The effects of antifracture therapies on the components of bone strength: assessment of fracture risk today and in the future.
To summarize the current knowledge regarding the impact of the most common antifracture medications on the various determinants of bone strength. Relevant English-language articles acquired from Medline from 1966 to January 2005 were reviewed. Searches included the keywords bone AND 1 of the following: strength, remodeling, microcrack, structure, mineralization, collagen, organic, crystallinity, osteocyte, porosity, diameter, anisotropy, stress risers, or connectivity AND alendronate, estrogen, etidronate, hormone replacement therapy, parathyroid hormone, risedronate, OR teriparatide. Abstracts from relevant conference proceedings were also reviewed for pertinent information. Antiresorptive therapies increase bone strength through decreasing bone turnover. This lower bone turnover results in a higher mean mineralization and decreases the number of active resorption pits within bone at any given time. These resorption pits are speculated to be areas of focal weakness and a higher number of them would, if all other things were equal, result in greater fragility. Parathyroid hormone therapy increases the rate of bone remodeling, which introduces many resorption pits, but this source of strength loss is thought to be compensated by rapid increases in bone mass. Both the antiresorptives, particularly bisphosphonates, and the parathyroid hormone therapy increase bone strength; however, the changes that are elicited to achieve this differ significantly.


Discovery of novel deoxyvasicinone derivatives with benzenesulfonamide substituents as multifunctional agents against Alzheimer's disease.
A series of deoxyvasicinone derivatives with benzenesulfonamide substituents were designed and synthesized to find a multifunctional anti-Alzheimer's disease (AD) drug. The results of the biological activity evaluation indicated that most compounds demonstrated selective inhibition of acetylcholinesterase (AChE). Among them, g17 exhibited the most potent inhibitory effect on AChE (IC50 = 0.24 ± 0.04 μM). Additionally, g17 exhibited promising properties as a metal chelator and inhibitor of amyloid β peptides self-aggregation (68.34 % ± 1.16 %). Research on oxidative stress has shown that g17 displays neuroprotective effects and effectively suppresses the intracellular accumulation of reactive oxygen species. Besides, g17 demonstrated remarkable anti-neuroinflammatory effects by significantly reducing the production of pro-inflammatory cytokines (such as NO, IL-1β, and TNF-α) and inhibiting the expression of inflammatory mediators iNOS and COX-2. In vivo studies showed that g17 significantly improved AD model mice's cognitive and memory abilities. Histological examination of mouse hippocampal tissue sections using hematoxylin and eosin staining revealed that g17 effectively mitigates neuronal damage. Considering the multifunctional properties of g17, it is regarded as a promising lead compound for treating AD.


Oil spill environmental sensitivity mapping of Rio de Janeiro, Brazil.
The current case study focuses on the Environmental Sensitivity Index (ESI) mapping of Guanabara Bay, Rio de Janeiro, Brazil - a region at risk from petroleum sector pollution. By mapping 981.5 km of coastline and classifying it in 10 oil sensitivity indices, we integrated biotic resources, socioeconomic attributes, and geoenvironmental diversity into a georeferenced database. Results reveal a high oil sensitivity of the bay, with approximately 89 % of the mapped coast scoring ESI 8 and ESI 10. These scores comprise, respectively, estuarine and solid substrate habitats that are sheltered from wave action. Notably, numerous manufacturing and oil handling plants, along with intensive urbanization, also contribute to the bay's oil sensitivity. Additionally, the rich biotic diversity in the study area, particularly in protected areas housing 79 conservation units, further amplifies its environmental vulnerability. This study aims to serve as a reference for detailed ESI mapping of coastal areas in tropical rainy zones with significant environmental diversity, industrial development, and a dense population.


Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy.
The purpose of this study was to assess changes in the tumor microvasculature induced by combination antiangiogenic therapy in MCF-7 breast tumor mouse models, using a noninvasive DCE-MRI method that minimizes the effect of water exchange. 3D quantitative DCE-MRI images were acquired with a heavily T1-weighted saturation recovery gradient echo sequence with a recovery delay of 20 ms. Tumor vascular volume (VV) and vascular permeability-surface area product (PS) were obtained through a linear regression of the albumin-Gd-DTPA-enhanced dynamic image intensity on MCF-7 breast tumor mouse models treated with combination bevacizumab/paclitaxel therapy. Measured tumor VV values were significantly higher than the values that have been reported previously using quantitative T1 mapping, and are in good agreement with micro-CT (computed tomography) results reported earlier from other tumor models. A trend of decreasing tumor PS was detected in the group of MCF-7 tumor bearing mice treated with the bevacizumab/paclitaxel combination regimen. VV and PS maps obtained by a heavily T1-weighted acquisition protocol revealed the large peripheral blood vessels as well as the permeable areas within the tumor. A 12-day/three-dose combination treatment of bevacizumab and paclitaxel resulted in delayed tumor growth and a trend of decreasing tumor vascular permeability surface area product.


Neurosurgery at the epicenter of the COVID-19 pandemic in Indonesia: experience from a Surabaya academic tertiary hospital.
Global outbreak of the novel coronavirus disease 2019 (COVID-19) has forced healthcare systems worldwide to reshape their facilities and protocols. Although not considered the frontline specialty in managing COVID-19 patients, neurosurgical service and training were also significantly affected. This article focuses on the impact of the COVID-19 outbreak at a low- and/or middle-income country (LMIC) academic tertiary referral hospital, the university and hospital policies and actions for the neurosurgical service and training program during the outbreak, and the contingency plan for future reference on preparedness for service and education. The authors collected data from several official databases, including the Indonesian Ministry of Health database, East Java provincial government database, hospital database, and neurosurgery operative case log. Policies and regulations information was obtained from stakeholders, including the Indonesian Society of Neurological Surgeons, the hospital board of directors, and the dean's office. The curve of confirmed COVID-19 cases in Indonesia had not flattened by the 2nd week of June 2020. Surabaya, the second-largest city in Indonesia, became the epicenter of the COVID-19 outbreak in Indonesia. The neurosurgical service experienced a significant drop in cases (50% of cases from normal days) along all lines (outpatient clinic, emergency room, and surgical ward). Despite a strict preadmission screening, postoperative COVID-19 infection cases were detected during the treatment course of neurosurgical patients, and those with a positive COVID-19 infection had a high mortality rate. The reduction in the overall number of cases treated in the neurosurgical service had an impact on the educational and training program. The digital environment found popularity in the educational term; however, digital resources could not replace direct exposure to real patients. The education stakeholders adjusted the undergraduate students' clinical postings and residents' working schemes for safety reasons. The neurosurgery service at an academic tertiary referral hospital in an LMIC experienced a significant reduction in cases. The university and program directors had to adapt to an off-campus and off-hospital policy for neurosurgical residents and undergraduate students. The hospital instituted a reorganization of residents for service. The digital environment found popularity during the outbreak to support the educational process.


MnSOD mediated by HSV vectors in the periaqueductal gray suppresses morphine withdrawal in rats.
Morphine appears to be the most active metabolite of heroin; therefore, the effects of morphine are important in understanding the ramifications of heroin abuse. Opioid physical dependence (withdrawal response) may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. However, the exact mechanisms of morphine withdrawal (MW) are not clear yet, and its treatment remains elusive. Periaqueductal gray (PAG) is one of the important sites in the pathogenesis of MW. Here, we used recombinant herpes simplex virus (HSV) vectors that encode the sod2 gene expressing manganese superoxide dismutase (MnSOD) to evaluate its therapeutic potential in MW. Microinjection of HSV vectors expressing MnSOD into the PAG reduced the MW syndrome. MnSOD vectors suppressed the upregulated mitochondrial superoxide, and endoplasmic reticulum stress markers (glucose-related protein 78 (GRP78) and activating transcription factor 6 alpha (ATF6α)) in the PAG induced by MW. Immunostaining showed that mitochondrial superoxide, GRP78 and ATF6α were colocalized with neuronal nuclei (a neuronal-specific marker), suggesting that they are located in the neurons in the PAG. These results suggest that overexpression of MnSOD by HSV vectors may relieve opioid dependence. This study may provide a novel therapeutic approach to morphine physical withdrawal response.


Effect of high temperature on the reproductive development of chickpea genotypes under controlled environments.
High temperature during the reproductive stage in chickpea (Cicer arietinum L.) is a major cause of yield loss. The objective of this research was to determine whether that variation can be explained by differences in anther and pollen development under heat stress: the effect of high temperature during the pre- and post-anthesis periods on pollen viability, pollen germination in a medium, pollen germination on the stigma, pollen tube growth and pod set in a heat-tolerant (ICCV 92944) and a heat-sensitive (ICC 5912) genotype was studied. The plants were evaluated under heat stress and non-heat stress conditions in controlled environments. High temperature stress (29/16°C to 40/25°C) was gradually applied at flowering to study pollen viability and stigma receptivity including flower production, pod set and seed number. This was compared with a non-stress treatment (27/16°C). The high temperatures reduced pod set by reducing pollen viability and pollen production per flower. The ICCV 92944 pollen was viable at 35/20°C (41% fertile) and at 40/25°C (13% fertile), whereas ICC 5912 pollen was completely sterile at 35/20°C with no in vitro germination and no germination on the stigma. However, the stigma of ICC 5912 remained receptive at 35/20°C and non-stressed pollen (27/16°C) germinated on it during reciprocal crossing. These data indicate that pollen grains were more sensitive to high temperature than the stigma in chickpea. High temperature also reduced pollen production per flower, % pollen germination, pod set and seed number.


Intra-tumoral Salmonella typhimurium induces a systemic anti-tumor immune response that is directed by low-dose radiation to treat distal disease.
Salmonella typhimurium is a facultative anaerobic bacterium able to multiply preferentially in tumors and inhibit their growth. The mechanisms through which Salmonella exerts its anti-cancer properties are not fully understood. We recently showed that intra-tumoral Salmonella injection results not only in the regression of even bulky tumor masses, but also impacts on the growth of distant untreated lesions. Here we describe how Salmonella exerts its systemic anti-cancer effects and means to potentiate them. The outburst of an early inflammatory reaction in the treated tumor promotes the development of an immunostimulatory cytokine environment both locally and in the draining lymph node. Within the next 10 days, an efficient cross-presentation of endogenous tumor antigens by dendritic cells at the tumor-draining lymph node leads to the priming of effective anti-tumor CD8+ T cell responses. This potentially broadly reactive T cell repertoire can be directed to other pre-established melanomas by low-dose radiotherapy enhancing the Salmonella anti-cancer effect. We demonstrate that Salmonella-based therapy coupled to low-dose radiotherapy dampens tumor immune escape mechanisms at different levels and allows controlling systemic disease in a CD8+ T cell-dependent manner.


RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass.
During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13, 2-[4-[[(3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin (Hb), increases release of oxygen from Hb, increasing oxygen availability to hypoxic tissues, and reverses the hypothermia-dependent increase in Hb oxygen affinity. We studied recovery of myocardial mechanical and metabolic function and examined myocardial morphology after cardioplegia, comparing RSR13 (1.75 mmol/L)-supplemented blood (RSR13-BC) to standard blood cardioplegia (BC). Twelve dogs underwent 15 minutes of 37 degrees C global ischemia on cardiopulmonary bypass, followed by 75 minutes of hypothermic cardioplegia (13 degrees C) with either BC (n=6) or RSR13-BC (n=6). There were no differences in baseline function between groups. Cardiac function was assessed after 30 minutes of 37 degrees C reperfusion (BC versus RSR13-BC, respectively) by measuring: % return to normal sinus rhythm (0/100%), % of baseline+dP/dt (33.7+/-1.7/76.3+/-1.9), % of baseline-dP/dt (26.6+/-2.0/81.1+/-1.6), stroke volume (3.5+/-0.5/7.1+/-0.9 mL), cardiac output (340+/-20/880+/-40.3 mL/min), and LVEDP (11.3+/-2.2/0. 3+/-2.9 mm Hg). Postischemic oxidative and metabolic parameters including myocardial lactate, pyruvate, ATP content, and percent water content also were determined. Histological analysis demonstrated preservation of endothelial and myocyte morphology in hearts receiving RSR13-BC compared with BC. These results indicate that in the setting of hypothermic cardiopulmonary bypass, RSR13 improves recovery of myocardial mechanical and metabolic function compared with standard hypothermic BC. Findings from this study suggest that RSR13-BC, by decreasing hemoglobin oxygen affinity, improves oxidative metabolism and preserves cellular morphology, resulting in significantly improved contractile recovery on reperfusion.


Fluctuation spectroscopy: a new approach for studying low-dimensional molecular metals.
Fluctuations (or noise) are often merely considered a nuisance, an unwanted disturbance limiting the accuracy of a scientific measurement. Electronic fluctuations, however, reveal hidden pieces of information not present in the mean quantity (the resistance) itself. Herein we describe resistance noise spectroscopy as a powerful new tool for investigating the low-frequency dynamics of electronic processes in low-dimensional organic conductors. Over the years, these molecular charge-transfer complexes have provided unprecedented model systems for exploring the physics of low-dimensional materials. The combination of low dimensionality with other parameters, specific to molecular conductors, sets the stage for Coulomb correlation effects to become relevant and, under certain circumstances, even to dominate the properties of the π-electron system. The combined effects of strong electron-electron and electron-phonon interactions give rise to the rich phenomenology of ground states encountered in these materials. To provide examples, we describe noise spectroscopy as a method to study the coupling of the correlated charge carriers to intramolecular modes of lattice vibrations and to investigate the inhomogeneous coexistence region of antiferromagnetic (Mott) insulating and superconducting phases.


Antileishmanial activity of meroditerpenoids from the macroalgae Cystoseira baccata.
The development of novel drugs for the treatment of leishmaniases continues to be crucial to overcome the severe impacts of these diseases on human and animal health. Several bioactivities have been described in extracts from macroalgae belonging to the Cystoseira genus. However, none of the studies has reported the chemical compounds responsible for the antileishmanial activity observed upon incubation of the parasite with the aforementioned extracts. Thus, this work aimed to isolate and characterize the molecules present in a hexane extract of Cystoseira baccata that was found to be bioactive against Leishmania infantum in a previous screening effort. A bioactivity-guided fractionation of the C. baccata extract was carried out and the inhibitory potential of the isolated compounds was evaluated via the MTT assay against promastigotes and murine macrophages as well as direct counting against intracellular amastigotes. Moreover, the promastigote ultrastructure, DNA fragmentation and changes in the mitochondrial potential were assessed to unravel their mechanism of action. In this process, two antileishmanial meroditerpenoids, (3R)- and (3S)-tetraprenyltoluquinol (1a/1b) and (3R)- and (3S)-tetraprenyltoluquinone (2a/2b), were isolated. Compounds 1 and 2 inhibited the growth of the L. infantum promastigotes (IC50 = 44.9 ± 4.3 and 94.4 ± 10.1 μM, respectively), inducing cytoplasmic vacuolization and the presence of coiled multilamellar structures in mitochondria as well as an intense disruption of the mitochondrial membrane potential. Compound 1 decreased the intracellular infection index (IC50 = 25.0 ± 4.1 μM), while compound 2 eliminated 50% of the intracellular amastigotes at a concentration > 88.0 μM. This work identified compound 2 as a novel metabolite and compound 1 as a biochemical isolated from Cystoseira algae displaying antileishmanial activity. Compound 1 can thus be an interesting scaffold for the development of novel chemotherapeutic molecules for canine and human visceral leishmaniases studies. This work reinforces the evidence of the marine environment as source of novel molecules.


The pseudorabies virus gII gene is closely related to the gB glycoprotein gene of herpes simplex virus.
We have looked for conserved DNA sequences between four herpes simplex virus type 1 (HSV-1) glycoprotein genes encoding gB, gC, gD, and gE and pseudorabies virus (PRV) DNA, HSV-1 DNA fragments representing these four glycoprotein-coding sequences were hybridized to restriction enzyme fragments of PRV DNA by the Southern blot procedure. Specific hybridization was observed only when HSV-1 gB DNA was used as probe. This region of hybridization was localized to a 5.2-kilobase (kb) region mapping at approximately 0.15 map units on the PRV genome. Northern blot (RNA blot) analysis, with a 1.2-kb probe derived from this segment, revealed a predominant hybridizing RNA species of approximately 3 kb in PRV-infected PK15 cells. DNA sequence analysis of the region corresponding to this RNA revealed a single large open reading frame with significant nucleotide homology with the gB gene of HSV-1 KOS 321. In addition, the beginning of the sequenced PRV region also contained the end of an open reading frame with amino acid homology to HSV-1 ICP 18.5, a protein that may be involved in viral glycoprotein transport. This sequence partially overlaps the PRV gB homolog coding sequence. We have shown that the PRV gene with homology to HSV-1 gB encoded the gII glycoprotein gene by expressing a 765-base-pair segment of the PRV open reading frame in Escherichia coli as a protein fused to beta-galactosidase. Antiserum, raised in rabbits, against this fusion protein immunoprecipitated a specific family of PRV glycoproteins of apparent molecular mass 110, 68, and 55 kilodaltons that have been identified as the gII family of glycoproteins. Analysis of the predicted amino acid sequence indicated that the PRV gII protein shares 50% amino acid homology with the aligned HSV-1 gB protein. All 10 cysteine residues located outside of the signal sequence, as well as 4 of 6 potential N-linked glycosylation sites, were conserved between the two proteins. The primary protein sequence for HSV-1 gB regions known to be involved in the rate of virus entry into the cells and cell-cell fusion, as well as regions known to be associated with monoclonal antibody resistance, were highly homologous with the PRV protein sequence. Furthermore, monospecific antibody made against PRV gII immunoprecipitated HSV-1 gB from infected cells. Taken together, these findings suggest significant conservation of structure and function between the two proteins and may indicate a common evolutionary history.


Influence of collagenase loading on long-term preservation of pig pancreas by the two-layer method for subsequent islet isolation.
The introduction of the two-layer method (TLM) for long-term human pancreas preservation revealed the enormous potential of TLM to improve graft function of isolated islets. It is still unclear whether pig islets can be successfully isolated from pancreases after prolonged cold ischemia. To clarify this question, pig pancreases were subjected to 7-hour preservation by University of Wisconsin solution (UWS) storage or TLM. Another aim was to verify whether TLM can be synergistically combined with intraductal collagenase injection before cold storage. After intraductal flush with UWS, organs were distended with 4.4 PZ-U/g of UWS-dissolved collagenase NB-8 and neutral protease adjusted to respectively 1.1, 0.2, 0.5, or 0.8 DMC-U/g for pancreases freshly procured (n=6) or distended with enzymes before (TLM preloaded, n=7) or after cold storage (UWS storage, n=4; TLM postloaded, n=10). Purified islet yield decreased from 429,200+/-86,700 islet equivalents (IEQ) in unstored pancreases to respectively 37,670+/-19620, 210,400+/-22900 and 238,000+/-26600 IEQ in UWS-stored (P<0.01), TLM-preloaded, or postloaded organs (P<0.05). Purity (>90%), viability (>95%), and insulin content were not different between groups. Islets from UWS-stored pancreases fragmented extensively, preventing further assessment of in vivo function. Compared with other experimental groups, islets from TLM-preloaded organs were characterized by enhanced basal and stimulated insulin release. Sustained normoglycemia was observed in diabetic nude mice transplanted with islets from TLM-postloaded or unstored pancreases in contrast with transient function in TLM-preloaded islets. This study demonstrates that significant amounts of intact pig islets can be isolated after prolonged pancreas preservation by TLM. Enzyme administration before TLM preservation decreases islet graft function.


Evidence for asthma susceptibility genes on chromosome 11 in an African-American population.
Initial genome-wide scan data provided suggestive evidence for linkage of the asthma phenotype in African-American (AA), but not Caucasian, families to chromosome 11q markers (peak at D11S1985; LOD=2). To refine this region, mapping analysis of 91 AA families (51 multiplex families and 40 asthmatic case-parent trios) was performed with an additional 17 markers flanking the initial peak linkage marker. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak non-parametric linkage score of 4.38 at marker D11S1337 (map position 68.6 cM). Furthermore, family-based association and transmission disequilibrium tests conducted on all 91 families showed significant evidence of linkage in the presence of disequilibrium for several individual markers in this region. A putative susceptibility locus was estimated to be at map position 70.8 cM with a confidence interval spanning the linkage peak. Evidence from both linkage and association analyses suggest that this region of chromosome 11 contains one or more susceptibility genes for asthma in these AA families.


