Regional variations in the economic burden attributable to excess weight, physical inactivity and tobacco smoking across British Columbia.
Prevalence rates of excess weight, tobacco smoking and physical inactivity vary substantially by geographical region within British Columbia (B.C.). The purpose of this study is to determine the potential reduction in economic burden in B.C. if all regions in the province achieved prevalence rates of these three risk factors equivalent to those of the region with the lowest rates. We used a previously developed approach based on population-attributable fractions to estimate the economic burden associated with the various risk factors. Sex-specific relative risk and age/sex-specific prevalence data was used in the modelling. The annual economic burden attributable to the three risk factors in B.C. was about $5.6 billion in 2013, with a higher proportion of this total attributable to excess weight ($2.6 billion) than to tobacco smoking ($2.0 billion). While B.C. has lower prevalence rates of the risk factors than any other Canadian province, there is significant variation within the province. If each region in the province were to achieve the best prevalence rates for the three risk factors, then $1.4 billion (24% of the $5.6 billion) in economic burden could be avoided annually. There are notable disparities in the prevalence of each risk factor across health regions within B.C., which were mirrored in each region's attributable economic burden. A variety of social, environmental and economic factors likely drive some of this geographical variation and these underlying factors should be considered when developing prevention programs.


Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease.
Adverse events leading to discontinuation or dose reduction of thiopurine therapy occur in 9-28% of patients with inflammatory bowel disease. To evaluate the influence of thiopurine methyltransferase status and thiopurine metabolites in a large patient population for the risk of developing adverse event. Three hundred and sixty-four patients with inflammatory bowel disease and present or previous thiopurine therapy were identified from a local database. The adverse event observed in 124 patients (34%) were more common in adults than children (40% vs. 15%; P < 0.001) and in low to intermediate (<or=9.0 U/mL red blood cell) than normal thiopurine methyltransferase activity (P = 0.02). Myelotoxicity developed later than other types of adverse event. An increased frequency of adverse event was observed in patients with tioguanine (thioguanine) nucleotide above 400 or methylated thioinosine monophosphate above 11 450 pmol/8 x 10(8) red blood cell. A shift to mercaptopurine was successful in 48% of azathioprine-intolerant patients and in all cases of azathioprine-induced myalgia or arthralgia. A pre-treatment determination of thiopurine methyltransferase status might be appropriate as patients with low to intermediate thiopurine methyltransferase activity are more prone to develop an adverse event; determination of metabolite levels can be useful in the case of an adverse event. Mercaptopurine therapy should be considered in azathioprine-intolerant patients.


Is the girl with Rett syndrome normal at birth?
The diagnosis of Rett syndrome is currently determined by a series of criteria, the first three of which are concerned with the initial period of normality. Using the Australian Rett Syndrome Database, information about this early period was obtained by questionnaires to paediatricians and families. For girls born between 37 and 42 weeks' gestation, 70.7% of girls with Rett syndrome had birthweights <3500g compared with 62.2% of singleton births of the same gestational age in Western Australia between 1980 and 1992. The mean head circumference at birth for infants with Rett syndrome was lower than the mean head circumference at birth for the reference populations after accounting for gestational age. Forty-one percent of parents reported that their daughter had some perinatal difficulty, while in 22.4% of cases clinicians reported some perinatal abnormality. In 46.5% of girls, parents reported that their daughter's development or behaviour had been unusual in the first 6 months. Our results provide further evidence that the girl with Rett syndrome may not be normal at birth.


Electrophysiological evidence for the modulation of retrieval orientation by depth of study processing.
Event-related potentials (ERPs) were employed to investigate whether brain activity elicited by retrieval cues in a memory test varies according to the encoding task undertaken at study. Two recognition memory test blocks were administered, preceded, in one case, by a "shallow" study task (alphabetic judgement) and, in the other case, by a "deep" task (sentence generation). ERPs elicited by the new words in each test block differed, the ERPs elicited in the block following the shallow study task exhibiting the more positive-going waveforms. This finding was taken as evidence that subjects adopt different "retrieval sets" when attempting to retrieve items that had been encoded in terms of alphabetic versus semantic attributes. Differences between the ERPs elicited by correctly classified old and new words (old/new effects) also varied with encoding task. The effects for deeply studied words resembled those found in previous ERP studies of recognition memory, whereas old/new effects for shallowly studied words were confined to a late-onsetting, right frontal positivity. Together, the findings indicate that the depth of study processing influences two kinds of memory-related neural activity, associated with memory search operations, and the processing of retrieved information, respectively.


Incidental findings in genetics research using archived DNA.
Despite calls by some commentators for disclosing incidental findings in genetics research, several factors weigh in favor of caution. The technology of genetics has the power to uncover a vast array of information. The most potent argument for restraint in disclosure is that much research is pursued without consent so that the individual participant may not know that research is being conducted at all. Often the work is done by investigators and at institutions with which the person has no prior contact. Past practice is also relevant; genetics researchers historically have chosen not to disclose incidental findings, of which misattributed paternity and pleiotropic alleles such as ApoE have been the most common. Many people choose not to have genetic tests when given a choice. It may be desirable to discuss the topic of incidental findings when consent for research is obtained, but given the risk of unwanted surprise when there has been no prior discussion, the potential utility of incidental findings should be very high before they are even offered to individuals.


Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation.
cGMP-binding phosphodiesterases contain two homologous allosteric cGMP-binding sites (sites a and b) that are arranged in tandem; they constitute a superfamily of mammalian cyclic nucleotide receptors distinct from the cyclic nucleotide-dependent protein kinases/cation channels family. The functional role of each of these two sites in the phosphodiesterases is not known. The cGMP-binding sites of one of these phosphodiesterases, the cGMP-binding cGMP-specific phosphodiesterase (cGB-PDE, PDE5), have been analysed by using site-directed mutagenesis. Mutations that affect cGMP binding to either one or both allosteric sites do not influence cGMP hydrolysis in the catalytic site under the conditions used. However, compared with wild-type enzyme, the D289A, D478A and D289A/D478A mutants, which are defective in cGMP binding to either site a or site b, or both allosteric sites, require much higher cGMP concentrations for the allosteric stimulation of phosphorylation by the catalytic subunit of cAMP-dependent protein kinase. The cGMP effect is on the cGB-PDE rather than on the catalytic subunit of the protein kinase because the latter enzyme does not require cGMP for activity. The D289N mutant, which has higher binding affinity for cGMP than does the wild-type enzyme, is phosphorylated at lower concentrations of cGMP than is the wild-type enzyme. It is concluded that cGMP binding to the allosteric sites of cGB-PDE does not directly affect catalysis, but binding to both of these sites regulates phosphorylation of this enzyme.


The effect of curcuma longa extract and significance of mordant as an alternative for eosin in H and E: A comparative study.
Hematoxylin and Eosin (H and E) staining is a common and routine staining method used in Histopathology. In origin, Hematoxylin is natural and Eosin is a synthetic dye. Synthetic dyes are widely accepted due to its staining efficiency. However, due to synthetic and toxic properties, natural alternatives have gained importance. In this present study, Curcuma Longa rhizome (Turmeric) extract with and without mordant are examined as a natural substitute for Eosin in H and E staining. This study assessed the staining quality of Turmeric (H and T) compared to Eosin (H and E) and the significance of mordant in H and T staining. A comparative study is conducted in a Histopathology laboratory in a tertiary care hospital. Five tissue specimens were collected and stained with H and T with mordant, H and T without mordant, and conventional H and E stain. Two independent pathologists examined the quality of each stain. The results are graded as excellent, good, and poor. These results are statistically compared and analyzed. Staining quality of Turmeric and Eosin are comparable to each other. At the same time, Turmeric gives yellow color instead of pink in Eosin. The result also shows that the addition of mordant in Turmeric significantly improves the staining quality. Turmeric with mordant can be used as an alternative stain to synthetic Eosin in H and E staining.


Origin of Electrocatalytic Activity in Amorphous Nickel-Metalloid Electrodeposits.
In transition metal-based alloys, the nonlinearity of the current at large cathodic potentials reduces the credibility of the linear Tafel slopes for the evaluation of electrocatalytic hydrogen activity. High-precision nonlinear fitting at low current densities describing the kinetics of electrochemical reactions due to charge transfer can overcome this challenge. To show its effectiveness, we introduce a glassy alloy with a highly asymmetric energy barrier: amorphous NiP electrocoatings (with different C and O inclusions) via changing the applied DC and pulsed current and NaH2PO2 content. The highest hydrogen evolution reaction (HER) activity with the lowest cathodic transfer coefficient α = 0.130 with high J0 = -1.07 mA cm-2 and the largest surface areas without any porosity are observed for the pulsed current deposition. The calculated α has a direct relation with morphology, composition, chemical state and coating thickness defined by the electrodeposition conditions. Here, a general evaluation criterion with practicality in assessment and high accuracy for electrocatalytic reactions applicable to different metallic alloy systems is presented.


A rare case of morbidly adherent placenta in a young Primigravida with RH negative pregnancy managed with peripartum subtotal hysterectomy.
Postpartum hemorrhage (PPH) can be defined as excessive bleeding (>500 ml) from the genital tract after the delivery of baby upto 6 weeks. PPH accounts for major cause of maternal mortality rate. Prevention and early intervention can prevent this complication of delivery. However condition like placenta accreta leads to retention of placenta and makes PPH inevitable. We present the case of massive postpartum hemorrhage secondary to Placenta accreta in young primigravida with RH negative pregnancy. Clinical findings and investigations were not significant during her admission. She delivered the baby via vaginal route but placenta was not expelled till 30 min. Due to failed manual removal of placenta patient was shifted to OT.Manual vacuum aspiration was done in OT setting and chunks of placenta along with blood clots were obtained.Uterine balloon tamponade was inserted. Due to persistent PV bleeding subtotal hysterectomy was carried out in line for placenta accreta. Placenta accreta being one of the life threatening obstetric condition, it should be diagnosed as early as possible and need prompt management so as to prevent maternal mortality. Due to increasing number of cesarean delivery the cases of placenta accreta has been rising but rarely in some cases can it present in young primigravida with Rh negative pregnancy. In the cases of morbidly adherent placenta it is necessary for obstetrician to early identify such conditions and timely intervene to save the mother's life. Moreover Rh negative could be a hidden risk factor.


