Communication about depression during rheumatoid arthritis patient visits.
To examine whether rheumatologists and rheumatoid arthritis (RA) patients with depressive symptoms communicate about depression. The data used in this study came from a randomized controlled trial to improve provider-patient communication about patients' agendas. The current secondary analysis used data collected at baseline, before any intervention occurred. A total of 200 RA patients from 4 rheumatology clinics participated in the study. Patient medical visits were audiotape recorded and patients were interviewed after their medical visits. Physicians recorded patients' American College of Rheumatology (ACR) functional status after their visits. Twenty-one (11%) patients were scored as having moderately severe to severe symptoms of depression. Patients who were rated by their physicians as having worse ACR functional status were more than twice as likely to have moderately severe to severe symptoms of depression (odds ratio 2.23, 95% confidence interval 1.1-4.6). Only 4 (19%) of the 21 patients who were scored as having moderately severe to severe symptoms of depression discussed depression during their medical visits, and patients initiated the discussion each time. Rheumatologists should consider assessing depressive symptoms among their patients, especially among those with worse functional status.


The epidemiology of prescribing errors: the potential impact of computerized prescriber order entry.
Adverse drug events (ADEs) are the most common cause of injury to hospitalized patients and are often preventable. Medication errors resulting in preventable ADEs most commonly occur at the prescribing stage. To describe the epidemiology of medication prescribing errors averted by pharmacists and to assess the likelihood that these errors would be prevented by implementing computerized prescriber order entry (CPOE). At a 700-bed academic medical center in Chicago, Ill, clinical staff pharmacists saved all orders that contained a prescribing error for a week in early 2002. Pharmacist investigators subsequently classified drug class, error type, proximal cause, phase of hospitalization, and potential for patient harm and rated the likelihood that CPOE would have prevented the prescribing error. A total of 1111 prescribing errors were identified (62.4 errors per 1000 medication orders), most occurring on admission (64%). Of these, 30.8% were rated clinically significant and were most frequently related to anti-infective medication orders, incorrect dose, and medication knowledge deficiency. Of all verified prescribing errors, 64.4% were rated as likely to be prevented with CPOE (including 43% of the potentially harmful errors), 13.2% unlikely to be prevented with CPOE, and 22.4% possibly prevented with CPOE depending on specific CPOE system characteristics. Prescribing errors are common in the hospital setting. While CPOE systems could improve practitioner prescribing, design and implementation of a CPOE system should focus on errors with the greatest potential for patient harm. Pharmacist involvement, in addition to a CPOE system with advanced clinical decision support, is vital for achieving maximum medication safety.


Social and reproductive conditions modulate urinary cortisol excretion in black tufted-ear marmosets (Callithrix kuhli).
The links between psychosocial stress, social status, reproductive function, and urinary cortisol were assessed in social groups of black tufted-ear marmosets (Callithrix kuhli). Urinary cortisol excretion was monitored in cases of intrafamily conflict ("sibling fights") and in daughters in four distinct social contexts: in the family group, while housed singly or in same-sex pairs, and while paired with a male pairmate. Cortisol excretion was elevated in participants in intra-family conflict on the day of and the day following the conflict, relative to concentrations a week prior to or following the conflict. Daughters in natal family groups had concentrations of cortisol that did not differ from reproductively active adult females. This finding held for daughters who were either anovulatory or undergoing ovulatory cycles while in the natal family group. Natal family members and male pairmates exerted buffering effects on levels of activity in the hypothalamic pituitary adrenal axis (HPA) in female C. kuhli. Placing females in solitary housing led to significantly increased cortisol excretion. In the 2 months subsequent to pairing with a male partner, excreted cortisol concentrations in females declined significantly. Daughters removed from their natal family group and housed with a sister did not exhibit increased cortisol levels. These data reveal that activity in the (HPA) axis in marmosets is sensitive to psychosocial stressors, and that urinary cortisol can provide a useful quantitative measure of HPA reactivity. As in other callitrichids, delayed breeding in daughters and reproductive anomalies in C. kuhli appear to be mediated by mechanisms other than elevated HPA activity.


Effects of Neural Stem Cell and Olfactory Ensheathing Cell Co-transplants on Tissue Remodelling After Transient Focal Cerebral Ischemia in the Adult Rat.
Effective transplant-mediated repair of ischemic brain lesions entails extensive tissue remodeling, especially in the ischemic core. Neural stem cells (NSCs) are promising reparative candidates for stroke induced lesions, however, their survival and integration with the host-tissue post-transplantation is poor. In this study, we address this challenge by testing whether co-grafting of NSCs with olfactory ensheathing cells (OECs), a special type of glia with proven neuroprotective, immunomodulatory, and angiogenic effects, can promote graft survival and host tissue remodelling. Transient focal cerebral ischemia was induced in adult rats by a 60-min middle cerebral artery occlusion (MCAo) followed by reperfusion. Ischemic lesions were verified by neurological testing and magnetic resonance imaging. Transplantation into the globus pallidus of NSCs alone or in combination with OECs was performed at two weeks post-MCAo, followed by histological analyses at three weeks post-transplantation. We found evidence of extensive vascular remodelling in the ischemic core as well as evidence of NSC motility away from the graft and into the infarct border in severely lesioned animals co-grafted with OECs. These findings support a possible role of OECs as part of an in situ tissue engineering paradigm for transplant mediated repair of ischemic brain lesions.


The origin of the measured chemical shift of 129Xe in UiO-66 and UiO-67 revealed by DFT investigations.
The NMR chemical shift of the xenon isotope 129Xe inside the metal-organic frameworks (MOFs) UiO-66 and UiO-67 (UiO - University of Oslo) has been investigated both with density functional theory (DFT) and in situ high-pressure 129Xe NMR measurements. The experiments reveal a decrease of the total chemical shift comparing the larger isoreticular MOF (UiO-67) with the smaller one (UiO-66), even though one may expect an increase due to the higher amount of adsorbed Xe atoms. We are able to calculate contributions to the chemical shift individually. This allows us to evaluate the shift inside the different pores independently. To compare the theoretical results with the experimental ones, we performed molecular dynamics simulations of Xe in the MOFs. For this purpose, the pores were completely filled with Xe to gain insight into the distribution of Xe at high pressures. The resulting trend of the total shift agrees well between the theoretical predictions and the experiments. Moreover, we are able to describe specific contributions to the total shift per pore, explaining the experimental behavior at an atomistic level.