Transcranial Direct Current Stimulation in the Treatment of Gait Disturbance in Post-Stroke Patients: An Overview of Systematic Reviews.
Transcranial direct current stimulation (tDCS) is a promising technique for brain modulation after a cerebrovascular accident (CVA). This treatment modality has been previously studied in the recovery of patients. The aim of this review is to analyse the evidence for the application of tDCS in the recovery of gait disturbance in stroke patients. This review was conducted according to the recommendations of the PRISMA statement. Three different electronic databases were searched for relevant results: PubMed, Scopus, and Cochrane, from 2015 to January 2022. We included reviews and meta-analyses that only considered randomised controlled trials (RCTs) that investigated the effects of transcranial direct current stimulation, in combination or not with other physiotherapy treatments, compared to no treatment, usual care, or alternative treatment on gait recovery. Our primary outcomes of interest were walking speed, mobility, and endurance; secondary outcomes included motor function. Thirteen studies with a total of 195 RCTs were included. Data on population, outcome measures, protocols, and outcomes were extracted. The Amstar-2 scale and the GRADE system of certainty of evidence were used. Only one study received high certainty of evidence, 5 received low certainty of evidence, and 7 received critically low certainty of evidence. Moderate to low-quality evidence showed a beneficial effect of tDCS on gait parameters, but not significantly. Although the tDCS produces positive changes in gait recovery in spatio-temporal parameters such as mobility, endurance, strength, and motor function, there is insufficient evidence to recommend this treatment. Higher-quality studies with larger sample sizes are needed for stronger conclusions.


Environmental hazards of WELGRO® Cu+Zn: A nano-enabled fertilizer.
Nanoagrochemicals have the potential to revolutionize agriculture towards a precision farming system, able to reduce application rates and consequently their environmental footprint, while keeping efficacy. Several nanoagrochemicals (including nanopesticides (Npes) and nanofertilizers (Nfer)) are already commercialized but the environmental risk assessment of these advanced materials is often lacking. In the present study, we studied the commercial fertilizer WELGRO® Cu + Zn and assessed its ecotoxicity to the soil invertebrate species Enchytraeus crypticus (Oligochaeta), further comparing it to its individual active substances CuO and ZnO. To get a comprehensive picture of possible effects, we used four types of highly relevant tests in LUFA 2.2 soil: 1) avoidance behaviour (2 days), 2) reproduction (OECD standard, 28 d), 3) its extension (56 d), and 4) the full life cycle (FLC) (46 d) - this high level of hazard screening allows for increased interpretation. The results confirmed the nano-features of WELGRO® and a higher toxicity than the mixture of the individual components CuO + ZnO. E. crypticus avoided the soil spiked with WELGRO® and CuO + ZnO, this being the most sensitive endpoint - avoidance behaviour. Both WELGRO® and the active substances were little to non-toxic based on the OECD standard test. However, the toxicity dramatically increased in the tests focussing on longer-term sustainability measures, i.e., 56 days, ca. 170 for WELGRO®. This seems related to the nano-features of WELGRO®, e.g., slow release of ions from the nanoparticles throughout time. The FLCt results showed WELGRO® affected hatching and juveniles' survival, being these the most sensitive life stages. Hence, under actual real world field usage scenarios, i.e., based on the recommended application rates, nanoenabled WELGRO® can affect oligochaete populations like enchytraeids, both via the immediate avoidance behaviour and also via prolonged exposure periods.


Comparison of microemulsion and conventional formulations of cyclosporine A in preventing acute rejection in de novo kidney transplant patients. The U.K. Neoral Renal Study Group.
The microemulsion preconcentrate formulation of cyclosporine A (CsA) (Neoral) exhibits more uniform pharmacokinetics than the conventional formulation (Sandimmun; SIM). This randomized, open-label, U.K. multicenter study compared the efficacy, safety, and tolerability of Neoral and SIM in preventing acute rejection in de novo renal transplant recipients. Adult cadaveric kidney recipients (n=293) received Neoral or SIM twice daily for 12 months. Initially identical Neoral and SIM doses were titrated, maintaining trough CsA levels within locally defined therapeutic limits. In the year after transplantation, acute rejection occurred in 34% of the Neoral and 47% of the SIM recipients (P=0.037). In the intent-to-treat population, fewer treatment failures (defined as acute rejection, graft loss, withdrawal, or death) occurred in the Neoral (45%) than the SIM recipients (58%) (P=0.015) and therapeutic CsA levels (> or =250 microg/L) were reached faster with Neoral than SIM (P=0.0017). Antibody treatment of refractory rejection was used slightly less in the Neoral group (Neoral: 10%; SIM: 12%). One-year patient and graft survival rates (excluding deaths with functioning grafts) were 95% and 88%, respectively, for Neoral and 96% and 89% for SIM. Both formulations were well tolerated. No differences were observed between therapies in the nature, frequency, or severity of adverse events. Neoral use was not associated with increased nephrotoxicity or excessive immunosuppression. Neoral reduced the incidence of acute rejection compared with SIM, without significant increases in adverse events. This was achieved without altering existing SIM protocols and was attributed to improved absorption of CsA from Neoral and less variability in whole blood CsA concentrations.


In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease.
Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.


Evaluation of osteopathic manipulative treatment training by practicing physicians in Ohio.
The authors mailed a survey designed to evaluate beliefs about osteopathic manipulative treatment (OMT) training to the 2318 osteopathic physicians registered with the Ohio Osteopathic Association. Responses were received from 871 osteopathic physicians (response rate, 38%). Fifty-three percent of the respondents had used OMT with patients at least once during the week before the survey. With regard to OMT training, 60% rated their experience during medical school as acceptable; during postgraduate training the acceptable rating dropped to 9%. Osteopathic manipulative treatment training through continuing medical education programs was rated as acceptable by 26% who had participated in these programs. Forty percent of the respondents reported that they were practicing less OMT now than when they originally entered practice, while 20% reported using OMT procedures more often. No significant correlation was observed between OMT training satisfaction during medical school and current use of OMT. However, a strong negative correlation was observed between satisfaction with postgraduate OMT training and OMT use. This survey did not detect any association between year of graduation and use of OMT.


Manifestations and Outcomes of Intracerebral Hemorrhage During the COVID-19 Pandemic in China: Multicenter, Longitudinal Cohort Study.
The COVID-19 pandemic has inevitably affected the distribution of medical resources, and epidemic lockdowns have had a significant impact on the nursing and treatment of patients with other acute diseases, including intracerebral hemorrhage (ICH). This study aimed to investigate how the COVID-19 pandemic affected the manifestations and outcomes of patients with ICH. Patients with acute ICH before (December 1, 2018-November 30, 2019) and during (December 1, 2019-November 30, 2020) the COVID-19 pandemic at 31 centers in China from the Chinese Cerebral Hemorrhage: Mechanism and Intervention (CHEERY) study were entered into the analysis. Demographic information and clinical manifestations and outcomes were collected and compared between the 2 groups. From December 1, 2018, to November 30, 2020, a total of 3460 patients with ICH from the CHEERY study were enrolled and eventually analyzed. The results showed that during the COVID-19 pandemic, patients with ICH were more likely to be older (P<.001) with a history of ischemic stroke (P=.04), shorter time from onset to admission (P<.001), higher blood pressure (P<.001), higher fasting blood glucose (P=.003), larger hematoma volume (P<.001), and more common deep ICH (P=.01) and intraventricular hemorrhage (P=.02). These patients required more intensive care unit treatment (P<.001) and preferred to go to the hospital directly rather than call an ambulance (P<.001). In addition, the COVID-19 pandemic was associated with an increased risk of pulmonary infection during hospitalization (adjusted risk ratio [RRadjusted] 1.267, 95% CI 1.065-1.509), lower probability of a 3-month good outcome (RRadjusted 0.975, 95% CI 0.956-0.995), and a higher probability of in-hospital (RRadjusted 3.103, 95% CI 2.156-4.465), 1-month (RRadjusted 1.064, 95% CI 1.042-1.087), and 3-month (RRadjusted 1.069, 95% CI 1.045-1.093) mortality. Our study indicated that the cloud of COVID-19 has adversely impacted the presentation and outcomes of ICH. Medical workers may pay more attention to patients with ICH, while the public should pay more attention to hypertension control and ICH prevention. Chinese Clinical Trial Registry ChiCTR1900020872; https://www.chictr.org.cn/showprojEN.html?proj=33817.


Moderate within-person variability in cortisol is related to executive function in early childhood.
Lab-based experimental studies with humans and in animal models demonstrate that the relation between glucocorticoid (GC) levels and performance on measures of higher-order cognitive ability such as executive function (EF) is best described by an inverted U-shape curve. Moderate levels of GCs (cortisol/corticosterone) are associated with comparatively better performance relative to GC levels that are particularly high or low. Although findings from experimental studies are definitive and have high internal validity, the external validity of this association as an aspect of children's development is unknown. Here we analyze data from the Family Life Project (N=1292), a prospective longitudinal sample of children and families in predominantly low-income and rural communities followed longitudinally from infancy through age 60 months. Consistent with the prior experimental literature, we found evidence of an inverted-U relation. For children with relatively low cortisol levels, on average, between the ages 7, 15, 24, and 48 months, those illustrating moderate fluctuations in their cortisol levels over this span tended to show subsequently better EF performance at 60 months, than did children with either highly stable or highly variable temporal profiles. This curvilinear function did not extend to children whose cortisol levels were high, on average. These children tended to show lower EF performance, irrespective the stability of their cortisol levels over time.


