Physical Activity Levels Among Adults in Uganda: Findings From a Countrywide Cross-Sectional Survey.
Being physically active is associated with lower risk of many noncommunicable diseases (NCDs). We analyzed physical activity (PA) data collected as part of Uganda's countrywide NCD risk factor survey conducted in 2014, to describe PA levels in Uganda. PA data were collected on the domains of work, travel and leisure. We calculated the percentage of participants meeting the World Health Organization (WHO) PA recommendations, and the types of intense-specific duration of PA. Prevalence ratios (PR) were used to identify factors associated with meeting WHO PA recommendations. Of the 3987 participants, 3758 (94.3%) met the WHO PA recommendations. Work-related PA of moderate intensity, and travel-related PA contributed most to participants' overall weekly duration of PA, each contributing 49.6% and 25.2% respectively. The median weekly duration of all moderate-intensity PA was 1470 minutes (interquartile range [IQR] = 540 to 2460). Weekly duration of all vigorous-intensity PA was low with a median of 0 minutes (IQR = 0 to 1080). The median daily sedentary time was 120 minutes (IQR = 60 to 240). Factors significantly associated with meeting WHO PA recommendations were body mass index and level of education. PA levels in Uganda are high, mostly achieved through travel and work-related activities of moderate intensity.


The prognostic and predictive value of mRNA expression of vascular endothelial growth factor family members in breast cancer: a study in primary tumors of high-risk early breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial.
The main prognostic variables in early breast cancer are tumor size, histological grade, estrogen receptor/progesterone receptor (ER/PgR) status, number of positive nodes and human epidermal growth factor receptor 2 (HER2) status. The present study evaluated the prognostic and/or predictive value of vascular endothelial growth factor (VEGF) family members in high-risk early breast cancer patients treated with adjuvant chemo-hormonotherapy. RNA was isolated from 308 formalin-fixed paraffin-embedded primary tumor samples from breast cancer patients enrolled in the HE10/97 trial, evaluating adjuvant dose-dense sequential chemotherapy with epirubicin followed by cyclophosphamide, methotrexate, fluorouracil (CMF) with or without paclitaxel (E-T-CMF versus E-CMF). A fully automated method based on magnetic beads was applied for RNA extraction, followed by one-step quantitative RT-PCR for mRNA analysis of VEGF-A, -B, -C and vascular endothelial growth factor receptor (VEGFR) 1, 2, 3. With a median follow-up of 8 years, 109 patients (35%) developed a relapse and 80 patients (26%) died. In high VEGF-C and VEGFR1 mRNA expressing tumors, ER/PgR-negative tumors (Fisher's exact test, P = 0.001 and P = 0.021, respectively) and HER2-positive tumors (P <0.001 and P = 0.028, respectively) were more frequent than in low VEGF-C and VEGFR1 expressing tumors, respectively. From the VEGF family members evaluated, high VEGFR1 mRNA expression (above the 75th percentile) emerged as a significant negative prognostic factor for overall survival (OS; hazard ratio (HR) = 1.60, 95% confidence interval (CI): 1.01 to 2.55, Wald's P = 0.047) and disease-free survival (DFS; HR = 1.67, 95% CI: 1.13 to 2.48, P = 0.010), when adjusting for treatment group. High VEGF-C mRNA expression was predictive for benefit from adjuvant treatment with paclitaxel (E-T-CMF arm) for OS (test for interaction, Wald's P = 0.038), while in multivariate analysis the interaction of VEGF-C with taxane treatment was significant for both OS (Wald's P = 0.019) and DFS (P = 0.041) and continuous VEGF-B mRNA expression values for OS (P = 0.019). The present study reports, for the first time, that VEGF-C mRNA overexpression, as assessed by qRT-PCR, has a strong predictive value in high-risk early breast cancer patients undergoing adjuvant paclitaxel-containing treatment. Further studies are warranted to validate the prognostic and/or predictive value of VEGF-B, VEGF-C and VEGFR1 in patients treated with adjuvant therapies and to reveal which members of the VEGF family could possibly be useful markers in identifying patients who will benefit most from anti-VEGF strategies. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998.


Differences in memory function between 5-HT1A receptor genotypes in patients with major depressive disorder.
While extensive literature on the role of the serotonin receptor 1A (5-HT1A-R) in cognition exists, the findings are largely from animal studies. There has been little research conducted into 5-HT1A-R genotypes and cognitive function in humans. This article evaluates the role of 5-HT1A-R genotypes on the profile of cognitive function in patients with major depressive disorder (MDD). The study sample was 455 MDD patients aged between 18 and 55 years. They had enrolled into a clinical trial and were tested prior to dosing on the baseline study day using the CDR System, an integrated set of 3 attention tests, 2 working memory tests, and 4 episodic memory tests. 5-HT1A-R genotyping for (SNP ID rs6295) had been conducted during the study screening period. Validated factor scores were derived from the 9 tests. It was found that patients with the C/C genotype for the C(1019)G polymorphism of the 5-HT1A-R were significantly superior in retaining and retrieving information, in both working and episodic memory, than those with either the C/G or the G/G genotypes. No differences were found in measures of attention or in the speed of retrieval of information from memory. This is, to our knowledge, the first relationship found between objective tests of cognitive function and 5-HT1A-R genotypes in MDD.


Thalassobacillus pellis sp. nov., a moderately halophilic, Gram-positive bacterium isolated from salted hides.
A Gram-positive, moderately halophilic and endospore-forming bacterium, designated strain 18OM(T), was isolated from salted animal hides. The cells were rods and produced ellipsoidal endospores at a terminal position. Strain 18OM(T) was motile, strictly aerobic and grew at 0.5-25 % (w/v) NaCl [optimal growth at 10 % (w/v) NaCl], at between pH 5.0 and 9.0 (optimal growth at pH 7.5) and at temperatures between 15 and 45 °C (optimal growth at 37 °C). Phylogenetic analysis based on 16S rRNA gene sequence comparisons showed that strain 18OM(T) was closely related to species of the genus Thalassobacillus within the phylum Firmicutes. The closest phylogenetic similarity was with Thalassobacillus devorans G-19.1(T) (98.4 %), Thalassobacillus cyri HS286(T) (97.9 %) and Thalassobacillus hwangdonensis AD-1(T) (97.4 %). The major cellular fatty acids were anteiso-C(15 : 0) (57.9 %), anteiso-C(17 : 0) (14.0 %), iso-C(15 : 0) (10.8 %) and iso-C(16 : 0) (8.1 %). The respiratory isoprenoid quinones were MK-7 (98.5 %) and MK-6 (1.5 %). The DNA G+C content was 42.9 mol%. These features confirmed the placement of strain 18OM(T) within the genus Thalassobacillus. The DNA-DNA hybridization values between strain 18OM(T) and T. devorans G-19.1(T), T. cyri HS286(T) and T. hwangdonensis AD-1(T) were 49 %, 9 % and 15 %, respectively, showing unequivocally that strain 18OM(T) constituted a novel genospecies. On the basis of phylogenetic analysis and phenotypic, genotypic and chemotaxonomic characteristics, strain 18OM(T) is considered to represent a novel species of the genus Thalassobacillus, for which the name Thalassobacillus pellis sp. nov. is proposed. The type strain is 18OM(T) ( = CECT 7566(T) = DSM 22784(T) = JCM 16412(T)).


After the flood: an evaluation of in-home drinking water treatment with combined flocculent-disinfectant following Tropical Storm Jeanne -- Gonaives, Haiti, 2004.
Tropical Storm Jeanne struck Haiti in September 2004, causing widespread flooding which contaminated water sources, displaced thousands of families and killed approximately 2,800 people. Local leaders distributed PūR, a flocculent-disinfectant product for household water treatment, to affected populations. We evaluated knowledge, attitudes, practices, and drinking water quality among a sample of PūR recipients. We interviewed representatives of 100 households in three rural communities who received PūR and PūR-related education. Water sources were tested for fecal contamination and turbidity; stored household water was tested for residual chlorine. All households relied on untreated water sources (springs [66%], wells [15%], community taps [13%], and rivers [6%]). After distribution, PūR was the most common in-home treatment method (58%) followed by chlorination (30%), plant-based flocculation (6%), boiling (5%), and filtration (1%). Seventy-eight percent of respondents correctly answered five questions about how to use PūR; 81% reported PūR easy to use; and 97% reported that PūR-treated water appears, tastes, and smells better than untreated water. Although water sources tested appeared clear, fecal coliform bacteria were detected in all sources (range 1 - >200 cfu/100 ml). Chlorine was present in 10 (45%) of 22 stored drinking water samples in households using PūR. PūR was well-accepted and properly used in remote communities where local leaders helped with distribution and education. This highly effective water purification method can help protect disaster-affected communities from waterborne disease.


An outbreak of mupirocin-resistant Staphylococcus aureus on a dermatology ward associated with an environmental reservoir.
To investigate a cluster of mupirocin-resistant Staphylococcus aureus on a dermatology ward. An outbreak of mupirocin-resistant S aureus was noted on the dermatology ward during a prospective epidemiologic study of methicillin-resistant S aureus (MRSA) and borderline methicillin-susceptible S aureus (BMSSA). Pulsed-field gel electrophoresis (PFGE) of whole-cell DNA digested with Sma I was used as a marker of strain identity. An 850-bed university hospital with a 12-bed inpatient dermatology ward. Most patients have severe, exfoliating dermatologic disorders. MRSA or BMSSA were isolated from 13 patients on the dermatology ward over a 14-month period. Eleven of these isolates (84.6%) were mupirocin-resistant. Nine isolates were present on admission (81.8%); 8 of these patients had been hospitalized on the same ward within the last two months. Nasal and hand cultures from 36 personnel were negative for mupirocin-resistant MRSA or BMSSA. Extensive environmental culturing revealed that a blood pressure cuff and the patients' communal shower were positive for mupirocin-resistant BMSSA. PFGE of all mupirocin-resistant isolates demonstrated that the nine patients and both environmental sources had identical DNA typing patterns. Changing of blood pressure cuffs between patients and more stringent cleaning of communal areas was initiated. Repeat environmental cultures were negative. S aureus is not usually associated with an environmental reservoir; however, these patients all had severe desquamation, which may have prolonged environmental contamination.