Is there any relationship between food habits in the last two decades and gastric cancer in North-Western Iran?
The aims of this case-control study were to assess the correlation between some food habits in the last two decades and gastric cancer in East Azerbaijan of Iran. In this hospital based case control study, 616 patients (212 gastric cancer patients, 404 cancer free patients) were recruited. Food habits of patients over the past two decades were assessed with a structured questionnaire. We used conditional logistic regression analysis for estimating crude and adjusted odds ratios (OR) and their respective 95% confidence intervals (95%CI). In this study, over-eating, consumption of high fat milk and yogurt and especial types of cheese increased the risk of gastric cancer (All<0.05). Consumption of such especial cheeses such as Koze and Khiki increased the risk of gastric cancer by 12.6 fold (95% CI:1.99-79.36) and 7.36 fold (95% CI:1.33- 40.54), respectively. In addition, high fat food, moldy food, and pickled vegetables consumption as well as reuse of cooking oil for frying were significantly associated with gastric cancer risk. Furthermore, intake of Ghorme (deep fried meat) was positively correlated with gastric cancer risk (OR:1.31;95%CI: 0.91-1.87). It can be confirmed that particular food habits which have been very common in East-Azerbaijan in the last two past decades increase risk of gastric cancer. According to our results and taking into account the long latency period of gastric cancer it can be concluded that nutrition education for a healthy diet should be performed from early childhood. However, further well designed cohort studies are needed to achieve more clear results.


A Plea for Optimizing Selection in Current Adjuvant Immunotherapy Trials for High-risk Nonmetastatic Renal Cell Carcinoma According to Expected Cancer-specific Mortality.
Tyrosine kinase inhibitor-based adjuvant therapy showed no survival benefits for patients with high-risk nonmetastatic renal cell carcinoma (nmRCC). Five randomized immune-oncology checkpoint inhibitor trials are ongoing. We assessed the effect of stage, grade, and histologic type on cancer-specific mortality (CSM) in candidates for 1 of the 4 North American ongoing immune-oncology checkpoint inhibitor trials of high-risk nmRCC. From the Surveillance, Epidemiology, and End Results database (2001-2015), we identified patients who had undergone surgery for nmRCC and had met the inclusion criteria for the PROSPER RCC (nivolumab in treating patients with localized kidney cancer undergoing nephrectomy), CheckMate 914 (a study comparing the combination of nivolumab and ipilimumab versus placebo in participants with localized renal cell carcinoma), KEYNOTE-564 [safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy], or IMmotion010 [a study of atezolizumab as adjuvant therapy in participants with renal cell carcinoma (RCC) at high risk of developing metastasis following nephrectomy] trials. Kaplan-Meier and multivariable Cox regression models were used to assess the 10-year CSM rates in the overall cohort according to stage, grade, and histologic characteristics, and in 4 generated random samples according to the eligible patients for each of the 4 trials. Of 116,750 patients who had undergone surgery for nmRCC, 18,559 (15.9%) had fulfilled the inclusion criteria for 1 of the 4 trials. The greatest proportion of higher stage and grade combinations and sarcomatoid histologic features would have qualified for IMmotion010, followed by KEYNOTE-564, CheckMate 914, and PROSPER RCC. Multivariable Cox regression models demonstrated the most unfavorable prognosis for stage N1 grade 3/4 (hazard ratio [HR], 11.5; P < .001), stage T4N0 grade 3/4 (HR, 9.8; P < .001), and sarcomatoid histologic features (HR, 5.5; P < .001). Among the 4 random samples, the difference in the qualifying criteria resulted in the greatest versus progressively lower CSM rates in the IMmotion010, KEYNOTE-564, CheckMate 914, and PROSPER RCC trials, respectively (P < .001). Our findings indicate that participation in adjuvant immunotherapy trials should be predominantly encouraged for patients with high-grade stage T3, T4, and N1 and patients with any stage with sarcomatoid pathologic features.


[Neuroimaging Alzheimer's disease: early diagnosis, monitoring, and mechanism understanding].
Neuroimaging offers a promising tool for the priority goals of current researches in Alzheimer's disease (AD) including early diagnosis, monitoring the progression of the disease and understanding the underlying mechanisms. The brain profiles of atrophy and hypometabolism associated with AD are well known and they can be used as support for early diagnosis, although the accuracy of each of these biomarkers on its own is not sufficient. An increasing number of studies highlights the relevance of disconnection processes in the development and progression of AD. The recent development of PET tracers such as the Pittsburg compound (PiB) allowing to visualize in vivo one of the neuropathological lesions characterizing AD (i.e. beta-amyloid depositions) offers a unique opportunity to better understand the mechanisms underlying this multifaceted disease.


Impact of microbial diversity on rapid detection of enterohemorrhagic Escherichia coli in surface waters.
Enterohemorrhagic Escherichia coli (EHEC) are a physiologically, immunologically and genetically diverse collection of strains that pose a serious water-borne threat to human health. Consequently, immunological and PCR assays have been developed for the rapid, sensitive detection of presumptive EHEC. However, the ability of these assays to consistently detect presumptive EHEC while excluding closely related non-EHEC strains has not been documented. We conducted a 30-month monitoring study of a major metropolitan watershed. Surface water samples were analyzed using an immunological assay for E. coli O157 (the predominant strain worldwide) and a multiplex PCR assay for the virulence genes stx(1), stx(2) and eae. The mean frequency of water samples positive for the presence of E. coli O157, stx(1) or stx(2) genes, or the eae gene was 50%, 26% and 96%, respectively. Quantitative analysis of selected enriched water samples indicated that even in samples positive for E. coli O157 cells, stx(1)/stx(2) genes, and the eae gene, the concentrations were rarely comparable. Seventeen E. coli O157 strains were isolated, however, none were EHEC. These data indicate the presence of multiple strains similar to EHEC but less pathogenic. These findings have important ramifications for the rapid detection of presumptive EHEC; namely, that current immunological or PCR assays cannot reliably identify water-borne EHEC strains.


Increased arteriolar wall-to-lumen ratio in a normotensive vascular bed in coarctation hypertension.
In rats with coarctation hypertension, resting resistance and resistance at maximal vasodilation are elevated in the hindquarters, although blood pressure in this vascular bed remains normal. To assess the nature of these non-pressure-related vascular abnormalities, we observed third- to fifth-order arterioles in the cremaster microcirculation using standard techniques and chloralose-urethan anesthesia in rats with coarctation or sham coarctation of the abdominal aorta. Four weeks after clipping, carotid pressure was significantly elevated in coarcted compared with sham-coarcted rats, but femoral pressure was not. The wall-to-lumen ratio and wall thickness in cremaster arterioles was elevated by 12-33% in coarcted compared with sham-coarcted rats in the resting state. After maximal arteriolar relaxation with topical nitroprusside, differences in wall-to-lumen ratio persisted. We also studied the microcirculation of one-kidney normotensive control and one-kidney, one-clip Goldblatt hypertensive rats. Femoral pressure in Goldblatt hypertensive rats was elevated, but changes in the microcirculation were similar to those observed in coarcted rats. These non-pressure-related changes in vascular structure in hypertension may result from systemic neural or humoral influences and/or growth factors local to vascular wall tissues.


Interfacial and Electronic Modulation via Localized Sulfurization for Boosting Lithium Storage Kinetics.
Structural modulation endows electrochemical hybrids with promising energy storage properties owing to their adjustable interfacial and/or electronic characteristics. For MXene-based materials, however, the facile but effective strategies for tuning their structural properties at nanoscale are still lacking. Herein, 3D crumpled S-functionalized Ti3 C2 Tx substrate is rationally integrated with Fe3 O4 /FeS heterostructures via coprecipitation and subsequent partial sulfurization to induce a highly active and stable electrode architecture. The unique heterostructures with tuned electronic properties can induce improved kinetics and structural stability. The surface engineering by S terminations on the MXene further unlocks extra (pseudo)capacitive lithium storage. Serving as anode for lithium storage, the optimized electrode delivers an excellent long-term cycling stability (913.9 mAh g-1 after 1000 cycles at 1 A g-1 ) and superior rate capability (490.4 mAh g-1 at 10 A g-1 ). Moreover, the (de)lithiation pathways associated with energy storage mechanisms are further revealed by operando X-ray diffraction, in situ electroanalytical techniques, and first-principles calculations. The hybrid electrode is proved to undergo stepwise phase transformations during discharging but a relatively uniform reconversion during charging, suggesting an asymmetric conversion mechanism. This work provides a novel strategy for designing high-performance hybrids and paves the way for in-depth understanding of complex lithium intercalation and conversion reactions.


Hot electron-driven photocatalysis and transient absorption spectroscopy in plasmon resonant grating structures.
Plasmon resonant grating structures provide an effective platform for distinguishing between the effects of plasmon resonant excitation and bulk metal absorption via interband transitions. By simply rotating the polarization of the incident light, we can switch between resonant excitation and non-resonant excitation, while keeping all other parameters of the measurement constant. With light polarized perpendicular to the lines in the grating (i.e., TE-polarization), the photocatalytic reaction rate (i.e., photocurrent) is measured as the angle of the incident laser light is tuned through the resonance with the grating. Here, hot holes photoexcited in the metal are used to drive the oxygen evolution reaction (OER), producing a measurable photocurrent. Using TE-polarized light, we observe sharp peaks in the photocurrent and sharp dips in the photoreflectance at approximately 9° from normal incidence, which corresponds to the conditions under which there is good wavevector matching between the incident light and the lines in the grating. With light polarized parallel to the grating (i.e., TM), we excite the grating structure non-resonantly and there is no angular dependence in the photocurrent or photoreflectance. In order to quantify the lifetime of these hot carriers, we performed transient absorption spectroscopy of these plasmon resonant grating structures. Here, we observe one feature in the spectra corresponding to interband transitions and another feature associated with the plasmon resonant mode in the grating. Both features decay over a time scale of 1-2 ps. The spectral responses of grating structures fabricated with Ag, Al, and Cu are also presented.