Severe Acute Kidney Injury With Significant Uremia in an Infant Found to Have Inferior Vena Cava, Bilateral Renal Vein, and Bilateral Renal Artery Thromboses.
Common neonatal etiologies of acute kidney injury (AKI) include renal vein and inferior vena cava thromboses, maternal use of nonsteroidal antiinflammatory drugs, and congenital renal disease. The incidence of renal vein thrombosis is estimated to be 0.5 per 1,000 neonatal intensive care unit admissions, with approximately half of cases extending to the inferior vena cava and with unilateral disease being significantly more common than bilateral. Data on abdominal venous thromboembolism in pediatric patients are limited, and the clinical presentation of renal vein thrombosis can vary, although most patients have at least one of the three cardinal signs: hematuria, thrombocytopenia, or abdominal mass. We present the case of a 5-month-old female transferred to our pediatric intensive care unit from an outside hospital with AKI and significant uremia (creatinine 6.01 mg/dL, blood urea nitrogen >200 mg/dL) secondary to inferior vena cava, bilateral renal vein, and bilateral renal artery thromboses. The patient was started on a heparin drip and subsequently underwent mechanical thrombectomy of her inferior vena cava and right renal vein in addition to site-directed tissue plasminogen activator to her renal veins, renal arteries, and inferior vena cava. Following the procedure, she developed severe coagulopathy and became hemodynamically labile. The coagulopathy was corrected, but further anticoagulation to prevent further thrombus propagation was not sustainable in the face of ongoing bleeding and hemodynamic instability, so the decision to withdraw mechanical support was made. Because of the varied presentations of renal vein thrombosis and because prompt intervention significantly improves survival and renal outcomes, a high index of suspicion is warranted when risk factors and any of the three cardinal features of renal vein thrombosis are present.


Oligopotent stem cells are distributed throughout the mammalian ocular surface.
The integrity of the cornea, the most anterior part of the eye, is indispensable for vision. Forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of loss of corneal transparency; treatments range from local medications to corneal transplants, and more recently to stem cell therapy. The corneal epithelium is a squamous epithelium that is constantly renewing, with a vertical turnover of 7 to 14 days in many mammals. Identification of slow cycling cells (label-retaining cells) in the limbus of the mouse has led to the notion that the limbus is the niche for the stem cells responsible for the long-term renewal of the cornea; hence, the corneal epithelium is supposedly renewed by cells generated at and migrating from the limbus, in marked opposition to other squamous epithelia in which each resident stem cell has in charge a limited area of epithelium. Here we show that the corneal epithelium of the mouse can be serially transplanted, is self-maintained and contains oligopotent stem cells with the capacity to generate goblet cells if provided with a conjunctival environment. Furthermore, the entire ocular surface of the pig, including the cornea, contains oligopotent stem cells (holoclones) with the capacity to generate individual colonies of corneal and conjunctival cells. Therefore, the limbus is not the only niche for corneal stem cells and corneal renewal is not different from other squamous epithelia. We propose a model that unifies our observations with the literature and explains why the limbal region is enriched in stem cells.


Phosphorylation of Escherichia coli poly(A) polymerase I and effects of this modification on the enzyme activity.
In Escherichia coli, RNA polyadenylation is catalyzed mainly by poly(A) polymerase I (PAP I). Here we demonstrate that a PAP I variant with a C-terminal His tag (PAP I-His) can be phosphorylated both in vivo and in an artificial in vitro system. The in vivo phosphorylation of PAP I-His impairs activity of this enzyme. Previous studies, performed by others, indicated that phosphorylation of His-tagged proteins usually reflects such a modification of their native counterparts in bacterial cells. Therefore, our results suggest that phosphorylation and dephosphorylation of PAP I may be important regulatory processes in the control of activity of this enzyme.


Synthesis and Characterization of Dendritic and Linear Glycol Methacrylates and Their Performance as Marine Antifouling Coatings.
Dendritic polyglycerol (PG) was covalently coupled to 2-hydroxyethyl methacrylate (HEMA) by an anionically catalyzed ring-opening polymerization generating a dendritic PG-HEMA with four PG repetition units (PG4MA). Coatings of the methacrylate monomer were prepared by grafting-through and compared against commercially available hydrophilic monomers of HEMA, poly(ethylene) glycol methacrylate (PEGMA), and poly(propylene) glycol methacrylate (PPGMA). The obtained coatings were characterized by modern surface analytical techniques, including water contact angle goniometry (sessile and captive bubble), attenuated total internal reflection Fourier transform infrared spectroscopy, and atomic force microscopy. The antifouling (AF) and fouling-release (FR) properties of the coatings were tested against the model organisms Cobetia marina and Navicula perminuta in laboratory-scale dynamic accumulation assays as well as in a dynamic short-term field exposure (DSFE) in the marine environment. In addition, the hydration of the coatings and their susceptibility toward silt uptake were evaluated, revealing a strong correlation between water uptake, silt incorporation, and field assay performance. While all glycol derivatives showed good resistance in laboratory settlement experiments, PPGMA turned out to be less susceptible to silt incorporation and outperformed PEGMA and PG4MA in the DSFE assay.


Microfilariae of the filarial nematode Litomosoides sigmodontis exacerbate the course of lipopolysaccharide-induced sepsis in mice.
Helminths facilitate their own survival by actively modulating the immune systems of their hosts. We investigated the impacts that different life cycle stages of the rodent filaria Litomosoides sigmodontis have on the inflammatory responses of mice injected with sublethal doses of lipopolysaccharide (LPS). Mice infected with female adult worms from prepatent infections, worms which have not yet started to release microfilariae, developed lower levels of proinflammatory cytokines in the peripheral blood after LPS challenge than sham-treated controls, demonstrating that female adult worms can mitigate the innate immune response. The presence of microfilariae in mice, however, through either direct injection or implantation of microfilaria-releasing adult female worms, turned the LPS challenge fatal. This lethal outcome was characterized by increased plasma levels of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), and IL-6, greater numbers of macrophages and granulocytes in the peripheral blood, and decreased body temperatures in microfilaria-infected mice. Microfilaria-infected mice deficient in IFN-gamma receptor and TNF receptor 1 had increased survival rates after LPS challenge compared to immune-competent mice, suggesting that microfilariae worsen LPS-induced sepsis through actions of IFN-gamma and TNF-alpha. In summary, we have demonstrated that infection of mice with L. sigmodontis female adult worms from prepatent infections protects mice injected with LPS whereas microfilariae worsen LPS-induced sepsis through the induction of proinflammatory cytokines and upregulation of granulocytes, NK cells, and monocytes in the peripheral blood.


S1, a novel pan-BH3 mimetic, induces apoptosis in Mcl-1-overexpressing cells through Bak.
Mcl-1, an anti-apoptotic Bcl-2 homolog that has a structurally divergent BH3-binding pocket, non-redundant action model, and unique characteristic of short life confers complete resistance to the BH3 mimetic ABT-737. Herein, we used S1, previously identified as a Mcl-1/Bcl-2 dual inhibitor and a pure BH3 mimetic, to explore the mechanism of Mcl-1's action and supply a strategy to challenge Mcl-1's protection. Apoptosis assay in SMMC-7721, HCT116, and K562 cells demonstrated that S1 can effectively challenge Mcl-1's anti-apoptotic effect. Notably, we discovered an unexpected dynamic change of Mcl-1 that directly correlates with resistance or commitment to apoptosis induced by both ABT-737 and S1. Co-immunoprecipitation assays demonstrated that Mcl-1 increase results from Bim trafficking from Bcl-2 to Mcl-1, while subsequent Bak released by S1 determines Mcl-1 decrease and full-blown apoptosis. Further experiments using Bak shRNA testified that Bak accounts for S1-induced apoptosis and Mcl-1 decrease. Consistently, Bax-deficient DU145 cells are sensitive to S1, whereas Bak-mutant MKN-28 cells are significantly more resistant. The in vitro model could be extended to an in vivo mouse xenograft model in which Mcl-1 confers resistance by increased protein level, and the release of Bak could serve as a biomarker of apoptosis.


SPECT/CT with a hybrid imaging system in the study of lower gastrointestinal bleeding with technetium-99m red blood cells.
Lower gastrointestinal (GI) hemorrhage is a complex clinical problem that requires disciplined evaluation for successful management. This study was conducted to evaluate the applicability of single photon emission computed tomography/computed tomography (SPECT/CT) in patients with acute lower gastrointestinal bleeding undergoing scintigraphy with 99mTc-labelled red blood cells (RBC), and to assess the additional clinical value of fused images when compared to the standard radionuclide scan. Twenty-seven patients presenting with acute lower GI tract hemorrhage were studied with conventional dynamic and planar 99mTc-RBC imaging. In 19 patients with positive findings on scans taken within 6 hours, a SPECT/CT study was immediately performed using a hybrid system composed of a dual-head, variable angle gamma camera and an X-ray tube. The number of patients in whom SPECT/CT changed the scintigraphic interpretation with regard to the presence or site of GI blood loss as confirmed by other diagnostic or therapeutical procedures was recorded. Image fusion was easy and successful in all patients showing perfect correspondence between SPECT and CT data and allowing precise anatomical localization of the sites of 99mTc-RBC extravasation. SPECT/CT had significant impact on the scintigraphic results in 7/19 patients (36.8%): in 6 patients it precisely localized the bleeding foci whose location could not be identified in standard scans and in one it excluded the presence of an active GI hemorrhage. SPECT/CT with a hybrid system is feasible and useful for facilitating imaging interpretation and improving the accuracy of 99mTc-RBC scintigraphy in patients with acute lower GI bleeding.