Determination of vascular dementia brain in distinct frequency bands with whole brain functional connectivity patterns.
Recent studies have shown that multivariate pattern analysis (MVPA) can be useful for distinguishing brain disorders into categories. Such analyses can substantially enrich and facilitate clinical diagnoses. Using MPVA methods, whole brain functional networks, especially those derived using different frequency windows, can be applied to detect brain states. We constructed whole brain functional networks for groups of vascular dementia (VaD) patients and controls using resting state BOLD-fMRI (rsfMRI) data from three frequency bands - slow-5 (0.01 ≈ 0.027 Hz), slow-4 (0.027∼0.073 Hz), and whole-band (0.01 ≈ 0.073 Hz). Then we used the support vector machine (SVM), a type of MVPA classifier, to determine the patterns of functional connectivity. Our results showed that the brain functional networks derived from rsfMRI data (19 VaD patients and 20 controls) in these three frequency bands appear to reflect neurobiological changes in VaD patients. Such differences could be used to differentiate the brain states of VaD patients from those of healthy individuals. We also found that the functional connectivity patterns of the human brain in the three frequency bands differed, as did their ability to differentiate brain states. Specifically, the ability of the functional connectivity pattern to differentiate VaD brains from healthy ones was more efficient in the slow-5 (0.01 ≈ 0.027 Hz) band than in the other two frequency bands. Our findings suggest that the MVPA approach could be used to detect abnormalities in the functional connectivity of VaD patients in distinct frequency bands. Identifying such abnormalities may contribute to our understanding of the pathogenesis of VaD.


Polymerization on the rocks: beta-amino acids and arginine.
We have studied the accumulation of long oligomers of beta-amino acids on the surface of minerals using the 'polymerization on the rocks' protocol. We find that long oligopeptides of beta-glutamic acid which cannot be formed in homogeneous aqueous solution are accumulated efficiently on the surface of hydroxylapatite using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) as condensing agent. The EDAC-induced oligomerization of aspartic acid on hydroxylapatite proceeds even more efficiently. Hydroxylapatite can also facilitate the ligation of the tripeptide (glu)3. The 'polymerization on the rocks' scenario is not restricted to negatively-charged amino acids. Oligoarginines are accumulated on the surface of illite using carbonyldiimidizole (CDI) as condensing agent. We find that FeS2 catalyzes the CDI-induced oligomerization of arginine, although it does not adsorb oligoarginines. These results are relevant to the formation of polypeptides on the primitive earth.


Solid-phase extraction method for patulin in apple juice and unfiltered apple juice.
Patulin, a mold metabolite, is commonly found in rotting apples. Some countries regulate patulin at levels ranging from 30 to 50 micrograms/L. Most analytical methods for patulin in apple juice include liquid-liquid partitions. A solid-phase extraction method has been developed for apple juice and unfiltered apple juice in the United States. A portion of the test sample (5 mL) was passed through a macroporous copolymer cartridge and was washed with 1 mL 1% sodium bicarbonate and then with 1 mL 1% acetic acid. Patulin was eluted with 3 mL 2% acetonitrile in anhydrous ethyl ether and was determined by reversed-phase liquid chromatography with UV detection at 276 nm. Recoveries ranged from 93 to 104% in test samples spiked at 20-100 micrograms/L.


Complications of ganciclovir implant surgery in patients with cytomegalovirus retinitis: the Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial.
To describe the complications of ganciclovir implant surgery in patients with cytomegalovirus retinitis. Prospective data collection within the context of a randomized, controlled clinical trial, comparing a regimen of the ganciclovir implant plus oral ganciclovir to one of intravenous cidofovir for the treatment of cytomegalovirus retinitis in patients with AIDS. Adverse events were compared for patients undergoing implant surgery in the following groups: primary versus replacement implant surgery, inpatient versus outpatient surgery, and general versus local anesthesia. Fifty-six eyes of 42 patients underwent a total of 74 ganciclovir implant surgeries. Vitreous hemorrhage was the most common adverse event, occurring in 10% of eyes undergoing surgery with local anesthesia but in no eyes undergoing surgery with general anesthesia. All vitreous hemorrhages resolved within 60 days. Patients in the general anesthesia and inpatient surgery groups tended to have a lower risk of complications in the first 30 days than did patients in the local anesthesia and outpatient surgery groups, but no differences in the complication rate were found after 60 days. Visual acuity was similar among these different groups. There were no cases of endophthalmitis. Ganciclovir implant surgery in patients with AIDS and cytomegalovirus retinitis was associated with a low risk of serious complications in the first 60 days after surgery. Vitreous hemorrhage was the most commonly observed complication and resolved in all cases.


Regulatory role of periodontal ligament fibroblasts for innate immune cell function and differentiation.
Innate immunity is crucial for an effective host defense against pathogenic microorganisms in periodontal tissues. As periodontal ligament (PDL) cells synthesize immunomodulatory cytokines, the aim of this in vitro study was to investigate whether these cells can interact with innate immune cells. Resting and inflammatory primed (IL-1β, TNF-α, HMGB1) human PDL cells were co-cultured with human monocyte-derived dendritic cells or macrophages. Migration, phenotypic maturation and modulation of phagocytosis of Porphyromonas gingivalis by immune cells were investigated upon co-culture with PDL cells and/or their released soluble factors. PDL cells interacted with immune cells under both non-inflammatory and inflammatory conditions. Immune cell migration was significantly enhanced by co-culture with PDL cells, which also affected their phenotypic maturation both through cell-cell contact and through released soluble mediators. The dendritic cell maturation markers CD83 and CD86 were upregulated as much as both 'alternatively activated' M2 macrophage maturation markers CD23 and CD163. In contrast, the 'classically activated' M1 macrophage maturation marker CD64 was downregulated. Finally, PDL cells significantly enhanced the phagocytosis of Porphyromonas gingivalis by immune cells. Our experiments revealed that PDL cells are not only structural elements of the periodontium, but actively influence immune responses by interaction with innate immune cells.


