl-70Z, as well as a C-terminal 67-aa deletion, partially abolished the enhancing effect on FcgammaR-mediated phagocytosis. A double mutant of Cbl-70Z containing both the G306E mutation and the C-terminal deletion completely lacked the ability to enhance phagocytosis. Thus, both the phosphotyrosine binding domain and the carboxyl-terminal tail were required for optimal enhancement of phagocytosis by Cbl-70Z. Functional phosphatidylinositol 3-kinase was required for Cbl-70Z to enhance phagocytosis, since wortmannin, a phosphatidylinositol 3-kinase inhibitor, inhibited FcgammaR-mediated phagocytosis in the presence of Cbl-70Z. These studies demonstrate that mutants of Cbl can modulate the phagocytic pathway mediated by FcgammaR and imply a functional involvement of c-Cbl in Fcgamma receptor-mediated phagocytosis.


An unstable strain of Aspergillus foetidus segregating proline auxotrophs.
Two basic colony types have been obtained through single conidial isolation from the Bode strain of Aspergillus foetidus as well as from mutants of this unstable strain. Type I is prototrophic whereas type II is an auxotroph requiring proline. When a type I strain is grown on complex medium it gradually becomes overwhelmed by type II sectors of growth. However, essentially pure cultures of type I can be maintained on minimal medium (lacking proline). The yield of glucoamylase from type II cultures is less than half that obtained with type I cultures. The instability of type I cultures when grown on complex medium can not be explained by heterokaryosis or the presence of virus-like particles found in the original Bode strain and its derivatives. The isolation of five stable prototrophic strains obtained as more rapidly growing sectors from type I subcultures grown on complex medium suggests that the instability most probably results from a duplicated chromosomal segment or other chromosomal aberration analogous to those described in A. nidulans.


Reduced inspiratory flow attenuates IL-8 release and MAPK activation of lung overstretch.
Lung overstretch involves mechanical factors, including large tidal volumes (VT), which induce inflammatory responses. The current authors hypothesised that inspiratory flow contributes to ventilator-induced inflammation. Buffer-perfused rabbit lungs were ventilated for 2 h with 21%, O2+5%, CO2, positive end-expiratory pressure of 2-3 cmH2O and randomly assigned to either: 1) normal VT (6 mL x kg(-1)) at respiratory rate (RR) 30, inspiration:expiration time ratio (I:E) 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1); 2) large VT (12 mL x kg(-1)) at RR 30, I:E 1:1, high inspiratory flow 12 mL x kg(-1) x s(-1) (HRHF); 3) large VT at RR 15, I:E 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1) (LRLF); or 4) large VT at RR 15, I:E 1:2.3, high inspiratory flow 10 mL x kg(-1) x s(-1) (LRHF). Physiological parameters, tumour necrosis factor (TNF)-alpha, interleukin (IL)-8 and activation of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK)1/2, p38 and stress-activated protein kinase (SAPK)/ c-Jun N-terminal kinase (JNK)) were measured. HRHF increased weight gain, perfusate IL-8 and phosphorylation of ERK1/2, p38 and SAPK/JNK. These responses were absent during LRLF but present during LRHF. Changes in TNF-alpha were small. Tissue IL-8 and phospho-ERK1/2 staining was localised primarily to smooth muscle, adventitia and bronchial epithelium within larger bronchioles and arterioles. These results indicate that mild overstretch of perfused lungs during high inspiratory flow enhances inflammatory signalling by cells in lung regions most affected by strong turbulent airflow.


A new procedure for the preparation of beta-keto-delta-lactones from sugars and their transformation into glycosyl acceptors in disaccharides synthesis
[reaction: see text] Glycals are effective starting materials for the synthesis of enantiopure beta-ketone-delta-lactones. They are easily transformed, through a two-step, one-pot reaction, into the corresponding alpha,alpha'-dioxothiones which in turn can be quantitatively trapped with dienophiles in inverse electron-demand [4 + 2] cycloadditions. The reaction of dioxothione 8b with endo and exo glucals allowed the elaboration of a new protocol to prepare 2-thio- or 2-deoxydisaccharides stereoselectively.


The lysosomal protease cathepsin L is an important regulator of keratinocyte and melanocyte differentiation during hair follicle morphogenesis and cycling.
We have previously shown that the ubiquitously expressed lysosomal cysteine protease, cathepsin L (CTSL), is essential for skin and hair follicle homeostasis. Here we examine the effect of CTSL deficiency on hair follicle development and cycling in ctsl(-/-) mice by light and electron microscopy, Ki67/terminal dUTP nick-end labeling, and trichohyalin immunofluorescence. Hair follicle morphogenesis in ctsl(-/-) mice was associated with several abnormalities. Defective terminal differentiation of keratinocytes occurred during the formation of the hair canal, resulting in disruption of hair shaft outgrowth. Both proliferation and apoptosis levels in keratinocytes and melanocytes were higher in ctsl(-/-) than in ctsl(+/+) hair follicles. The development of the hair follicle pigmentary unit was disrupted by vacuolation of differentiating melanocytes. Hair cycling was also abnormal in ctsl(-/-) mice. Final stages of hair follicle morphogenesis and the induction of hair follicle cycling were retarded. Thereafter, these follicles exhibited a truncated resting phase (telogen) and a premature entry into the first growth phase. Further abnormalities of telogen development included the defective anchoring of club hairs in the skin, which resulted in their abnormal shedding. Melanocyte vacuolation was again apparent during the hair cycle-associated reconstruction of the hair pigmentary unit. A hallmark of these ctsl(-/-) mice was the severe disruption in the exiting of hair shafts to the skin surface. This was mostly because of a failure of the inner root sheath (keratinocyte layer next to the hair shaft) to fully desquamate. These changes resulted in a massive dilation of the hair canal and the abnormal routing of sebaceous gland products to the skin surface. In summary, this study suggests novel roles for cathepsin proteases in skin, hair, and pigment biology. Principal target tissues that may contain protein substrate(s) for this cysteine protease include the developing hair cone, inner root sheath, anchoring apparatus of the telogen club, and organelles of lysosomal origin (eg, melanosomes).


A comparison of different vaccination schemes used in sheep combining inactivated bluetongue vaccines against serotypes 4 and 8.
Eight different vaccination schemes using four commercially available inactivated Bluetongue vaccines against serotypes 4 and 8 in three different combinations (setting 1-3) were tested under field conditions for their ability to generate a measurable immune response in sheep. Animals of setting 1 (groups A-D) were simultaneously vaccinated using either individual injections at different locations (groups A & D) or double injection by a twin-syringe (groups B & C). For both application methods, a one-shot vaccination (groups C & D) was compared to a boosted vaccination (groups A & B). Sheep of setting 2 (groups E-G) were vaccinated in an alternating, boosted pattern at fortnightly intervals starting with serotype 4 (groups E & F) or vice versa (group G). Group H of setting 3 was vaccinated simultaneously and vaccines were injected individually as a one-shot application. Each group consisted of 30 sheep. The immunogenic response was tested in all sheep (n = 240) by ELISA (IDScreen®Bluetongue Competition), while serum neutralisation tests were performed in five to six sheep from each group (n = 45). All vaccine combinations were well tolerated by all sheep. Of all vaccines and schemes described, the simultaneous double injected boosted vaccination of setting 1 (group B) yielded the highest median serotype-specific titres 26 weeks after the first vaccination (afv) and 100% seropositive animals (ELISA) one year afv. In setting 1, there were no relevant significant differences in the immunogenic response between simultaneously applied vaccines at different sites or at the same injection site. Importantly, a one-shot vaccination induced comparable immunogenicity to a boosted injection half a year afv. Low serotype-specific neutralising antibody levels were detected in settings 2 and 3 and are attributed to diverse factors which may have influenced the measured immunogenicity.