Multimorbidity patterns and the association with health status of the oldest-old in long-term care facilities in China: a two-step analysis.
The increasing prevalence of multimorbidity has created a serious global public health problem in aging populations. Certain multimorbidity patterns across different age ranges and their association with health status remain unclear. The main aim of this study is to identify multimorbidity patterns discrepancies and associated health status between younger-old and oldest-old. The Ethics Committee of Nanjing Medical University approved the study protocol (No.2019-473). Convenience sampling method was used to recruit older adults aged ≥ 60 years with multimorbidity from July to December 2021 from 38 Landsea long-term care facilities in China. The multimorbidity patterns were analyzed using network analysis and two-step cluster analysis. One-Way ANOVA was utilized to explore their association with health status including body function, activity of daily living, and social participation. A Sankey diagram visualized the flow of health status within different multimorbidity patterns. This study is reported following the STROBE guidelines. A total of 214 younger-old (60-84 years) and 173 oldest-old (≥ 85 years) were included. Leading coexisting diseases were cardiovascular disease (CD), metabolic and endocrine disease (MED), neurological disease (ND), and orthopedic disease (OD). Cluster 1 (53, 24.8%) of CD-ND (50, 94.3%; 31, 58.8%), cluster 2 (39, 18.2%) of MED-ND-CD (39, 100%; 39, 100%; 37, 94.9%), cluster 3 (37, 17.3%) of OD-CD-MED-ND (37, 100%; 33, 89.2%; 27, 73.0%; 16, 43.2%), and cluster 4 (34, 15.9%) of CD-MED (34, 100%; 34, 100%) were identified in the younger-old. In the oldest-old, the primary multimorbidity patterns were: cluster 1 (33, 19.1%) of CD-respiratory disease-digestive disease-urogenital disease (CD-RD-DSD-UD) (32, 97.0%; 9, 27.3%; 8, 24.2%; 7, 21.2%), cluster 2 (42, 24.3%) of ND-CD-MED (42, 100%; 35, 83.3%; 14, 33.3%), cluster 3 (28, 16.2%) of OD-CD-MED (28, 100%; 25, 89.3%; 18, 64.3%), and cluster 4 (35, 20.2%) of CD-MED (35, 100%; 35, 100%). Younger-old with CD-ND or MED-ND-CD, and oldest-old with ND-CD-MED have worse health status compared with other multimorbidity patterns (e.g., CD-MED and OD-CD-MED). Discrepancies in common patterns of multimorbidity across age groups suggest that caregivers in long-term care facilities should consider changes in multimorbidity patterns with ageing when developing prevention plans for individualized management. Neurological disease concurrent with other diseases was the major determinant of health status, especially for the oldest-old. Interventions targeting multimorbidity need to be focused, yet generic. It is essential to assess complex needs and health outcomes that arise from different multimorbidity patterns and manage them through an interdisciplinary approach and consider their priorities to gain high-quality primary care for older adults living in long-term care facilities.


Properdin deficiency in murine models of nonseptic shock.
Hereditary properdin deficiency is linked to susceptibility to meningococcal disease (Neisseria meningitidis serotypes Y and W-135) with high mortality. Its relative contribution toward the outcome of nonseptic shock has not been investigated. Using properdin-deficient C57BL/6 mice and their littermates, this study examines their survival of zymosan-induced and LPS-induced shock. Properdin-deficient mice were more resistant to zymosan shock compared with wild-type mice, which showed greater impairment of end-organ function 24 h after zymosan injection, higher TNF-alpha production by alveolar and peritoneal macrophages, higher TNF-alpha, and, inversely, lower IL-10 levels in peritoneal lavage and circulation and higher plasma C5a levels. Properdin-deficient mice showed significantly higher mortality in LPS shock, elevated TNF-alpha, and, inversely, reduced IL-10 production by peritoneal macrophages as well as lower plasma C5a levels compared with wild-type littermates. NO production by peritoneal macrophages and plasma alpha1-antitrypsin levels at 24 h after the injection of LPS or zymosan were decreased in properdin-deficient mice in both models, and fewer histopathologic changes in liver were observed in properdin-deficient animals. This study provides evidence that properdin deficiency attenuates zymosan-induced shock and exacerbates LPS-induced shock.


NADPH oxidase activity controls phagosomal proteolysis in macrophages through modulation of the lumenal redox environment of phagosomes.
The phagosomal lumen in macrophages is the site of numerous interacting chemistries that mediate microbial killing, macromolecular degradation, and antigen processing. Using a non-hypothesis-based screen to explore the interconnectivity of phagosomal functions, we found that NADPH oxidase (NOX2) negatively regulates levels of proteolysis within the maturing phagosome of macrophages. Unlike the NOX2 mechanism of proteolytic control reported in dendritic cells, this phenomenon in macrophages is independent of changes to lumenal pH and is also independent of hydrolase delivery to the phagosome. We found that NOX2 mediates the inhibition of phagosomal proteolysis in macrophages through reversible oxidative inactivation of local cysteine cathepsins. We also show that NOX2 activity significantly compromises the phagosome's ability to reduce disulfides. These findings indicate that NOX2 oxidatively inactivates cysteine cathepsins through sustained ablation of the reductive capacity of the phagosomal lumen. This constitutes a unique mechanism of spatiotemporal control of phagosomal chemistries through the modulation of the local redox environment. In addition, this work further implicates the microbicidal effector NOX2 as a global modulator of phagosomal physiologies, particularly of those pertinent to antigen processing.


Residues of the rotavirus RNA-dependent RNA polymerase template entry tunnel that mediate RNA recognition and genome replication.
To replicate its segmented, double-stranded RNA (dsRNA) genome, the rotavirus RNA-dependent RNA polymerase, VP1, must recognize viral plus-strand RNAs (+RNAs) and guide them into the catalytic center. VP1 binds to the conserved 3' end of rotavirus +RNAs via both sequence-dependent and sequence-independent contacts. Sequence-dependent contacts permit recognition of viral +RNAs and specify an autoinhibited positioning of the template within the catalytic site. However, the contributions to dsRNA synthesis of sequence-dependent and sequence-independent VP1-RNA interactions remain unclear. To analyze the importance of VP1 residues that interact with +RNA on genome replication, we engineered mutant VP1 proteins and assayed their capacity to synthesize dsRNA in vitro. Our results showed that, individually, mutation of residues that interact specifically with RNA bases did not diminish replication levels. However, simultaneous mutations led to significantly lower levels of dsRNA product, presumably due to impaired recruitment of +RNA templates. In contrast, point mutations of sequence-independent RNA contact residues led to severely diminished replication, likely as a result of improper positioning of templates at the catalytic site. A noteworthy exception was a K419A mutation that enhanced the initiation capacity and product elongation rate of VP1. The specific chemistry of Lys419 and its position at a narrow region of the template entry tunnel appear to contribute to its capacity to moderate replication. Together, our findings suggest that distinct classes of VP1 residues interact with +RNA to mediate template recognition and dsRNA synthesis yet function in concert to promote viral RNA replication at appropriate times and rates.


Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome.
Acute respiratory distress syndrome (ARDS) in a deadly disease that can be brought on by endotoxins such as lipopolysaccharide (LPS). ARDS is characterized by vascular permeability, a severe inflammatory response, lung leukocyte infiltration, and resultant lung edema. Polymerase δ-interacting protein 2 (Poldip2) is a novel regulator of blood-brain barrier permeability; however, its role in regulating lung permeability and vascular inflammation is unknown. Here, the role of Poldip2 in regulating vascular permeability and inflammation in a mouse model of ARDS was assessed. Heterozygous deletion of Poldip2 was found to reduce LPS-induced mortality within 20 h, lung inflammatory signaling, and leukocyte infiltration. Moreover, reduced Poldip2-suppressed LP-induced vascular cell adhesion molecule (VCAM)-1 induction, leukocyte recruitment, and mitochondrial reactive oxygen species (ROS) production in vitro These data indicate that Poldip2 is an important regulator of the debilitating consequences of ARDS, potentially through the regulation of mitochondrial ROS-induced inflammatory signaling. Consequently, inhibition of Poldip2 may be a viable option for therapeutic discovery moving forward.


Infertility Treatments Resulting in Twin Pregnancy: Does It Increase the Risk for Future Childhood Malignancy.
Background: Controversy exists in the literature regarding the possible association between infertility treatments in singleton pregnancies and long-term risk for childhood malignancy. Data regarding infertility treatments in twins and long-term childhood malignancies are scarce. Objective: We sought to investigate whether twins conceived following infertility treatments are at an increased risk for childhood malignancy. Study design: A population-based retrospective cohort study, comparing the risk for future childhood malignancy in twins conceived by infertility treatments (in vitro fertilization and ovulation induction) and those who were conceived spontaneously. Deliveries occurred between the years 1991 and 2021 in a tertiary medical center. A Kaplan-Meier survival curve was used to compare the cumulative incidence of childhood malignancies, and a Cox proportional hazards model was constructed to control for confounders. Results: During the study period, 11,986 twins met the inclusion criteria; 2910 (24.3%) were born following infertility treatments. No statistically significant differences were noted between the groups comparing the rate (per 1000) of childhood malignancies (2.0 in the infertility treatments group vs. 2.2 in the comparison group, OR 1.04, 95% CI 0.41-2.62; p = 0.93). Likewise, the cumulative incidence over time was comparable between the groups (log-rank test, p = 0.87). In a Cox regression model, controlling for maternal and gestational age, no significant differences in childhood malignancies were noted between the groups (adjusted HR = 0.82, 95% CI 0.49-1.39, p = 0.47). Conclusions: In our population, twins conceived following infertility treatments are not at an increased risk for childhood malignancies.