Progressive Resistance Training Volume: Effects on Muscle Thickness, Mass, and Strength Adaptations in Resistance-Trained Individuals.
Aube, D, Wadhi, T, Rauch, J, Anand, A, Barakat, C, Pearson, J, Bradshaw, J, Zazzo, S, Ugrinowitsch, C, and De Souza, EO. Progressive resistance training volume: effects on muscle thickness, mass, and strength adaptations in resistance-trained individuals. J Strength Cond Res 36(3): 600-607, 2022-This study investigated the effects of 12-SET, 18-SET, and 24-SET lower-body weekly sets on muscle strength and mass accretion. Thirty-five resistance-trained individuals (one repetition maximum [1RM] squat: body mass ratio [1RM: BM] = 2.09) were randomly divided into 12-SET: n = 13, 18-SET: n = 12, and 24-SET: n = 10. Subjects underwent an 8-week resistance-training (RT) program consisting of 2 weekly sessions. Muscle strength (1RM), repetitions to failure (RTF) at 70% of 1RM, anterior thigh muscle thickness (MT), at the medial MT (MMT) and distal MT (DMT) points, as well as the sum of both sites (ΣMT), along with region of interest for fat-free mass (ROI-FFM) were measured at baseline and post-testing. For the 1RM, there was a main time effect (p ≤ 0.0001). However, there was a strong trend toward significance (p = 0.052) for group-by-time interaction, suggesting that 18-SET increased 1RM back squat to a greater extent compared with 24-SET (24-SET: 9.5 kg, 5.4%; 18-SET: 25.5 kg, 16.2%; 12-SET: 18.3 kg, 11.3%). For RTF, only a main time-effect (p ≤ 0.0003) was observed (24-SET: 5.7 reps, 33.1%; 18-SET: 2.4 reps, 14.5%; 12-SET: 5.0 reps, 34.8%). For the MMT, DMT, ΣMT, and ROI-FFM, there was only main time-effect (p ≤ 0.0001) (MMT: 24-SET: 0.15 cm, 2.7%; 18-SET: 0.32 cm, 5.7%; 12-SET: 0.38 cm, 6.4%-DMT: 24-SET: 0.39 cm, 13.1%; 18-SET: 0.28 cm, 8.9%; 12-SET: 0.34 cm, 9.7%-ΣMT: 24-SET: 0.54 cm, 6.1%; 18-SET: 0.60 cm, 6.7%; 12-SET: 0.72 cm, 7.7%, and ROI-FFM: 24-SET: 0.70 kg, 2.6%; 18-SET: 1.09 kg, 4.2%; 12-SET: 1.20 kg, 4.6%, respectively). Although all of the groups increased maximum strength, our results suggest that the middle dose range may optimize the gains in back squat 1RM. Our findings also support that differences in weekly set number did not impact in MT and ROI-FFM adaptations in subjects who can squat more than twice their body mass.


[A survey of psychiatrists to determine their level of familiarity with anti-N-methyl-D-aspartate receptor encephalitis].
As anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis develops with incipient psychiatric symptoms in most patients, they initially seek medical care at psychiatric services. It would be desirable, therefore, for psychiatrists to be well aware of anti-NMDAR encephalitis. From this point of view, we conducted a questionnaire survey of psychiatrists to explore the present status of their level of awareness about anti-NMDAR encephalitis. A questionnaire survey of 115 psychiatrists engaged in medical care in Toyama Prefecture was conducted to explore their level of familiarity with anti-NMDAR encephalitis. Responses to the questionnaire were received from 76 psychiatrists (response collection rate 66.1%). The mean tenure in the medical profession was 23.5 ± 13.8 years for the 76 psychiatrists, of whom 61 (80.3%) were psychiatric specialists. As for the level of awareness of anti-NMDAR encephalitis, there were 37 doctors (48.7%) who were "not aware of this disorder," 23 (30.3%) who were "aware of only the name of this disorder," and 16 (21.0%) who had "knowledge of an outline of this disorder." While the level of familiarity of doctors with "knowledge of an outline of this disorder" was unrelated to whether the doctor was a specialist, the tenure in the medical profession was significantly shorter for these doctors than for the others (P < 0.05). Of the doctors who were "not aware of this disorder" and those who were "aware of only the name of this disorder," a high percentage comprised physicians working at hospitals/clinics specializing in psychiatry (P < 0.05). Only 7 doctors had encountered case(s) of anti-NMDAR encephalitis (9.2%), and among them, a significantly high percentage was on the staff of polyclinic hospitals (P < 0.05). The present survey revealed low levels of familiarity of psychiatrists with anti-NMDAR encephalitis, and this highlights the importance of further improving the awareness of psychiatrists about the concept of anti-NMDAR encephalitis.


Decreased admissions and hospital costs with a neutral effect on mortality following lowering of the troponin T cutoff point to the 99th percentile.
The implementation of high-sensitivity cardiac troponin T (hs-cTnT) assays and a cutoff based on the 99th cTnT percentile in the evaluation of patients with suspected acute coronary syndrome has not been uniform due to uncertain effects on health benefits and utilization of limited resources. Clinical and laboratory data from patients with chest pain or dyspnea at the emergency de¬partment (ED) were evaluated before (n = 20516) and after (n = 18485) the lowering of the hs-cTnT cutoff point from 40 ng/L to the 99th hs-cTnT percentile of 14 ng/L in February 2012. Myocardial infarction (MI) was diagnosed at the discretion of the attending clinicians responsible for the patient. Following lowering of the hs-cTnT cutoff point fewer ED patients with chest pain or dyspnea as the principal complaint were analyzed with an hs-cTnT sample (81% vs. 72%, p < 0.001). Overall 30-day mortality was unaffected but increased among patients not analyzed with an hs-cTnT sample (5.3% vs. 7.6%, p < 0.001). The MI frequency was unchanged (4.0% vs. 3.9%, p = 0.72) whereas admission rates decreased (51% vs. 45%, p < 0.001) as well as hospital costs. Coronary angiographies were used more frequently (2.8% vs. 3.3%, p = 0.004) but with no corresponding change in coronary interventions. At the participating hospital, lowering of the hs-cTnT cutoff point to the 99th percentile decreased admissions and hospital costs but did not result in any apparent prognostic or treatment benefits for the patients.


Compositional Categories of Ancient Glass.
From chemical analyses of ancient glasses found in Europe, Western Asia, and Africa from roughly the 15th century B.C. until the 12th century A.D., five main compositional categories have become apparent. With the possible exception of lead glasses which are only occasionally encountered in finds from this period, each of the main categories was prevalent over a wide geographic area for a period of at least several centuries. The categories are described in terms of the expected ranges of concentrations of the five elements, magnesium, potassium, manganese, antimony, and lead, which most clearly differentiate the groups.


Protracted development of responses to whisker deflection in rat trigeminal ganglion neurons.
The rodent whisker-to-barrel pathway constitutes a major model system for studying experience-dependent brain development. Yet little is known about responses of neurons to whisker stimulation in young animals. Response properties of trigeminal ganglion (NV) neurons in 2-, 3-, and 4-week-old and adult rats were examined using extracellular single-unit recordings and controlled whisker stimuli. We found that the receptive field size of NV neurons is mature in 2-week-old animals while response latencies, magnitudes, and angular tuning continue to develop between 2 weeks of age and adulthood. At the earliest time recorded, NV neurons respond to stimulation of only one whisker and can be characterized as slowly or rapidly adapting (SA, RA). The proportion of SA and RA neurons remains constant during development. Consistent with known on-going myelination of NV axons, response latencies decrease with age, becoming adult-like during the third and fourth postnatal weeks for RA and SA neurons, respectively. Unexpectedly, we found that evoked response magnitudes increase several-fold during development becoming adult-like only during the fourth postnatal week. In addition, RA neurons become less selective for whisker deflection angle with age. Maturation of response magnitude and angular tuning is consistent with developmental changes in the mechanical properties of the whisker, the whisker follicle, and the surrounding tissues. The findings indicate that whisker-derived tactile inputs mature during the first postnatal month when whisker-related cortical circuits are susceptible to long-term modification by sensory experience. Thus normal developmental changes in sensory input may influence functional development of cortical circuits.


mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging.
Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic/mammalian target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats. Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging. Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD.


Epidemiology of silicone-gel breast implants.
Silicone breast implants have been marketed in the United States since 1963. Questions remain unanswered on the safety of these medical devices despite their popularity and availability. In 1992, the Food and Drug Administration restricted the availability of silicone-gel breast implants to women requiring them for reconstruction after breast cancer or for other medical indications. Inflatable saline breast implants have remained available for either reconstruction or for cosmetic augmentation while manufacturers completed studies addressing issues of safety and effectiveness. The Food and Drug Administration (FDA) has less concern today regarding a putative association between breast implants and autoimmune disease because of epidemiologic studies that have indicated that there is not a large increase in risk for connective tissue disease in women with breast implants. These studies have not ruled out a small increase in risk of connective tissue disease to these women nor have they addressed the issue of an atypical syndrome related to silicone. The FDA has continuing concerns over local complications that are related to breast implants. The current review provides a brief discussion of the regulatory history of silicone implants and of FDA concerns over breast implants, implant prevalence, studies of systemic and local complications related to breast implants, and a brief description of the FDA study of silicone-gel breast implant rupture.


The relation of sugar intake to beta cell function in overweight Latino children.
Few studies have investigated the association between sugar intake and insulin dynamics in children, and none have examined this association in overweight Latino youth. We aimed to examine the relation between dietary components, especially sugar intake, and insulin dynamics in overweight Latino youth. We examined 63 overweight Latino children aged 9-13 y. Dietary intake was determined by 3-d records, and body composition was measured with dual-energy X-ray absorptiometry. Insulin sensitivity (S(I)), acute insulin response (AIR), and disposition index (an index of beta cell function) were measured by using a frequently sampled intravenous-glucose-tolerance test and minimal modeling. Hierarchical regression analysis ascertained the potential independent relation between insulin dynamics and dietary components. The relation between macronutrient intake and any variable related to insulin dynamics was not significant. However, higher total sugar intake, although not related to S(I), was significantly associated with lower AIR (beta = -0.296, P = 0.045) and lower beta cell function (beta = -0.421, P = 0.043), independent of the covariates age, sex, body composition, Tanner stage, and energy intake. Sugar-sweetened beverage intakes trended toward inverse association with lower AIR (beta = -0.219, P = 0.072) and beta cell function (beta = -0.298, P = 0.077). In overweight Latino children, higher intakes of sugar and sugar-sweetened beverages were associated with lower AIR and disposition index, which suggested that these children already have early signs of poor beta cell function. These results emphasize the need for early nutritional interventions to reduce daily sugar intake in overweight Latino children and potentially reduce their risk for type 2 diabetes.