Analysis of Stable Chelate-free Gadolinium Loaded Titanium Dioxide Nanoparticles for MRI-Guided Radionuclide Stimulated Cancer Treatment.
Recent studies demonstrate that titanium dioxide nanoparticles (TiO2 NPs) are an effective source of reactive oxygen species (ROS) for photodynamic therapy and radionuclide stimulated dynamic therapy (RaST). Unfortunately tracking the in vivo distribution of TiO2 NPs noninvasively remains elusive. Given the use of gadolinium (Gd) chelates as effective contrast agents for magnetic resonance imaging (MRI), this study aims to (1) develop hybrid TiO2-Gd NPs that exhibit high relaxivity for tracking the NPs without loss of ROS generating capacity; and (2) establish a simple colorimetric assay for quantifying Gd loading and stability. A chelate-free, heat-induced method was used to load Gd onto TiO2 NPs, which was coated with transferrin (Tf). A sensitive colorimetric assay and inductively coupled plasma mass spectrometry (ICP-MS) were used to determine Gd loading and stability of the TiO2-Gd-Tf NPs. Measurement of the relaxivity was performed on a 1.4 T relaxometer and a 4.7 T small animal magnetic resonance scanner to estimate the effects of magnetic field strength. ROS was quantified by activated dichlorodihydrofluorescein diacetate fluorescence. Cell uptake of the NPs and RaST were monitored by fluorescence microscopy. Both 3 T and 4.7 T scanners were used to image the in vivo distribution of intravenously injected NPs in tumor-bearing mice. A simple colorimetric assay accurately determined both the loading and stability of the NPs compared with the expensive and complex ICP-MS method. Coating of the TiO2-Gd NPs with Tf stabilized the nanoconstruct and minimized aggregation. The TiO2-Gd-Tf maintained ROS-generating capability without inducing cell death at a wide range of concentrations but induced significant cell death under RaST conditions in the presence of F-18 radiolabeled 2-fluorodeoxyglucose. The longitudinal (r1 = 10.43 mM-1s-1) and transverse (r2 = 13.43 mM-1s-1) relaxivity of TiO2-Gd-Tf NPs were about twice and thrice, respectively, those of clinically used Gd contrast agent (Gd-DTPA; r1 = 3.77 mM-1s-1 and r2 = 5.51 mM-1s-1) at 1.4 T. While the r1 (8.13 mM-1s-1) reduced to about twice that of Gd-DTPA (4.89 mM-1s-1) at 4.7 T, the corresponding r2 (87.15 mM-1s-1) increased by a factor 22.6 compared to Gd-DTPA (r2 = 3.85). MRI of tumor-bearing mice injected with TiO2-Gd-Tf NPs tracked the NPs distribution and accumulation in tumors. This work demonstrates that Arsenazo III colorimetric assay can substitute ICP-MS for determining the loading and stability of Gd-doped TiO2 NPs. The new nanoconstruct enabled RaST effect in cells, exhibited high relaxivity, and enhanced MRI contrast in tumors in vivo, paving the way for in vivo MRI-guided RaST.


Dietary supplementation with cholesterol and docosahexaenoic acid increases the activity of the arginine-nitric oxide pathway in tissues of young pigs.
Nitric oxide (NO), synthesized from l-arginine by tetrahydrobiopterin (BH4)-dependent NO synthase (NOS), is critical for neurological and muscular development and function. This study was designed to test the hypothesis that cholesterol and docosahexaenoic acid (DHA) may modulate the arginine-NO pathway in tissues of the young pig. Sixteen newborn pigs were nursed by sows for 24h and then assigned to one of four treatment groups, representing supplementation with 0.0%, 0.2% cholesterol, 0.2% DHA, or cholesterol plus DHA to the basal milk-formula. All piglets were euthanized at 49 days of age. Brain, liver and gastrocnemius muscle were analyzed for BH4, NADPH and arginine, GTP cyclohydrolase-I (GTP-CH) and NOS activities, and NOS protein isoforms. Hepatic NOS activity was below the detection limit in all pigs. DHA supplementation (P<0.01) increased GTP-CH activities, as well as BH4 and NADPH concentrations in brain, liver, and muscle by 24-46%, while enhancing (P<0.05) NOS activities by 45-48% in brain and muscle. Dietary cholesterol supplementation increased (P<0.05) NOS and GTP-CH activities by 17-26% in brain but had no effect in liver or muscle. The enhanced NOS activity in the brain or muscle of cholesterol- or DHA-supplemented piglets was attributable to the combined effects of increased eNOS and nNOS activation (changes in phosphorylation levels) and total iNOS protein. Additionally, DHA and cholesterol enhanced (P<0.05) arginine concentrations in brain (35-42%), but not in liver or muscle. These tissue-specific effects of cholesterol and DHA on NO synthesis may play an important role in postnatal growth and development.


Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization.
Mutations of a putative cyclic-nucleotide-binding domain (CNBD) can disrupt the function of the hyperpolarization-activated cyclic-nucleotide-gated channel (HCN2) and the human ether-a-go-go-related gene potassium channel (HERG). Loss of function caused by C-terminal truncation, which includes all or part of the CNBD in HCN and HERG, has been related to abnormal channel trafficking. Similar defects have been reported for several of the missense mutations of HERG associated with long QT syndrome type 2 (LQT2). Thus, we postulate that normal processing of these channels depends upon the presence of the CNBD. Here, we show that removal of the entire CNBD prevents Golgi transit, surface localization and function of HERG channel tetramers. This is also true when any of the structural motifs of the CNBD is deleted, suggesting that deletion of any highly conserved region along the entire length of the CNBD can disrupt channel trafficking. Furthermore, we demonstrate that defective trafficking is a consequence of all LQT2 mutations in the CNBD, including two mutations not previously assessed and two others for which there are conflicting results in the literature. The trafficking sensitivity of the CNBD might be of general significance for other ion channels because complete deletion of the CNBD or mutations at highly conserved residues within the CNBD of the related ERG3 channel and HCN2 also prevent Golgi transit. These results broadly implicate the CNBD in ion-channel trafficking that accounts for the commonly observed loss of function associated with CNBD mutants and provides a rationale for distinct genetic disorders.


Mental health responses to the COVID-19 pandemic: a latent class trajectory analysis using longitudinal UK data.
The mental health of the UK population declined at the onset of the COVID-19 pandemic. Convenience sample surveys indicate that recovery began soon after. Using a probability sample, we tracked mental health during the pandemic to characterise mental health trajectories and identify predictors of deterioration. This study was a secondary analysis of five waves of the UK Household Longitudinal Study (a large, national, probability-based survey that has been collecting data continuously since January, 2009) from late April to early October, 2020 and pre-pandemic data taken from 2018-19. Mental health was assessed using the 12-item General Health Questionnaire (GHQ-12). We used latent class mixed models to identify discrete mental health trajectories and fixed-effects regression to identify predictors of change in mental health. Mental health was assessed in 19 763 adults (≥16 years; 11 477 [58·1%] women and 8287 [41·9%] men; 3453 [17·5%] participants from minority ethnic groups). Mean population mental health deteriorated with the onset of the pandemic and did not begin improving until July, 2020. Latent class analysis identified five distinct mental health trajectories up to October 2020. Most individuals in the population had either consistently good (7437 [39·3%] participants) or consistently very good (7623 [37·5%] participants) mental health across the first 6 months of the pandemic. A recovering group (1727 [12·0%] participants) showed worsened mental health during the initial shock of the pandemic and then returned to around pre-pandemic levels of mental health by October, 2020. The two remaining groups were characterised by poor mental health throughout the observation period; for one group, (523 [4·1%] participants) there was an initial worsening in mental health that was sustained with highly elevated scores. The other group (1011 [7·0%] participants) had little initial acute deterioration in their mental health, but reported a steady and sustained decline in mental health over time. These last two groups were more likely to have pre-existing mental or physical ill-health, to live in deprived neighbourhoods, and be of Asian, Black or mixed ethnicity. Infection with SARS-CoV-2, local lockdown, and financial difficulties all predicted a subsequent deterioration in mental health. Between April and October 2020, the mental health of most UK adults remained resilient or returned to pre-pandemic levels. Around one in nine individuals had deteriorating or consistently poor mental health. People living in areas affected by lockdown, struggling financially, with pre-existing conditions, or infection with SARS-CoV-2 might benefit most from early intervention. None.


Duplex real-time reverse transcriptase PCR to determine cytokine mRNA expression in a hamster model of New World cutaneous leishmaniasis.
The Syrian hamster, Mesocricetus auratus, has distinct immunological features and is uniquely susceptible to intracellular pathogens. Studies in hamsters are limited by the relative unavailability of tools to conduct immunological studies. To address this limitation we developed duplex real-time reverse transcriptase (RT) PCR assays for the relative quantification of the mRNAs of hamster cytokines, chemokines, and related immune response molecules. Real-time RT-PCR primers and probes were synthesized for analysis of interleukin (IL)-4, IFN-gamma, TNF-alpha, IL-10, IL-12p40, TGF-beta, IL-13, IL-21, chemokine ligand (CCL) 22, CCL17, Chemokine (C-C motif) receptor 4 and FoxP3 expression. Standard curves and validation experiments were performed for each real-time RT-PCR assay, allowing us to use the comparative Ct (2-DeltaDeltaCt) method to calculate changes in gene expression. Application of the real-time RT PCR assays to a biological model was demonstrated by comparing mRNA expression in skin and lymph node tissues between uninfected and Leishmania panamensis infected hamsters. The duplex real-time RT PCR assays provide a powerful approach for the quantification of cytokine transcription in hamsters, and their application to a model of cutaneous leishmaniasis suggests that a balanced type 1 and type 2 cytokine response contributes to the chronic, nonprogressive course of disease. These new molecular tools will further facilitate investigation into the mechanisms of disease in the hamster, not only for models of leishmaniasis, but also for other viral, bacterial, fungal, and parasitic infections.


Evaluating the Real-World Representativeness of Participants with Mild Cognitive Impairment in Canadian Research Protocols: a Comparison of the Characteristics of a Memory Clinic Patients and Research Samples.
Studies of mild cognitive impairment (MCI) employ rigorous eligibility criteria, resulting in sampling that may not be representative of the broader clinical population. To compare the characteristics of MCI patients in a Calgary memory clinic to those of MCI participants in published Canadian studies. Clinic participants included 555 MCI patients from the PROspective Registry of Persons with Memory SyMPToms (PROMPT) registry in Calgary. Research participants included 4,981 individuals with MCI pooled from a systematic literature review of 112 original, English-language peer-reviewed Canadian studies. Both samples were compared on baseline sociodemographic variables, medical and psychiatric comorbidities, and cognitive performance for MCI due to Alzheimer's disease and Parkinson's disease. Overall, clinic patients tended to be younger, more often male, and more educated than research participants. Psychiatric disorders, traumatic brain injury, and sensory impairment were commonplace in PROMPT (up to 83% affected) but > 80% studies in the systematic review excluded these conditions. PROMPT patients also performed worse on global cognition measures than did research participants. Stringent eligibility criteria in Canadian research studies excluded a considerable subset of MCI patients with comorbid medical or psychiatric conditions. This exclusion may contribute to differences in cognitive performance and outcomes compared to real-world clinical samples.