Protein degradation, as with protein synthesis, is required during not only long-term spatial memory consolidation but also reconsolidation.
The formation of long-term memory requires protein synthesis, particularly during initial memory consolidation. This process also seems to be dependant upon protein degradation, particularly degradation by the ubiquitin-proteasome system. The aim of this study was to investigate the temporal requirement of protein synthesis and degradation during the initial consolidation of allocentric spatial learning. As memory returns to a labile state during reactivation, we also focus on the role of protein synthesis and degradation during memory reconsolidation of this spatial learning. Male CD1 mice were submitted to massed training in the spatial version of the Morris water maze. At various time intervals after initial acquisition or after a reactivation trial taking place 24 h after acquisition, mice received an injection of either the protein synthesis inhibitor anisomycin or the protein degradation inhibitor lactacystin. This injection was performed into the hippocampal CA3 region, which is specifically implicated in the processing of spatial information. Results show that, in the CA3 hippocampal region, consolidation of an allocentric spatial learning task requires two waves of protein synthesis taking place immediately and 4 h after acquisition, whereas reconsolidation requires only the first wave. However, for protein degradation, both consolidation and reconsolidation require only one wave, taking place immediately after acquisition or reactivation, respectively. These findings suggest that protein degradation is a key step for memory reconsolidation, as for consolidation. Moreover, as protein synthesis-dependent reconsolidation occurred faster than consolidation, reconsolidation did not consist of a simple repetition of the initial consolidation.


Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.
Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy.


Maternal Undernourishment in Guinea Pigs Leads to Fetal Growth Restriction with Increased Hypoxic Cells and Oxidative Stress in the Brain.
We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for brain hypoxia and oxidative stress. Guinea pigs were fed ad libitum (control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1) was injected into pregnant sows. Fetuses were then necropsied and brain tissues were processed for HP-1 (hypoxia marker) and 4HNE, 8-OHdG, and 3-nitrotyrosine (oxidative stress markers) immunoreactivity (IR). FGR-MNR fetal and brain weights were decreased 38 and 12%, respectively, with brain/fetal weights thereby increased 45% as a measure of brain sparing, and more so in males than females. FGR-MNR HP-1 IR was increased in most of the brain regions studied, and more so in males than females, while 4HNE and 8-OHdG IR were increased in select brain regions, but with no sex differences. Chronic hypoxia is likely to be an important signaling mechanism in the FGR brain, but with males showing more hypoxia than females. This may involve sex differences in adaptive decreases in growth and normalizing of oxygen, with implications for sex-specific alterations in brain development and risk for later neuropsychiatric disorder.


Safety and efficacy of cetuximab-containing chemotherapy after immune checkpoint inhibitors for patients with squamous cell carcinoma of the head and neck: a single-center retrospective study.
Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.


Direct involvement of phosphatidylinositol 4-phosphate in secretion in the yeast Saccharomyces cerevisiae.
The SEC14 gene encodes an essential phosphatidylinositol (PtdIns) transfer protein required for formation of Golgi-derived secretory vesicles in yeast. Suppressor mutations that rescue temperature-sensitive sec14 mutants provide an approach for determining the role of Sec14p in secretion. One suppressor, sac1-22, causes accumulation of PtdIns(4)P. SAC1 encodes a phosphatase that can hydrolyze PtdIns(4)P and certain other phosphoinositides. These findings suggest that PtdIns(4)P is limiting in sec14 cells and that elevation of PtdIns(4)P production can suppress the secretory defect. Correspondingly, we found that PtdIns(4)P levels were decreased significantly in sec14-3 mutants shifted to 37 degrees C and that sec14-3 cells could grow at an otherwise nonpermissive temperature (34 degrees C) when carrying a plasmid overexpressing PIK1, encoding one of two essential PtdIns 4-kinases. This effect is specific because overexpression of the other PtdIns 4-kinase gene (STT4) or a PtdIns 3-kinase gene (VPS34) did not rescue sec14-3 cells. To further address Pik1p function in secretion, two different pik1(ts) mutants were examined. Upon shift to restrictive temperature (37 degrees C), the PtdIns(4)P levels dropped by about 60% in both pik1(ts) strains within 1 h. During the same period, cells displayed a reduction (40-50%) in release of a secreted enzyme (invertase). However, similar treatment did not effect maturation of a vacuolar enzyme (carboxypeptidase Y). These findings indicate that, first, PtdIns(4)P limitation is a major contributing factor to the secretory defect in sec14 cells; second, Sec14p function is coupled to the action of Pik1p, and; third, PtdIns(4)P has an important role in the Golgi-to-plasma membrane stage of secretion.


Characterization of hypoxia induced gene 1: expression during rat central nervous system maturation and evidence of antisense RNA expression.
Although recent studies have provided a detailed understanding of cellular interactions occurring during the development of the CNS, little is known about the molecular signals which during the peri and postnatal periods ensure its maturation and functionality. Using the mammalian spinal cord as a model, we have designed experiments to examine the main changes in gene expression occurring during this critical transition. In this paper we describe the cloning and characterization of the rat hypoxia induced gene-1 (Hig-1), its expression pattern during spinal cord maturation and in situ localization of its mRNA. We show an increase in Hig-1 expression between P1 and P15 in the spinal cord and a differential spatial pattern. In the P1 spinal cord we observed preferential expression in regions of dorsal laminae II and III and laminae IX ventrally; while in P8, the distribution was more widespread and overall expression was increased. Hig-1 is also widely expressed in the brain. Results of in situ hybridization experiments, as well as particular features concerning ESTs, led us to propose the expression of an antisense mRNA. Primer-specific RTPCR demonstrates the presence of this aHig-1 transcript whose structure has not yet been characterized. The high homology between putative rHig-1 protein and human- and murine-predicted sequences, as well as its characteristic expression in the Central Nervous System, are indicative of a specific role which could be related to apoptosis signaling during postnatal maturation.


Primary Care Nurse Practitioner Wage Differences by Employment Setting.
Previous studies reported that primary care nurse practitioners working in primary care settings may earn less than those working in specialty care settings. However, few studies have examined why such wage difference exists. This study used human capital theory to determine the degree to which the wage differences between dingsPCNPs working in primary care versus specialty care settings is driven by the differences in PCNPs' characteristics. Feasible generalized least squares regression was used to examine the wage differences for PCNPs working in primary care and specialty care settings. A cross-sectional, secondary data analysis was conducted using the restricted file of 2012 National Sample Survey of Nurse Practitioners. Oaxaca-Blinder decomposition technique was used to explore the factors contributing to wage differences.The results suggested that hourly wages of PCNPs working in primary care settings were, on average, 7.1% lower than PCNPs working in specialty care settings, holding PCNPs' socio-demographic, human capital, and employment characteristics constant. Approximately 4% of this wage difference was explained by PCNPs' characteristics; but 96% of these differences were due to unexplained factors. A large, unexplained wage difference exists between PCNPs working in primary care and specialty care settings.


Rapid resumption of interrupted visual search. New insights on the interaction between vision and memory.
A modified visual search task demonstrates that humans are very good at resuming a search after it has been momentarily interrupted. This is shown by exceptionally rapid response time to a display that reappears after a brief interruption, even when an entirely different visual display is seen during the interruption and two different visual searches are performed simultaneously. This rapid resumption depends on the stability of the visual scene and is not due to display or response anticipations. These results are consistent with the existence of an iterative hypothesis-testing mechanism that compares information stored in short-term memory (the perceptual hypothesis) with information about the display (the sensory pattern). In this view, rapid resumption occurs because a hypothesis based on a previous glance of the scene can be tested very rapidly in a subsequent glance, given that the initial hypothesis-generation step has already been performed.


Double right coronary artery; fistula and atherosclerosis: rare combination.
Combination of the primary congenital coronary artery anomalies, fistula and atherosclerosis rarely occur. We report a 50-year-old male who presented with severe chest pain, for which he underwent a coronary angiography. Injection into the right coronary artery (RCA) demonstrated a double RCA running very closely together in the atrioventricular groove. The superior one gave rise to a coronary fistula leading to the right ventricle and the inferior one was atherosclerotic. Both of them terminated as a posterior descending artery. The left system showed occlusion of the left anterior descending and major obtuse marginal. Both were corrected surgically.


[Psychogenic tremor: clinical, electrophysiologic and psychopathologic assessment].
There are few studies analyzing the incidence, clinical characteristics and diagnostic work-up of psychogenic tremor. We studied the clinical and electrophysiological characteristics and the associated psychopathology in a series of patients with psychogenic tremor. All patients (n = 8) diagnosed with documented or clinically established psychogenic tremor in the movement disorders section of our Department of Neurology in a two-years period were analysed. Psychogenic tremor was diagnosed in 9.5% of the patients that consulted for postural or action tremor of the upper limbs. In all cases tremor had a variable frequency and amplitude and improvement with distraction. Electrophysiological studies revealed asynchronic muscle activity and considerable variation of the dominant frequency when weight was added to the patient hands. Six patients were initially misdiagnosed of essential tremor (n = 3); Parkinson's disease (n = 1); and cerebrovascular disease (n = 2). Final psychiatric diagnoses were depression (n = 4); conversive disorder (n = 2); and malignering (n = 2). Psychogenic tremor is a relatively frequent cause of tremor in a Movement Disorders Clinic and has a characteristic clinical and electrophysiological pattern.