Safety and immunogenicity of an intranasal sendai virus-based vaccine for human parainfluenza virus type I and respiratory syncytial virus (SeVRSV) in adults.
SeVRSV is a replication-competent Sendai virus (SeV)-based vaccine carrying the respiratory syncytial virus (RSV) fusion protein (F) gene. Unmanipulated, non-recombinant SeV is a murine parainfluenza virus type 1 (PIV-1) and serves as a Jennerian vaccine for human PIV-1 (hPIV-1). SeV protects African green monkeys (AGM) from infection after hPIV-1 challenge. The recombinant SeVRSV additionally targets RSV and protects AGM from lower respiratory infections after RSV challenge. The present study is the first to report on the safety, viral genome detection, and immunogenicity following SeVRSV vaccination of healthy adults. Seventeen and four healthy adults received intranasal SeVRSV and PBS, respectively, followed by six months of safety monitoring. Virus genome (in nasal wash) and vaccine-specific antibodies (in sera) were monitored for two and four weeks, respectively, post-vaccination. The vaccine was well-tolerated with only mild to moderate reactions that were also present in the placebo group. No severe reactions occurred. As expected, due to preexisting immunity toward hPIV-1 and RSV in adults, vaccine genome detection was transient. There were minimal antibody responses to SeV and negligible responses to RSV F. Results encourage further studies of SeVRSV with progression toward a clinical trial in seronegative children. Abbreviations: AE-adverse event; SAE-serious adverse event; SeV-Sendai virus; RSV-respiratory syncytial virus; PIV-1-parainfluenza virus-type 1; hPIV-1-human parainfluenza virus-type 1; F-RSV fusion protein; SeVRSV-recombinant SeV carrying the RSV F gene; Ab-antibody; MSW-medically significant wheezing; NOCMC-new onset chronic medical condition, mITT-modified Intent to Treat; ALRI-acute lower respiratory tract infection.


Holographic plasmonic lenses for surface plasmons with complex wavefront profile.
We present a direct-method solution toward the general problem of plasmonic wavefront manipulation and shaping to realize pre-designated functionalities based on the surface-wave holography (SWH) method. We demonstrate theoretically and experimentally the design and fabrication of holographic plasmonic lenses over surface plasmons with complex wavefront profiles. We show that visible light at 632.8 nm transmitting through a high-aspect-ratio slit or a micro-rectangle hole in a silver film can be focused to a preset three-dimensional point spot in free space via appropriately manipulating the interaction of excited surface plasmons with the nanoscale groove pattern of the holographic lens. The experiment results of scanning near-field optical microscopy for measuring the three-dimensional optical field distribution agree well both with designs and with numerical simulations, and this strongly supports the effectiveness and efficiency of the SWH method in the design of plasmonic devices that can fulfill manipulation and transformation of complicated-profile surface plasmons.


Issues of ligand accessibility and mobility in initial cell attachment.
The influence of lateral ligand mobility on cell attachment and receptor clustering has previously been explored for membrane-anchored molecules involved in cell-cell adhesion. In this study, we considered instead a cell binding motif from the extracellular matrix. Even though the lateral mobility of extracellular matrix ligands in membranes does not occur in vivo, we believe it is of interest for cell engineering in vitro. As is the case for cell-cell adhesion molecules, lateral mobility of extracellular matrix ligands could influence cell attachment and, subsequently, cell behavior in cell culture. In this paper, the accessibility and functionality of extracellular matrix ligands presented at surfaces were evaluated for the conditions of laterally mobile versus non-mobile ligands by studying ligand-antibody binding events and early cell attachment as a function of ligand concentration. We compare the initial attachment of rat-derived adult hippocampal progenitor (AHP) cells on laterally mobile, supported phospholipid bilayer membranes to non-mobile, poly-L-lysine-grafted-poly(ethylene glycol) (PLL-g-PEG) polymer films functionalized with a range of laminin-derived IKVAV-containing peptide densities. To this end, synthesis of a new PLL-g-PEG/PEG-IKVAV polymer is described. The characterization of available IKVAV peptides on both surface presentations schemes was explored by studying the mass uptake of anti-IKVAV antibodies using a combination of the surface-sensitive techniques quartz crystal microbalance with dissipation monitoring, surface plasmon resonance spectroscopy, and optical waveguide lightmode spectroscopy. IKVAV-containing peptides presented on laterally mobile, supported phospholipid bilayers and non-mobile PLL-g-PEG were recognized by the anti-IKVAV antibody in a dose-dependent manner, indicating that the amount of available IKVAV ligands increases proportionally with ligand density over the concentrations tested. Attachment of AHP cells to IKVAV-functionalized PLL-g-PEG and supported phospholipid bilayers followed a sigmoidal dependence on peptide concentration, with a critical concentration of approximately 3 pmol/cm2 IKVAV ligands required to support initial AHP cell attachment for both surface modifications. There appeared to be little influence of IKVAV peptide mobility on the initial attachment of AHP cells. Although the spread in the cell attachment data was larger for the PLL-g-PEG surface modification, this was reduced when observed after 24 h, indicating that the cells might need longer times to establish attachment strengths equivalent to those observed on peptide-functionalized supported lipid bilayers. The present study is a step toward understanding the influence of extracellular-matrix-derived ligand mobility on cell fate. Further analysis should focus on the systematic tuning of lateral ligand diffusion, as well as a comparison between the response of non-spreading cells (i.e., AHPs), versus spreading cells (i.e., fibroblasts).


Advances and challenges in understanding histone demethylase biology.
Within the last decade we have witnessed significant progress in the field of chromatin methylation, ranging from the discovery that chromatin methylation is reversible, to the identification of two classes of oxidative chromatin demethylases. Multiple genetic and cellular studies emphasize the role of members of the amine oxidase and 2-oxoglutarate oxygenase enzyme families involved in methyl-lysine in physiology and disease. Advances in understanding of the underlying biochemistry have resulted in development of first series of clinical inhibitors and tool compounds which continue to resolve and help understand the complex relationships between chromatin modification, control of gene expression and metabolic states.


Computational reverse-engineering of a spider-venom derived peptide active against Plasmodium falciparum SUB1.
Psalmopeotoxin I (PcFK1), a protein of 33 aminoacids derived from the venom of the spider Psalmopoeus Cambridgei, is able to inhibit the growth of Plasmodium falciparum malaria parasites with an IC50 in the low micromolar range. PcFK1 was proposed to act as an ion channel inhibitor, although experimental validation of this mechanism is lacking. The surface loops of PcFK1 have some sequence similarity with the parasite protein sequences cleaved by PfSUB1, a subtilisin-like protease essential for egress of Plasmodium falciparum merozoites and invasion into erythrocytes. As PfSUB1 has emerged as an interesting drug target, we explored the hypothesis that PcFK1 targeted PfSUB1 enzymatic activity. Molecular modeling and docking calculations showed that one loop could interact with the binding site of PfSUB1. The calculated free energy of binding averaged -5.01 kcal/mol, corresponding to a predicted low-medium micromolar constant of inhibition. PcFK1 inhibited the enzymatic activity of the recombinant PfSUB1 enzyme and the in vitro P. falciparum culture in a range compatible with our bioinformatics analysis. Using contact analysis and free energy decomposition we propose that residues A14 and Q15 are important in the interaction with PfSUB1. Our computational reverse engineering supported the hypothesis that PcFK1 targeted PfSUB1, and this was confirmed by experimental evidence showing that PcFK1 inhibits PfSUB1 enzymatic activity. This outlines the usefulness of advanced bioinformatics tools to predict the function of a protein structure. The structural features of PcFK1 represent an interesting protein scaffold for future protein engineering.


Quantitative analysis of vitreous inflammation using optical coherence tomography in patients receiving sub-Tenon's triamcinolone acetonide for uveitic cystoid macular oedema.
To evaluate the vitreous signals obtained on spectral domain optical coherence tomography (SD-OCT) in patients with uveitic cystoid macular oedema (CMO) and compare these signals before and after sub-Tenon's triamcinolone acetonide injection. Retrospective study with standardised longitudinal imaging preintervention and postintervention. The study cohort comprises 22 patients (22 eyes) with uveitic CMO receiving a sub-Tenon's triamcinolone acetonide (STTA) injection. Post hoc analysis of SD-OCT images using custom software provided an 'absolute' measurement of vitreous signal intensity, which was expressed as a ratio to the retinal pigment epithelium intensity ('VIT/RPE-relative intensity') in arbitrary units. Difference in VIT/RPE-relative intensity before and after treatment. Treatment with STTA resulted in a significant reduction in VIT/RPE-relative intensity, which was associated with both a reduction in central retinal thickness (CRT) and improvement in visual acuity. Mean (SD) VIT/RPE-relative intensity pretreatment was 0.139 (0.074) versus 0.053 (0.028) post-treatment (p=3×10-5). Mean (SD) CRT was 581 μm (119 μm) pretreatment versus 333 μm (95 μm) post-treatment (p=2×10-8); the mean reduction in CRT was 248 (95% CI 189 to 306). The correlation coefficient between VIT/RPE-relative intensity and CRT was 0.534 (p=0.011) and between VIT/RPE-relative intensity and visual acuity was 0.702 (p=0.0001). This study provides evidence that the OCT-derived VIT/RPE-relative intensity may be useful as a quantitative and objective marker of disease activity and treatment response in uveitis complicated by CMO. This first longitudinal study of this novel OCT parameter is an encouraging step in the development of sensitive objective OCT-based endpoints for trials of efficacy in uveitis.