Quantifying leaf venation patterns: two-dimensional maps.
The leaf vasculature plays crucial roles in transport and mechanical support. Understanding how vein patterns develop and what underlies pattern variation between species has many implications from both physiological and evolutionary perspectives. We developed a method for extracting spatial vein pattern data from leaf images, such as vein densities and also the sizes and shapes of the vein reticulations. We used this method to quantify leaf venation patterns of the first rosette leaf of Arabidopsis thaliana throughout a series of developmental stages. In particular, we characterized the size and shape of vein network areoles (loops), which enlarge and are split by new veins as a leaf develops. Pattern parameters varied in time and space. In particular, we observed a distal to proximal gradient in loop shape (length/width ratio) which varied over time, and a margin-to-center gradient in loop sizes. Quantitative analyses of vein patterns at the tissue level provide a two-way link between theoretical models of patterning and molecular experimental work to further explore patterning mechanisms during development. Such analyses could also be used to investigate the effect of environmental factors on vein patterns, or to compare venation patterns from different species for evolutionary studies. The method also provides a framework for gathering and overlaying two-dimensional maps of point, line and surface morphological data.


Accuracy of multiparametric MRI for prostate cancer detection: a meta-analysis.
The purpose of this diagnostic meta-analysis was to determine the diagnostic accuracy of multiparametric MRI for prostate cancer detection using anatomic T2-weighted imaging combined with two functional techniques: diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI). We searched electronic databases, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 3, 2012. We included diagnostic accuracy studies using a combination of T2-weighted imaging, DWI, and DCE-MRI to detect prostate cancer with histopathologic data from prostatectomy or biopsy as the reference standard. The methodologic quality was assessed with version 2 of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool by two independent reviewers. Sensitivity and specificity of all studies were calculated from 2 × 2 tables, and the results were plotted in a hierarchic summary receiver operating characteristic plot. Seven studies that met the inclusion criteria (526 patients) could be analyzed. The pooled data showed a specificity of 0.88 (95% CI, 0.82-0.92) and sensitivity of 0.74 (95% CI, 0.66-0.81) for prostate cancer detection, with negative predictive values (NPVs) ranging from 0.65 to 0.94. Subgroup analyses showed no significant difference between the subgroups. The high specificity with variable but high NPVs and sensitivities implies a potential role for multiparametric MRI in detecting prostate cancer.


Temporal patterns of fruit fly (Drosophila) evolution revealed by mutation clocks.
Drosophila melanogaster has been a canonical model organism to study genetics, development, behavior, physiology, evolution, and population genetics for nearly a century. Despite this emphasis and the completion of its nuclear genome sequence, the timing of major speciation events leading to the origin of this fruit fly remain elusive because of the paucity of extensive fossil records and biogeographic data. Use of molecular clocks as an alternative has been fraught with non-clock-like accumulation of nucleotide and amino-acid substitutions. Here we present a novel methodology in which genomic mutation distances are used to overcome these limitations and to make use of all available gene sequence data for constructing a fruit fly molecular time scale. Our analysis of 2977 pairwise sequence comparisons from 176 nuclear genes reveals a long-term fruit fly mutation clock ticking at a rate of 11.1 mutations per kilobase pair per Myr. Genomic mutation clock-based timings of the landmark speciation events leading to the evolution of D. melanogaster show that it shared most recent common ancestry 5.4 MYA with D. simulans, 12.6 MYA with D. erecta+D. orena, 12.8 MYA with D. yakuba+D. teisseri, 35.6 MYA with the takahashii subgroup, 41.3 MYA with the montium subgroup, 44.2 MYA with the ananassae subgroup, 54.9 MYA with the obscura group, 62.2 MYA with the willistoni group, and 62.9 MYA with the subgenus Drosophila. These and other estimates are compatible with those known from limited biogeographic and fossil records. The inferred temporal pattern of fruit fly evolution shows correspondence with the cooling patterns of paleoclimate changes and habitat fragmentation in the Cenozoic.


New perspectives on the regulation of type II inflammation in asthma.
Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are directed towards the amelioration of downstream consequences of type-2 immune responses (i.e. β-agonists) or broad-spectrum immunosuppression (i.e. corticosteroids). However, few approaches to date have been focused on the primary prevention of immune deviation. Advances in molecular phenotyping reveal heterogeneity within the asthmatic population with multiple endotypes whose varying expression depends on the interplay between numerous environmental factors and the inheritance of a broad range of susceptibility genes. The most common endotype is one described as "type-2-high" (i.e. high levels of interleukin [IL]-13, eosinophilia, and periostin). The identification of multiple endotypes has provided a potential explanation for the observations that therapies directed at typical Th2 cytokines (IL-4, IL-5, and IL-13) and their receptors have often fallen short when they were tested in a diverse group of asthmatic patients without first stratifying based on disease endotype or severity. However, despite the incorporation of endotype-dependent stratification schemes into clinical trial designs, variation in drug responses are still apparent, suggesting that additional genetic/environmental factors may be contributing to the diversity in drug efficacy. Herein, we will review recent advances in our understanding of the complex pathways involved in the initiation and regulation of type-2-mediated immune responses and their modulation by host factors (genetics, metabolic status, and the microbiome). Particular consideration will be given to how this knowledge could pave the way for further refinement of disease endotypes and/or the development of novel therapeutic strategies for the treatment of asthma .


Binding of bisubstrate analog promotes large structural changes in the unregulated catalytic trimer of aspartate transcarbamoylase: implications for allosteric regulation.
A central problem in understanding enzyme regulation is to define the conformational states that account for allosteric changes in catalytic activity. For Escherichia coli aspartate transcarbamoylase (ATCase; EC) the active, relaxed (R state) holoenzyme is generally assumed to be represented by the crystal structure of the complex of the holoenzyme with the bisubstrate analog N-phosphonacetyl-L-aspartate (PALA). It is unclear, however, which conformational differences between the unliganded, inactive, taut (T state) holoenzyme and the PALA complex are attributable to localized effects of inhibitor binding as contrasted to the allosteric transition. To define the conformational changes in the isolated, nonallosteric C trimer resulting from the binding of PALA, we determined the 1.95-A resolution crystal structure of the C trimer-PALA complex. In contrast to the free C trimer, the PALA-bound trimer exhibits approximate threefold symmetry. Conformational changes in the C trimer upon PALA binding include ordering of two active site loops and closure of the hinge relating the N- and C-terminal domains. The C trimer-PALA structure closely resembles the liganded C subunits in the PALA-bound holoenzyme. This similarity suggests that the pronounced hinge closure and other changes promoted by PALA binding to the holoenzyme are stabilized by ligand binding. Consequently, the conformational changes attributable to the allosteric transition of the holoenzyme remain to be defined.