A tolerability assessment of new respiratory protective devices developed for health care personnel: A randomized simulated clinical study.
U.S. health care personnel (HCP) have reported that some respiratory protective devices (RPD) commonly used in health care have suboptimal tolerability. Between 2012 and 2016, the U.S. National Institute for Occupational Safety and Health, and the Veterans Health Administration collaborated with two respirator manufacturers, Company A and B, to bring new RPD with improved tolerability to the U.S. health care marketplace. The purpose of this study was to compare the tolerability of four new prototype RPD to two models commonly used in U.S. health care delivery. A randomized, simulated workplace study was conducted to compare self-reported tolerability of four new prototype RPD (A1, A2, B1, and B2) worn by HCP and two N95 control respirators commonly used in U.S. health care delivery, the 1870 and 1860, manufactured by 3M Corporation. A new survey tool, the Respirator Comfort, Wearing Experience, and Function Instrument (R-COMFI), developed previously in part for the current study, was used as the primary outcome metric. With a maximum total score of 47, lower R-COMFI scores reflected better self-reported tolerability. Poisson regression analyses were used to estimate prototype relative risks compared to controls. Conducted between 2014 and 2015 in two inpatient care rooms at the North Florida/South Georgia Veterans Health System, among 383 participants who enrolled, 335 (87.5%) completed the study. Mean total R-COMFI scores for the 3M 1870, 3M 1860, and prototypes A1, A2, B1, and B2 were 8.26, 9.36, 5.79, 7.70, 6.09, and 5.71, respectively. Compared to the 3M 1870, total R-COMFI unadjusted relative risks (RR) and 95 percent confidence intervals (CI) were A1 (RR 0.70, CI 0.60, 0.82), A2 (RR 0.93, CI 0.82, 1.06), B1 (RR 0.74, CI 0.64, 0.85), and B2 (RR 0.69, CI 0.60, 0.80). Compared to the 3M 1860, prototype total R-COMFI unadjusted RR and 95 percent CI were A1 (RR 0.62, CI 0.53, 0.72), A2 (RR 0.82, CI 0.73, 0.93), B1 (RR 0.65, CI 0.57, 0.74), and B2 (RR 0.61, CI 0.53, 0.70). Similarly, models adjusted for demographic characteristics showed that prototypes A1, B1, and B2 significantly improved tolerability scores compared to both controls, while prototype A2 was significantly improved compared to the 3M 1860. Compared to the 3M 1870 and 3M 1860, two RPDs commonly used in U.S. health care delivery, tolerability improved for three of four newly developed prototypes in this simulated workplace study. The R-COMFI tool, used in this study to assess tolerability, should be useful for future comparative studies of RPD.


Transport engineering design of AND and NOR gates with a 1,4-2-phenyl-dithiolate molecule.
We have explored logical AND and NOR gate responses of a 1,4-2-phenyl-dithiolate molecule threaded by a magnetic flux ϕ in two-terminal junctions by using the Green's function method in the framework of a nearest-neighbor tight-binding approximation. Here, we put emphasis on the logical gate voltages, and obtain the electrical transmission and current-voltage characteristics with metal-molecule-metal (m-M-m) tunnel junctions. The hopping integral among two neighboring atoms in the molecule was quantitatively estimated by means of density functional theory (DFT) calculations. Our results show that the AND and NOR responses are explored through our molecular junction for a typical value of the magnetic flux. The numerical results may shed light on the next applications of molecular systems and make them a good, promising candidate for field-effect transistors.


AAV production in stable packaging cells requires expression of adenovirus 22/33K protein to allow episomal amplification of integrated rep/cap genes.
Efficient manufacture of recombinant adeno-associated virus (rAAV) vectors for gene therapy remains challenging. Packaging cell lines containing stable integration of the AAV rep/cap genes have been explored, however rAAV production needs to be induced using wild-type adenoviruses to promote episomal amplification of the integrated rep/cap genes by mobilizing a cis-acting replication element (CARE). The adenovirus proteins responsible are not fully defined, and using adenovirus during rAAV manufacture leads to contamination of the rAAV preparation. 'TESSA' is a helper adenovirus with a self-repressing Major Late Promoter (MLP). Its helper functions enable efficient rAAV manufacture when the rep and cap genes are provided in trans but is unable to support rAAV production from stable packaging cells. Using rAAV-packaging cell line HeLaRC32, we show that expression of the adenovirus L4 22/33K unit is essential for rep/cap amplification but the proteins are titrated away by binding to replicating adenovirus genomes. siRNA-knockdown of the adenovirus DNA polymerase or the use of a thermosensitive TESSA mutant decreased adenovirus genome replication whilst maintaining MLP repression, thereby recovering rep/cap amplification and efficient rAAV manufacture. Our findings have direct implications for engineering more efficient adenovirus helpers and superior rAAV packaging/producer cells.


[Anatomy and physiology of the periodontium in adults under the conditions of orthodontic tooth movement].
During orthodontic tooth movement, the periodontal ligament (PDL) transduces the applied forces to the surrounding bone and is involved in the induced remodelling of periodontal fibres and alveolar bone. Due to its delicate localization between two hard tissues, the PDL is, however, prone to traumatic injuries resulting from excessive forces. With regard to the necessary remodelling processes, the adult PDL is illprepared, as all relevant physiologic cell activities, such as rate of mitosis or fibre and bone turnover, are considerably slower and have to be activated first. Furthermore, these cell activities apparently cannot be stimulated to the same level as in juvenile tissues. Thus, tooth movement, particularly in the beginning of treatment, is inevitably slower in adults than in young individuals. Any attempt to accelerate movement by applying heavier forces bears the risk of possible traumatic injuries to periodontal and root tissues.


Active DNA demethylation in mammalian preimplantation embryos: new insights and new perspectives.
DNA methylation and demethylation are crucial for modulating gene expression and regulating cell differentiation. Functions and mechanisms of DNA methylation/demethylation in mammalian embryos are still far from being understood clearly. In this review we firstly describe new insights into DNA demethylation mechanisms, and secondly introduce the differences in active DNA methylation patterns in zygotes and early embryos in various mammalian species. Thirdly, we attempt to clarify the functions of DNA demethylation in early embryos. Most importantly we summarize the importance of active DNA demethylation and its possible relevance to human IVF clinics. Finally research perspectives regarding DNA demethylation are also discussed.


Cadaveric and Ultrasound Validation of Percutaneous Electrolysis Approach at the Distal Biceps Tendon: A Potential Treatment for Biceps Tendinopathy.
Distal biceps brachii tendinopathy is a musculoskeletal pain condition-comprising chronic intrasubstance degeneration with alterations of the tendon structure-that is difficult to treat. Preliminary evidence suggests a positive effect for pain and related disability of percutaneous electrolysis treatment in patients with tendinopathy. Ultrasound is an excellent diagnostic tool to identify tendon injuries, such as tendinopathy, and to guide treatment approaches. Different approaches using ultrasound evaluation of the biceps tendon have been described. Our aim was to determine the validity and safety of a percutaneous electrolysis approach, targeting insertion of the distal tendon of biceps brachii, in both human (ultrasound-guided) and Thiel-embalmed cadaver (not ultrasound-guided) models. There were two approaches evaluated: an anterior approach with the elbow in extension and the forearm in supination and a posterior approach with the elbow in flexion and the forearm in pronation. A needle was inserted following the tendon up to its insertion into the radial tuberosity. The anterior approach, both in cadaveric study and US-guided intervention, revealed a close relationship between the distal biceps tendon and the brachial artery. The mean distance of the depth of the biceps tendon distal to the brachial artery was 0.21 ± 0.021 cm in the cadavers and 0.51 ± 0.024 cm in subjects. It was also found that the anterior approach has a potential technical difficulty due to the anatomical location of the brachial artery. With the posterior approach, it was possible to safely identify the tendon insertion and the needle approach, since no important vascular and nervous structures were visualized in the window of insertion of the needle. The clinician rated the posterior approach as low difficulty in all subjects. Current results would support a posterior approach with US guidance as a safe approach for applying the percutaneous electrolysis technique for insertional tendinopathies of the distal biceps brachii tendon. The current study did not assess the effectiveness of the proposed intervention; accordingly, future studies investigating the clinical effectiveness of the proposed intervention are needed.


Automated cell identification and tracking using nanoparticle moving-light-displays.
An automated technique for the identification, tracking and analysis of biological cells is presented. It is based on the use of nanoparticles, enclosed within intra-cellular vesicles, to produce clusters of discrete, point-like fluorescent, light sources within the cells. Computational analysis of these light ensembles in successive time frames of a movie sequence, using k-means clustering and particle tracking algorithms, provides robust and automated discrimination of live cells and their motion and a quantitative measure of their proliferation. This approach is a cytometric version of the moving light display technique which is widely used for analyzing the biological motion of humans and animals. We use the endocytosis of CdTe/ZnS, core-shell quantum dots to produce the light displays within an A549, epithelial, lung cancer cell line, using time-lapse imaging with frame acquisition every 5 minutes over a 40 hour time period. The nanoparticle moving light displays provide simultaneous collection of cell motility data, resolution of mitotic traversal dynamics and identification of familial relationships allowing construction of multi-parameter lineage trees.


Effect of long- and short-term exposure to laser light at 1070 nm on growth of Saccharomyces cerevisiae.
The effect of a 1070-nm continuous and pulsed wave ytterbium fiber laser on the growth of Saccharomyces cerevisiae single cells is investigated over a time span of 4 to 5 h. The cells are subjected to optical traps consisting of two counterpropagating plane wave beams with a uniform flux along the x, y axis. Even at the lowest continuous power investigated-i.e., 0.7 mW-the growth of S. cerevisiae cell clusters is markedly inhibited. The minimum power required to successfully trap single S. cerevisiae cells in three dimensions is estimated to be 3.5 mW. No threshold power for the photodamage, but instead a continuous response to the increased accumulated dose is found in the regime investigated from 0.7 to 2.6 mW. Furthermore, by keeping the delivered dose constant and varying the exposure time and power-i.e. pulsing-we find that the growth of S. cerevisiae cells is increasingly inhibited with increasing power. These results indicate that growth of S. cerevisiae is dependent on both the power as well as the accumulated dose at 1070 nm.