Dural arachnoid granulations and "giant" arachnoid granulations.
Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300 years ago, two issues draw particular attention: first, the radiological features and differential diagnosis of the so-called giant AGs (GAGs) and second, their possible association with various disease processes. In order to evaluate the frequency, size and normal distribution of GAGs, an anatomical study of the dural sinuses was carried out. It involved all the autopsies performed during the period August 2002-February 2005 and included 651 cases: 306 females and 345 males, aged 13-99 years (mean 69 years). Grossly visible GAGs were identified in 24 cases: 7 females and 17 males, aged 45-92 years (mean 69 years). This is the largest population-based anatomical study on GAGs. It shows that GAGs, in general a rare finding (3.68%), are rather common in the adult population, especially in the elderly (aged >65 years) and that they can reach remarkable size (up to 2.5 cm and more in diameter). Giant AGs should be considered in the radiological differential diagnosis of intradural lesions, particularly those occurring in the transverse sinus of the elderly.


Adherence to a randomized controlled trial of aerobic exercise in breast cancer survivors: the Yale exercise and survivorship study.
To examine predictors of exercise adherence in breast cancer survivors. Seventy-five breast cancer survivors were randomly assigned to exercise (n = 37) or usual care (n = 38). Demographic, prognostic, physiologic, and psychosocial information was collected at baseline and 6 months. The exercise goal was 30 min of exercise 5 days/week for 6 months. Women randomized to exercise participated in moderate-intensity recreational exercise for 123 +/- 52 min/week (81% of the prescribed 150 min/week) over 6 months. Baseline variables associated with better adherence were lower body mass index (BMI), smaller waist circumference, higher amounts of physical activity 6 months prior to enrollment, being in the preparation vs. contemplation Stage of Change and higher FACT-B breast cancer subscale score. After adjusting for these variables, lower BMI and higher Stage of Change continued to be associated with better adherence (p < 0.05). Future studies of exercise and breast cancer prognosis should target obese women for participation, as well as women just beginning to contemplate participation and its benefits after a cancer diagnosis.


Base-catalyzed intramolecular hydroamination of cyclohexa-2,5-dienes: insights into the mechanism through DFT calculations and application to the total synthesis of epi-elwesine.
The base-catalyzed intramolecular hydroamination of 1-ethylaminocyclohexa-2,5-dienes is described. The transformation proceeds through isomerization of the cyclohexa-1,4-dienyl fragment into the corresponding conjugated 1,3-diene prior to the hydroamination step. Attaching a chiral glycinol ether auxiliary on the amino group allows the protonation to occur with complete diastereocontrol. The resulting lithium amide then adds onto the 1,3-dienyl moiety, affording the desired fused pyrrolidine ring along with the corresponding lithium allylic anion. Protonation of the latter then proceeds with high regiocontrol to favor the resulting allylic amines. In contrast, when the reaction was performed on primary amines, fused pyrrolidines bearing a homoallylic amino group were obtained. The stereochemical course of the process and determination of the reaction pathways were established based on calculations performed at the DFT level. Finally, application of the methodology to the enantioselective synthesis of (+)-epi-elwesine, a crinane alkaloid, is described.


Endoparasite control management on horse farms--lessons from worm prevalence and questionnaire data.
Increasing prevalence of anthelmintic resistance in equine nematodes calls for a reexamination of current parasite control programmes to identify factors influencing control efficacy and development of resistance. To investigate if associations occur between prevalence of parasitic nematodes and management practices. German horse farms (n = 76) were investigated in 2003 and 2004. Information on farm and pasture management with respect to endoparasite control measures obtained using a questionnaire survey. Faecal examinations were performed in parallel. Horses (n = 2000) were examined by faecal nematode egg counts, grouped into foals, yearlings and mature individuals for statistical analyses. Farms were categorised into 3 types, riding, stud farms and small holdings. Count regression models were used to analyse strongyle faecal egg count data. Following dichotomisation of faecal egg count (FEC) data, prevalence of strongyle and Parascaris equorum infections were assessed by logistic regression models as a function from various management factors. Yearlings on stud farms showed a 2-fold higher risk of being positive for strongyle FEC, higher (i.e. > or =3 per year) anthelmintic drug treatment frequencies were associated with reduced strongyle infection rates only in mature individuals but not in foals or yearlings, foals on farms fertilising pastures with horse manure had a significantly higher risk of being P. equorum FEC positive and yearlings on stud farms were more often showing incomplete FECR following anthelmintic treatment compared to yearlings on other farm types. The mean yearly treatment frequencies per age group were: foals 4.52, yearlings 3.26 and mature horses 2.72 times, respectively. To delay the development of anthelmintic, resistance management should include additional nonchemotherapeutic parasite control strategies, FEC-monitoring, controlled quarantine treatment of new arrivals and control of efficacy by the faecal egg count reduction test on a regular basis.


A patient on long-term proton pump inhibitors develops sudden seizures and encephalopathy: an unusual presentation of hypomagnesaemia.
Objective. To present an unusual but known cause of hypomagnesaemia induced-hypocalcaemia in a chronic GORD patient with severe symptoms with a review of the current literature. Methods. Analysis of the clinical and laboratory findings of the patient and discussion of the multi-factorial nature of his disease and the underlying mechanisms. Results. Our patient described features of magnesium deficiency such as weakness, muscle twitches, and fits with clinical signs of hypocalcaemia: a carpal pedal spasm and paraesthesia. Preadmission blood results revealed low calcium and magnesium levels. He was admitted to ITU, when he presented with seizures and developed encephalopathy. The total vitamin D level was 52.4 nmol/L (>49.9). His U&Es and LFTs were within the normal range with the exception of potassium. He was on Omeprazole for his GORD. With omission of the PPI 1 day after admission and replacement therapy, his ion levels normalised. Conclusion. Hypomagnesaemia is often undiagnosed and is associated with multiple biochemical abnormalities. Treatment focus should be aimed at stopping the PPI and replacing the magnesium. Over use of PPIs is a problem in practice, with the FDA issuing a warning over long-term use. Continued monitoring and decision making on dose reduction/withdrawal is essential to avoid complications.


Are rural Ohio Appalachia cancer survivors needs different than urban cancer survivors?
Limited information is available about rural cancer survivors' needs and if they differ from urban cancer survivors. A convenience sample of cancer survivors completed a self-administered survey. Rural Appalachia (n = 99) and urban non-Appalachia (n = 107) cancer survivors completed the survey. Urban survivors reported more needs than rural survivors (p < 0.001), but worry about cancer recurrence and concern about fatigue were reported most often by both urban and rural survivors. Urban survivors (n = 87; 81.3%) and rural survivors (n = 72; 72.9%) indicated that they searched for cancer information, but rural survivors were more likely to obtain information from family members and healthcare providers (p < 0.05). Rural survivors differed from urban survivors by reporting less effort to get the information they needed (p < 0.05) and less concern about the quality of the information (p < 0.01), but they reported having a harder time understanding the information they found (p < 0.05). Rural and urban survivors' most frequent needs focused on cancer recurrence and fatigue. Rural survivors reported fewer needs compared to urban survivors; however, our findings suggest certain needs may be more important to rural survivors. While most survivors reported searching for information about cancer, rural and urban survivors use different sources for finding information and have varying experiences in their searches. There is an ongoing need to provide survivorship care that is tailored to the unique needs of cancer survivors. It is essential to provide educational materials for all cancer survivors, but using different communication channels for urban versus rural survivors may be beneficial.


Endocarditis in burn patients: clinical and diagnostic considerations.
Burned patients are at high risk for invasive procedures, bacteremia, and other infectious complications. Previous publications describe high incidence, delayed diagnosis, and high mortality for endocarditis in burned patients, but do not address use of contemporary diagnostic criteria. Further analysis of the clinical presentation and diagnosis may aid in the earlier recognition and decreased mortality of endocarditis in burned patients. At a 40 bed burn center, during the period from 1 January 2003 to 1 August 2006, blood culture, electronic inpatient, echocardiographic, and autopsy records were reviewed for cases of endocarditis and persistent bacteremia (blood culture positivity for the same organism separated by 24h). In addition, we reviewed cases of burn-related bacterial endocarditis published in the English language. We compared the clinical and diagnostic aspects of our identified cases with those in the published literature. There were 90 episodes of persistent bacteremia or fungemia in 56 of 1250 patients admitted during the study period. Echocardiography was performed on 19, identifying 4 cases of endocarditis. One additional case of endocarditis was identified post-mortem. Time until echocardiography ranged from 6 to 176 days after onset of bacteremia. Case patient age ranged from 31 to 64 years, and total burn surface area ranged from 34 to 80%. Endocarditis occurred in 0.4% of burn unit admissions and in 8.9% of these patients with persistent bacteremia. Sites involved included the mitral valve (3), tricuspid valve (2), aortic valve (1), and pulmonic valve (1). Pathogens included Staphylococcus aureus, Pseudomonas aeruginosa, and one case of Enterococcus faecium. Diagnostic clues were minimal. Case mortality was 100%. A literature review revealed 17 publications describing confirmed bacterial endocarditis in burned patients. These cases revealed a predilection for infection by S. aureus and P. aeruginosa, a relative paucity of diagnostic clues prior to death, and a trend towards ante-mortem diagnosis and increased survival with use of diagnostic echocardiography. The incidence and mortality of endocarditis in burned patients remain high. Clinical clues for endocarditis in this cohort are minimal and diagnosis may be delayed. For burned patients with persistent bacteremia, especially S. aureus or P. aeruginosa of unknown source, the diagnosis of endocarditis should be entertained and early echocardiography considered.


Characteristics of six-month tobacco use outcomes of Black patients seeking smoking cessation intervention.
Although Blacks experience disproportionately greater morbidity and mortality attributable to smoking than other racially-classified social groups, few studies have examined the impact of clinical interventions for nicotine dependence within this population. The main objective of this study was to examine 6-month outcomes among 146 self-identified adult Black patients who received an individually-tailored nicotine dependence intervention in an academic medical setting. Measures included a baseline demographic questionnaire and telephone follow-up to obtain self-reported 6-month tobacco use status. Univariate analysis was performed to assess the association of baseline patient characteristics with tobacco abstinence at 6 months following the clinic intervention. Of the 146 patients, 83% were seen in an outpatient clinic setting, while 17% were seen as inpatients in the hospital. At baseline, 53% reported smoking an average of 20 or more cigarettes per day, 32% were highly nicotine dependent, and 53% were in the preparation or action stage of change. Six months following the intervention, the 7-day point-prevalence tobacco abstinence rate was 43/146 (29%; 95% C.I. 22% to 37%). An individualized nicotine dependence intervention conducted in an academic medical setting yielded encouraging abstinence rates for Black smokers.