Identification and characterization of maize ACD6-like gene reveal ZmACD6 as the maize orthologue conferring resistance to Ustilago maydis.
Enhancing broad-spectrum resistance is a major goal of crop breeding. However, broad-spectrum resistance has not been thoroughly investigated, and its underlying molecular mechanisms remain elusive. In the model plant Arabidopsis (Arabidopsis thaliana), ACCELERATED CELL DEATH6 (ACD6) is a key component of broad-spectrum resistance that acts in a positive feedback loop with salicylic acid (SA) to regulate multiple pattern recognition receptors. However, the role of ACD6 in disease resistance in crop plants is unclear. Here, we show that the transcript of ANK23, one of the 15 ACD6-like genes in maize (Zea mays), is induced by SA and by infection with the pathogenic fungus Ustilago maydis. Heterologous expression of ANK23 restored disease resistance in the Arabidopsis mutant acd6-2. We show that ANK23 is a maize ortholog of ACD6 and therefore rename ANK23 as ZmACD6. Furthermore, using CRISPR/Cas9, we generated ZmACD6 knockout maize plants, which are more susceptible to U. maydis than wild-type plants. We also identified a maize line (SC-9) with relatively high ZmACD6 expression levels from a diverse natural maize population. SC-9 has increased disease resistance to U. maydis and defense activation, suggesting a practical approach to cultivate elite varieties with enhanced disease resistance.


Comparative effects of enalapril and verapamil on myocardial blood flow in systemic hypertension.
The comparative effects of calcium channel blockers and ACE inhibitors on myocardial blood flow (MBF) in hypertensive patients after long-term treatment are still unknown. Twenty hypertensive subjects with normal coronary arteries were randomly assigned to verapamil 240 to 480 mg/d or enalapril 10 to 40 mg/d. MBF was quantified at rest, during pacing tachycardia, and after dipyridamole by positron emission tomography and 13N-ammonia before and 6 months after treatment after 1 week of pharmacological washout. In both groups, blood pressure and heart rate during flow measurements were not different before and after therapy. Before treatment, mean MBF at rest, during pacing tachycardia, and after dipyridamole infusion was similar in the two groups; however, pacing and dipyridamole flows were significantly lower than those obtained in a control group of normotensive subjects. After treatment, in the enalapril-treated patients, MBF did not change in the three study conditions. In the verapamil-treated patients, MBF did not change at rest and significantly increased during pacing and after dipyridamole. The inhomogeneity of regional MBF distribution, evaluated from the coefficient of variation, decreased at rest after both treatments and, in the enalapril group, also during pacing. No relation was found between changes in MBF and changes in left ventricular mass. In arterial hypertension, MBF during pacing tachycardia and after dipyridamole is impaired. Successful therapy with verapamil increases MBF response to these stimuli, independent of changes in perfusion pressure and left ventricular mass. These results suggest that verapamil directly improves coronary microcirculatory function in hypertension. Enalapril does not significantly change MBF but reduces the inhomogeneity of regional flow distribution.


Age-related changes in plasma concentrations of the HIV protease inhibitor lopinavir.
The advent of highly active antiretroviral therapy in the treatment of HIV disease has substantially extended the lifespan of individuals infected with HIV resulting in a growing population of older HIV-infected individuals. The efficacy and safety of antiretroviral agents in the population are important concerns. There have been relatively few studies assessing antiretroviral pharmacokinetics in older patients. Thirty-seven subjects aged 18-30 years and 40 subjects aged 45-79 years, naive to antiretroviral therapy, received lopinavir/ritonavir (400/100) bid, emtricitibine 200 mg qd, and stavudine 40 mg bid. Trough lopinavir concentrations were available for 44 subjects, collected at 24, 36, and 96 weeks. At week 24, older age was associated with higher lopinavir trough concentrations, and a trend was observed toward older age being associated with higher lopinavir trough concentrations when all time points were evaluated. In the young cohort, among subjects with two or more measurements, there was a trend toward increasing intrasubject trough lopinavir concentrations over time. Using a nonlinear, mixed-effects population pharmacokinetic model, age was negatively associated with lopinavir clearance after adjusting for adherence. Adherence was assessed by patient self-reports; older patients missed fewer doses than younger patients (p = 0.02). No difference in grade 3-4 toxicities was observed between the two age group. Older patients have higher trough lopinavir concentrations and likely decreased lopinavir clearance. Age-related changes in the pharmacokinetics of antiretroviral drugs may be of increasing importance as the HIV-infected population ages and as older individuals comprise an increasing proportion of new diagnoses.


THE EFFECTS OF OPIUM ADDICTION ON THYROID AND SEX HORMONES IN DIABETIC AND NON-DIABETIC MALE AND FEMALE RATS.
Opium is a narcotic drug that is commonly abused. The prescription of pharmaceutical derivatives of opium is limited due to their possible harmful effects on the body's metabolism and tolerability by patients. The aim of the present study was to evaluate the effects of chronic opium consumption on some sexual and thyroid hormones in diabetic and non-diabetic male and female rats. This experimental study was conducted on 56 Wistar rats. The animals were divided into diabetic addicted (DA), diabetic non-addicted (DNA), non-diabetic addicted (NDA) and non-diabetic non-addicted (NDNA) groups of male and female rats. Peripheral blood samples were collected to measure the thyroid and sex hormone levels. Student's t-test was used to compare the mean values of the hormones between two groups. T3 serum level in male addicted groups significantly increased in comparison with non-addicted ones in both diabetic and non-diabetic groups. The testosterone level of male rats decreased due to the consumption of opium while it was significantly increased in diabetic and NDNA female rats in comparison with non-addicts. In DNA female animals, the mean level of 17-hydroxyprogesterone increased significantly compared with non-diabetic groups, however, it decreased in addicted females (diabetic and non-diabetic) in comparison with non-addicts. The level of DHEA-S increased significantly in diabetic and NDA male rats as compared with the non-addicted group. Opium affects the endocrine system in a sex-dependent manner, and opium could have different effects in diabetic and non-diabetic conditions.


Gout in the Hmong in the United States.
To compare characteristics of gout in Hmong patients versus whites, and examine if Hmong ethnicity is associated with risk of tophaceous gout. A retrospective chart review of Hmong and White patients with gout in a large health care system (Health Partners) in St. Paul, Minnesota, from January 2001 to March 2008, to compare clinical characteristics and risk factors for gout. Multivariable-adjusted hierarchical logistic regressions examined the association of Hmong ethnicity with risk of tophaceous gout, adjusting for age, sex, hypertension, diuretic use, and kidney function. The analytic dataset consisted of 89 Hmong patients and 84 White controls, all of whom had ethnicity confirmed, an International Classification of Diseases, ninth revision code for gout and had at least 2 physician-documented diagnoses of gout. The Hmong group was younger (58.3 vs. 66.3 years, P = 0.04), had an earlier onset of symptoms (37.4 vs. 55.0 years, P < 0.001) and higher mean serum uric acid levels during follow-up (9.1 vs. 7.6 mg/dL, P < or = 0.001). Hmong had higher rates of tophaceous gout (31.5% vs. 10.7%, P = 0.001), including hand tophi (21.3% vs. 3.6%, P < 0.001). In multivariable analyses that adjusted for age, sex, hypertension, diuretic, use, and kidney function, Hmong ethnicity was significantly associated with risk of tophaceous gout, with odds ratio 4.3 (95% confidence interval: 1.5, 12.2). Hmong patients have an earlier onset of gout symptoms. Hmong race is an independent risk factor for tophaceous gout. Future studies need to examine whether genetic or other comorbid factors predict this higher risk of more severe gout in Hmong.


Interleukins, interferons, and establishment of pregnancy in pigs.
Early pregnancy in mammals requires complex and highly orchestrated cellular and molecular interactions between specialized cells within the endometrium and the conceptus. Proinflammatory cytokines are small signaling proteins released by leukocytes that augment innate and adaptive immune responses. They are also released by the mammalian trophectoderm as the conceptus apposes the uterine surface for implantation. On approximately day 12 of development in pigs, the conceptus undergoes a rapid morphological transformation referred to as elongation while simultaneously releasing estrogens and a novel conceptus form of interleukin-1 beta (IL1β). Following elongation, pig conceptuses express interferon gamma (IFNγ) and, in lesser amounts, interferon delta (IFNδ). Significant IFN signaling takes place within the endometrium between day 14 and 18 of pregnancy as the conceptus intimately associates with the uterine epithelium. Based on studies carried out in pigs and other mammals, the combined spacio-temporal activities of conceptus estrogens, IL1β, and IFN set in motion a series of coordinated events that promote establishment of pregnancy. This is achieved through enhancement of conceptus development, uterine receptivity, maternal-fetal hemotropic exchange, and endometrial leukocyte function. These events require activation of specific signaling pathways within the uterine luminal epithelium, glandular epithelium, and stroma. Here, we review proinflammatory cytokine expression by pig conceptuses and the hypothesized actions of these molecules during establishment of pregnancy.