Contribution of immature granulocyte level to diagnosis in pleural effusion.
In this study, we aimed to evaluate the diagnostic value of neutrophil and immature granulocyte levels in peripheral blood in cases with pleural effusion. Between May 2019 and May 2020, a total of 117 patients (43 males, 74 females; mean age: 63.1±18.1 years; range, 18 to 93 years) who had pleural effusion and analysis of pleural fluid were retrospectively analyzed. All patients were evaluated in terms of age, sex, presence of comorbid diseases, approach to the pleural fluid, biochemical values of peripheral blood and pleural fluid, hemogram series of peripheral blood, diagnosis of pleural fluid, and mortality. Of the patients, 66 (54.5%) were diagnosed with benign pleural effusion and 51 (43.5%) were diagnosed with malignant pleural effusion. Number of cases with known primary malignancy was 54 (46.1%). Immature granulocyte count number and percentage of venous blood in the malignant pleural effusion group was significantly higher than the group with benign pleural effusion (p<0.05). As a hemogram parameter, immature granulocyte level is an easily applicable, cheap, and a non-invasive method in the outpatient settings.


Defining quality indicators for emergency care delivery: findings of an expert consensus process by emergency care practitioners in Africa.
Facility-based emergency care delivery in low-income and middle- income countries is expanding rapidly, particularly in Africa. Unfortunately, these efforts rarely include measurement of the quality or the impact of care provided, which is essential for improvement of care provision. Our aim was to determine context-appropriate quality indicators that will allow uniform and objective data collection to enhance emergency care delivery throughout Africa. We undertook a multiphase expert consensus process to identify, rank and refine quality indicators. A comprehensive review of the literature identified existing indicators; those associated with a substantial burden of disease in Africa were categorised and presented to consensus conference delegates. Participants selected indicators based on inclusion criteria and priority clinical conditions. The indicators were then presented to a group of expert clinicians via on-line survey; all meeting agreements were refined in-person by a separate panel and ranked according to validity, feasibility and value. The consensus working group selected seven conditions addressing nearly 75% of mortality in the African region to prioritise during indicator development, and the final product at the end of the multiphase study was a list of 76 indicators. This comprehensive process produced a robust set of quality indicators for emergency care that are appropriate for use in the African setting. The adaptation of a standardised set of indicators will enhance the quality of care provided and allow for comparison of system strengthening efforts and resource distribution.


Colistin and Polymyxin B Minimal Inhibitory Concentrations Determined by Etest Found Unreliable for Gram-Negative Bacilli.
A reliable method of polymyxin B and E (colistin) susceptibility testing remains elusive. These drugs diffuse poorly into agar, creating potentially inaccurate Etest and disk diffusion results, and testing by these methods is not recommended. Broth microdilution is the reference testing method, although it can be sometimes difficult to interpret. Currently, when a colistin susceptibility test is ordered for a patient in the Ochsner Health System, our diagnostic microbiology laboratory performs the Etest. As an in-house quality assessment project, we compared colistin and polymyxin B minimal inhibitory concentrations (MICs) determined by Etest with MICs determined by broth microdilution to evaluate whether colistin MICs are accurately being reported by Etest. A total of 143 nonduplicate clinical isolates from Ochsner patients during 2015-2016 were tested: Acinetobacter baumannii (n=60), Pseudomonas aeruginosa (n=44), and Enterobacteriaceae (n=39) (13 Escherichia coli, 15 Klebsiella spp, and 11 Enterobacter spp). Colistin and polymyxin B MICs were determined by Etest and broth microdilution. Using broth microdilution, 16/143 (11%) isolates were nonsusceptible to colistin, and 12/143 (8%) were nonsusceptible to polymyxin B. With Etest, 4/143 (3%) isolates were nonsusceptible to colistin, and 7/143 (5%) were nonsusceptible to polymyxin B. Essential agreement of colistin and polymyxin B MICs between broth microdilution and Etest was 84/143 (59%) and 87/143 (61%), respectively. Categorical agreement for colistin and polymyxin B was 127/143 (89%) and 126/143 (88%), respectively. We found a high rate of discrepancy between colistin and polymyxin B Etest and broth microdilution MICs. Very major errors (colistin/polymyxin B-susceptible by Etest, colistin/polymyxin B-resistant by broth microdilution) were detected in 10% of isolates tested with colistin and 8% of polymyxin B-tested isolates. The data from this study confirm that broth microdilution should be performed for susceptibility testing of polymyxins.


NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes.
Egress of lipoprotein-derived cholesterol from lysosomes requires two lysosomal proteins, polytopic membrane-bound Niemann-Pick C1 (NPC1) and soluble Niemann-Pick C2 (NPC2). The reason for this dual requirement is unknown. Previously, we showed that the soluble luminal N-terminal domain (NTD) of NPC1 (amino acids 25-264) binds cholesterol. This NTD is designated NPC1(NTD). We and others showed that soluble NPC2 also binds cholesterol. Here, we establish an in vitro assay to measure transfer of [(3)H]cholesterol between these two proteins and phosphatidylcholine liposomes. Whereas NPC2 rapidly donates or accepts cholesterol from liposomes, NPC1(NTD) acts much more slowly. Bidirectional transfer of cholesterol between NPC1(NTD) and liposomes is accelerated >100-fold by NPC2. A naturally occurring human mutant of NPC2 (Pro120Ser) fails to bind cholesterol and fails to stimulate cholesterol transfer from NPC1(NTD) to liposomes. NPC2 may be essential to deliver or remove cholesterol from NPC1, an interaction that links both proteins to the cholesterol egress process from lysosomes. These findings may explain how mutations in either protein can produce a similar clinical phenotype.


Effects of proliferation and differentiation of mesenchymal stem cells on compressive mechanical behavior of collagen/β-TCP composite scaffold.
The primary aim of this study is to characterize the effects of cell culture on the compressive mechanical behavior of the collagen/β-tricalcium phosphate (TCP) composite scaffold. The composite and pure collagen scaffolds were fabricated by the solid-liquid phase separation technique and the subsequent freeze-drying method. Rat bone marrow mesenchymal stem cells (rMSCs) were then cultured in these scaffolds up to 28 days. Compression test of the scaffolds with rMSCs were conducted periodically. Biological properties such as cell number, alkaline phosphatase (ALP) activity, and gene expressions of osteogenetic bone markers were evaluated during cell culture. The microstructural changes in the scaffolds during cell culture were also examined using a scanning electron microscope. The compressive elastic modulus was then correlated with those of the biological properties and microstructures to understand the mechanism of variational behavior of the macroscopic elastic property. The composite scaffold exhibited higher ALP activity and more active generation of osteoblastic markers than the collagen scaffold, indicating that β-TCP can activate the differentiation of rMSCs into osteoblasts and extracellular matrix (ECM) formation such as type I collagen and the following mineralization. The variational behavior of the compressive modulus of the composite scaffold was affected by both the material degradation and the proliferation of cells and the ECM formation. In the first stage, the modulus of the composite scaffold tended to increase due to cell proliferation and the following formation of network structure. In the second stage, the modulus tended to decrease because the material degradation such as ductile deformation of collagen and decomposition of β-TCP were more effective on the property than the ECM formation. In the third stage, active calcification by formation and growth of mineralized nodules resulted in the recovery of modulus. It is concluded that the introduction of β-TCP powder into the porous collagen matrix is very effective to improve the mechanical and biological properties of collagen scaffold prepared for bone tissue engineering. Furthermore, the compressive modulus of the composite scaffold is strongly affected by the material degradation and the ECM formation by stem cells under in vitro culture condition.