Modifiable causes of premature death in middle-age in Western Europe: results from the EPIC cohort study.
Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death. We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models. We identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31-32 %) and 14 % (95 % CI, 12-16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8-12 %) and high blood pressure (9 %; 95 % CI, 7-11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55-59 %), being 35 % (95 % CI, 32-37 %) among never smokers and 74 % (95 % CI, 73-75 %) among current smokers. While smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed.


CAPER is vital for energy and redox homeostasis by integrating glucose-induced mitochondrial functions via ERR-α-Gabpa and stress-induced adaptive responses via NF-κB-cMYC.
Ever since we developed mitochondria to generate ATP, eukaryotes required intimate mito-nuclear communication. In addition, since reactive oxygen species are a cost of mitochondrial oxidative phosphorylation, this demands safeguards as protection from these harmful byproducts. Here we identified a critical transcriptional integrator which eukaryotes share to orchestrate both nutrient-induced mitochondrial energy metabolism and stress-induced nuclear responses, thereby maintaining carbon-nitrogen balance, and preserving life span and reproductive capacity. Inhibition of nutrient-induced expression of CAPER arrests nutrient-dependent cell proliferation and ATP generation and induces autophagy-mediated vacuolization. Nutrient signaling to CAPER induces mitochondrial transcription and glucose-dependent mitochondrial respiration via coactivation of nuclear receptor ERR-α-mediated Gabpa transcription. CAPER is also a coactivator for NF-κB that directly regulates c-Myc to coordinate nuclear transcriptome responses to mitochondrial stress. Finally, CAPER is responsible for anaplerotic carbon flux into TCA cycles from glycolysis, amino acids and fatty acids in order to maintain cellular energy metabolism to counter mitochondrial stress. Collectively, our studies reveal CAPER as an evolutionarily conserved 'master' regulatory mechanism by which eukaryotic cells control vital homeostasis for both ATP and antioxidants via CAPER-dependent coordinated control of nuclear and mitochondrial transcriptomic programs and their metabolisms. These CAPER dependent bioenergetic programs are highly conserved, as we demonstrated that they are essential to preserving life span and reproductive capacity in human cells-and even in C. elegans.


Caspase-8 and caspase-3 small interfering RNA decreases ischemia/reperfusion injury to the liver in mice.
Ischemia/reperfusion injury (I/R injury) of the liver remains a significant problem during liver surgery and transplantation. I/R injury is associated with liver apoptosis, which is mediated by death receptors such as Fas and tumor necrosis factor alpha (TNF-alpha), and/or mitochondrial dysfunction induced by cellular stress. Caspase-8 is presumed to be the apex of the death-mediated apoptosis pathway, whereas caspase-3 belongs to the "effector" proteases in the apoptosis cascade. Synthetic small interfering RNAs (siRNAs) specifically suppress gene expression by RNA interference. Therefore, we evaluated the therapeutic efficacy of caspase-8 and caspase-3 siRNA in a murine model of liver I/R injury. In C57BL/6 mice, 45% or 70% of the liver mass was clamped for 90 minutes. For survival analysis, total hepatic ischemia was induced for 45 minutes. In vivo delivery of siRNA was performed via the portal vein by high-volume injection (0.5 nmol of siRNA in 1 mL containing 10% lipiodol) 60 minutes before ischemia. As a control, animals received either vehicle or non-sense siRNA (siRNA-scrambled). Liver uptake of siRNA was analyzed in transgenic mice who express beta-galactosidase (beta-gal) (C57BL/6J-TgN(MTn-LacZ)204Bri) after administration of siRNA-LacZ. A 3- to 4-fold decrease in beta-gal activity was accomplished at 0.5 nmol. No significant change in beta-gal activity was demonstrated in mice receiving non-sense siRNA. Immunohistochemical studies found that 60% of the liver cells efficiently took up siRNA. Significant reduction in serum aspartate transaminase was found in animals treated with siRNA caspase-8 or caspase-3 compared with siRNA-scrambed or vehicle-treated controls. More than a 60% reduction in caspase-8 and caspase-3 gene expression and activities was accomplished after siRNA administration. Animals treated with siRNA presented lower infiltration of polymorphonuclear leukocytes and better preservation of the liver architecture compared with controls. All of the control mice subjected to total liver ischemia died within 5 days. In contrast, 30% of the animals given siRNA caspase-8 and 50% of those treated with siRNA caspase-3 survived indefinitely (>30 days). Small interfering RNA targeted to caspase-8 and caspase-3 provided significant protection against I/R injury to the liver. This approach could be therapeutic in liver transplantation and other conditions associated with I/R injury to the liver.


Waiting by mistake: symbolic representation of rewards modulates intertemporal choice in capuchin monkeys, preschool children and adult humans.
In the Delay choice task subjects choose between a smaller immediate option and a larger delayed option. This paradigm, also known as intertemporal choice task, is frequently used to assess delay tolerance, interpreting a preference for the larger delayed option as willingness to wait. However, in the Delay choice task subjects face a dilemma between two preferred responses: "go for more" (i.e., selecting the larger, but delayed, option) vs. "go for sooner" (i.e., selecting the immediate, but smaller, option). When the options consist of visible food amounts, at least some of the choices of the larger delayed option might be due to a failure to inhibit a prepotent response towards the larger option rather than to a sustained delay tolerance. To disentangle this issue, we tested 10 capuchin monkeys, 101 preschool children, and 88 adult humans in a Delay choice task with food, low-symbolic tokens (objects that can be exchanged with food and have a one-to-one correspondence with food items), and high-symbolic tokens (objects that can be exchanged with food and have a one-to-many correspondence with food items). This allows evaluating how different methods of representing rewards modulate the relative contribution of the "go for more" and "go for sooner" responses. Consistently with the idea that choices for the delayed option are sometimes due to a failure at inhibiting the prepotent response for the larger quantity, we expected high-symbolic tokens to decrease the salience of the larger option, thus reducing "go for more" responses. In fact, previous findings have shown that inhibiting prepotent responses for quantity is easier when the problem is framed in a symbolic context. Overall, opting for the larger delayed option in the visible-food version of the Delay choice task seems to partially result from an impulsive preference for quantity, rather than from a sustained delay tolerance. In capuchins and children high-symbolic stimuli decreased the individual's preference for the larger reward by distancing from its appetitive features. Conversely, the sophisticated symbolic skills of adult humans prevented the distancing effect of high-symbolic stimuli in this population, although this result may be due to methodological differences between adult humans and the other two populations under study. Our data extend the knowledge concerning the influence of symbols on both human and non-human primate behavior and add a new element to the interpretation of the Delay choice task. Since high-symbolic stimuli decrease the individual's preference for the larger reward by eliminating those choices due to prepotent responses towards the larger quantity, they allow to better discriminate responses based on genuine delay aversion. Thus, these findings invite greater caution in interpreting the results obtained with the visible-food version of the Delay choice task, which may overestimate delay tolerance.


Pharmacokinetics and pharmacodynamics of enantiomers of pimobendan in patients with dilated cardiomyopathy and congestive heart failure after single and repeated oral dosing.
Pharmacokinetics and pharmacodynamics of pimobendan were studied in eight patients with dilated cardiomyopathy and chronic congestive heart failure after single dosing and after 2-week repeated dosing of 5 mg racemic pimobendan. Enantiomers of pimobendan and its demethylated metabolite in plasma and in red blood cells were measured. In the single-dose study, the peak plasma levels of 16.3 +/- 4.0 and 17.0 +/- 3.1 ng/ml of (+)- and (-)-pimobendan were observed at 0.9 hour after dosing. The concentration-time curves followed a two-compartment model, with terminal half-lives of 2.56 +/- 0.35 and 2.93 +/- 0.33 hours for (+)- and (-)-pimobendan (p > 0.05), respectively. The oral volumes of distribution after equilibrium were 3.26 +/- 0.74 and 3.13 +/- 0.75 L/kg, and oral clearances were 28.6 +/- 7.0 and 21.9 +/- 4.1 ml/min/kg for (+)- and (-)-pimobendan (p > 0.05), respectively. In red blood cells, the respective (+)- and (-)-pimobendan concentrations were 5.8 and 8.4 times higher than those in plasma, indicating a stereoselective partitioning of drugs between plasma and red blood cells. The pharmacodynamic effect of pimobendan was evaluated by echocardiography. The ejection fraction, mean velocity of circumferential fiber shortening, aortic flow peak velocity, cardiac index, and stroke volume index significantly increased 50% to 60%. The left ventricular end-systolic dimension, systolic blood pressure, and diastolic blood pressure significantly decreased 8% to 11%. These effects lasted for more than 8 hours. In a 2-week repeated-dose study, there was no significant dose accumulation in plasma and red blood cells. The pharmacokinetic parameters were similar to those in the single-dose study, except for significantly shorter absorption half-lives. The baseline levels of cardiac index and stroke volume index were significantly higher than the baseline levels in the single-dose study. This suggests an accumulation of pharmacodynamic effects despite a relatively short elimination half-life.


A prospective survey of Pseudomonas aeruginosa colonization and infection in the intensive care unit.
Pseudomonas aeruginosa (PA) surveillance may improve empiric antimicrobial therapy, since colonizing strains frequently cause infections. This colonization may be 'endogenous' or 'exogenous', and the source determines infection control measures. We prospectively investigated the sources of PA, the clinical impact of PA colonization upon admission and the dynamics of colonization at different body sites throughout the intensive care unit stay. Intensive care patients were screened on admission and weekly from the pharynx, endotracheal aspirate, rectum and urine. Molecular typing was performed using Enterobacterial Repetitive Intergenic Consensus Polymerase Chain reaction (ERIC-PCR). Between November 2014 and January 2015, 34 patients were included. Thirteen (38%) were colonized on admission, and were at a higher risk for PA-related clinical infection (Hazard Ratio = 14.6, p = 0.0002). Strains were often patient-specific, site-specific and site-persistent. Sixteen out of 17 (94%) clinical isolates were identical to strains found concurrently or previously on screening cultures from the same patient, and none were unique. Ventilator associated pneumonia-related strains were identical to endotracheal aspirates and pharynx screening (87-75% of cases). No clinical case was found among patients with repeated negative screening. PA origin in this non-outbreak setting was mainly 'endogenous' and PA-strains were generally patient- and site-specific, especially in the gastrointestinal tract. While prediction of ventilator associated pneumonia-related PA-strain by screening was fair, the negative predictive value of screening was very high.