Altered organization of the visual cortex in FHONDA syndrome.
A fundamental scheme in the organization of the early visual cortex is the retinotopic representation of the contralateral visual hemifield on each hemisphere. We determined the cortical organization in a novel congenital visual pathway disorder, FHONDA-syndrome, where the axons from the temporal retina abnormally cross to the contralateral hemisphere. Using ultra-high field fMRI at 7 T, the population receptive field (pRF) properties of the primary visual cortex were modeled for two affected individuals and two controls. The cortical activation in FHONDA was confined to the hemisphere contralateral to the stimulated eye. Each cortical location was found to contain a pRF in each visual hemifeld and opposing hemifields were represented as retinotopic cortical overlays of mirror-symmetrical locations across the vertical meridian. Since, the enhanced crossing of the retinal fibers at the optic chiasm observed in FHONDA has been previously assumed to be exclusive to the pigment-deficiency in albinism, our direct evidence of abnormal mapping in FHONDA highlights the independence of pigmentation and development of the visual cortex. These findings thus provide fundamental insights into the developmental mechanisms of the human visual system and underline the general relevance of the interplay of subcortical stability and cortical plasticity.


Assessment of urinary excretion of antimalarial drugs in large-scale chemotherapeutic eradication projects.
Assessment of the urinary excretion of an antimalarial drug is a useful means of checking the amount of drug administered and the regularity of intake. The author describes the various methods available for the qualitative and quantitative estimation of antimalarial drugs in urine and discusses their relative merits, with special reference to their suitability for use in the field. He points out the difficulties involved in estimating the urinary excretion of antimalarials in large-scale chemotherapeutic eradication projects and stress the importance of simplifying testing techniques as far as possible.


Propositions for refinement of the hybrid surgical technique for treatment of thoraco-abdominal aortic aneurysm.
Traditional open repair of thoraco-abdominal aortic aneurysms Crawford type II-IV carries a high perioperative risk and mortality. The hybrid technique for combined surgical and endovascular treatment offers an interesting alternative with reduced risk of paraparesis and possibly a reduced mortality rate. Propositions for refinement of this approach are outlined based on a single centre experience.


A randomized clinical trial of analgesia in children with acute abdominal pain.
To evaluate the effects of intravenous morphine on pain reduction, physical examination, and diagnostic accuracy in children with acute abdominal pain. A randomized, double-blind, placebo-controlled clinical trial was conducted at an emergency department of a tertiary care children's hospital. Children aged 5-18 years with abdominal pain of < or =5 days' duration, pain score > or =5 on a 0-10 visual analog scale, and need for surgical evaluation were eligible. Following the initial assessment, patients were randomized to receive either 0.1 mg/kg morphine or an equal volume of saline. The pediatric emergency medicine physician and surgical consultant independently recorded the areas of tenderness to palpation and percussion, and their diagnoses before the study medication and 15 to 30 minutes later. Sixty patients were enrolled, and 29 received morphine and 31 received saline. The demographic characteristics between the two groups were similar. The median reduction of pain score between the two study groups was 2 (95% CI = 1 to 4; p = 0.002). There was no significant change in the areas of tenderness in both study groups. Children with surgical conditions had persistent tenderness to palpation and/or percussion. There was no significant change in the diagnostic accuracy between the study groups and between the physician groups. All patients requiring laparotomy were identified and no significant complication was noted in the morphine group. Intravenous morphine provides significant pain reduction to children with acute abdominal pain without adversely affecting the examination, and morphine does not affect the ability to identify children with surgical conditions.


Immunohistochemical distribution of amyloid deposits in 25 cows diagnosed with systemic AA amyloidosis.
The distribution of amyloid deposits was histopathologically and immunohistochemically examined in 25 cows aged 5 to 10 years that had been diagnosed with systemic AA amyloidosis. This examination revealed that amyloid deposits were also present in the hypophysis, ovary, uterus, mammary gland and skeletal muscle, in addition to the liver, kidney, spleen, pancreas, thyroid gland, adrenal gland, gastrointestinal mucosa, heart, lung and lymph nodes. The examined cows tended to have chronic inflammations, including chronic mastitis (six cases) or chronic pneumonia (four cases), which is thought of as a causative agent of AA amyloidosis. In contrast, five cases did not exhibit any chronic inflammation.


Substrate deprivation: a new therapeutic approach for the glycosphingolipid lysosomal storage diseases.
The glycosphingolipid (GSL) lysosomal storage diseases are a family of human metabolic diseases that, in their severest forms, cause death in early infancy, as a result of progressive neurodegeneration. They are caused by mutations in the genes encoding the glycohydrolases or the activator proteins that catabolise GSLs within lysosomes. In these diseases the GSL substrate of the defective enzyme accumulates in the lysosome, where it is stored and leads to cellular dysfunction and disease. The therapeutic options for treating these diseases are relatively limited; in fact, there are currently no available therapies for most of these disorders. The problem is further compounded by difficulties in delivering therapeutic agents to the central nervous system, which is where the pathology is frequently manifested. To date, research effort has mainly focused on strategies for augmenting enzyme concentrations to compensate for the underlying defect. These strategies include bone-marrow transplantation, enzyme-replacement therapy and gene therapy. Our group has been exploring the alternative strategy of substrate deprivation. This approach aims to balance the rate of GSL synthesis with the impaired rate of GSL breakdown. Studies using an asymptomatic mouse model of Tay-Sachs disease have shown that substrate deprivation prevents GSL storage. In a severe neurodegenerative mouse model of Sandhoff disease, substrate deprivation delayed the onset of symptoms and disease progression, and significantly increased life expectancy. The implications of this research for human therapy have been discussed.


Metacognitive beliefs as psychological predictors of social functioning: An investigation with young people at risk of psychosis.
Poor social functioning has been found to be present in those at risk for psychosis. This study aimed to examine metacognitive beliefs as potential predictors of structured activity (measure of social functioning) in those with an At Risk Mental State (ARMS). Regression and correlation analyses were conducted. The sample included 109 young people. Age was found to be positively correlated to structured activity. Metacognitive beliefs concerning uncontrollability and danger of worry were found to negatively predict structured activity. This was after controlling for age, gender, treatment allocation, cognitive schemas, positive symptom severity, social anxiety, and depression. Metacognitive danger items were most important. Age was the only control variable found to be an independent predictor of structured activity in the regression model, despite negative bi-variate relationships with structured activity found across three cognitive schema subscales and social anxiety. This is the first study to find that higher negative metacognitive beliefs about uncontrollability and danger predict lower social functioning in an ARMS sample, and that the perception of thoughts being dangerous was of particular importance. Psychological interventions should consider targeting this metacognitive dimension to increase social functioning. Future longitudinal research is required to strengthen findings in this area.


Two-dimensional echocardiography and Doppler ultrasound in managing obstetric patients.
To test the usefulness of ultrasound-derived measurements of intracardiac filling pressures and cardiac performance in the noninvasive management of obstetric patients with an indication for hemodynamic monitoring. We included patients with oliguria unresponsive to crystalloid boluses, with hypertension unresponsive to hydralazine, and at high risk for pulmonary edema who were determined to be candidates for invasive monitoring. They were first studied with two-dimensional echocardiography and Doppler ultrasound using a technique previously validated at our institution. Cardiac dimensions, filling pressures, and function were assessed at the bedside. Subsequently, management decisions were made based on these findings. Fourteen patients were studied. Two received a pulmonary artery catheter after noninvasive evaluation indicated a need for continuous monitoring. The 12 patients managed without the need for a pulmonary artery catheter included women with intractable hypertension (one patient), pulmonary edema (two patients), complex cardiac lesions (two patients), oliguria (five patients), intractable hypertension and oliguria (one patient), and unexplained dyspnea with peripheral arterial oxygen desaturation (one patient). Although some patients received as much as 8 L of crystalloid, none developed pulmonary edema or left ventricular failure. In all 12 cases, the ultrasound monitoring allowed successful noninvasive management of the patient. This pilot study suggests that two-dimensional echocardiography and Doppler examination may be an effective alternative to invasive monitoring in the management of selected pregnant patients.


Predicting and preventing supervisory workplace aggression.
The authors examined factors that lead to and prevent aggression toward supervisors at work using two samples: doctoral students and correctional service guards. The results supported that perceived interpersonal injustice mediates the relationship between perceptions of supervisory control over work performance and psychological aggression directed at supervisors, and further that psychological aggression toward supervisors is positively associated with physical acts of aggression directed at supervisors, supporting the notion of an escalation of aggressive workplace behaviors. Moreover, employees' perceptions of organizational sanctions (i.e., negative consequences for disobeying organizational policies) against aggression appear to play an important role in the prevention of workplace aggression by moderating the relationship between injustice and aggression targeting supervisors.


Exploiting bone niches: progression of disseminated tumor cells to metastasis.
Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair.