The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: a multiple regression analysis.
Sensitization of stress-responsive neurobiological systems as a possible consequence of early adverse experience has been implicated in the pathophysiology of mood and anxiety disorders. In addition to early adversities, adulthood stressors are also known to precipitate the manifestation of these disorders. The present study sought to evaluate the relative role of early adverse experience vs. stress experiences in adulthood in the prediction of neuroendocrine stress reactivity in women. A total of 49 women (normal volunteers, depressed patients, and women with a history of early abuse) underwent a battery of interviews and completed dimensional rating scales on stress experiences and psychopathology, and were subsequently exposed to a standardized psychosocial laboratory stressor. Outcome measures were plasma adrenocorticotropin (ACTH) and cortisol responses to the stress test. Multiple linear regression analyses were performed to identify the impact of demographic variables, childhood abuse, adulthood trauma, major life events in the past year, and daily hassles in the past month, as well as psychopathology on hormonal stress responsiveness. Peak ACTH responses to psychosocial stress were predicted by a history of childhood abuse, the number of separate abuse events, the number of adulthood traumas, and the severity of depression. Similar predictors were identified for peak cortisol responses. Although abused women reported more severe negative life events in adulthood than controls, life events did not affect neuroendocrine reactivity. The regression model explained 35% of the variance of ACTH responses. The interaction of childhood abuse and adulthood trauma was the most powerful predictor of ACTH responsiveness. Our findings suggest that a history of childhood abuse per se is related to increased neuroendocrine stress reactivity, which is further enhanced when additional trauma is experienced in adulthood.


Performance degradation in coherent polarization multiplexed systems as a result of polarization dependent loss.
The ultimate limits introduced by polarization dependent loss (PDL) in coherent polarization multiplexed systems using advanced signal processing are studied. An analytical framework for effectively assessing the penalties is established and applied to systems with and without dynamically optimized launch polarization control. In systems with no launch polarization control, the PDL induced penalty is described by a simple formula and it is independent of the choice of constellation, or modulation format. The gain from optimizing launch polarizations is studied numerically and the mechanisms limiting it are described.


Human Acellular Dermis versus Submuscular Tissue Expander Breast Reconstruction: A Multivariate Analysis of Short-Term Complications.
Acellular dermal matrix (ADM) allografts and their putative benefits have been increasingly described in prosthesis based breast reconstruction. There have been a myriad of analyses outlining ADM complication profiles, but few large-scale, multi-institutional studies exploring these outcomes. In this study, complication rates of acellular dermis-assisted tissue expander breast reconstruction were compared with traditional submuscular methods by evaluation of the American College of Surgeon's National Surgical Quality Improvement Program (NSQIP) registry. Patients who underwent immediate tissue expander breast reconstruction from 2006-2010 were identified using surgical procedure codes. Two hundred forty tracked variables from over 250 participating sites were extracted for patients undergoing acellular dermis-assisted versus submuscular tissue expander reconstruction. Thirty-day postoperative outcomes and captured risk factors for complications were compared between the two groups. A total of 9,159 patients underwent tissue expander breast reconstruction; 1,717 using acellular dermis and 7,442 with submuscular expander placement. Total complications and reconstruction related complications were similar in both cohorts (5.5% vs. 5.3%, P=0.68 and 4.7% vs. 4.3%, P=0.39, respectively). Multivariate logistic regression revealed body mass index and smoking as independent risk factors for reconstructive complications in both cohorts (P<0.01). The NSQIP database provides large-scale, multi-institutional, independent outcomes for acellular dermis and submuscular breast reconstruction. Both thirty-day complication profiles and risk factors for post operative morbidity are similar between these two reconstructive approaches.


Automorphosis of etiolated pea seedlings in space is simulated by a three-dimensional clinostat and the application of inhibitors of auxin polar transport.
Etiolated pea (Pisum sativum L. cv. Alaska) seedlings grown under microgravity conditions in space show automorphosis: bending of epicotyls, inhibition of hook formation and changes in root growth direction. In order to determine the mechanisms of microgravity conditions that induce automorphosis, we used a three-dimensional clinostat and obtained the successful induction of automorphosis-like growth of etiolated pea seedlings. Kinetic studies revealed that epicotyls bent at their basal region towards the clockwise direction far from the cotyledons from the vertical line (0 degrees) at approximately 40 degrees in seedlings grown both at 1 g and in the clinostat within 48 h after watering. Thereafter, epicotyls retained this orientation during growth in the clinostat, whereas those at 1 g changed their growth direction against the gravity vector and exhibited a negative gravitropic response. On the other hand, the plumular hook that had already formed in the embryo axis tended to open continuously by growth at the inner basal portion of the elbow; thus, the plumular hook angle initially increased; this was followed by equal growth on the convex and concave sides at 1 g, resulting in normal hook formation; in contrast, hook formation was inhibited on the clinostat. The automorphosis-like growth and development of etiolated pea seedlings was induced by auxin polar transport inhibitors (9-hydroxyfluorene-9-carboxylic acid, N-(1-naphthyl)phthalamic acid and 2,3,5-triiodobenzoic acid), but not by anti-auxin (p-chlorophenoxyisobutyric acid) at 1 g. An ethylene biosynthesis inhibitor, 1-aminooxyacetic acid, inhibited hook formation at 1 g, and ethylene production of etiolated seedlings was suppressed on the clinostat. Clinorotation on the clinostat strongly reduced the activity of auxin polar transport of epicotyls in etiolated pea seedlings, similar to that observed in space experiments (Ueda J, Miyamoto K, Yuda T, Hoshino T, Fujii S, Mukai C, Kamigaichi S, Aizawa S, Yoshizaki I, Shimazu T, Fukui K (1999) Growth and development, and auxin polar transport in higher plants under microgravity conditions in space: BRIC-AUX on STS-95 space experiment. J Plant Res 112: 487492). These results suggest that clinorotation on a three-dimensional clinostat is a valuable tool for simulating microgravity conditions, and that automorphosis of etiolated pea seedlings is induced by the inhibition of auxin polar transport and ethylene biosynthesis.