Validation of age-adjusted pelvic incidence minus lumbar lordosis and lordosis distribution index for assessing adjacent-segment disease after short-level lumbar fusion surgery: minimum 5 years of follow-up.
The purpose of this study was to investigate the influence of sagittal alignment according to age-adjusted pelvic incidence minus lumbar lordosis (PI-LL) and lordosis distribution index (LDI) on the occurrence of adjacent-segment disease (ASD) after lumbar fusion surgery. This study retrospectively reviewed 234 consecutive patients with lumbar degenerative diseases who underwent 1- or 2-level lumbar fusion surgery. Demographic and radiographic (preoperative and 3-month postoperative) data were collected and compared between ASD and non-ASD groups. Binary logistic regression analysis was performed to evaluate adjusted associations between potential variables and ASD development. A subanalysis was further conducted to assess their relationships in the range of different PI values. With a mean follow-up duration of 70.6 months (range 60-121 months), 118 patients (50.4%) were diagnosed as having cranial radiological ASD. Univariate analyses showed that older age, 2-level fusion, worse preoperative pelvic tilt and LL, lower pre- and postoperative LDI, and more improvement in sagittal vertical axis were significantly correlated with the occurrence of ASD. No significant differences in the PI-LL and age-adjusted PI-LL (offset) were detected between ASD and non-ASD groups. Multivariate analysis identified postoperative LDI (OR 0.971, 95% CI 0.953-0.989, p = 0.002); 2-level fusion (OR 3.477, 95% CI 1.964-6.157, p < 0.001); and improvement of sagittal vertical axis (OR 0.992, 95% CI 0.985-0.998, p = 0.039) as the independent variables for predicting the occurrence of ASD. When stratified by PI, LDI was identified as an independent risk factor in the groups with low and average PI. Lower segmental lordosis (OR 0.841, 95% CI 0.742-0.954, p = 0.007) could significantly increase the incidence of ASD in the patients with high LDI. Age-adjusted PI-LL may have limited ability to predict the development of ASD. LDI could exert an important effect on diagnosing the occurrence of ASD in the cases with low and average PI, but segmental lordosis was a more significant risk factor than LDI in individuals with high PI.


Health spending projections through 2017: the baby-boom generation is coming to Medicare.
The outlook for national health spending calls for continued steady growth. Spending growth is projected to be 6.7 percent in 2007, similar to its rate in 2006. Average annual growth over the projection period is expected to be 6.7 percent. Slower growth in private spending toward the end of the period is expected to be offset by stronger growth in public spending. The health share of gross domestic product (GDP) is expected to increase to 16.3 percent in 2007 and then rise throughout the projection period, reaching 19.5 percent of GDP by 2017.


The nature of binding of quinolate complex on the surface of ZnS quantum dots.
We report that the Z-type binding rather than X-type binding was favored when 8-hydroxyquinoline (HQ) reacted with presynthesized ZnS quantum dots (Qdots) to form surface zinc quinolinate complexes having a preferred stoichiometry of 1 : 2 (surface Zn2+ : HQ). Importantly, the higher solubility in polar solvents and high desorption coefficient (following Langmuir binding isotherm) of HQ-treated ZnS Qdot in DMSO solvent compared with those in methanol clearly indicated the favorable Z-type binding of HQ and thus the formation of surface octahedral ZnQ2 complex. Furthermore, the characteristics peaks in the 1H-nuclear magnetic resonance (NMR) spectrum of the desorbed species and the ligand density calculation of the surface complex (formed due to the reaction between HQ and ZnS Qdot) supported the octahedral ZnQ2 complex formation. Interestingly, the presence of dangling sulphide and the loss of planarity of ZnQ2 complex on the surface of ZnS Qdots (in turn gaining structural rigidity) may be the reasons for the Z-type binding of HQ. The specific binding might be the reason for superior optical properties and thermal stability of the surface ZnQ2 complex compared to the free ZnQ2 complex as such. The results can be considered important towards understanding the coordination chemistry of inorganic complex on the surface of Qdots and thus for their application potential.


First-principles study on the gas-phase decomposition of bio-oil oxygenated compounds over the palladium catalyst surface.
Unprocessed bio-oils derived from the thermochemical conversion of lignocellulosic biomass suffer from low energy density primarily due to the presence of high amounts of oxygen functional groups. Therefore, the elimination of oxygen atoms over a suitable catalyst surface is viewed as one of the appropriate mechanisms for elevating the quality of bio-oils. Here, in this computational study, three oxygenated bio-oil model compounds, namely, 2-butenal, butan-2,3-diol, and butan-2,3-dione were considered as the representative compounds of the oxygenated catalogue of bio-oils. The decomposition mechanisms of these model compounds along with microkinetic modelling were studied over a palladium catalyst surface to produce low or no oxygen-containing products under the density functional theory (DFT) framework. Propene and methane were observed as the major products in the decomposition processes of 2-butenal and butan-2,3-dione, respectively. Butan-2,3-diol showed no major products due to high barriers. The increase in temperature was observed to be beneficial for improving the reaction rate constants; however, in many cases, the elevation of temperature shifted the equilibrium towards the reactants. CO acted as one of the major inhibitors due to the decarbonylation reaction of aldehydes.


Activity of wild-type and hybrid Bacillus thuringiensis delta-endotoxins against Agrotis ipsilon.
Twelve Cry1 and two Cry9 delta-endotoxins from Bacillus thuringiensis were tested for their activity against black cutworm ( Agrotis ipsilon). A. ipsilon was not susceptible to many toxins, but three toxins had significant activity. Cry9Ca was the most toxic, followed by Cry1Aa and Cry1Fb. Hybrids between these three active proteins were made by in vivo recombination and analyzed for activity against A. ipsilon. Analysis of hybrids between Cry1Aa and Cry1Fb indicated that domain I of Cry1Aa protein was involved in its higher activity.


Neither maternal nor fetal mutation (E474Q) in the alpha-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome.
An association between maternal HELLP syndrome and fetal long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been proposed. LCHAD catalyzes the third step in the beta-oxidation of fatty acids in mitochondria. Whereas about 75% of LCHAD-deficient patients carry a G-to-C mutation at nucleotide position 1528 (Glu474Gln, E474Q) on both chromosomes, compound heterozygosity for E474Q on one chromosome and a second different LCHAD mutation on the other can be observed in up to 25% of LCHAD-deficiency cases; only very few patients carry two mutations different from E474Q. Genetic analysis of the mother alone is insufficient in case of compound heterozygosity. Since information on the fetal carrier status of the E474Q mutation in maternal HELLP syndrome is rare, we investigated the frequency of the E474Q mutation in families where the mother had HELLP syndrome. The occurrence of the E474Q mutation was analyzed by PCR and RFLP in 103 mothers with HELLP syndrome, in 82 children of affected pregnancies and in 21 fathers in families where fetal DNA was not available. In addition, 103 control women with only uncomplicated pregnancies were investigated. The mutation E474Q was not detected in the study population. Neither maternal nor fetal heterozygosity for the E474Q mutation is a relevant factor of HELLP syndrome.


Hormonal response to lipid and carbohydrate meals during the acute postprandial period.
Optimizing the hormonal environment during the postprandial period in favor of increased anabolism is of interest to many active individuals. Data are conflicting regarding the acute hormonal response to high fat and high carbohydrate feedings. Moreover, to our knowledge, no studies have compared the acute hormonal response to ingestion of lipid and carbohydrate meals of different size. We compared the hormonal response to lipid and carbohydrate meals of different caloric content during the acute postprandial period. Nine healthy men (22 ± 2 years) consumed in a random order, cross-over design one of four meals/beverages during the morning hours in a rested and fasted state: dextrose at 75 g (300 kcals), dextrose at 150 g (600 kcals), lipid at 33 g (300 kcals), lipid at 66 g (600 kcals). Blood samples were collected Pre meal, and at 0.5 hr, 1 hr, 2 hr, and 3 hr post meal. Samples were assayed for testosterone, cortisol, and insulin using ELISA techniques. Area under the curve (AUC) was calculated for each variable, and a 4 × 5 ANOVA was used to further analyze data. A meal × time effect (p = 0.0003) was noted for insulin, with values highest for the dextrose meals at the 0.5 hr and 1 hr times, and relatively unaffected by the lipid meals. No interaction (p = 0.98) or meal (p = 0.39) effect was noted for testosterone, nor was an interaction (p = 0.99) or meal (p = 0.65) effect noted for cortisol. However, a time effect was noted for both testosterone (p = 0.04) and cortisol (p < 0.0001), with values decreasing during the postprandial period. An AUC effect was noted for insulin (p = 0.001), with values higher for the dextrose meals compared to the lipid meals (p < 0.05). No AUC effect was noted for testosterone (p = 0.85) or cortisol (p = 0.84). These data indicate that 1) little difference is noted in serum testosterone or cortisol during the acute postprandial period when healthy men consume lipid and dextrose meals of different size; 2) Both testosterone and cortisol experience a drop during the acute postprandial period, which is similar to what is expected based on the normal diurnal variation--feeding with lipid or dextrose meals does not appear to alter this pattern; 3) dextrose meals of either 75 g or 150 g result in a significant increase in serum insulin, in particular at 0.5 hr and 1 hr post-ingestion; 4) lipid meals have little impact on serum insulin.


A bone-targeting delivery system carrying osteogenic phytomolecule icaritin prevents osteoporosis in mice.
Targeting delivery system has been widely used in packaging drugs for medical therapies attributed to its high efficiency and efficacy. A Traditional Chinese Medicine (TCM) formula consisting of Herba Epimedii has previously been shown to effectively treat postmenopausal osteoporosis. We have subsequently found that icaritin, which was a flavonoid isolated from both Herba Epimedii and its serum metabolites after oral administration, inhibited the adipogenic capacity of bone mesenchymal stem cells (BMSCs) while promoted their osteogenesis. However, previous pharmacokinetic analyses have shown that icaritin had a short half-life in blood and only trace amounts of the molecule reach the bone tissue. To overcome this limitation, we developed a bone-targeting liposome containing an oligopeptide of eight aspartate residues (Asp8), which had previously been shown to specifically target the bone, encapsulating icaritin. In vivo, we found that the Asp8-icaritin-liposome enhanced bone formation in ovariectomized mice compared to an icaritin-liposome control lacking the Asp8 moiety. Through in vitro mechanistic studies we further found that icaritin inhibited adipogenesis through an Akt/GSK-3β/β-catenin signaling pathway. Taken together, our study shows that Asp8-liposome as a bone-targeting delivery system is effective to carry an osteogenic phytomolecule for facilitating and enhancing its therapeutic effects on the prevention of estrogen depletion-induced osteoporosis.


Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus.
The mechanisms underlying the generation of NMDA receptor-dependent LTP in the CA1 region of the hippocampus continue to receive a great deal of attention because of the postulated importance of LTP as a synaptic mechanism for learning and memory. It is well accepted that the initial induction of LTP occurs in the postsynaptic cell, but the site of expression remains controversial. One prominent hypothesis is that LTP involves the release of one or more retrograde messengers that act on the presynaptic terminal to enhance transmitter release. Recently, evidence has been presented that retrograde messengers function to activate presynaptic guanylyl cyclase and that the resulting rise in presynaptic cGMP levels, when accompanied by presynaptic activity, is responsible for generating an early component of LTP. We have tested this hypothesis by examining whether synaptic strength is increased by coupling tetanic stimulation with application of a membrane-permeable analog of cGMP. The experiments were done in the presence of an NMDA receptor antagonist to block postsynaptic induction mechanisms. Under a variety of experimental conditions, this manipulation failed to generate LTP, suggesting that an increase in cGMP levels accompanied by presynaptic activity is not sufficient to generate LTP in the CA1 region of the hippocampus.


Variation in the Ability to Taste Bitter Thiourea Compounds: Implications for Food Acceptance, Dietary Intake, and Obesity Risk in Children.
The ability to taste bitter thiourea compounds, such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), is inherited. Polymorphisms in the bitter-taste receptor TAS2R38 explain the majority of phenotypic variation in the PROP phenotype. It has been hypothesized that the PROP phenotype is a marker for perception of a variety of chemosensory experiences. In this review, we discuss studies that have investigated the relationship between bitter-taste response and dietary behaviors and chronic health in children. Investigators have hypothesized that children who are PROP tasters have lower liking and consumption of bitter foods, such as cruciferous vegetables. Additionally, several studies suggest that children who are unable to taste PROP (i.e., nontasters) like and consume more dietary fat and are prone to obesity. The relationship between the PROP phenotype and obesity is influenced by multiple confounders, including sex, food access, ethnicity, and socioeconomic status. Future studies that adjust for these variables are needed.


Uric acid and incident dementia over 12 years of follow-up: a population-based cohort study.
In patients with gout, maintaining too low serum uric acid (SUA) level with urate-lowering therapy is a concern because uric acid is thought to be neuroprotective. However, the relation between SUA and dementia remains debated. This study aimed to investigate the impact of SUA level on the incidence of dementia. We assessed the longitudinal association between SUA level and incident dementia (Diagnostic and Statistical Manual of Mental Disorders Version IV (DSM-IV) criteria) in a large cohort of healthy older people from the community (Three-City Dijon cohort). Additionally, we investigated the relation between SUA level and MRI markers of brain ageing (white matter hyperintensity volume (WMHV), lacunes and hippocampal volume). The study sample comprised 1598 people (mean (SD) age 72.4(4.1) years, 38.3% male). During the 13,357 person-years of follow-up (median duration: 10.1 years), dementia developed in 110 participants (crude incidence rate: 8.2/1000 person-years). After multiple adjustments, the multivariate HR with the highest (≥75th percentile) versus lowest SUA level was 1.79 (95% CI 1.17 to 2.73; p=0.007). The association was stronger with vascular or mixed dementia (HR=3.66 (95% CI 1.29 to 10.41), p=0.015) than Alzheimer's disease (HR=1.55 (95% CI 0.92 to 2.61), p=0.10). There was a non-significant trend towards an association between high SUA level and extensive WMHV (p=0.10), a biomarker of small vessel disease, but not hippocampal volume (p=0.94) or lacunes (p=0.86). The association between SUA level and vascular or mixed dementia might be affected by interim strokes. Risk of dementia, especially vascular or mixed dementia, may be increased with high SUA levels in elderly people.


Prestroke and Poststroke Antithrombotic Therapy in Patients With Atrial Fibrillation: Results From a Nationwide Cohort.
Antithrombotic therapies are effective in both primary and secondary stroke prophylaxis in high-risk patients with atrial fibrillation (AF), but they are often underused in community practice. To examine prestroke and poststroke antithrombotic treatment patterns and long-term outcomes in patients with AF presenting with ischemic stroke. A retrospective cohort study of Danish patients with AF, with a prestroke CHA2DS2-VASc score of 1 or higher for men and 2 or higher for women, and presenting with ischemic stroke was conducted from January 1, 2004, to January 31, 2017. Data on hospital admission, prescription fillings, and vital status were assessed using several Danish nationwide registries. Patients who survived 100 days after discharge were divided into 3 groups according to poststroke antithrombotic therapy: oral anticoagulation (OAC) therapy, antiplatelet therapy alone, or no antithrombotic therapy. Long-term outcomes (thromboembolic events and bleeding complications) were examined using multivariable Cox regression analyses across the 3 groups. Among 30 626 patients with AF admitted with ischemic stroke, 11 139 patients (36.3%) received OAC therapy (44.3% female; median age, 79 years [interquartile range, 73-85 years]), 11 874 (38.8%) received antiplatelet therapy alone (55.0% female; median age, 82 years [interquartile range, 75-88 years]), and 7613 (24.9%) received no antithrombotic therapy before stroke (53.8% female; median age, 80 years [interquartile range, 71-86 years]). Following stroke, 31.3% of those receiving antiplatelet therapy alone and 43.7% of those receiving no antithrombotic therapy before stroke shifted to OAC therapy. Yet, 37.5% of patients with stroke did not receive OAC therapy following stroke. However, OAC treatment rates increased over time. During a maximum of 10 years of follow-up, 17.5%, 21.2%, and 21.5% experienced a new thromboembolic event and 72.7%, 86.4%, and 86.2% died among those treated with OAC therapy, antiplatelet therapy, or no antithrombotic therapy, respectively. Poststroke OAC therapy was associated with lower risk of recurrent thromboembolic events (adjusted hazard ratio, 0.81; 95% CI, 0.73-0.89) and no significant difference in bleeding complications (adjusted hazard ratio, 0.97; 95% CI, 0.86-1.10), compared with no poststroke antithrombotic therapy. In contrast, there were no significant differences for those treated with poststroke antiplatelet therapy and no antithrombotic therapy. Patients with AF receiving poststroke OAC therapy had lower risk of recurrent thromboembolic events. Our findings suggest a substantial opportunity for improving primary and secondary stroke prophylaxis in high-risk patients with AF.


Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity.
Insulin resistance is associated with visceral adiposity, and interventions that reduce this depot, e.g., diet and exercise, improve insulin resistance. Thiazolidinediones (TZDs) also improve insulin action but paradoxically increase total fat mass, perhaps through remodeling (recruitment of smaller fat cells) and redistribution of adipose tissue. We assessed the effects of pioglitazone versus diet and exercise on fat distribution and the relationship between fat distribution and insulin sensitivity in upper body obesity. Thirty-nine upper body obese, insulin-resistant, nondiabetic men and premenopausal women were randomly assigned to receive either 30 mg/day pioglitazone or a diet and exercise program for 20 weeks. Before and after the intervention, insulin sensitivity, body composition, body fat distribution (waist-to-hip ratio [WHR], computed tomography abdomen, and dual-energy X-ray absorptiometry), and abdominal and femoral fat cell size were assessed. Diet and exercise resulted in an 11.8 +/- 1.1 kg weight loss. Both diet and exercise and pioglitazone improved insulin sensitivity, but only the former was associated with loss of intra-abdominal fat. Pioglitazone increased total body fat, which preferentially accumulated in the lower body depot in both men and women. WHRs decreased in both groups. Abdominal fat cell size decreased (P = 0.06) after diet and exercise. No statistically significant changes in fat cell size were observed in pioglitazone-treated volunteers. In nondiabetic upper body obese subjects, increasing insulin sensitivity via diet and exercise accompanies reductions in visceral fat. Pioglitazone treatment also improves insulin sensitivity and lowers WHR, but this is due to a selective increase in lower body fat. This confirms a site-specific responsiveness of adipose tissue to TZD and suggests that improvements in insulin sensitivity by pioglitazone are achieved independent of changes in intra-abdominal fat.


Relationship between living alone and common mental disorders in the 1993, 2000 and 2007 National Psychiatric Morbidity Surveys.
Given the high prevalence of common mental disorders (CMDs) and individuals living alone in the United Kingdom, the goal of this study using English nationally representative data was to examine the association between living alone and CMDs, and to identify potential mediating factors of this association. The data were drawn from the 1993, 2000 and 2007 National Psychiatric Morbidity Surveys. CMDs were assessed using the Clinical Interview Schedule-Revised (CIS-R), a questionnaire focusing on past week neurotic symptoms. The presence of CMDs was defined as a CIS-R total score of 12 and above. Multivariable logistic regression and mediation analyses were conducted to analyze the association between living alone and CMDs, and to identify mediators in this association. The prevalence of CMDs was higher in individuals living alone than in those not living alone in all survey years. Multivariable analysis showed a positive association between living alone and CMDs in all survey years (1993: odds ratio [OR] = 1.69; 2000: OR = 1.63; and 2007: OR = 1.88). Overall, loneliness explained 84% of the living alone-CMD association. Living alone was positively associated with CMDs. Interventions addressing loneliness among individuals living alone may be particularly important for the mental wellbeing of this vulnerable population.


[The influence of viscosity on adhesion and invasion of Salmonella strains in an in vitro model].
The influence of viscosity on the adhesion and invasion behaviour of Salmonella strains of different origin was investigated using an in-vitro-model. These processes seem to be strain-dependent. Compared to the controls, the number of internalized Salmonella was elevated. This increase was a result of the greater number of Salmonella which adhered to Caco-2-cells and was detected only for strains from organs of calves having died from salmonellosis. The average motility of these strains was determined to be 1.6 +/- 0.5 mm/h. A possible association between adhesion ability and motility was discussed.


Values and preferences of contraceptive methods: a mixed-methods study among sex workers from diverse settings.
There is limited information on contraceptive values and preferences of sex workers. We conducted a mixed-method study to explore contraceptive values and preferences among sex workers. We conducted an online survey with individuals from 38 countries (n = 239), 6 focus group discussions (FGD, n = 68) in Zimbabwe, and 12 in-depth phone interviews (IDI) across 4 world regions, in June and July of 2019. Participants were asked about awareness of contraceptives, methods they had used in the past, and the determinants of their choices. Differences between respondents from high-, low- and middle- income countries were examined. Qualitative data were analysed thematically. Survey participants reported an awareness of modern contraceptive methods. FGDs found that younger women had lower awareness. Reports of condomless sex were common and modern contraceptive use was inconsistent. Determinants of contraceptive choices differed by setting according to results of the survey, FGD, and IDI. Regardless of country income level, determinants of contraceptive choices included ease of use, ease of access to a contraceptive method, and fewer side effects. Healthcare provider attitudes, availability of methods, and clinic schedules were important considerations. Most sex workers are aware of contraceptives, but barriers include male partners/clients, side effects, and health system factors such as access and clinic attitudes towards sex workers.