Radiologic imaging of the transplanted bowel.
The radiologic evaluation of the transplanted bowel is largely unknown and rather complex because it involves several techniques that depend on indications and times that have not been fully defined. From December 2000 to November 2002 in the Section of Radiology I of the University of Modena and Reggio Emilia (Modena, Italy), 11 patients with transplanted bowel were studied with different methods: traditional radiologic evaluation with contrast agent (all patients), evaluation of transit time with radiopaque markers (five patients), ultrasonographic (US) evaluation of the intestinal wall and Doppler US of the vascular axes (five patients), computed tomographic (CT) evaluation (all patients), and magnetic resonance (MR) evaluation of the bowel and the vascular axes (five patients). Traditional contrast examination enabled evaluation of the gastroesophageal transit and cardia functionality; anatomy and integrity of the anastomoses (proximal and distal); time of gastric emptying; morphology, tone, and kinesis of the transplanted small bowel loops and time of global transit. The study of transit with radiopaque markers was carried out in five patients to define the time of transit through the entire transplanted bowel, confirm recovery of intestinal motility, and identify possible abnormalities. The US examination was carried out in five patients to evaluate the morphology, thickness, and echo structural features of the intestinal loops. Color Doppler was performed to visualize the superior mesenteric artery and a wall arteriole of the sampled loop. CT examination was performed 2 to 4 weeks after surgery to evaluate the anatomy of the transplanted organs, arterial and venous anastomoses in case of complications identified with other methods or suspected, and periodically in the follow-up of patients who underwent transplantation due to Gardner syndrome. The protocol for MR evaluation of the bowel included coronal single-shot fast spin-echo T2-weighted sequences, axial and/or sagittal single-shot fast spin-echo T2-weighted sequences, coronal fast multiplanar spoiled gradient-echo (FMP- SPGR) sequences, coronal FMPSPGR sequences with and without administration of intravenous paramagnetic contrast agent, and axial or sagittal FMPSPGR fat-saturated sequences performed after dynamic gadolinium administration. The study of transit with radiopaque markers was useful in patients with chronic intestinal pseudo-obstruction because it identified recovery and normalization of motility. Traditional contrast examination of the gastrointestinal tract continues to play an important role in transplanted patients because it is a simple examination that allows evaluation of the graft anatomy and recovery of motility of the residual native bowel and the transplanted loops. Moreover, it plays a crucial role in early detection of major postoperative complications such as intestinal obstruction, perforation, fistulas, and anastomotic complications (stenosis and dehiscence). CT examination is crucial for the detection of fluid collections, abscesses, and fistulas because it can serve as a guide of drainage and during follow-up of patients with Gardner syndrome can be used to investigate all possible sites in which desmoids might arise in addition to their relation to the graft. Because patients with transplanted bowel are generally rather a young population of reproductive age and because of technologic advances, MR may represent an effective method that does not use ionizing radiation and can therefore substitute for traditional radiologic evaluation. US represents a quick examination technique that is easily available and well tolerated by patients, and it has a role to play in the follow-up of transplanted patients and in the identification of major postoperative complications. However, its role in monitoring possible rejection remains to be defined with studies on wider and more representative samples.


Genetic structure of the grey side-gilled sea slug (Pleurobranchaea maculata) in coastal waters of New Zealand.
Pleurobranchaea maculata is a rarely studied species of the Heterobranchia found throughout the south and western Pacific-and recently recorded in Argentina-whose population genetic structure is unknown. Interest in the species was sparked in New Zealand following a series of dog deaths caused by ingestions of slugs containing high levels of the neurotoxin tetrodotoxin. Here we describe the genetic structure and demographic history of P. maculata populations from five principle locations in New Zealand based on extensive analyses of 12 microsatellite loci and the COI and CytB regions of mitochondrial DNA (mtDNA). Microsatellite data showed significant differentiation between northern and southern populations with population structure being associated with previously described regional variations in tetrodotoxin concentrations. However, mtDNA sequence data did not support such structure, revealing a star-shaped haplotype network with estimates of expansion time suggesting a population expansion in the Pleistocene era. Inclusion of publicly available mtDNA sequence sea slugs from Argentina did not alter the star-shaped network. We interpret our data as indicative of a single founding population that fragmented following geographical changes that brought about the present day north-south divide in New Zealand waters. Lack of evidence of cryptic species supports data indicating that differences in toxicity of individuals among regions are a consequence of differences in diet.


Relative intranuclear magnesium and phosphorus contents in normal and tumor cells of the human thyroid gland as revealed by energy-dispersive X-ray microanalysis.
Energy dispersive X-ray microanalysis was performed on altogether 42 surgically removed tissue specimens of 32 patients, which were taken either from intact thyroid parts or various histopathologically verified tumors of the thyroid gland. The tissue specimens were processed with the freeze-fracture-freeze-drying technique and then analyzed in the so-called bulk specimen form. The studies were carried out during the years 1980-81, when intranuclear monovalent ionic composition was studied in detail. From the retained total elemental peak list, it was possible to calculate retrospectively the relative intranuclear Mg and P contents. The data processed by nested (hierarchical) analysis of variance show that the intranuclear Mg content of the 5 diagnostic groups (normal thyroid tissue, thyroiditis, benign adenomas, differentiated carcinomas and undifferentiated thyroid tumors) increases significantly, in parallel with the increasing malignancy, but the P content remains unchanged. One can conclude that the elevated intranuclear Mg content in the tumors of high malignancy may be of diagnostic importance, and a warning signal for the therapeutic approaches based on Mg-supplementations.


The first structure of an RNA m5C methyltransferase, Fmu, provides insight into catalytic mechanism and specific binding of RNA substrate.
The crystal structure of E. coli Fmu, determined at 1.65 A resolution for the apoenzyme and 2.1 A resolution in complex with AdoMet, is the first representative of the 5-methylcytosine RNA methyltransferase family that includes the human nucleolar proliferation-associated protein p120. Fmu contains three subdomains which share structural homology to DNA m(5)C methyltransferases and two RNA binding protein families. In the binary complex, the AdoMet cofactor is positioned within the active site near a novel arrangement of two conserved cysteines that function in cytosine methylation. The site is surrounded by a positively charged cleft large enough to bind its unique target stem loop within 16S rRNA. Docking of this stem loop RNA into the structure followed by molecular mechanics shows that the Fmu structure is consistent with binding to the folded RNA substrate.


Mapping of Language-and-Memory Networks in Patients With Temporal Lobe Epilepsy by Using the GE2REC Protocol.
Preoperative mapping of language and declarative memory functions in temporal lobe epilepsy (TLE) patients is essential since they frequently encounter deterioration of these functions and show variable degrees of cerebral reorganization. Due to growing evidence on language and declarative memory interdependence at a neural and neuropsychological level, we propose the GE2REC protocol for interactive language-and-memory network (LMN) mapping. GE2REC consists of three inter-related tasks, sentence generation with implicit encoding (GE) and two recollection (2REC) memory tasks: recognition and recall. This protocol has previously been validated in healthy participants, and in this study, we showed that it also maps the LMN in the left TLE (N = 18). Compared to healthy controls (N = 19), left TLE (LTLE) showed widespread inter- and intra-hemispheric reorganization of the LMN through reduced activity of regions engaged in the integration and the coordination of this meta-network. We also illustrated how this protocol could be implemented in clinical practice individually by presenting two case studies of LTLE patients who underwent efficient surgery and became seizure-free but showed different cognitive outcomes. This protocol can be advantageous for clinical practice because it (a) is short and easy to perform; (b) allows brain mapping of essential cognitive functions, even at an individual level; (c) engages language-and-memory interaction allowing to evaluate the integrative processes within the LMN; (d) provides a more comprehensive assessment by including both verbal and visual modalities, as well as various language and memory processes. Based on the available postsurgical data, we presented preliminary results obtained with this protocol in LTLE patients that could potentially inform the clinical practice. This implies the necessity to further validate the potential of GE2REC for neurosurgical planning, along with two directions, guiding resection and describing LMN neuroplasticity at an individual level.


Control of transcription by Pontin and Reptin.
Pontin and Reptin are two closely related members of the AAA+ family of DNA helicases. They have roles in diverse cellular processes, including the response to DNA double-strand breaks and the control of gene expression. The two proteins share residence in different multiprotein complexes, such as the Tip60, Ino80, SRCAP and Uri1 complexes in animals, which are involved (directly or indirectly) in transcriptional regulation, but they also function independently from each other. Both Reptin and Pontin repress certain transcriptional targets of Myc, but only Reptin is required for the repression of specific beta-catenin and nuclear factor-kappaB targets. Here, I review recent studies that have addressed the mechanisms of transcriptional control by Pontin and Reptin.