Cold Kit for Prostate-Specific Membrane Antigen (PSMA) PET Imaging: Phase 1 Study of 68Ga-Tris(Hydroxypyridinone)-PSMA PET/CT in Patients with Prostate Cancer.
68Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as 68Ga-labeled N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED)-PSMA-11, are promising small molecules for targeting prostate cancer. A new radiopharmaceutical, 68Ga-labeled tris(hydroxypyridinone) (THP)-PSMA, has a simplified design for single-step kit-based radiolabeling. It features the THP ligand, which forms complexes with 68Ga3+ rapidly at a low concentration, at room temperature, and over a wide pH range, enabling direct elution from a 68Ge/68Ga generator into a lyophilized radiopharmaceutical kit in 1 step without manipulation. The aim of this phase 1 study was to assess the safety and biodistribution of 68Ga-THP-PSMA. Methods: Cohort A comprised 8 patients who had proven prostate cancer and were scheduled to undergo prostatectomy; they had Gleason scores of 7-10 and a mean prostate-specific antigen level of 7.8 μg/L (range, 5.4-10.6 μg/L). They underwent PET/CT after the administration of 68Ga-THP-PSMA. All patients proceeded to prostatectomy (7 with pelvic nodal dissection). Dosimetry from multi-time-point PET imaging was performed with OLINDA/EXM. Cohort B comprised 6 patients who had positive 68Ga-HBED-PSMA-11 PET/CT scanning results and underwent comparative 68Ga-THP-PSMA scanning. All patients were monitored for adverse events. Results: No adverse events occurred. In cohort A, 6 of 8 patients had focal uptake in the prostate (at 2 h: average SUVmax, 5.1; range, 2.4-9.2) and correlative 3+ staining of prostatectomy specimens on PSMA immunohistochemistry. The 2 68Ga-THP-PSMA scans with negative results had only 1+/2+ staining. The mean effective dose was 2.07E-02 mSv/MBq. In cohort B, 68Ga-THP-PSMA had lower physiologic background uptake than 68Ga-HBED-PSMA-11 (in the parotid glands, the mean SUVmax for 68Ga-THP-PSMA was 3.6 [compared with 19.2 for 68Ga-HBED-PSMA-11]; the respective corresponding values in the liver were 2.7 and 6.3, and those in the spleen were 2.7 and 10.5; P < 0.001 for all). In 5 of 6 patients, there was concordance in the number of metastases identified with 68Ga-HBED-PSMA-11 and 68Ga-THP-PSMA. Thirteen of 15 nodal abnormalities were subcentimeter. In 22 malignant lesions, the tumor-to-liver contrast with 68Ga-THP-PSMA was similar to that with 68Ga-HBED-PSMA (4.7 and 5.4, respectively; P = 0.15), despite a higher SUVmax for 68Ga-HBED-PSMA than for 68Ga-THP-PSMA (30.3 and 10.7, respectively; P < 0.01). Conclusion:68Ga-THP-PSMA is safe and has a favorable biodistribution for clinical imaging. Observed focal uptake in the prostate was localized to PSMA-expressing malignant tissue on histopathology. Metastatic PSMA-avid foci were also visualized with 68Ga-THP-PSMA PET. Single-step production from a Good Manufacturing Practice cold kit may enable rapid adoption.


Re(Setting) Epigenetic Clocks: An Important Avenue Whereby Social Conditions Become Biologically Embedded across the Life Course.
Research on biological embedding of the social environment has been expedited by increased availability of biomarkers. Recently, this arsenal of measures has been expanded to include epigenetic clocks that indicate in years the extent to which an individual is older or younger than their chronological age. These measures of biological aging, especially GrimAge, are robust predictors of both illness and time to death. Importantly for sociologists, several studies have linked social conditions to these indices of aging. The present study extends this research using longitudinal data from a sample of 223 black women participating in the Family and Community Health Study. We find that changes in income and living arrangements over an 11-year period predict changes in speed of biological aging. These results provide further support for the idea that epigenetic aging is a mechanism whereby social conditions become biologically embedded. The utility of epigenetic clocks for sociological studies of health are discussed.


A functional application of the spacing effect to improve learning and memory in persons with multiple sclerosis.
The present study examined the utility of using spaced learning trials (when trials are distributed over time) versus massed learning trials (consecutive learning trials) in the acquisition of everyday functional tasks. In a within-subjects design, 20 participants with multiple sclerosis (MS) and 18 healthy controls (HC) completed two route learning tasks and two paragraph reading tasks. One task in each area was presented in the "spaced" condition, in which the task was presented to the participants three times with 5-minutes break between each trial, and the second task in each area was presented in the "massed" condition, in which the task was presented three consecutive times to the participants. The dependent variables consisted of recall and recognition of the paragraphs and routes both immediately and 30 minutes following initial learning. Results showed that for paragraph learning, the spaced condition significantly enhanced memory performance for this task relative to the massed condition. However, this effect was not demonstrated in the route learning task. Thus, the spacing effect can be beneficial to enhance recall and performance of activities of daily living for individuals with MS; however, this effect was significant for verbal tasks stimuli, but not for visual tasks stimuli. It will be important during future investigations to better characterize the factors that maximize the spacing effect.


Functional gastrointestinal disorders in 35,447 adults and their association with body mass index.
Functional gastrointestinal disorders' (FGIDs) associations with body mass index (BMI) have not been thoroughly investigated in the general population. To investigate the overlap between functional dyspepsia (FDy), irritable bowel syndrome (IBS), functional constipation (FC) and functional diarrhoea (FDh) and the relationship between BMI and those diagnoses in a large French adult population. Subjects participating in the Nutrinet-Santé cohort study completed a questionnaire based on Rome III criteria. Anthropometrics, socio-demographical and lifestyle data were collected via self-administered questionnaires. Associations between BMI and FGIDs were investigated with multivariate logistic regression. A total of 35 447 subjects were included in the analysis. Among subjects with FGIDs, 10.4% presented more than one disorder. [FDy coexisted with IBS (23.6%) and FC (15.1%)]. Associations between BMI and FDy differed according to sex. In females, higher odds were observed for underweight and obesity subgroups (OR = 1.26 (95% CI: 0.99-1.59), OR = 1.35 (1.08-1.69), OR = 1.20 (0.81-1.77), OR = 1.47 (0.89-2.42) for underweight, class I, II and III obesity respectively compared with normal BMI), forming a U-shaped relationship confirmed with nonlinear model (P < 0.001). In females, FDh was associated with BMI [OR = 1.05 (1.03-1.07), P < 0.001]. In males, a negative association between BMI and IBS was observed [OR = 0.97 (0.94-0.99), P=0.04]. Other associations were not significant. Our study showed an important overlap in FGIDs, supporting the contention of common pathophysiological mechanisms. Relationships between BMI and FGIDs appeared to be sex-dependent. Interaction by sex in the association between BMI and FGIDs should therefore be further explored.


Sexual activity and body image: examining gender variability and the influence of psychological distress in cancer patients.
Psychosocial factors impacting on the overall quality of life for cancer patients may differ between men and women. This study examined the influence that psychological distress, clinical, and social variables have on sexual activity and body image in adult oncology patients. Symptom data was collected from the Memorial Symptom Assessment Scale (MSAS). Analysis indicated women and patients with reported functional limitations were more likely to be less satisfied with how they looked. The final model showed that younger adults, Caucasians, those who were married and patients with some functional limitations were more likely to have problems with sexual interest/activity. Gender was not a significant predictor of having problems with sexual interest/activity. These results can be used by clinicians to identify patients who may be at an increased risk for negative body image and problems in sexual functioning. Further research regarding gender differences in cancer-related psychological symptoms is needed to assist healthcare professionals in providing comprehensive care while alleviating unresolved and interrelated health and psychosocial symptoms.


Cardiac involvement in proximal myotonic myopathy.
Proximal myotonic myopathy (PROMM) is a recently described autosomal dominantly inherited disorder resulting in proximal muscles weakness, myotonia, and cataracts. A few patients with cardiac involvement (sinus bradycardia, supraventricular bigeminy, conduction abnormalities) have been reported. The cases of three relatives with PROMM (weakness of neck flexors and proximal extremity muscles, calf hypertrophy, myotonia, cataracts) are reported: a 54 year old man, his 73 year old mother, and 66 year old aunt. All three presented with conduction abnormalities and one had repeated, life threatening, sustained monomorphic ventricular tachycardia. This illustrates that severe cardiac involvement may occur in PROMM.


Emergence of contact injuries in invasion team sports: an ecological dynamics rationale.
The incidence of contact injuries in team sports is considerable, and injury mechanisms need to be comprehensively understood to facilitate the adoption of preventive measures. In Association Football, evidence shows that the highest prevalence of contact injuries emerges in one-on-one interactions. However, previous studies have tended to operationally report injury mechanisms in isolation, failing to provide a theoretical rationale to explain how injuries might emerge from interactions between opposing players. In this position paper, we propose an ecological dynamics framework to enhance current understanding of behavioural processes leading to contact injuries in team sports. Based on previous research highlighting the dynamics of performer-environment interactions, contact injuries are proposed to emerge from symmetry-breaking processes during on-field interpersonal interactions among competing players and the ball. Central to this approach is consideration of candidate control parameters that may provide insights on the information sources used by players to reduce risk of contact injuries during performance. Clinically, an ecological dynamics analysis could allow sport practitioners to design training sessions based on selected parameter threshold values as primary and/or secondary preventing measures during training and rehabilitation sessions.


Symbiotic characterization of isoleucine+valine and leucine auxotrophs of Sinorhizobium meliloti.
Ten isoleucine+valine and three leucine auxotrophs of Sinorhizobium meliloti Rmd201 were obtained by random mutagenesis with transposon Tn5 followed by screening of Tn5 derivatives on minimal medium supplemented with modified Holliday pools. Based on intermediate feeding, intermediate accumulation and cross-feeding studies, isoleucine+valine and leucine auxotrophs were designated as ilvB/ilvG, ilvC and ilvD, and leuC/leuD and leuB mutants, respectively. Symbiotic properties of all ilvD mutants with alfalfa plants were similar to those of the parental strain. The ilvB/ilvG and ilvC mutants were Nod-. Inoculation of alfalfa plants with ilvB/ilvG mutant did not result in root hair curling and infection thread formation. The ilvC mutants were capable of curling root hairs but did not induce infection thread formation. All leucine auxotrophs were Nod+ Fix-. Supplementation of leucine to the plant nutrient medium did not restore symbiotic effectiveness to the auxotrophs. Histological studies revealed that the nodules induced by the leucine auxotrophs did not develop fully like those induced by the parental strain. The nodules induced by leuB mutants were structurally more advanced than the leuC/leuD mutant induced nodules. These results indicate that ilvB/ilvG, ilvC and one or two leu genes of S. meliloti may have a role in symbiosis. The position of ilv genes on the chromosomal map of S. meliloti was found to be near ade-15 marker.