Normal values of left ventricular systolic and diastolic function derived from signal-averaged acoustic quantification waveforms: a multicenter study.
Automated border-detection techniques such as acoustic quantification have proven accurate and useful for quantifying left ventricular (LV) function. We acquired LV acoustic quantification waveforms from the parasternal short-axis window in 140 healthy patients in the age range of 16 to 78 years. Signal-averaged waveforms were analyzed for parameters of systolic and diastolic performance. The average fractional area change was 54 +/- 12%, and there were no significant changes in LV systolic function in the age range studied. There were significant changes in diastolic parameters with aging. The percentage of contribution to total LV filling occurring during atrial filling nearly tripled during the 6 decades studied, from 13% in the youngest cohort to 36% in the eighth decade of life. This study provides normal reference values for systolic and diastolic parameters of LV function determined from signal-averaged acoustic quantification waveforms acquired from the parasternal short-axis view in adult and adolescent patients over a wide age range.


Intravenous iron supplementation effect on tissue iron and hemoproteins in chronically phlebotomized lambs.
Chronic phlebotomy is an important mechanism of iron loss in premature infants. We studied inter- and intraorgan iron allocation in 10 twin lamb pairs undergoing an acute 40-50% reduction in red cell volume followed by smaller intermittent phlebotomies over an 11-day period. One twin received no supplemental iron sucrose, while the other received an average daily intravenous dose of iron sucrose of either 1 (n = 3), 2 (n = 3), 5 (n = 3), or 15 (n = 1) mg.kg-1.day-1. The total iron content of the red blood cells, liver, skeletal muscle, heart, and brain was directly related to iron dose up to 2 mg.kg-1.day-1. Tissue iron concentrations remained stable until liver iron was < 200 g/g dry wt, after which iron was preferentially directed to red blood cells over skeletal muscle, heart, and brain. Hemoprotein concentrations decreased proportionately to tissue iron, except myocardial cytochrome c, which remained preserved. Any available iron in phlebotomized, rapidly growing lambs is preferentially directed to red blood cells, and lambs require iron supplementation to maintain tissue iron and hemoprotein concentrations. A decrease in nonheme tissue iron results in the high prioritization of iron among iron-containing proteins.


PHYSICS: Toward Atom Chips.
As a novel approach for turning the peculiar features of quantum mechanics into practical devices, researchers are investigating the use of ultracold atomic clouds above microchips. Such "atom chips" may find use as sensitive probes for gravity, acceleration, rotation, and tiny magnetic forces. In their Perspective, Fortagh and Zimmermann discuss recent advances toward creating atom chips, in which current-carrying conductors in the chips create magnetic microtraps that confine the atomic clouds. Despite some intrinsic limits to the performance of atom chips, existing technologies are capable of producing atom chips, and many possibilities for their construction remain to be explored.


Microbial diversity associated with the hydrothermal shrimp Rimicaris exoculata gut and occurrence of a resident microbial community.
Rimicaris exoculata dominates the megafauna of several Mid-Atlantic Ridge hydrothermal sites. Its gut is full of sulphides and iron-oxide particles and harbours microbial communities. Although a trophic symbiosis has been suggested, their role remains unclear. In vivo starvation experiments in pressurized vessels were performed on shrimps from Rainbow and Trans-Atlantic Geotraverse sites in order to expel the transient gut contents. Microbial communities associated with the gut of starved and reference shrimps were compared using 16S rRNA gene libraries and microscopic observations (light, transmission and scanning electron microscopy and FISH analyses). We show that the gut microbiota of shrimps from both sites included mainly Deferribacteres, Mollicutes, Epsilon- and Gammaproteobacteria. For the first time, we have observed filamentous bacteria, inserted between microvilli of gut epithelial cells. They remained after starvation periods in empty guts, suggesting the occurrence of a resident microbial community. The bacterial community composition was the same regardless of the site, except for Gammaproteobacteria retrieved only in Rainbow specimens. We observed a shift in the composition of the microbiota of long-starved specimens, from the dominance of Deferribacteres to the dominance of Gammaproteobacteria. These results reinforce the hypothesis of a symbiotic relationship between R. exoculata and its gut epibionts.


Small, dense low-density lipoproteins (LDL) are predictors of cardio- and cerebro-vascular events in subjects with the metabolic syndrome.
Small, dense low-density lipoproteins (LDL) are a feature of the metabolic syndrome (MS) but their predictive role still remains to be established. We performed a 2-year follow-up study in 124 subjects with MS (63 +/- 6 years), as defined by the American Heart Association/National Heart, Lung and Blood Institute guidelines, to assess clinical and biochemical predictors of cerebro- and cardio-vascular events. Beyond traditional cardiovascular risk factors, we measured LDL size and subclasses by gradient gel electrophoresis. Clinical events were registered in the 25% of subjects. At univariate analysis subjects with events had increased prevalence of elevated fasting glucose (P = 0.0117), smoking (P = 0.0015), family history of coronary artery disease (P = 0.0033) and higher levels of total- and LDL-cholesterol (P = 0.0027 and P = 0.0023, respectively); LDL size was lower (P < 0.0001), due to reduced larger subclasses and increased small, dense LDL (all P < 0.0001). At multivariate analysis the following were independent predictors of events (univariate odd ratios were calculated): low HDL-cholesterol (OR 15.4, P = 0.0238), elevated fasting glucose (OR 12.1, P = 0.0102), elevated small, dense LDL (OR 11.7, P = 0.0004), elevated blood pressure (OR 9.2, P = 0.0392), smoking (OR 4.8, P = 0.0054). This is the first study that assessed the predictive role of small, dense LDL beyond traditional cardiovascular risk factors in subjects with MS.


Racial disparities in outcomes of spinal surgery for lumbar stenosis.
A retrospective, cross-sectional study. To evaluate racial disparities in outcomes of lumbar stenosis surgery. Racial inequalities have been described in the outcomes of cardiovascular and orthopedic procedures. There have been minimal investigation of racial disparities in complications and costs of lumbar laminectomies and fusions. We analyzed the Medicaid data set of Thomson Reuter's MarketScan database. African-American and non-Hispanic white patients who underwent laminectomy or fusion for lumbar stenosis with at least 2 years postoperative data were included. We examined the effect of race on the rate of reoperations, complications, and the cost associated with surgery. African-American patients in the Medicaid database were at no higher risk for reoperation in the 2 years after an operation for lumbar stenosis than white patients (7.14% vs. 7.89%, P = 0.7895). However, we did find that African-American patients were more likely to experience postoperative complications of any kind, even after adjusting for length of hospital stay, comorbidities, sex, and age (adjusted odds ratio = 1.819, P = 0.0123 for immediate complication; adjusted odds ratio = 1.746, P = 0.0141 for 30-d complication; and adjusted odds ratio = 1.611, P = 0.0410 for 90-d complication). White patients had a significantly shorter length of stay (3 vs. 5 d, P < 0.007) and accrued fewer hospital-related costs ($16,148 vs. $24,267, P < 0.0007). African-American patients, despite having more comorbidities in our sample, were prescribed significantly fewer medications in the 2 years after index procedures (91 vs. 138 prescriptions, P < 0.0007) and had fewer medication costs during the 2 years after surgery ($5297 vs. $8450, P < 0.0007). At the national level, there are several racial disparities in the rate of complications, length of stay, and costs after surgery for lumbar spinal stenosis. 3.


Gastrointestinal phenomena in childhood typhoid fever.
Ninety-four children with typhoid fever presented with the primary complaints of fever, diarrhea, and vomiting. Fifty-two percent had hepatomegaly and derangements of SGOT and LDH. None developed hepatic decompensation and all had rapid clinical recovery. The abnormal liver function test served no prognostic purpose.


Measures of clinical severity, quality of life, and psychological distress in patients with psoriasis: a cluster analysis.
The impact of psoriasis on patients' quality of life may be quite destructive, and measures of disease status alone seem to have questionable validity in describing the true burden of illness. Our aim was to study, in patients with psoriasis, the relationship between classical measures of clinical status (i.e., PASI and SAPASI) and quality-of-life indexes (i.e., Skindex-29, Dermatology Life Quality Index, Psoriasis Disability Index, Impact of Psoriasis Questionnaire). In addition, two psychological distress indexes (i.e., Psoriasis Life Stress Inventory, 12-item General Health Questionnaire) were assessed. Data were collected between February 2000 and July 2001 at the inpatient wards of the Dermatological Institute IDI-IRCCS, Rome, Italy, in the framework of a large project on clinical, epidemiologic, emotional, and quality-of-life aspects of psoriasis. A cluster analysis of all the above-mentioned instruments was conducted on 786 eligible patients hospitalized with a diagnosis of psoriasis. Correlations between instruments were also analyzed in subsets of patients based on the main variables of interest. The instruments clustered in two distinct groups, one formed by clinical severity measurements and the other grouping all the quality-of-life and psychological indexes. The correlations between instruments observed in the subgroups determined by different sociodemographic and clinical variables showed the same pattern. In conclusion, the dissimilarity between clinical severity assessment and patient-centered measures stresses the need for a more comprehensive assessment of severity of psoriasis.


An expected utility maximizer walks into a bar…
We conducted field experiments at a bar to test whether blood alcohol concentration (BAC) correlates with violations of the generalized axiom of revealed preference (GARP) and the independence axiom. We found that individuals with BACs well above the legal limit for driving adhere to GARP and independence at rates similar to those who are sober. This finding led to the fielding of a third experiment to explore how risk preferences might vary as a function of BAC. We found gender-specific effects: Men did not exhibit variations in risk preferences across BACs. In contrast, women were more risk averse than men at low BACs but exhibited increasing tolerance towards risks as BAC increased. Based on our estimates, men and women's risk preferences are predicted to be identical at BACs nearly twice the legal limit for driving. We discuss the implications for policy-makers.