Relationships between plasma levels of matrix metalloproteinases and neurohormonal profile in patients with heart failure.
Both neurohormonal derangements and alterations in the myocardial extracellular matrix are thought to contribute to adverse ventricular remodelling that results in worsening heart failure (HF). There is also emerging preclinical information to suggest that these signalling pathways mutually regulate in HF. To assess the relationships between plasma levels of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP), and neurohormonal profiles in chronic HF. In this substudy of 184 HF patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, plasma norepinephrine and epinephrine were measured with HPLC; atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II, aldosterone, and endothelin-1 were measured with immunoassays; MMP-2, MMP-9, and TIMP-1 were measured with 2-site sandwich ELISA assays. We used Spearman's rank correlation to examine the relationships between plasma MMP and neurohormone levels. Circulating ANP, BNP, and endothelin-1 levels were positively correlated with MMP-2 and TIMP-1 levels. Plasma level of aldosterone showed a weak positive correlation with MMP-9, but there was no significant correlation between angiotensin II, epinephrine or norepinephrine and MMP-2, MMP-9, or TIMP-1. These findings suggest that specific neurohormones and extracellular matrix modulators may play a coordinated role in the pathogenesis of HF.


Topics in library technology: labeling techniques.
Labels which do not fit on the spines of books should be placed on the upper rather than lower left corner of the front cover, because the upper corner becomes visible first when a volume is tilted from the shelf. None of the past methods of marking call numbers on the spines or covers of books-direct hand lettering by pen, brush, or stylus; affixing cold release characters; embossing by hot type; or gluing labels which are handlettered, typed, or printed-nor even present automatic data processing systems have offered all the advantages of the relatively new Se-Lin labeling system: legibility, reasonable speed of application, automatic protective covering, permanent bonding, and no need for a skilled letterer. Labels seem unaesthetic to some librarians, but their advantages outweigh this consideration. When only one or a few copies of the same call number are required, Se-Lin is the best system now available for libraries marking over 1,000 books a year.


Use of radial artery for coronary revascularization.
Techniques of harvesting, strategies and techniques of implantation are presented. The radial artery, along with the internal thoracic artery, has wide application in coronary artery bypass grafting. The radial artery is implanted as a standard aorto-coronary, Y graft or extension graft. The application is extended by the use of sequential techniques.


Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum.
Although exercise usually improves motor performance, the underlying cellular changes in the cerebellum remain to be elucidated. This study aimed to investigate whether and how chronic treadmill exercise in young rats induced Purkinje cell changes to improve motor performance and rendered the cerebellum less vulnerable to toxin insults. After 1-wk familiarization of treadmill running, 6-wk-old male Wistar rats were divided into exercise and sedentary groups. The exercise group was then subjected to 8 wk of exercise training at moderate intensity. The rotarod test was carried out to evaluate motor performance. Purkinje cells in cerebellar slices were visualized by lucifer yellow labeling in single neurons and by calbindin immunostaining in groups of neurons. Compared with sedentary control rats, exercised rats not only performed better in the rotarod task, but also showed finer Purkinje cell structure (higher dendritic volume and spine density with the same dendritic field). The exercise-improved cerebellar functions were further evaluated by monitoring the long-lasting effects of intraventricular application of OX7-saporin. In the sedentary group, OX7-saporin treatment retarded the rotarod performance and induced ∼60% Purkinje cell loss in 3 wk. As a comparison, the exercise group showed much milder injuries in the cerebellum by the same toxin treatment. In conclusion, exercise training in young rats increased the dendritic density of Purkinje cells, which might play an important role in improving the motor performance. Furthermore, as Purkinje cells in the exercise group were relatively toxin resistant, the exercised rats showed good motor performance, even under toxin-treated conditions.


Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression.
Stimulation of antitumor immune mechanisms is the primary goal of cancer immunotherapy, and accumulating evidence suggests that effective alteration of the host-tumor relationship involves immunomodulating cytokines and also the presence of costimulatory molecules. To examine the antitumor effect of direct in vivo gene transfer of murine interleukin 12 (IL-12) and B7-1 into tumors, we developed an adenovirus (Ad) vector, AdIL12-B7-1, that encodes the two IL-12 subunits in early region 1 (E1) and the B7-1 gene in E3 under control of the murine cytomegalovirus promoter. This vector expressed high levels of IL-12 and B7-1 in infected murine and human cell lines and in primary murine tumor cells. In mice bearing tumors derived from a transgenic mouse mammary adenocarcinoma, a single intratumoral injection with a low dose (2.5 x 10(7) pfu/mouse) of AdIL12-B7-1 mediated complete regression in 70% of treated animals. By contrast, administration of a similar dose of recombinant virus encoding IL-12 or B7-1 alone resulted in only a delay in tumor growth. Interestingly, coinjection of two different viruses expressing either IL-12 or B7-1 induced complete tumor regression in only 30% of animals treated at this dose. Significantly, cured animals remained tumor free after rechallenge with fresh tumor cells, suggesting that protective immunity had been induced by treatment with AdIL12-B7-1. These results support the use of Ad vectors as a highly efficient delivery system for synergistically acting molecules and show that the combination of IL-12 and B7-1 within a single Ad vector might be a promising approach for in vivo cancer therapy.


Uncontrolled hypertension at the dentist: a case report of integrated healthcare.
Hypertension is a risk factor for major cardiovascular events and it is usually detected and managed by general medical practitioners (GPs) in primary care. However, it is estimated that 4.8 million adults are living with untreated high blood pressure (BP) in the UK. Health authorities are encouraging more collaborative work across health professions to find and refer individuals with undiagnosed hypertension. In this case, in 2022, a 65-year-old man with a previous history of hypertension, taking antihypertensive medication, attended a BP clinic at the University of Plymouth, Peninsula Dental School as part of a hypertension case finding pilot. His systolic and diastolic BP were 150 and 85 mmHg, respectively, and as per the trial protocol, a referral letter was sent to his GP for suspected further assessment and investigation. Then, an onward referral was made to secondary care and the participant was subsequently hospitalised for 13 days for treatment of heart failure and suspected acute coronary syndrome. This case report highlights that BP readings taken in a primary care dental setting can be very useful and recommends better integration of dental services into primary care to reduce the risk of major cardiovascular events.


Characterization of sewage sludge organic matter using solid-state carbon-13 nuclear magnetic resonance spectroscopy.
Six sewage sludges from five sewage treatment plants in Australia were characterized using solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. Spectra were acquired both before and after removal of mineral components through treatment with hydrofluoric acid (HF). Carbon mass balance indicated that little organic matter was lost on HF treatment, which significantly improved NMR sensitivity and spectral resolution, and decreased acquisition time and hence cost of NMR analysis. Two NMR techniques were used, the standard cross polarization (CP) technique and Bloch decay (BD). The BD technique had not been applied previously to the analysis of sewage sludge. For each sludge sample, both before and after HF treatment, the BD spectrum contained significantly more alkyl carbon. Spin counting, another technique applied to sewage sludge here for the first time, showed that the BD spectra of the HF-treated sludges were quantitative, while approximately 30% of the CP NMR signal went undetected. The discrepancy between CP and BD spectra was attributed to the presence of alkyl carbon with such high molecular mobility that the efficiency of cross polarization is affected. This study shows that sewage sludge organic matter is significantly different in chemistry to soil organic matter and has implications for the application of sewage sludge to agricultural land.


Anti-BP180 and anti-BP230 enzyme-linked immunosorbent assays for diagnosis and disease activity tracking of bullous pemphigoid: A prospective cohort study.
Autoantibodies against BP180 and BP230 play major roles in bullous pemphigoid (BP). We are the first to describe the values of serum anti-BP180 IgG and anti-BP230 IgG enzyme-linked immunosorbent assays (ELISA) for diagnosis and disease monitoring of BP among Thai patients. We aimed to determine the diagnostic performance of anti-BP180 IgG and anti-BP230 IgG in BP, to correlate disease activity with autoantibody levels through follow-ups, and to relate BP comorbidities with disease activity and autoantibody levels. Consecutive patients suspected of having BP were included. Skin biopsy, direct immunofluorescence, and serum anti-BP180 IgG and anti-BP230 IgG tests were performed. BP disease area index (BPDAI) was evaluated at diagnosis and throughout follow-ups. Of 131 patients, 68 were diagnosed with BP, and 63 were included as controls. Sensitivity and specificity of serum anti-BP180 IgG were 69.1% and 90.5%, respectively, while those of serum anti-BP230 IgG were 55.9% and 85.5%, respectively. Using anti-BP180 and anti-BP230 IgG antibodies resulted in a 7% increase in sensitivity compared with using anti-BP180 IgG antibody alone. Significant correlation with BPDAI was found for both autoantibodies at diagnosis but only for anti-BP180 IgG at follow-ups (p = 0.013). BP patients with positivity to anti-BP180 or anti-BP230 IgG had significantly higher BPDAI than did those without (p = 0.005). BP was associated with neurological diseases (p = 0.025), while patients with diabetes had higher disease activity (p = 0.010). While both serum autoantibodies are useful for diagnosing BP in patients with suspicious clinical features, only anti-BP180 IgG allowed prediction of disease activity over time.