Cortical Processing of Arithmetic and Simple Sentences in an Auditory Attention Task.
Cortical processing of arithmetic and of language rely on both shared and task-specific neural mechanisms, which should also be dissociable from the particular sensory modality used to probe them. Here, spoken arithmetical and non-mathematical statements were employed to investigate neural processing of arithmetic, compared with general language processing, in an attention-modulated cocktail party paradigm. Magnetoencephalography (MEG) data were recorded from 22 human subjects listening to audio mixtures of spoken sentences and arithmetic equations while selectively attending to one of the two speech streams. Short sentences and simple equations were presented diotically at fixed and distinct word/symbol and sentence/equation rates. Critically, this allowed neural responses to acoustics, words, and symbols to be dissociated from responses to sentences and equations. Indeed, the simultaneous neural processing of the acoustics of words and symbols was observed in auditory cortex for both streams. Neural responses to sentences and equations, however, were predominantly to the attended stream, originating primarily from left temporal, and parietal areas, respectively. Additionally, these neural responses were correlated with behavioral performance in a deviant detection task. Source-localized temporal response functions (TRFs) revealed distinct cortical dynamics of responses to sentences in left temporal areas and equations in bilateral temporal, parietal, and motor areas. Finally, the target of attention could be decoded from MEG responses, especially in left superior parietal areas. In short, the neural responses to arithmetic and language are especially well segregated during the cocktail party paradigm, and the correlation with behavior suggests that they may be linked to successful comprehension or calculation.SIGNIFICANCE STATEMENT Neural processing of arithmetic relies on dedicated, modality independent cortical networks that are distinct from those underlying language processing. Using a simultaneous cocktail party listening paradigm, we found that these separate networks segregate naturally when listeners selectively attend to one type over the other. Neural responses in the left temporal lobe were observed for both spoken sentences and equations, but the latter additionally showed bilateral parietal activity consistent with arithmetic processing. Critically, these responses were modulated by selective attention and correlated with task behavior, consistent with reflecting high-level processing for speech comprehension or correct calculations. The response dynamics show task-related differences that were used to reliably decode the attentional target of sentences or equations.


Common representation of pain and negative emotion in the midbrain periaqueductal gray.
Human neuroimaging offers a powerful way to connect animal and human research on emotion, with profound implications for psychological science. However, the gulf between animal and human studies remains a formidable obstacle: human studies typically focus on the cortex and a few subcortical regions such as the amygdala, whereas deeper structures such as the brainstem periaqueductal gray (PAG) play a key role in animal models. Here, we directly assessed the role of PAG in human affect by interleaving in a single fMRI session two conditions known to elicit strong emotional responses--physical pain and negative image viewing. Negative affect and PAG activity increased in both conditions. We next examined eight independent data sets, half featuring pain stimulation and half negative image viewing. In sum, these data sets comprised 198 additional participants. We found increased activity in PAG in all eight studies. Taken together, these findings suggest PAG is a key component of human affective responses.


Synaptic physiology of horizontal connections in the cat's visual cortex.
Horizontal connections are a principal component of intrinsic cortical circuitry. They arise mainly from pyramidal cells and course parallel to the brain's surface for distances as long as 8 mm, linking columns with shared orientation preference and allowing cells to integrate visual information from outside their receptive fields. We examined the synaptic physiology of the horizontal pathway in slices of the cat's striate cortex and found that activating lateral fibers produced both excitation and inhibition. We recorded the postsynaptic responses of identified pyramidal cells in layer 2 + 3 of area 17 to electrical shocks applied at three sites: in the home column of the impaled neuron either in layer 2 + 3 or 4, or at a lateral distance of 0.9-3 mm in layer 2 + 3. Within the home column, suprathreshold stimuli produced compound EPSPs with action potentials, followed by fast, GABAAergic IPSPs and a slower, GABABergic IPSP. For the distant stimulating site, the threshold response was an EPSP. Stronger shocks frequently evoked a disynaptic, GABAAergic IPSP that truncated the EPSP and could dominate the postsynaptic response. At the resting potential, the horizontally evoked EPSP was too small to elicit spikes. With depolarization of the membrane, however, it grew several hundred-fold. This amplification was blocked by N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), but not by 2-amino-5-phosphonovalerate (APV), indicating that it was mediated by Na+ channels, rather than by NMDA receptors. We propose that the horizontal connections provide the means for stimuli outside the receptive field to modulate activity elicited within its confines. The voltage-dependent enhancement of the laterally evoked EPSP may explain why stimulating the surround by itself fails to drive cells but can facilitate their response to stimuli within the receptive field. The ability to initiate disynaptic inhibition from lateral sites shows that recruiting appropriate groups of horizontal fibers can also have a suppressive effect. Thus, the effect of horizontal input is state dependent, with the size and sign of the laterally evoked response changing according to the balance of converging inputs.


Wild edible plants used by communities in and around selected forest reserves of Teso-Karamoja region, Uganda.
The consumption of wild plants is an ancient tradition which serves multiple purposes. Cognizant that Teso-Karamoja region is frequently affected by food scarcity and is not adequately surveyed for its flora, this study sought to establish an inventory and use of wild edible plants by the communities living in and around the forest reserves. Data was collected using semi-structured questionnaires administered to 240 respondents living in and around eight forest reserves between November 2017 and May 2018. One focus group discussion (8-12 members) per forest reserve and field excursions to collect the plant voucher specimens were also conducted. The data was analyzed using descriptive statistics, relative frequency of citation (RFC), and the factor of informants' consensus (FIC). A total of 100 plant species in 47 families were reported as edible. Carissa spinarum, Strychnos innocua, Balanites aegyptiaca, Tamarindus indica, and Ximenia americana presented the highest RFC, while the families Rubiaceae, Fabaceae, Anacardiaceae, Amaranthaceae, and Moraceae had more than five species each. Grasses (Poaceae) comprised only 1% of the edible species and trees 35%, while shrubs were the most important source of wild food (RFC = 0.47). The fruits contributed 63% while leaves (29%), seeds (9%), tubers (5%), and gum (1%). The fruits were considered as the most important use category (RFC = 0.78). Respondent homogeneity was none for gum but very high for seeds (FIC - 0.93). Only 36% of species are cooked, while 64% are eaten in raw. Harvesting is done rudimentarily by digging (5%), collecting from the ground (fruits that fall down) (13%), and plucking from mother plants (82%). Only 9% of the species were collected throughout the year, 27% in the dry season, and 64% in the rainy season. The consumption of these plants is attributed to food scarcity, spicing staple food, nutri-medicinal value, cultural practice, and delicacy. A high diversity of wild edible plant species exists in the forest reserves of Teso-Karamoja region. The shrubs and fruits are the most locally important life forms and use category, respectively. These edible plant species are important throughout the year because their consumption serves multiple purposes.