Lipoprotein-inspired nanoparticles for cancer theranostics.
Over hundreds of millions of years, animals have evolved endogenous lipoprotein nanoparticles for shuttling hydrophobic molecules to different parts of the body. In the last 70 years, scientists have developed an understanding of lipoprotein function, often in relationship to lipid transport and heart disease. Such biocompatible, lipid-protein complexes are also ideal for loading and delivering cancer therapeutic and diagnostic agents, which means that lipoprotein and lipoprotein-inspired nanoparticles also offer opportunities for cancer theranostics. By mimicking the endogenous shape and structure of lipoproteins, the nanocarrier can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. The small size (less than 30 nm) of the low-density (LDL) and high-density (HDL) classes of lipoproteins allows them to maneuver deeply into tumors. Furthermore, lipoproteins can be targeted to their endogenous receptors, when those are implicated in cancer, or to other cancer receptors. In this Account, we review the field of lipoprotein-inspired nanoparticles related to the delivery of cancer imaging and therapy agents. LDL has innate cancer targeting potential and has been used to incorporate diverse hydrophobic molecules and deliver them to tumors. Nature's method of rerouting LDL in atherosclerosis provides a strategy to extend the cancer targeting potential of lipoproteins beyond its narrow purview. Although LDL has shown promise as a drug nanocarrier for cancer imaging and therapy, increasing evidence indicates that HDL, the smallest lipoprotein, may also be of use for drug targeting and uptake into cancer cells. We also discuss how synthetic HDL-like nanoparticles, which do not include human or recombinant proteins, can deliver molecules directly to the cytoplasm of certain cancer cells, effectively bypassing the endosomal compartment. This strategy could allow HDL-like nanoparticles to be used to deliver drugs that have increased activity in the cytoplasm. Lipoprotein nanoparticles have evolved to be ideal delivery vehicles, and because of that specialized function, they have the potential to improve cancer theranostics.


Monitoring interfacial lectin binding with nanomolar sensitivity using a plasmon field effect transistor.
By immobilizing glycopolymers onto the surface of the recently developed plasmonic field effect transistor (FET), the recognition between lectins and surface-immobilized glycopolymers can be detected over a wide dynamic range (10-10 to 10-4 M) in an environment that resembles the glycocalyx. The binding to the sensor surface by various lectins was tested, and the selectivities and relative binding affinity trends observed in solution were maintained on the sensor surface, and the significantly higher avidities are attributed to cluster-glycoside effects that occur on the surface. The combination of polymer surface chemistry and optoelectronic output in this device architecture produces amongst the highest reported detection sensitivity for ConA. This work demonstrates the benefits that arise from combining emerging device architectures and soft-matter systems to create cutting edge nanotechnologies that lend themselves to fundamental biological studies and integration into point-of-use diagnostics and sensors.


Biochemical aspects of cardiac muscle differentiation.
Experiments were designed to determine whether DNA synthesis ceases in terminally differentiating cardiac muscle of the rat because the activity of the putative replicative DNA polymerase (DNA polymerase alpha) is lost or whether the activity of this enzyme is lost because DNA synthesis ceases. DNA-template availability and 3'-hydroxyl termini in nuclei and chromatin, isolated from cardiac muscle at various times during the developmental period in which DNA synthesis and the activity of DNA polymerase alpha are decreasing, were measured by using Escherichia coli DNA polymerase I, Micrococcus luteus DNA polymerase and DNA polymerase alpha under optimal conditions. Density-shift experiments with bromodeoxyuridine triphosphate and isopycnic analysis indicate that DNA chains being replicated semi-conservatively in vivo continue to be elongated in isolated nuclei by exogenous DNA polymerases. DNA template and 3'-hydroxyl termini available to exogenously added DNA polymerases do not change as cardiac muscle differentiates and the rate of DNA synthesis decreases and ceases in vivo. Template availability and 3'-hydroxyl termini are also not changed in nuclei isolated from cardiac muscle in which DNA synthesis had been inhibited by administration of isoproterenol and theophylline to newborn rats. DNA-template availability and 3'-hydroxyl termini, however, were substantially increased in nuclei and chromatin from cardiac muscle of adult rats. This increase is not due to elevated deoxyribonuclease activity in nuclei and chromatin of the adult. Electron microscopy indicates that this increase is also not due to dispersal of the chromatin or disruption of nuclear morphology. Density-shift experiments and isopycnic analysis of DNA from cardiac muscle of the adult show that it is more fragmented than DNA from cardiac-muscle cells that are, or have recently ceased, dividing. These studies indicate that DNA synthesis ceases in terminally differentiating cardiac muscle because the activity of a replicative DNA polymerase is lost, rather than the activity of this enzyme being lost because DNA synthesis ceases.


The development of quality indicators for community pharmacy care.
To develop a national system of quality indicators for community pharmacy care, reported by community pharmacies. After preliminary validation, an online consensus study was conducted. Pharmacy practice experts (round 1) and practising pharmacists (round 2) were approached. Face-validity scores for risk of harm and quality of care were obtained, as well as data on feasibility and clarity. To field test the data collection a random sample of 30 community pharmacies reported on the indicators, and were visited by a healthcare inspector to discuss practical and interpretation issues. After preliminary validation of 159 topics, 53 indicators were rated in round 1 by 14 of the 16 experts who were approached. The resulting 48 indicators were rated by 76 pharmacists of the 150 pharmacists who were approached (response 50%). Of the 48 indicators in the second round, 33 (69%) were rated face valid (median relevance score ≥ 7) for risk of harm to patients, while 43 (90%) were rated face valid for quality of care. In the field test the participating pharmacies reported on the resulting set of 44 indicators. This resulted in an adjusted set of 42 indicators. The set contains indicators on patient counselling (6), clinical risk management (10), compounding (7), dispensing (3), monitoring of medication use (11) and quality management (5). A set of 42 quality indicators was developed for community pharmacy care. It is expected that this will have a positive impact on quality and safety of community pharmacy care in the Netherlands.


SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways.
SIRT3, one of seven mammalian sirtuins, is a NAD-dependent deacetylase. SIRT3 localizes to mitochondria where it deacetylates and thus activates acetyl-CoA synthetase 2 (AceCS2), indicating a role for SIRT3 in metabolism. Here we provide evidence that SIRT3 also impacts upon apoptosis and cell growth control. Using RNAi under basal (non-stress) conditions we show that SIRT3 is required for apoptosis induced by selective silencing of Bcl-2 in HCT116 human epithelial cancer cells. Identical treatment of ARPE19 epithelial non-cancer cells induces G(1) growth arrest which also proved to be SIRT3-dependent. Previously we have identified SIRT1 and JNK2 as constitutive suppressors of apoptosis in HCT116 cells. We now demonstrate that SIRT3 functions in JNK2-regulated apoptosis but is dispensable for SIRT1-regulated apoptosis. SIRT3 is also dispensable for stress-induced apoptosis. Thus the pro-apoptotic functioning of SIRT3 is selectively coupled with defined pathways regulating cell survival under basal conditions.


Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network.
During blastocyst formation, inner cell mass (ICM) cells differentiate into either epiblast (Epi) or primitive endoderm (PrE) cells, labeled by Nanog and Gata6, respectively, and organized in a salt-and-pepper pattern. Previous work in the mouse has shown that, in absence of Nanog, all ICM cells adopt a PrE identity. Moreover, the activation or the blockade of the Fgf/RTK pathway biases cell fate specification towards either PrE or Epi, respectively. We show that, in absence of Gata6, all ICM cells adopt an Epi identity. Furthermore, the analysis of Gata6(+/-) embryos reveals a dose-sensitive phenotype, with fewer PrE-specified cells. These results and previous findings have enabled the development of a mathematical model for the dynamics of the regulatory network that controls ICM differentiation into Epi or PrE cells. The model describes the temporal dynamics of Erk signaling and of the concentrations of Nanog, Gata6, secreted Fgf4 and Fgf receptor 2. The model is able to recapitulate most of the cell behaviors observed in different experimental conditions and provides a unifying mechanism for the dynamics of these developmental transitions. The mechanism relies on the co-existence between three stable steady states (tristability), which correspond to ICM, Epi and PrE cells, respectively. Altogether, modeling and experimental results uncover novel features of ICM cell fate specification such as the role of the initial induction of a subset of cells into Epi in the initiation of the salt-and-pepper pattern, or the precocious Epi specification in Gata6(+/-) embryos.


Randomized trial in malignant biliary obstruction: plastic vs partially covered metal stents.
To compare efficacy and complications of partially covered self-expandable metal stent (pcSEMS) to plastic stent (PS) in patients treated for malignant, infrahilar biliary obstruction. Multicenter prospective randomized clinical trial with treatment allocation to a pcWallstent(®) (SEMS) or a 10 French PS. Palliative patients aged ≥ 18, for infrahilar malignant biliary obstruction and a Karnofsky performance scale index > 60% from 6 participating North American university centers. Primary endpoint was time to stent failure, with secondary outcomes of death, adverse events, Karnofsky performance score and short-form-36 scale administered on a three-monthly basis for up to 2 years. Survival analyses were performed for stent failure and death, with Cox proportional hazards regression models to determine significant predictive characteristics. Eighty-five patients were accrued over 37 mo, 42 were randomized to the SEMS group and 83 patients were available for analyses. Time to stent failure was 385.3 ± 52.5 d in the SEMS and 153.3 ± 19.8 d in the PS group, P = 0.006. Time to death did not differ between groups (192.3 ± 23.4 d for SEMS vs 211.5 ± 28.0 d for PS, P = 0.70). The only significant predictor was treatment allocation, relating to the time to stent failure (P = 0.01). Amongst other measured outcomes, only cholangitis differed, being more common in the PS group (4.9% vs 24.5%, P = 0.029). The small number of patients in follow-up limits longitudinal assessments of performance and quality of life. From an initially planned 120 patients, only 85 patients were recruited. Partially covered SEMS result in a longer duration till stent failure without increased complication rates, yet without accompanying measurable benefits in survival, performance, or quality of life.