SoxB1 transcription factors restrict organizer gene expression by repressing multiple events downstream of Wnt signalling.
Formation of the organizer is one of the most central patterning events in vertebrate development. Organizer-derived signals are responsible for establishing the CNS and patterning the dorsal ventral axis. The mechanisms promoting organizer formation are known to involve cooperation between Nodal and Wnt signalling. However, the organizer forms in a very restricted region, suggesting the presence of mechanisms that repress its formation. Here, we show in zebrafish that the transcription factor Sox3 represses multiple steps in the signalling events that lead to organizer formation. Although beta-catenin, Bozozok and Squint are known to play major roles in establishing the dorsal organizer in vertebrate embryos, overexpression of any of these is insufficient to induce robust expression of markers of the organizer in ectopic positions in the animal pole, where Sox3 is strongly expressed. We show that a dominant-negative nuclear localisation mutant of Sox3 can cause ectopic expression of organizer genes via a mechanism that activates all of these earlier factors, resulting in later axis duplication including major bifurcations of the CNS. We also find that the related SoxB1 factor, Sox19b, can act redundantly with Sox3 in these effects. It therefore seems that the broad expression of these SoxB1 genes throughout the early epiblast and their subsequent restriction to the ectoderm is a primary regulator of when and where the organizer forms.


Chemerin regulates NK cell accumulation and endothelial cell morphogenesis in the decidua during early pregnancy.
Although decidual natural killer (NK) cell accumulation and vascular remodeling are critical steps to ensure successful pregnancy, the molecular mechanisms controlling these events are poorly defined. Herein we analyzed whether chemerin, a recently identified chemoattractant involved in many pathophysiological processes, could be expressed in the uterine compartment and could regulate events relevant for the good outcome of pregnancy. Chemerin expression in human primary culture of stromal (ST) cells, extravillous trophoblast cells, and decidual endothelial cells (DEC) was analyzed by RT-PCR, ELISA, and Western blot. Migration through ST or DEC of peripheral blood and decidual (d) NK cells from pregnant women was performed using a transwell assay. A DEC capillary-like tube formation assay was used to evaluate endothelial morphogenesis. Chemerin is differentially expressed by decidual cells during early pregnancy being present at high levels in ST and extravillous trophoblast cells but not in DEC. Notably, ST cells from pregnant women exhibit and release higher levels of chemerin as compared with ST cells from menopausal or fertile nonpregnant women. Chemerin can support peripheral blood NK cell migration through both DEC and ST cells. Although dNK cells exhibit lower chemerin receptor (CMKLR1) expression than their blood counterpart, CMKLR1 engagement on dNK cells resulted in both ERK activation and migration through decidual ST cells. Interestingly, DEC also express CMKLR1 and undergo ERK activation and capillary-like tube structure formation upon exposure to chemerin. Our data indicate that chemerin is up-regulated during decidualization and might contribute to NK cell accumulation and vascular remodeling during early pregnancy.


The effects of 2-methoxyoestrogen sulphamates on the in vitro and in vivo proliferation of breast cancer cells.
2-Methoxyoestrogen sulphamates are a new class of compounds, which inhibit breast cancer cell proliferation and are also potent inhibitors of steroid sulphatase (STS) activity. In the present study, we have used two cell proliferation assays (MTS and AB) to identify potent new compounds in this class. Similar IC(50) values were obtained using these assays with two of the most potent compounds identified being 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE) and 2-methoxyoestradiol-17beta-cyanomethyl-3-O-sulphamate (2-MeOE2CyMATE). Both compounds inhibited the proliferation of MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cells. Using the AB assay, which allows repeat measurements of cell proliferation without killing cells, both compounds were shown to inhibit cell proliferation in an irreversible manner. As STS may be involved in the removal of the sulphamoyl moiety of these compounds, which could reduce their potency, their ability to inhibit the proliferation of MCF-7 cells transfected with the cDNA for STS was also examined. Although the STS activity was 20-fold higher in these cells than in non-transfected MCF-7 cells, no decrease in the ability of these compounds to inhibit cell proliferation was detected. To test the efficacy of these compounds in vivo, nude mice were inoculated with MCF-7 cells in Matrigel and stimulated to grow with oestradiol. Three weeks after the oral administration of 2-MeOE2bisMATE or 2-MeOE2CyMATE (20mg/kg/day, 5 days/week) tumour volumes had regressed by 52% and 22%, respectively. Both compounds also inhibited liver and tumour STS activity by >90%. The potent anti-proliferative effects of these compounds, and their ability to inhibit tumour growth and STS activity in vivo, indicates that they are suitable for development as novel therapeutic agents, which should be active against a wide range of cancers.


Technical Note: An approach to building a Monte Carlo simulation model for a double scattering proton beam system.
The purpose of this study was to demonstrate and develop a Monte Carlo (MC) simulation model for a passive double scattering compact proton therapy system based on limited information of the mechanical components. We built a virtual machine source model (VMSM) which included a detailed definition of each beam-modifying component in the nozzle. Conceptually, it is similar to the conventional virtual analytical source model (VASM), except that the numerical machine nozzle or beamline is constructed in the VMSM, whereas in the VASM analytical parameters characterizing the energy spectrum and source fluence distribution are sought. All major beam shaping components were included in the VMSM and the model simulates interactions of the beam with a rotating range modulation wheel (RMW) combined with the beam current modulation. The RMWs, the first and second scatterer in the system were generated and tuned to reproduce measurement data as closely as possible. To validate the model, we compared the percent depth dose curves, spread out Bragg peaks (SOBPs) and lateral profiles against measured commissioning beam data. The agreement of beam range between the MC calculation and measurement was within 1 mm for all beam options. The distal-falloff length was in good agreement as well (<1 mm for the large and deep groups, <1.5 mm for the small group). Agreement to within 2.5 mm of measured SOBP widths was obtained for all MC calculations. For lateral profiles, differences were found to be less than 2 mm. We demonstrated that with limited geometrical information it is possible to build an acceptable source model for MC simulations of a passive double scattering compact proton therapy system. The agreement between the measurements and the MC model provides validation for use of the model for further studies of the dosimetric effects in patient treatments.


Divide and conquer: A perspective on biochips for single-cell and rare-molecule analysis by next-generation sequencing.
Recent advances in biochip technologies that connect next-generation sequencing (NGS) to real-world problems have facilitated breakthroughs in science and medicine. Because biochip technologies are themselves used in sequencing technologies, the main strengths of biochips lie in their scalability and throughput. Through the advantages of biochips, NGS has facilitated groundbreaking scientific discoveries and technical breakthroughs in medicine. However, all current NGS platforms require nucleic acids to be prepared in a certain range of concentrations, making it difficult to analyze biological systems of interest. In particular, many of the most interesting questions in biology and medicine, including single-cell and rare-molecule analysis, require strategic preparation of biological samples in order to be answered. Answering these questions is important because each cell is different and exists in a complex biological system. Therefore, biochip platforms for single-cell or rare-molecule analyses by NGS, which allow convenient preparation of nucleic acids from biological systems, have been developed. Utilizing the advantages of miniaturizing reaction volumes of biological samples, biochip technologies have been applied to diverse fields, from single-cell analysis to liquid biopsy. From this perspective, here, we first review current state-of-the-art biochip technologies, divided into two broad categories: microfluidic- and micromanipulation-based methods. Then, we provide insights into how future biochip systems will aid some of the most important biological and medical applications that require NGS. Based on current and future biochip technologies, we envision that NGS will come ever closer to solving more real-world scientific and medical problems.


Targeted chromosomal knockouts in Mycoplasma pneumoniae.
Most gene knockouts in mycoplasmas are achieved through labor-intensive transposon mutagenesis. Here, we describe a method for making targeted deletions in Mycoplasma pneumoniae by use of homologous recombination. In this method, M. pneumoniae is transformed with a plasmid carrying an antibiotic resistance marker flanked by 1-kb regions surrounding the target gene. Following selection for the antibiotic resistance, colonies are screened for double crossovers which indicate complete deletion of the target open reading frame.


Enhancement of Electricity Production in Microbial Fuel Cells Using a Biosurfactant-Producing Co-Culture.
Microbial fuel cells are bio-electrochemical devices that enable the conversion of chemical energy into bioelectricity. In this manuscript, the use of biosurfactants (Tween 80 and surfactin) and the effect of coculturing E. coli and L. plantarum were used to investigate the generation of bioelectricity coming from an H-type microbial fuel cell. In this setup, E. coli acts as an electron donor while L. plantarum acts as an in situ biosurfactant producer. It was observed that the use of exogenous surfactants enhanced electricity production compared to conventional E. coli cultures. The utilization of Tween 80 and surfactin increased the power generation from 204 µW m-2 to 506 µW m-2 and 577 µW m-2, respectively. Furthermore, co-culturing E. coli and L. plantarum also resulted in a higher power output compared to pure cultures (132.8% more when compared to using E. coli alone and 68.1% more when compared to using L. plantarum alone). Due to the presence of surfactants, the internal resistance of the cell was reduced. The experimental evidence collected here clearly indicates that the production of endogenous surfactants, as well as the addition of exogenous surfactants, will enhance MFC electricity production.