Intact lipid imaging of mouse brain samples: MALDI, nanoparticle-laser desorption ionization, and 40 keV argon cluster secondary ion mass spectrometry.
We have investigated the capability of nanoparticle-assisted laser desorption ionization mass spectrometry (NP-LDI MS), matrix-assisted laser desorption ionization (MALDI) MS, and gas cluster ion beam secondary ion mass spectrometry (GCIB SIMS) to provide maximum information available in lipid analysis and imaging of mouse brain tissue. The use of Au nanoparticles deposited as a matrix for NP-LDI MS is compared to MALDI and SIMS analysis of mouse brain tissue and allows selective detection and imaging of groups of lipid molecular ion species localizing in the white matter differently from those observed using conventional MALDI with improved imaging potential. We demonstrate that high-energy (40 keV) GCIB SIMS can act as a semi-soft ionization method to extend the useful mass range of SIMS imaging to analyze and image intact lipids in biological samples, closing the gap between conventional SIMS and MALDI techniques. The GCIB SIMS allowed the detection of more intact lipid compounds in the mouse brain compared to MALDI with regular organic matrices. The 40 keV GCIB SIMS also produced peaks observed in the NP-LDI analysis, and these peaks were strongly enhanced in intensity by exposure of the sample to trifluororacetic acid (TFA) vapor prior to analysis. These MS techniques for imaging of different types of lipids create a potential overlap and cross point that can enhance the information for imaging lipids in biological tissue sections. Graphical abstract Schematic of mass spectral imaging of a mouse brain tissue using GCIB-SIMS and MALDI techniques.


Rehabilitation and Psychosocial Determinants of Cochlear Implant Outcomes in Older Adults.
The cochlear implant (CI) has been shown to be associated with better hearing, cognitive abilities, and functional independence. There is variability however in how much benefit each recipient derives from his or her CI. This study's primary objective is to determine the effects of individual and environmental characteristics on CI outcomes. Seventy-six adults who developed postlingual severe to profound hearing loss and received their first unilateral CI at 65 years and older were eligible for the study. Fifty-five patients were asked to participate and the 33 (60%) with complete data were classified as "group 1." The remaining patients were placed in "group 2." Primary outcomes included changes in quality of life and open-set speech perception scores. Independent variables included age, health status, trait emotional intelligence (EI), comfort with technology, and living arrangements. Survey outcomes and audiological measurements were collected prospectively at 12 months after surgery, whereas preoperative data were collected retrospectively. Comparisons between groups 1 and 2 were made. Wilcoxon signed rank test, Spearman correlations, Mann-Whitney tests, Chi-square tests, and linear regressions were performed only on group 1 data. Having a CI was associated with improved quality of life and speech perception. Familiarity with electronic tablets was associated with increased 12-month postoperative AzBio gains when adjusted for preoperative AzBio scores (adjusted p = 0.019), but only marginally significant when a family-wise error correction was applied (p = 0.057). Furthermore, patients who lived with other people scored at least 20 points higher on the AzBio sentences than those who lived alone (adjusted p = 0.046). Finally, consultation with an auditory rehabilitation therapist was associated with higher self-reported quality of life (p = 0.035). This study suggests that in a cohort of older patients cochlear implantation is associated with a meaningful increase in both quality of life and speech perception. Furthermore, it suggests the potential importance of adjunct support and services, including the tailoring of CI rehabilitation sessions depending on the patient's familiarity with technology and living situation. Investment in rehabilitation and other services is associated with improvements in quality of life and may mitigate clinical, individual and social risk factors for poor communication outcome.


Ceramide induces mitochondrial abnormalities in insulin-secreting INS-1 cells: potential mechanisms underlying ceramide-mediated metabolic dysfunction of the beta cell.
C2-ceramide, a cell permeable analogue of ceramide [CER] markedly reduced mitochondrial membrane potential [MMP] in insulin-secreting INS cells, which was followed by a significant accumulation of cytochrome c [Cyt c] into the cytosolic compartment. In a manner akin to CER, exposure of these cells to interleukin-1beta [IL-1beta] also resulted in reduction in MMP and cytosolic accumulation of Cyt c. Further, long-term exposure of these cells to either CER [but not its inactive analogue] or IL-1beta caused a marked reduction in their metabolic viability. However, unlike IL-1beta, which increased nitric oxide [NO] release, CER-treatment of INS cells had no effects of CER on NO release were demonstrable. Together, these findings suggest that CER-induced mitochondrial effects may not be mediated via iNOS gene expression and NO production. CER also activated an okadaic acid -sensitive protein phosphatase [CAPP] in the purified mitochondrial fraction, suggesting that CAPP might represent one of the target proteins for CER in the beta cell mitochondria. Together, our findings suggest direct detrimental effects of CER on mitochondrial function in beta cells leading to their dysfunction and demise via apoptosis. Moreover, our findings provide evidence for a potential difference in the mechanisms underlying CER- and IL-1beta-induced mitochondrial defects and apoptotic demise of the effete beta cell.


Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.
Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.


A novel deletion partly removing the AVP gene causes autosomal recessive inheritance of early-onset neurohypophyseal diabetes insipidus.
Familial neurohypophyseal diabetes insipidus (FNDI) typically presents with age-dependent penetrance and autosomal dominant inheritance caused by missense variations in one allele of the AVP gene encoding the arginine vasopressin (AVP) prohormone. We present the molecular genetic characteristics underlying an unusual form of FNDI occurring with very early onset and seemingly autosomal recessive inheritance. By DNA amplification and sequencing, we identified a novel variant allele of the AVP gene carrying a 10,396 base pair deletion involving the majority of the AVP gene as well as its regulatory sequences in the intergenic region between the AVP and the OXT gene, encoding the oxytocin prohormone. We found two chromosomes carrying the deletion in affected family members and one in unaffected family members suspected to transmit the deleted allele. Whole-genome array analysis confirmed the results and excluded the presence of any additional major pathogenic abnormalities. The deletion is predicted to abolish the transcription of the AVP gene, thus the fact that family members heterozygous for the deletion remain healthy argues, in general, against haploinsufficiency as the pathogenic mechanism FNDI. Accordingly, our data is strong support to the prevailing idea that dominant inheritance of FNDI is due to a dominant-negative effect exerted by variant AVP prohormone.