Toxicity Assay for Citrinin, Zearalenone and Zearalenone-14-Sulfate Using the Nematode Caenorhabditis elegans as Model Organism.
To keep pace with the rising number of detected mycotoxins, there is a growing need for fast and reliable toxicity tests to assess potential threats to food safety. Toxicity tests with the bacterial-feeding nematode Caenorhabditis elegans as the model organism are well established. In this study the C. elegans wildtype strain N2 (var. Bristol) was used to investigate the toxic effects of the food-relevant mycotoxins citrinin (CIT) and zearalenone-14-sulfate (ZEA-14-S) and zearalenone (ZEA) on different life cycle parameters including reproduction, thermal and oxidative stress resistance and lifespan. The metabolization of the mycotoxins by the nematodes in vivo was investigated using HPLC-MS/MS. ZEA was metabolized in vivo to the reduced isomers α-zearalenol (α-ZEL) and β-ZEL. ZEA-14-S was reduced to α-/β-ZEL-14-sulfate and CIT was metabolized to mono-hydroxylated CIT. All mycotoxins tested led to a significant decrease in the number of nematode offspring produced. ZEA and CIT displayed negative effects on stress tolerance levels and for CIT an additional shortening of the mean lifespan was observed. In the case of ZEA-14-S, however, the mean lifespan was prolonged. The presented study shows the applicability of C. elegans for toxicity testing of emerging food mycotoxins for the purpose of assigning potential health threats.


5-Azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extracellular regulated kinase.
5-Azacytidine (5-Aza) induces differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes. However, the underlying mechanisms are not well understood. Our previous work showed that 5-Aza induces human bone marrow-derived MSCs to differentiate into cardiomyocytes. Here, we demonstrated that 5-Aza induced cardiac differentiation of human umbilical cord-derived MSCs (hucMSCs) and explored the potential signaling pathway. Our results showed that hucMSCs had cardiomyocyte phenotypes after 5-Aza treatment. In addition, myogenic cells differentiated from hucMSCs were positive for mRNA and protein of desmin, β-myosin heavy chain, cardiac troponin T, A-type natriuretic peptide, and Nkx2.5. Human diploid lung fibroblasts treated with 5-Aza expressed no cardiac-specific genes. 5-Aza did not induce hucMSCs to differentiate into osteoblasts. Further study revealed that 5-Aza treatment activated extracellular signal related kinases (ERK) in hucMSCs, but protein kinase C showed no response to 5-Aza administration. U0126, a specific inhibitor of ERK, could inhibit 5-Aza-induced expression of cardiac-specific genes and proteins in hucMSCs. Increased phosphorylation of signal transducers and activators of transcription 3, and up-regulation of myocyte enhancer-binding factor-2c and myogenic differentiation antigen in 5-Aza-treated hucMSCs were also suppressed by U0126. Taken together, these results suggested that sustained activation of ERK by 5-Aza contributed to the induction of the differentiation of hucMSCs into cardiomyocytes in vitro.


Removal of high NO3- concentrations in saline water through autotrophic denitrification by the bacterium Thiobacillus denitrificans strain MP.
Autotrophic denitrification by Thiobacillus denitrificans MP isolated from mangrove was investigated in both a sulphur-limestone column reactor and a fermenter. More than 97.5% of the nitrate (NO3-) in the 250 mg NO3(-)-N/L strong influent was removed after 14.3 hours in the column reactor. Influent NO3- was completely depleted in the lower part of the column as the hydraulic retention time increased and a slight pH drop was also observed along the reactor column due to the exhaustion of the buffering ability of the limestone. Trace amounts of oxygen present in the lower part of the reactor column resulted in the accumulation of nitrite and subsequent inhibition of further denitrification. The species composition of the bacterial community in the higher parts of the reactor column was morphologically more diverse than in the lower part. Denitrification by T. denitrificans MP reached an optimal level when the dissolved oxygen was maintained between 1.5-2% of saturation level in the automated fermenter. The stoichiometric ratios of deltaSO4(2-) produced/deltaNO3(-)-N removed were 6.81 and 9.32 in the reactor column and fermenter, respectively. This study suggests that efficient removal of high NO3- concentrations in water or wastewater can be achieved using autotrophic bacteria immobilized on surfaces of sulphur granules in the column system.


Human rights and COVID-19 triage: a comment on the Bath protocol.
In their discussion paper of November 2020, Cook et al present a draft protocol for navigating circumstances in which emergency services are overwhelmed. Their paper suggests that COVID-related triage decisions should be based on clinical assessment, patient and family consultation, and a range of ethical considerations. In this response, we note that the protocol exhibits an ambiguity that is likely to result in irresolvable dilemmas when put into practice. This ambiguity is exemplified in the paper's prime ethical imperative (to 'save more lives and more years of life'), which takes the form of an undefined conjunction whose practical implications are left unspecified. We see this ambiguity in the prime imperative as one manifestation of a broader set of tensions in the protocol. We show that the discipline of human rights provides an essential supplement to the ethical framework on which Cook and colleagues rely, providing a framework for understanding and working through triage dilemmas involving age, discrimination and equality.


Chiral recognition and atropisomerism in the sevoflurane dimer.
We have examined the stereoselectivity of molecular recognition between two molecules of the anesthetic sevoflurane using broadband rotational spectroscopy. The transient axial chirality of sevoflurane is revealed upon the formation of the dimer, as two different diastereoisomers made of either homo- or heterochiral species are detected in a supersonic jet expansion. The conformational assignment was confirmed by the observation of eighteen different isotopologues in natural abundance (all possible (13)C's and two (18)O species of the homochiral form). The two clusters are formed in practically equal proportions (1.1 : 1), probably due to their similar hydrogen bonding topologies. In both clusters the complex is stabilized by a primary C-H···O hydrogen bond, assisted by weak C-HF interactions. This intermolecular binding regime is characterized by a mixture of electrostatic and dispersive interactions, midway between classical hydrogen bonds and van der Waals clusters.


Pre-pubertal accelerometer-assessed physical activity and timing of puberty in British boys and girls: the Millennium Cohort Study.
Early puberty timing is associated with adverse health outcomes. We aimed to examine prospective associations between objectively measured physical activity and puberty timing in boys and girls. In the UK Millennium Cohort Study, physical activity volume and intensities at 7 years were measured using accelerometers. Status of several pubertal traits and age at menarche were reported at 11, 14 and 17 years. Age at menarche in girls was categorized into tertiles. Other puberty traits were categorized into earlier or later than the median ages calculated from probit models, separately in boys and girls. Multivariable regression models, with adjustment for maternal and child characteristics including body mass index (BMI) at age 7 years as potential confounders, were performed to test the associations of total daily activity counts and fractions of activity counts across intensities (in compositional models) with puberty timing, separately in boys (n = 2531) and girls (n = 3079). Higher total daily activity counts were associated with lower risks for earlier (vs later) growth spurt, body hair growth, skin changes and menarche in girls, and more weakly with lower risks for earlier skin changes and voice breaking in boys (odds ratios = 0.80-0.87 per 100 000 counts/day). These associations persisted on additional adjustment for BMI at 11 years as a potential mediator. No association with puberty timing was seen for any physical activity intensity (light, moderate or vigorous). More physical activity regardless of intensity may contribute to the avoidance of earlier puberty timing, independently of BMI, particularly in girls.


A method for rapid and simultaneous mapping of genetic loci and introgression sizes in nematode species.
Caenorhabditis briggsae is emerging as an attractive model organism not only in studying comparative biology against C. elegans, but also in developing novel experimentation avenues. In particular, recent identification of a new Caenorhabditis species, C. sp.9 with which it can mate and produce viable progeny provides an opportunity for studying the genetics of hybrid incompatibilities (HI) between the two. Mapping of a specific HI locus demands repeated backcrossing to get hold of the specific genomic region underlying an observed phenotype. To facilitate mapping of HI loci between C. briggsae and C. sp.9, an efficient mapping method and a genetic map ideally consisting of dominant markers are required for systematic introgression of genomic fragments between the two species. We developed a fast and cost-effective method for high throughput mapping of dominant loci with resolution up to 1 million bps in C. briggsae. The method takes advantage of the introgression between C. briggsae and C. sp.9 followed by PCR genotyping using C. briggsae specific primers. Importantly, the mapping results can not only serve as an effective way for estimating the chromosomal position of a genetic locus in C. briggsae, but also provides size information for the introgression fragment in an otherwise C. sp.9 background. In addition, it also helps generate introgression line as a side-product that is invaluable for the subsequent mapping of HI loci. The method will greatly facilitate the construction of a genetic map consisting of dominant markers and pave the way for systematic isolation of HI loci between C. briggsae and C. sp.9 which has so far not been attempted between nematode species. The method is designed for mapping of a dominant allele, but can be easily adapted for mapping of any other type of alleles in any other species if introgression between a sister species pair is feasible.


Prognostic Value of the Amount of Bleeding After Aneurysmal Subarachnoid Hemorrhage: A Quantitative Volumetric Study.
Quantitative estimation of the hemorrhage volume associated with aneurysm rupture is a new tool of assessing prognosis. To determine the prognostic value of the quantitative estimation of the amount of bleeding after aneurysmal subarachnoid hemorrhage, as well the relative importance of this factor related to other prognostic indicators, and to establish a possible cut-off value of volume of bleeding related to poor outcome. A prospective cohort of 206 patients consecutively admitted with the diagnosis of aneurysmal subarachnoid hemorrhage to Hospital 12 de Octubre were included in the study. Subarachnoid, intraventricular, intracerebral, and total bleeding volumes were calculated using analytic software. For assessing factors related to prognosis, univariate and multivariate analysis (logistic regression) were performed. The relative importance of factors in determining prognosis was established by calculating their proportion of explained variation. Maximum Youden index was calculated to determine the optimal cut point for subarachnoid and total bleeding volume. Variables independently related to prognosis were clinical grade at admission, age, and the different bleeding volumes. The proportion of variance explained is higher for subarachnoid bleeding. The optimal cut point related to poor prognosis is a volume of 20 mL both for subarachnoid and total bleeding. Volumetric measurement of subarachnoid or total bleeding volume are both independent prognostic factors in patients with aneurysmal subarachnoid hemorrhage. A volume of more than 20 mL of blood in the initial noncontrast computed tomography is related to a clear increase in poor outcome risk. : aSAH, aneurysmal subarachnoid hemorrhage.