Propagation of finite cross-section laser beams in sea water.
An expression is derived for the mean irradiance distribution of a finite cross-section laser beam propa: gating in sea water. The effects of large-scale refractive variations on beam quality due to temperature and salinity fluctuations and the incoherent scattering of suspended biological particles with indices of refraction close to that of sea water are included. The analysis is general; it is valid in both the near and the far field of the laser transmitting aperture and also for an arbitrary complex electromagnetic optical wavefunction in the exit pupil of the transmitting aperture. Analytic results are presented for the beam pattern and spot size of a Gaussian laser beam. In particular, the manner in which image resolution, beam spread, and the parameters that describe the inhomogeneities in the water are quantitatively related is discussed. Furthermore, we present a general procedure for estimating beam spot size. Finally some comments regarding focused-beam propagation and limiting angular resolution are given. It is shown that when underwater inhomogeneities dominate the small-angle scattering, the limiting angular resolution is independent of wavelength.


The risk of ischemic stroke after an acute myocardial infarction in patients with decreased renal function.
Data on the incidence, trends over time and predictors of ischemic stroke after an acute myocardial infarction (AMI) are sparse for patients with chronic kidney disease (CKD). Data for unselected AMI patients were obtained from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA) between 2003 and 2010. Patients with and without CKD were compared. Multiple logistic regression was performed to identify predictors of ischemic stroke during the hospitalization for AMI, Kaplan-Meier analysis was used to analyze the 1-year postdischarge ischemic stroke trends over time and Cox regression analysis was used to identify predictors. Of 118,434 AMI patients, 40,679 had CKD. The CKD patients had more extensive previous cardiovascular disease and received less reperfusion and secondary preventive therapies than the patients without CKD. An inhospital ischemic stroke occurred in 2.3 and 1.2% of CKD and non-CKD patients, respectively. The incidence of ischemic stroke during hospitalization for AMI was stable during the study period. The occurrence of ischemic stroke after hospital discharge decreased between 2003-2004 and 2009-2010 from 4.1 to 2.5% in CKD patients and from 2.0 to 1.3% in non-CKD patients, respectively. Percutaneous coronary intervention (PCI) and statins were independently associated with a reduced risk of stroke after discharge from hospital. Ischemic stroke is a more common complication after an AMI in CKD patients than in non-CKD patients, but the risk has decreased in recent years. The increased use of PCI and statins may have contributed to this reduction.


On the existence of a central respiratory oxygen sensor.
A commonly held view that dominates both the scientific and educational literature is that in terrestrial mammals the central nervous system lacks a physiological hypoxia sensor capable of triggering increases in lung ventilation in response to decreases in Po2 of the brain parenchyma. Indeed, a normocapnic hypoxic ventilatory response has never been observed in humans following bilateral resection of the carotid bodies. In contrast, almost complete or partial recovery of the hypoxic ventilatory response after denervation/removal of the peripheral respiratory oxygen chemoreceptors has been demonstrated in many experimental animals when assessed in an awake state. In this essay we review the experimental evidence obtained using in vitro and in vivo animal models, results of human studies, and discuss potential mechanisms underlying the effects of CNS hypoxia on breathing. We consider experimental limitations and discuss potential reasons why the recovery of the hypoxic ventilatory response has not been observed in humans. We review recent experimental evidence suggesting that the lower brain stem contains functional oxygen sensitive elements capable of stimulating respiratory activity independently of peripheral chemoreceptor input.


Computer methods of assessment of patients state for practical use in clinical laboratory.
Results in the development of computer methods of assessment of patient state are presented as tasks of; diagnostics, gravity of disease assessment, selection of treatment based upon analysis of alternatives, forecast of the patient's state. Practice-oriented PC-based inquiry-consulting system is given as a result of this study. The system combines clinical data base and analysis functions, including the elements of artificial intelligence techniques in a user-friendly interface.


Conservation success as a function of good alignment of social and ecological structures and processes.
How to create and adjust governing institutions so that they align (fit) with complex ecosystem processes and structures across scales is an issue of increasing concern in conservation. It is argued that lack of such social-ecological fit makes governance and conservation difficult, yet progress in explicitly defining and rigorously testing what constitutes a good fit has been limited. We used a novel modeling approach and data from case studies of fishery and forest conservation to empirically test presumed relationships between conservation outcomes and certain patterns of alignment of social-ecological interdependences. Our approach made it possible to analyze conservation outcome on a systems level while also providing information on how individual actors are positioned in the complex web of social-ecological interdependencies. We found that when actors who shared resources were also socially linked, conservation at the level of the whole social-ecological system was positively affected. When the scales at which individual actors used resources and the scale at which ecological resources were interconnected to other ecological resources were aligned through tightened feedback loops, conservation outcome was better than when they were not aligned. The analysis of individual actors' positions in the web of social-ecological interdependencies was helpful in understanding why a system has a certain level of social-ecological fit. Results of analysis of positions showed that different actors contributed in very different ways to achieve a certain fit and revealed some underlying difference between the actors, for example in terms of actors' varying rights to access and use different ecological resources.


Feminine famishment: Graphic medicine and anorexia nervosa.
Socio-cultural rigidities regarding the shape and size of a woman's body have not only created an urgency to refashion themselves according to a range of set standards but also generated an infiltrating sense of body dissatisfaction and poor self-esteem leading to eating disorders. Interestingly, through an adept utilisation of the formal strengths of the medium of comics, many graphic medical anorexia narratives offer insightful elucidations on the question of how the female body is not merely a biological construction, but a biocultural construction too. In this context, by drawing theoretical postulates from Susan Bordo, David Morris and other theoreticians of varying importance, and by close reading Lesley Fairfield's Tyranny and Katie Green's Lighter than My Shadow, this article considers anorexia as the bodily manifestation of a cultural malady by analysing how cultural attitudes regarding body can be potential triggers of eating disorders in girls. Furthermore, this article also investigates why comics is the appropriate medium to provide a nuanced representation of the corporeal complications and socio-cultural intricacies of anorexia.


Estimating the average length of hospitalization due to pneumonia: a fuzzy approach.
Exposure to air pollutants is associated with hospitalizations due to pneumonia in children. We hypothesized the length of hospitalization due to pneumonia may be dependent on air pollutant concentrations. Therefore, we built a computational model using fuzzy logic tools to predict the mean time of hospitalization due to pneumonia in children living in São José dos Campos, SP, Brazil. The model was built with four inputs related to pollutant concentrations and effective temperature, and the output was related to the mean length of hospitalization. Each input had two membership functions and the output had four membership functions, generating 16 rules. The model was validated against real data, and a receiver operating characteristic (ROC) curve was constructed to evaluate model performance. The values predicted by the model were significantly correlated with real data. Sulfur dioxide and particulate matter significantly predicted the mean length of hospitalization in lags 0, 1, and 2. This model can contribute to the care provided to children with pneumonia.


Expression and localization of thymidine phosphorylase/platelet-derived endothelial cell growth factor in skin and cutaneous tumors.
Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TPase/PD-ECGF) is a catabolic enzyme that has been shown to be chemotactic for endothelial cells in vitro and angiogenic in vivo. TPase/PD-ECGF expression is increased in a variety of tumors. In the skin, TPase is active in normal keratinocytes in vitro and in vivo. Our objective was to study the expression and localization of TPase/PD-ECGF by immunohistochemical analysis in normal skin and cutaneous tumors and to correlate this information with enzymatic activity of TPase. TPase/PD-ECGF expression was observed in keratinocytes with intense staining of the infundibulum of hair follicles but no staining of hair bulbs. Expression localized primarily to the nucleus of keratinocytes in the basal layer but was more intense and cytoplasrmic in suprabasal keratinocytes. Increased expression of TPase/PD-ECGF in differentiated cells was confirmed by in vitro studies of TPase activity. In cutaneous tumors, there was positive staining for TPase/ PD-ECGF in squamous cell carcinomas (10/10), eccrine poromas (3/4), eccrine syringomas (4/4), trichoepitheliomas (1/3), and tumors of the follicular infundibulum (2/3) and melanomas (5/8). There was no staining of any intradermal nevi (0/2), basal cell carcinomas (0/10) or Merkel cell carcinoma (0/1). We conclude TPase/PD-ECGF is found throughout the epidermis and its expression increases with differentiation of keratinocytes. In cutaneous tumors, expression of TPase/PD-ECGF may be linked to the cell of origin of the tumor as well as the tumor's degree of differentiation.


A Thermophilic Phage Endolysin Fusion to a Clostridium perfringens-Specific Cell Wall Binding Domain Creates an Anti-Clostridium Antimicrobial with Improved Thermostability.
Clostridium perfringens is the third leading cause of human foodborne bacterial disease and is the presumptive etiologic agent of necrotic enteritis among chickens. Treatment of poultry with antibiotics is becoming less acceptable. Endolysin enzymes are potential replacements for antibiotics. Many enzymes are added to animal feed during production and are subjected to high-heat stress during feed processing. To produce a thermostabile endolysin for treating poultry, an E. coli codon-optimized gene was synthesized that fused the N-acetylmuramoyl-L-alanine amidase domain from the endolysin of the thermophilic bacteriophage ɸGVE2 to the cell-wall binding domain (CWB) from the endolysin of the C. perfringens-specific bacteriophage ɸCP26F. The resulting protein, PlyGVE2CpCWB, lysed C. perfringens in liquid and solid cultures. PlyGVE2CpCWB was most active at pH 8, had peak activity at 10 mM NaCl, 40% activity at 150 mM NaCl and was still 16% active at 600 mM NaCl. The protein was able to withstand temperatures up to 50° C and still lyse C. perfringens. Herein, we report the construction and characterization of a thermostable chimeric endolysin that could potentially be utilized as a feed additive to control the bacterium during poultry production.