[Morphological types of cardiomyocyte loss in acute myocardial infarct in ischemic heart disease patients].
Histologic and polarization-microscopic studies of the cardiac infarct area in 64 persons who had died several hours to 3 weeks following an angina attack led to the identification of three types of dying for cardiac muscle cells on the basis of a morphologic criterion (state of myofibrils), described as relaxational, contractional, and lytic, respectively. The cells showing these different types of dying differed with regard to time of appearance, frequency of occurrence, and location in the lesional area, which suggested that each of the three types of dying occurs by a distinct mechanism.


Incidence and Outcomes of Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Registry-based Descriptive Trial in Kobe City.
The current study aims to evaluate the incidence and results of aneurysmal subarachnoid hemorrhage (aSAH) throughout Kobe City. Based on a multicenter retrospective registry-based descriptive trial involving all 13 primary stroke centers in Kobe City, patients with aSAH treated between October 2017 and September 2019 were studied. A total of 334 patients were included, with an estimated age-adjusted incidence of 11.12 per 100,000 person-years. Curative treatment was given to 94% of patients, with endovascular treatment (51%) preferred over surgical treatment (43%). Of the patients, 12% were treated by shunt surgery for sequential hydrocephalus with a worse outcome at 30 days or discharge (14% vs. 46%, odds ratio (OR): 0.19, 95% confidence interval (CI): 0.088-0.39, p-value <0.001). As for vasospasm and delayed cerebral ischemia, most patients were given intravenous fasudil infusion (73%), with endovascular treatment for vasospasm in 24 cases (7.2%). The fasudil group had more good outcomes (42% vs. 30%, OR: 1.64, 95% CI: 0.95-2.87, p-value = 0.075) and significantly less death (3.3% vs. 35%, OR: 0.064, 95% CI: 0.024-0.15, p-value <0.001) at 30 days or discharge. Mortality rose from 12% at 30 days or discharge to 17% at 1 year, but neurological function distribution improved over time (modified Rankin Scale 0-2 was 39% at 30 days or discharge, 53% at 60 days, and 63% at 1 year). Our retrospective registered trial presented various statistics on aSAH, summarizing the current treatment status and prognosis.


Two-stage activation for alpha5beta1 integrin binding to surface-adsorbed fibronectin.
By analyzing the functional binding of alpha5beta1 integrin to adsorbed fibronectin in intact cells, we demonstrate that integrin activation results in linear increases in adhesion strength as a function of ligand density, suggesting that modulation of the receptor-ligand interaction is the dominant mechanism for adhesion during the initial stages of adhesion and that cooperative binding contributes little to initial adhesion strength. Using this experimental framework, we show the existence of three distinct activation states for alpha5beta1 integrin binding to adsorbed fibronectin for both passive, antibody-induced and active, cell-controlled activation. During the initial phase of adhesion, alpha5beta1 integrin is activated in an energy-dependent process from the nonbinding ground state to an intermediate state in which the receptor binds fibronectin and provides significant mechanical coupling. In later stages of adhesion maturation, alpha5beta1 integrin is activated to a higher binding state, which provides significant increases in adhesion strength compared with the intermediate state. These multiple binding states most likely result from different integrin conformations and reflect distinct interactions between alpha5beta1 and sites on adsorbed fibronectin. Multiple activation states for alpha5beta1 suggest the existence of distinct stages in adhesion signaling and strengthening and can provide a versatile mechanism for the regulation of adhesive interactions.


Lessons From the Implementation of Mo-Buzz, a Mobile Pandemic Surveillance System for Dengue.
Approximately 128 countries and 3.9 billion people are at risk of dengue infection. Incidence of dengue has increased over the past decades, becoming a growing public health concern for countries with populations that are increasingly susceptible to this vector-borne disease, such as Sri Lanka. Almost 55,150 dengue cases were reported in Sri Lanka in 2016, with more than 30.40% of cases (n=16,767) originating from Colombo, which struggles with an outdated manual paper-based dengue outbreak management system. Community education and outreach about dengue are also executed using paper-based media channels such as pamphlets and brochures. Yet, Sri Lanka is one of the countries with the most affordable rates of mobile services in the world, with penetration rates higher than most developing countries. To combat the issues of an exhausted dengue management system and to make use of new technology, in 2015, a mobile participatory system for dengue surveillance called Mo-Buzz was developed and launched in Colombo, Sri Lanka. This paper describes the system's components and uptake, along with other similar disease surveillance systems. We developed Mo-Buzz and tested its feasibility for dengue. Two versions of the app were developed. The first was for use by public health inspectors (PHIs) to digitize form filling and recording of site visit information, and track dengue outbreaks on a real-time dengue hotspot map using the global positioning system technology. The system also provides updated dengue infographics and educational materials for the PHIs to educate the general public. The second version of Mo-Buzz was created for use by the general public. This system uses dynamic mapping to help educate and inform the general public about potential outbreak regions and allow them to report dengue symptoms and post pictures of potential dengue mosquito-breeding sites, which are automatically sent to the health authorities. Targeted alerts can be sent to users depending on their geographical location. We assessed the usage and the usability of the app and its impact on overall dengue transmission in Colombo. Initial uptake of Mo-Buzz for PHIs was low; however, after more training and incentivizing of usage, the uptake of the app in PHIs increased from less than 10% (n=3) to 76% (n=38). The general public user evaluation feedback was fruitful in providing improvements to the app, and at present, a number of solutions are being reviewed as viable options to boost user uptake. From our Mo-Buzz study, we have learned that initial acceptance of such systems can be slow but eventually positive. Mobile and social media interventions, such as Mo-Buzz, are poised to play a greater role in shaping risk perceptions and managing seasonal and sporadic outbreaks of infectious diseases in Asia and around the world.


Interannual study of spot urine-evaluated sodium excretion in young Japanese women.
The authors investigated interannual differences in the sodium excretion levels of young healthy Japanese women as estimated from spot urine analysis at Nakamura Gakuen University from 1995 to 2015. Participants included 4931 women aged 18 to 20 years who were classified into three time periods according to year of health check: first (1995-2001), second (2002-2007), and third (2008-2015). Estimated daily urinary sodium and potassium excretion levels and the sodium to potassium ratio were 120.6±31.9 mmol, 35.2±8.1 mmol, and 3.5±0.9, respectively. Adjusted for body weight, sodium excretion, and potassium excretion significantly decreased in the second and third period compared with the first period (P<.001). Systolic blood pressure also decreased in the same way between time periods (P<.001). Estimated urinary excretion levels of sodium and potassium in young Japanese women have decreased over the past 20 years independently of body weight.


[Spectral division of conformational states of spin-labeled tRNA Phe from Escherichia coli].
A spectral division method of two conformational states of spin-labeled macromolecules is presented. The method is suitable in conditions of highly anisotropic motion of spin label and is based on titration of experimental spectra of spin-labeled macromolecule by theoretical ones. Theoretical spectra simulation uses the Freed theory and spin-Hamiltonian parameters, derived from independent experiments. Nomogrammes and formula for calculation of order parameter Sz and correlation time tau c in temperature-viscosity experiment are available. The method was applied to spectral division of two conformational states of spin-labeled tRNAPhe from E. coli and spectral parameters Sz and tau c were obtained for both states. ESR spectra of these conformational states at t degree = 20 degrees differ strongly from one another by order parameter Sz. The first conformer, that is characterised by a greater order parameter has no globular conformational transition (in terms of changes of the hydrodynamic macromolecule radius) between 2 degrees and 20 degrees, but local conformational changes take place in this temperature region.


Comparative potential of juvenile and adult human articular chondrocytes for cartilage tissue formation in three-dimensional biomimetic hydrogels.
Regeneration of human articular cartilage is inherently limited and extensive efforts have focused on engineering the cartilage tissue. Various cellular sources have been studied for cartilage tissue engineering including adult chondrocytes, and embryonic or adult stem cells. Juvenile chondrocytes (from donors below 13 years of age) have recently been reported to be a promising cell source for cartilage regeneration. Previous studies have compared the potential of adult and juvenile chondrocytes or adult and osteoarthritic (OA) chondrocytes. To comprehensively characterize the comparative potential of young, old, and diseased chondrocytes, here we examined cartilage formation by juvenile, adult, and OA chondrocytes in three-dimensional (3D) biomimetic hydrogels composed of poly(ethylene glycol) and chondroitin sulfate. All three human articular chondrocytes were encapsulated in the 3D biomimetic hydrogels and cultured for 3 or 6 weeks to allow maturation and extracellular matrix formation. Outcomes were analyzed using quantitative gene expression, immunofluorescence staining, biochemical assays, and mechanical testing. After 3 and 6 weeks, juvenile chondrocytes showed a greater upregulation of chondrogenic gene expression than adult chondrocytes, while OA chondrocytes showed a downregulation. Aggrecan and type II collagen deposition and glycosaminoglycan accumulation were high for juvenile and adult chondrocytes but not for OA chondrocytes. Similar trend was observed in the compressive moduli of the cartilage constructs generated by the three different chondrocytes. In conclusion, the juvenile, adult and OA chondrocytes showed differential responses in the 3D biomimetic hydrogels. The 3D culture model described here may also provide a useful tool to further study the molecular differences among chondrocytes from different stages, which can help elucidate the mechanisms for age-related decline in the intrinsic capacity for cartilage repair.


Sexually antagonistic coevolution for sexual harassment can act as a barrier to further invasions by parthenogenesis.
The assumption of a twofold cost of sex not only complicates the maintenance of sex but also sets conditions for sexual conflict: in organisms with the twofold cost, males often sexually harass females. Sexual harassment is detrimental to female fitness and thus might help maintain sexual populations if male harassment inflicts a harsher cost on parthenogens than on sexual females (asymmetric harassment cost). However, the generality of this concept is now considered doubtful because selective harassment of parthenogens results in loss of mating opportunities for males. Using three mathematical models, I show here that sexual harassment still can impose the asymmetric cost on parthenogens. First, I apply the Lotka-Volterra model to show the degree of asymmetric harassment cost that permits sex to be maintained stably in the population. Second, using adaptive dynamics, I examine whether sexually antagonistic coevolution for sexual harassment, which occurs only in sexual populations, can promote the asymmetric harassment cost. Finally, an individual-based model, which assumes a spatial structure unlike that in the other two, demonstrates that the asymmetric evolution of harassment cost prevents further invasions of parthenogens from different patches into sexual lineages; these mechanisms may account for allopatric distributions of sexual and parthenogenetic lineages as well as the maintenance of sex.