A re-evaluation and validation of ontogeny functions for cytochrome P450 1A2 and 3A4 based on in vivo data.
Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in paediatric physiologically based pharmacokinetic models, have been reported to under-predict the in vivo clearances of some model substrates in neonates and infants. We report ontogeny functions for these enzymes as paediatric to adult relative intrinsic clearance per mg of hepatic microsomal protein, based on the deconvolution of in vivo pharmacokinetic data and by accounting for the impact of known clinical condition on hepatic unbound intrinsic clearance for caffeine and theophylline as markers of CYP1A2 activity and for midazolam as a marker of CYP3A4 activity. The function for CYP1A2 describes an increase in relative intrinsic metabolic clearance from birth to 3 years followed by a decrease to adult values. The function for CYP3A4 describes a continuous rise in relative intrinsic metabolic clearance, reaching the adult value at about 1.3 years of age. The new models were validated by showing improved predictions of the systemic clearances of ropivacaine (major CYP1A2 substrate; minor CYP3A4 substrate) and alfentanil (major CYP3A4 substrate) compared with those using a previous ontogeny function based on in vitro data (alfentanil: mean squared prediction error 3.0 vs. 6.8; ropivacaine: mean squared prediction error 2.3 vs.14.2). When implementing enzyme ontogeny functions, it is important to consider potential confounding factors (e.g. disease) that may affect the physiological conditions of the patient and, hence, the prediction of net in vivo clearance.


Nimesulide improves the symptomatic and disease modifying effects of leflunomide in collagen induced arthritis.
Nimesulide is a COX-2 inhibitor used for symptomatic relief of rheumatoid arthritis. Leflunomide is an anti-pyrimidine used to manage the progression of rheumatoid arthritis. Herein we studied the influence of nimesulide and leflunomide combination in terms of disease symptoms and progression using collagen-induced arthritis model in mice, as a model for rheumatoid arthritis. Collagen induced arthritis was induced by immunization with type II collagen. Assessment of joint stiffness and articular hyperalgesia were evaluated using a locomotor activity cage and the Hargreaves method, respectively. Disease progression was assessed via arthritic index scoring, X-ray imaging, myeloperoxidase enzyme activity and histopathologic examination. Nimesulide induced only transient symptomatic alleviation on the top of decreased leucocytic infiltration compared to arthritis group. However, nimesulide alone failed to induce any significant improvement in the radiological or pathological disease progression. Leflunomide alone moderately alleviates the symptoms of arthritis and moderately retarded the radiological and pathological disease progression. Combination of nimesulide and leflunomide significantly improved symptomatic (analgesia and joint stiffness) and arthritic disease progression (radiological, pathological and Myeloperoxidase enzyme activity) in collagen induced arthritis animal model.


COVID-19 Resurgence: Lessons Learned to Inform the South African Response.
The risk of recurring coronavirus disease (COVID-19) resurgences that threaten Africa's health care systems, newly opened communities, schools, and businesses looms as communities abandon precautionary measures, such as mask-wearing, physical distancing, and regular handwashing. In this piece, we unpack the handling of both the first wave and subsequent resurgence in the context of 3 countries that are experiencing such a resurgence at the time of writing (December 2020): Israel, France, and the United Kingdom. While it is difficult to extrapolate on what to expect in South Africa, based on experience in these 3 countries, South Africa's preparedness for a COVID-19 resurgence should place emphasis on the role of expanded testing and isolation capacity, strengthening enforcement of adherence to non-pharmaceutical interventions, and protection of high-risk populations.


Comparative evaluation of knee stability following reconstruction of the anterior cruciate ligament with the bone-patellar tendon-bone and the double semitendinosus-gracilis methods: 1- and 2-year prospective study.
An account of a prospective study of anterior cruciate ligament reconstructions with the bone-patellar tendon-bone autograft (BPTB) and the doubled semitendinosus-gracilis autograft (ST-GR) is given in 39 patients and 22 patients, respectively. The BPTB patients were younger, and there were more women in the ST-GR group. There were no statistical differences in the clinical and instrumental evaluations of stability after 1 and 2 years (Lachman and Jerk test, KT1000) between the two groups. Slightly better results were obtained in the BPTB group: mean 0.80 and 0.96 (first and second years) versus 1.18 and 1.20. Both methods, in fact, resulted in very satisfactory anterior knee stability, even when applied in two dissimilar groups of patients.


Prevention of Gestational Diabetes: The Role of Dietary Intake, Physical Activity, and Weight before, during, and between Pregnancies.
Gestational diabetes mellitus (GDM) is the most common complication of pregnancy and a significant clinical and public health problem with lifelong and intergenerational adverse health consequences for mothers and their offspring. The preconception, early pregnancy, and interconception periods represent opportune windows to engage women in preventive and health promotion interventions. This review provides an overview of findings from observational and intervention studies on the role of diet, physical activity, and weight (change) during these periods in the primary prevention of GDM. Current evidence suggests that supporting women to increase physical activity and achieve appropriate weight gain during early pregnancy and enabling women to optimize their weight and health behaviors prior to and between pregnancies have the potential to reduce rates of GDM. Translation of current evidence into practice requires further development and evaluation of co-designed interventions across community, health service, and policy levels to determine how women can be reached and supported to optimize their health behaviors before, during, and between pregnancies to reduce GDM risk.


Assessment of necrotic core with intraplaque hemorrhage in atherosclerotic carotid artery plaque by MR imaging with 3D gradient-echo sequence in patients with high-grade stenosis. Clinical article.
The aim of this study was to assess the histopathological differences between advanced atherosclerotic carotid artery (CA) plaques with signal hyperintensity on T1-weighted MR images and those without, focusing on necrotic core size and intraplaque hemorrhage (IPH). Thirty-five patients scheduled for carotid endarterectomy underwent preoperative CA MR imaging using 3D inversion-recovery-based T1-weighted imaging (magnetization-prepared rapid acquisition gradient-echo [MPRAGE]). The signal intensity of the CA plaque on MPRAGE sequences was classified as "high" when the intensity was more than 200% that of adjacent muscle. A total of 96 axial MR images obtained in 35 patients were compared with corresponding histological sections from 36 excised specimens. The area of the necrotic core in histological sections was compared between specimens with and without high signal intensity on MPRAGE sequences. The IPH was histopathologically graded according to the size of the area positive for glycophorin A as revealed by immunohistochemical staining. The difference between plaques with and without high signal intensity was investigated with respect to the degree of IPH. The relationship of the severity of IPH to size of the necrotic core was also evaluated. The area of the necrotic core in plaques with high signal intensity on MPRAGE sequences was significantly larger than that in plaques without high signal intensity (median 51.2% [interquartile range 43.3-66.8%] vs 49.0% [33.2-57.6%], p = 0.029). Carotid artery plaques with high signal intensity had significantly more severe IPH than plaques with lower signal intensity (p < 0.0001). The severity of IPH was significantly associated with the size of the necrotic core (p < 0.0001). Atherosclerotic CA plaques with high signal intensity on MPRAGE sequences had large necrotic cores with IPH in patients with high-grade stenosis; MPRAGE is useful for the evaluation of CA plaque progression.


UVB irradiation renders corneal allografts tolerogenic for allospecific delayed hypersensitivity responses.
Heterotopic corneal allografts treated with ultraviolet (UV) radiation not only failed to elicit allospecific delayed-type hypersensitivity (DTH) responses in mice but rendered the hosts tolerant to subsequent immunization with normally immunogenic corneal allografts. The immunological tolerance induced by UV-treated grafts was cyclophosphamide sensitive and antigen specific. Adoptive transfer studies revealed that the tolerance to donor alloantigens could be transferred with CD4+, CD8- T cells which suppressed alloimmune DTH responses at the afferent but not the efferent limb. The capacity of UV-treated corneal allografts to induce allospecific tolerance was related to UV irradiation and not simply a result of loss of corneal viability. Formalin-fixed corneal allografts could not produce similar tolerization for DTH responses. Selective debridement of either the corneal epithelium or endothelium revealed that the corneal endothelium was the critical layer necessary for UV-dependent tolerance induction. Furthermore, the initial exposure to UV irradiation must occur through the endothelium and not the epithelium. Thus, the single-cell layered corneal endothelium is the target for the immunomodulatory effects of UV irradiation on corneal allografts.


MG-1: a specificity identifying members of the macrophage and granulocyte lineages of mice.
An antigen (MG-1) which behaves as a lineage marker for immature granulocytes and cells of the monocytic series in mice is described. It is identified by rabbit anti-mouse brain antiserum, which has been exhaustively absorbed with thymocytes, red blood cells, and a Thy-1 negative variant of a T-cell lymphoma. MG-1 is present on immature granulocytes, declines in its surface expression as the cells differentiate and is absent from the most mature cells (segmented) of the series. Early monocytes are strongly positive for MG-1 and, with maturity, the amount of cell surface antigen increases. Adherent, phagocytic macrophages are brilliantly positive when stained with anti-MG-1 antiserum in an immunofluorescence assay. The antigen is present on most of the adherent cells of the lung, spleen and peritoneum. Many multipotential stem cells also express low levels of this antigen as do some bone marrow B cells.


Birth length and weight as predictors of breast cancer prognosis.
Birth size, and particularly birth length, is positively associated with breast cancer risk in adulthood. The objective of this study was to examine whether birth size is associated with survival among breast cancer patients. Information on birth size (weight, length and ponderal index (kg/length (m3)) was collected from birth archives for 331 breast cancer patients who were diagnosed at two university hospitals in Norway (Bergen and Trondheim). The patients were followed from the time of diagnosis until death from breast cancer, death from another cause, or to the end of follow-up, and birth size was related to survival, using Cox regression analysis. Breast cancer patients with birth length > or = 52 cm had nearly twice the risk of dying (hazard ratio, 1.92, 95% confidence interval, 1.09-3.41) from breast cancer compared to women with birth length less than 48 cm, after adjustment for place of birth and year of diagnosis.Similar analyses related to birth weight and ponderal index showed no clear association with breast cancer survival. Poorer outcome of breast cancer patients with high birth length may reflect effects of factors that stimulate longitudinal growth and simultaneously increase the risk of metastases and fatal outcome. It is possible that the insulin-like growth factor (IGF) system is involved in the underlying mechanisms.