Transcriptional reprogramming during reloading of atrophied rat soleus muscle.
The hypothesis was tested that differential, coregulated transcriptional adaptations of various cellular pathways would occur early with increased mechanical loading of atrophied skeletal muscle and relate to concurrent damage of muscle fibers. Atrophy and slow-to-fast fiber transformation of rat soleus muscle was provoked by 14 days of hindlimb suspension (HS). Subsequent reloading of hindlimbs caused a fourfold increase in the percentage of muscle fibers, demonstrating endomysial tenascin-C staining. Five days after reloading, when 10% of the fibers were damaged, the normal muscle weight and slow-type fiber percentage were reestablished. Microarray analysis revealed major, biphasic patterns of gene expressional alterations with reloading that distinguish between treatments and gene ontologies. Transcript levels of factors involved in protein synthesis and certain proteasomal mRNAs were increased after 1 day of reloading and correlated to the percentage of fibers surrounded by tenascin-C. By contrast, levels of gene messages for fatty acid transporters, respiratory chain constituents, and voltage-gated cation channels were transiently reduced after 1 day of muscle loading and associated with the number of damaged fibers and the regain in muscle weight. This coregulation points toward important retooling of oxidative metabolism and the T- and SR-tubular systems with rebuilding of slow fibers. The observations demonstrate that early nuclear reprogramming with reloading of atrophic soleus muscle is coordinated and links to the processes involved in mechanical damage and regeneration of muscle fibers.


Large-aperture, tapered fiber-coupled, 10-kHz particle-image velocimetry.
We demonstrate the design and implementation of a fiber-optic beam-delivery system using a large-aperture, tapered step-index fiber for high-speed particle-image velocimetry (PIV) in turbulent combustion flows. The tapered fiber in conjunction with a diffractive-optical-element (DOE) fiber-optic coupler significantly increases the damage threshold of the fiber, enabling fiber-optic beam delivery of sufficient nanosecond, 532-nm, laser pulse energy for high-speed PIV measurements. The fiber successfully transmits 1-kHz and 10-kHz laser pulses with energies of 5.3 mJ and 2 mJ, respectively, for more than 25 min without any indication of damage. It is experimentally demonstrated that the tapered fiber possesses the high coupling efficiency (~80%) and moderate beam quality for PIV. Additionally, the nearly uniform output-beam profile exiting the fiber is ideal for PIV applications. Comparative PIV measurements are made using a conventionally (bulk-optic) delivered light sheet, and a similar order of measurement accuracy is obtained with and without fiber coupling. Effective use of fiber-coupled, 10-kHz PIV is demonstrated for instantaneous 2D velocity-field measurements in turbulent reacting flows. Proof-of-concept measurements show significant promise for the performance of fiber-coupled, high-speed PIV using a tapered optical fiber in harsh laser-diagnostic environments such as those encountered in gas-turbine test beds and the cylinder of a combustion engine.


Interaction of organ donor families and recipients.
An exploratory descriptive study of donor families and recipients of cadaveric organs was done to determine their feelings about direct contact with each other. Direct contact was desired by 70% of donor families and 75% of recipients. Donor families wanted to see firsthand the benefit of the transplant to another person. Recipients primarily wanted to express gratitude. Both groups think they have a right to meet. Although both think these interactions should be professionally regulated and facilitated, they do not think the transplant center or the organ procurement organization is responsible for the outcome of a meeting. Donor families and recipients think the process should be gradual with prior correspondence. On the basis of our findings, we have developed a list of suggested guidelines to use when facilitating an interaction.


Effect of Comorbidity on Prostate Cancer-Specific Mortality: A Prospective Observational Study.
Purpose To determine the effect of comorbidity on prostate cancer (PCa)-specific mortality across treatment types. Patients and Methods These are the results of a population-based observational study in Sweden from 1998 to 2012 of 118,543 men who were diagnosed with PCa with a median follow-up of 8.3 years (interquartile range, 5.2 to 11.5 years) until death from PCa or other causes. Patients were categorized by patient characteristics (marital status, educational level) and tumor characteristics (serum prostate-specific antigen, tumor grade and clinical stage) and by treatment type (radical prostatectomy, radical radiotherapy, androgen deprivation therapy, and watchful waiting). Data were stratified by Charlson comorbidity index (0, 1, 2, or ≥ 3). Mortality from PCa and other causes and after stabilized inverse probability weighting adjustments for clinical patient and tumor characteristics and treatment type was determined. Kaplan-Meier estimates and Cox proportional hazards regression models were used to calculate hazard ratios. Results In the complete unadjusted data set, we observed an effect of increased comorbidity on PCa-specific and other-cause mortality. After adjustments for patient and tumor characteristics, the effect of comorbidity on PCa-specific mortality was lost but maintained for other-cause mortality. After additional adjustment for treatment type, we again failed to observe an effect for comorbidity on PCa-specific mortality, although it was maintained for other-cause mortality. Conclusion This large observational study suggests that comorbidity affects other cause-mortality but not PCa-specific- mortality after accounting for patient and tumor characteristics and treatment type. Regardless of radical treatment type (radical prostatectomy or radical radiotherapy), increasing comorbidity does not seem to significantly affect the risk of dying from PCa. Consequently, differences in oncologic outcomes that were observed in population-based comparative effectiveness studies of PCa treatments may not be a result of the varying distribution of comorbidity among treatment groups.


Extent, pattern, and correlates of remote memory impairment in Alzheimer's disease and Parkinson's disease.
Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease.


Evaluation of Contemporary Trends in Femoral Neck Fracture Management Reveals Discrepancies in Treatment.
Recent evidence supports total hip arthroplasty (THA) as compared to hemiarthroplasty (HA) for the management of displaced femoral neck fractures in a significant subset of elderly patients. The purpose of this study was to examine trends in femoral neck fracture management over the last 12 years. Using the National Inpatient Sample database, we identified patients treated for femoral neck fractures between 1998 and 2010 with THA, HA, or internal fixation (IF). We examined treatment trends and demographic variables including patient age, gender, socioeconomic status, and payer and hospital characteristics. We identified 362 127 femoral neck fracture patients treated between 1998 and 2010. Overall, there were statistically significant increases in rates of THA and HA, whereas rates of IF decreased. Total hip arthroplasty varied based on patient age, with significant increases occurring in age-groups 0 to 49 years, 50 to 59 years, 60 to 69 years, and 70 to 79 years. Utilization of THA varied significantly based on socioeconomic status and race. Patient sex, urban versus rural hospital location, and teaching versus nonteaching hospital status were not related to rates of THA. Rates of THA for femoral neck fractures increased between 1998 and 2010 in patients younger than 80 years, suggesting that surgeons are responding to clinical evidence supporting THA for the treatment of elderly femoral neck fractures. This is the first study to demonstrate this change and expose disparities in practice patterns over time in response to this evidence in the United States. Further research is indicated to explore the effect of socioeconomic status and race on femoral neck fracture management.


Does Soil Contribute to the Human Gut Microbiome?
Soil and the human gut contain approximately the same number of active microorganisms, while human gut microbiome diversity is only 10% that of soil biodiversity and has decreased dramatically with the modern lifestyle. We tracked relationships between the soil microbiome and the human intestinal microbiome. We propose a novel environmental microbiome hypothesis, which implies that a close linkage between the soil microbiome and the human intestinal microbiome has evolved during evolution and is still developing. From hunter-gatherers to an urbanized society, the human gut has lost alpha diversity. Interestingly, beta diversity has increased, meaning that people in urban areas have more differentiated individual microbiomes. On top of little contact with soil and feces, hygienic measures, antibiotics and a low fiber diet of processed food have led to a loss of beneficial microbes. At the same time, loss of soil biodiversity is observed in many rural areas. The increasing use of agrochemicals, low plant biodiversity and rigorous soil management practices have a negative effect on the biodiversity of crop epiphytes and endophytes. These developments concur with an increase in lifestyle diseases related to the human intestinal microbiome. We point out the interference with the microbial cycle of urban human environments versus pre-industrial rural environments. In order to correct these interferences, it may be useful to adopt a different perspective and to consider the human intestinal microbiome as well as the soil/root microbiome as 'superorganisms' which, by close contact, replenish each other with inoculants, genes and growth-sustaining molecules.


Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin.
Selected vulnerability of neurons in Huntington's disease suggests that alterations occur in a cellular process that is particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal models of Huntington's disease (mouse and squid), but the molecular basis of this effect remains unknown. We found that polyQ-Htt inhibited FAT through a mechanism involving activation of axonal cJun N-terminal kinase (JNK). Accordingly, we observed increased activation of JNK in vivo in cellular and mouse models of Huntington's disease. Additional experiments indicated that the effects of polyQ-Htt on FAT were mediated by neuron-specific JNK3 and not by ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in Huntington's disease. Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provide a molecular basis for polyQ-Htt-induced inhibition of FAT.