Monocyte procoagulant activity in glomerulonephritis associated with systemic lupus erythematosus.
Monocyte infiltration and activation of the coagulation system have been implicated in the pathophysiology of glomerulonephritis. In this study, spontaneous procoagulant activity (PCA) was measured in circulating mononuclear cells to determine whether elevated PCA correlated with the presence of proliferative glomerulonephritis in patients with systemic lupus erythematosus (SLE). No increase in PCA was found in 20 patients with end-stage renal failure, 8 patients with glomerulonephritis without SLE, and 10 patients undergoing abdominal surgical or orthopedic procedures as compared with 20 normal controls. In eight patients with SLE but with no apparent active renal disease, PCA was not elevated above normal basal levels. Seven additional patients with SLE who had only mesangial proliferation on biopsy also had no increase in PCA. In contrast, eight patients with focal or diffuse proliferative lupus nephritis, and one patient with membranous nephritis who ultimately developed a proliferative lesion, had a marked increase in PCA with greater than 100 times the base-line levels. The activity was shown to originate in the monocyte fraction of the mononuclear cells and was shown to be capable of cleaving prothrombin directly. The prothrombinase activity was not Factor Xa, because it was not neutralized by anti-Factor X serum and was not inhibited by an established panel of Factor Xa inhibitors. Monocyte plasminogen activator determinations did not correlate with renal disease activity. We conclude that monocyte procoagulant activity, a direct prothrombinase, seems to correlate with endocapillary proliferation in lupus nephritis and could be a mediator of tissue injury.


A comparative study of three methods for the visualization of von Willebrand factor (vWF) multimers.
This study was performed to compare three visualization methods for the detection of vWF multimers: autoradiography (125I), electroblot with a horseradish peroxidase system (BLOT-HRP), and an avidin-biotin peroxidase system (AV-BIO). Each method was evaluated according to: 1) ability to visually detect bands and subbands thereby identifying von Willebrand's disease (vWD) subtypes and normals, 2) reagent availability, 3) cost, and 4) time requirements. Additionally, resolvability was evaluated utilizing low, intermediate, and high resolution gels prepared with both low and high gelling temperature agaroses with subsequent visualization by the three detecting systems. With intermediate resolution gels, our results showed that all three visualization methods could discern pathologic patterns from normal. In addition, the avidin-biotin peroxidase system demonstrated the best band discreteness with low resolution gels used to detect unusually high molecular weight multimers. With high resolution gels used for subtyping type II vWD, we found the internal band structure was best demonstrated using LGT agarose and the electroblot horseradish peroxidase system.


Nutritional nystagmus in infants.
Two infants presented with acquired infantile nystagmus. On examination, they manifested peculiar facies, growth and developmental delay, failure to thrive, and a Wernicke's type of nystagmus. Suspicion of a B vitamin deficiency resulted in correct diagnosis of dietary deficiency and/or enzymatic defect. In both instances, dietary treatment with B vitamins resulted in resolution of the nystagmus and improved growth and development of both individuals. Physicians, especially pediatricians and ophthalmologists, should be alert to the possibility of a Wernicke's type nystagmus in such infants, since the diagnosis may be critical to accurate diagnosis and treatment.


Intra-arterial blood pressure and heart rate reactivity to behavioral stress in normotensive, borderline, and mild hypertensive men.
Intra-arterial blood pressure (BP) stress reactivity was studied in newly detected, World Health Organization-classified (1978), age-matched normotensive (NT; n = 33), borderline hypertensive (BHT; n = 30), and hypertensive (HT; n = 32) men recruited through routine health examinations. They underwent a relaxation baseline followed by 8 standardized behavioral challenges. BHT and HT men displayed exaggerated BP reactivity compared with NT men, particularly on perceptual-motor and social tasks, and HT men showed higher reactivity than NT men in the cold pressor test. These results are the first to show reactivity differences between NT men and BHT or HT men in an intra-arterial experiment. Diastolic BP (DBP) discriminated the groups better than systolic BP (SBP) or heart rate (HR). The few differences in SBP compared with DBP among the groups combined with hardly any differences in HR indicate the predominance of vascular factors in middle-aged as opposed to younger men with borderline or mild hypertension.


Effects of High-Flow Nasal Cannula on Right Heart Dysfunction in Patients with Acute-on-Chronic Respiratory Failure and Pulmonary Hypertension.
High-flow nasal cannula (HFNC) has several benefits in patients affected by different forms of acute respiratory failure, based on its own mechanisms. We postulated that HFNC may have some advantages over conventional oxygen therapy (COT) on the heart function in patients with acute-on-chronic respiratory failure with concomitant pulmonary hypertension (PH). We therefore designed this retrospective observational study to assess if HFNC improves the right and left ventricle functions and morphologies, arterial blood gases (ABGs), and patients' dyspnea, compared to COT. We enrolled 17 hospitalized patients receiving HFNC, matched with 17 patients receiving COT. Echocardiographic evaluation was performed at the time of admission (baseline) and 10 days after (T10). HFNC showed significant improvements in right ventricular morphology and function, and a reduction in sPAP. However, there were no significant changes in the left heart measurements with HFNC application. Conversely, COT did not lead to any modifications in echocardiographic measurements. In both groups, oxygenation significantly improved from baseline to T10 (in the HFNC group, from 155 ± 47 to 204 ± 61 mmHg while in the COT group, from 157 ± 27 to 207 ± 27 mmHg; p < 0.0001 for both comparisons). In conclusion, these data suggest an improvement of oxygenation with both treatments; however, only HFNC was able to improve the right ventricular morphology and function after 10 days from the beginning of treatment in a small cohort of patients with acute-on-chronic respiratory failure with PH.


Robust Outlier-Adaptive Filtering for Vision-Aided Inertial Navigation.
With the advent of unmanned aerial vehicles (UAVs), a major area of interest in the research field of UAVs has been vision-aided inertial navigation systems (V-INS). In the front-end of V-INS, image processing extracts information about the surrounding environment and determines features or points of interest. With the extracted vision data and inertial measurement unit (IMU) dead reckoning, the most widely used algorithm for estimating vehicle and feature states in the back-end of V-INS is an extended Kalman filter (EKF). An important assumption of the EKF is Gaussian white noise. In fact, measurement outliers that arise in various realistic conditions are often non-Gaussian. A lack of compensation for unknown noise parameters often leads to a serious impact on the reliability and robustness of these navigation systems. To compensate for uncertainties of the outliers, we require modified versions of the estimator or the incorporation of other techniques into the filter. The main purpose of this paper is to develop accurate and robust V-INS for UAVs, in particular, those for situations pertaining to such unknown outliers. Feature correspondence in image processing front-end rejects vision outliers, and then a statistic test in filtering back-end detects the remaining outliers of the vision data. For frequent outliers occurrence, variational approximation for Bayesian inference derives a way to compute the optimal noise precision matrices of the measurement outliers. The overall process of outlier removal and adaptation is referred to here as "outlier-adaptive filtering". Even though almost all approaches of V-INS remove outliers by some method, few researchers have treated outlier adaptation in V-INS in much detail. Here, results from flight datasets validate the improved accuracy of V-INS employing the proposed outlier-adaptive filtering framework.


Roberts syndrome fibroblasts showing cisplatin hypersensitivity have normal host cell reactivation of cisplatin-treated adenovirus and normal capacity of cisplatin-treated cells for adenovirus DNA synthesis.
Roberts syndrome (RS) is a rare, recessively inherited disorder characterized by growth retardation, limb reductions and craniofacial deformities. Cells from a subset of afflicted individuals, termed RS+, display unusual separation or puffing of the heterochromatic regions of their chromosomes and are hypersensitive to several DNA-damaging agents including mitomycin C (MMC) and cisplatin, both of which can induce interstrand crosslinks in DNA. For this reason, we have investigated the ability of RS+ fibroblasts to repair cisplatin-induced DNA lesions using adenoviris as a probe. Host cell reactivation of cisplatin-treated adenovirus (Ad) was significantly reduced in nucleotide excision repair (NER)-deficient xeroderma pigmentosum (XP) cells but was normal in the two RS+ fibroblast strains and the Fanconi's anemia (FA)fibroblast strain tested. The capacity of cisplatin-treated cells for Ad DNA synthesis was reduced in XP and FA cells compared to normal human cells, but was not reduced in RS+ cells. These results indicate that the hypersensitivity of RS+ cells to cisplatin is not due to a deficiency in NER nor due to a deficiency in the pathway which leads to cisplatin hypersensitivity in FA cells. It is possible that the abnormal heterochromatin organisation of RS+ cells selectively renders the heterochromatic regions of the genome more susceptible to mutagen damage and/or less available for repair.


Interionic interactions in conducting nanoconfinement.
Interionic interactions in conducting nanopores determine how counterions may be packed in the pores subject to the applied voltage. In ideal metals, interactions are exponentially screened by metallic electrons. However, modern nanoporous electrodes are predominantly made of carbon materials. To what extent is this screening affected by a different mode of dielectric response in such materials? To answer this question we study Coulomb interaction of charges in cylindrical and slit pores that allow finite electric field penetration into the pore walls, as well as the Coulomb interaction in a nanogap between two thin walls of graphene modeled by a non-local dielectric function. In all cases studied the screening was found to be subtly different than in metallic nanopores, but still strong enough to support realization of the so called superionic state in such pores.