Alcohol, drug use, and sexual risk among young African American women in North Carolina: Is educational attainment protective?
Previous research shows that educational attainment is a protective factor for substance use and sexual risk among adolescents and young adults. Evidence also shows that this relationship may differ by race/ethnicity and gender. This study aimed to elucidate the relationship between educational attainment, substance use and sexual risk among African American women in emerging adulthood. This study uses cross-sectional data from 646 African American women (aged 18 to 25) enrolled in a randomized trial of a behavioral HIV risk-reduction intervention. At enrollment, participants completed a risk behavior assessment via audio-computer assisted self-interview and provided a urine sample for drug screening. Bivariate logistic regression analyses were conducted to examine substance use and sexual risk factors associated with educational attainment: completing some college or more vs. completing high school or less). Participants who completed some college or more (52%) were more likely to report heavy alcohol use (four or more drinks in one day) in the past 30 days (OR=1.48; p=0.014) and more likely to report alcohol or other drug use just before or during last sex (OR=1.43; p=0.026) compared with participants who completed high school or less. Completing some college or more was protective for having a positive urine screen for cocaine (OR=0.43; p=0.018) and reporting condomless sex at last sex (OR=0.71; p=0.041). Differences in positive marijuana screens, reporting a previous STI, or reporting their partner used alcohol or other drugs at last sex were not statistically significant. The findings reveal notable differences in the magnitude and direction of associations between educational attainment and substance use and sexual risk. Although educational attainment is subject to change because of the frequent pursuit of education during emerging adulthood, the findings may have important implications for tailoring HIV risk-reduction interventions to key populations, such as African American women.


The effect of physical activity on anhedonia in individuals with depressive symptoms.
The therapeutic effect of antidepressants has been demonstrated for anhedonia in patients with depression. However, antidepressants may cause side-effects, such as cardiovascular dysfunction. Although physical activity has minor side-effects, it may serve as an alternative for improving anhedonia and depression. We sought to investigate whether physical activity reduces the level of anhedonia in individuals with depression. Fifty-six university students with moderate depressive symptoms (Beck Depression Inventory total score > 16) were divided into three training groups: the Running Group (RG, n = 19), the Stretching Group (SG, n = 19), and the Control Group (n = 18). We employed the Monetary Incentive Delay (MID) task and the Temporal Experience of Pleasure Scale (TEPS) to evaluate hedonic capacity. All participants in the RG and SG received 8 weeks of jogging and stretching training, respectively. The RG experienced an increase in the level of arousal during anticipation of a future reward and recalled less negativity towards the loss condition. The SG exhibited enhanced scores on the Anticipatory and Consummatory Pleasure subscales of the TEPS after training. Moreover, in the RG, greater improvements in anticipatory arousal ratings for pleasure and remembered valence ratings for negative affect were associated with longer training duration, lower maximum heart rate, and higher consumed calories during training. To conclude, physical activity is effective in improving anticipatory anhedonia in individuals with depressive symptoms.


Shielding of a lipooligosaccharide IgM epitope allows evasion of neutrophil-mediated killing of an invasive strain of nontypeable Haemophilus influenzae.
Nontypeable Haemophilus influenzae is a frequent cause of noninvasive mucosal inflammatory diseases but may also cause invasive diseases, such as sepsis and meningitis, especially in children and the elderly. Infection by nontypeable Haemophilus influenzae is characterized by recruitment of neutrophilic granulocytes. Despite the presence of a large number of neutrophils, infections with nontypeable Haemophilus influenzae are often not cleared effectively by the antimicrobial activity of these immune cells. Herein, we examined how nontypeable Haemophilus influenzae evades neutrophil-mediated killing. Transposon sequencing (Tn-seq) was used on an isolate resistant to neutrophil-mediated killing to identify genes required for its survival in the presence of human neutrophils and serum, which provided a source of complement and antibodies. Results show that nontypeable Haemophilus influenzae prevents complement-dependent neutrophil-mediated killing by expression of surface galactose-containing oligosaccharide structures. These outer-core structures block recognition of an inner-core lipooligosaccharide epitope containing glucose attached to heptose HepIII-β1,2-Glc by replacement with galactose attached to HepIII or through shielding HepIII-β1,2-Glc by phase-variable attachment of oligosaccharide chain extensions. When the HepIII-β1,2-Glc-containing epitope is expressed and exposed, nontypeable Haemophilus influenzae is opsonized by naturally acquired IgM generally present in human serum and subsequently phagocytosed and killed by human neutrophils. Clinical nontypeable Haemophilus influenzae isolates containing galactose attached to HepIII that are not recognized by this IgM are more often found to cause invasive infections. Importance: Neutrophils are white blood cells that specialize in killing pathogens and are recruited to sites of inflammation. However, despite the presence of large numbers of neutrophils in the middle ear cavity and lungs of patients with otitis media or chronic obstructive pulmonary disease, respectively, the bacterium nontypeable Haemophilus influenzae is often not effectively cleared from these locations by these immune cells. In order to understand how nontypeable Haemophilus influenzae is able to cause inflammatory diseases in the presence of neutrophils, we determined the mechanism that underlies resistance to neutrophil-mediated killing. We have shown that nontypeable Haemophilus influenzae prevents binding of antibodies of the IgM subtype through changes in their surface lipooligosaccharide structure, thereby preventing complement activation and clearance by human neutrophils.


Rapid Computational Analysis of DNA Origami Assemblies at Near-Atomic Resolution.
Structural DNA nanotechnology plays an ever-increasing role in advanced biomolecular applications. Here, we present a computational method to analyze structured DNA assemblies rapidly at near-atomic resolution. Both high computational efficiency and molecular-level accuracy are achieved by developing a multiscale analysis framework. The sequence-dependent relative geometry and mechanical properties of DNA motifs are characterized by the all-atom molecular dynamics simulation and incorporated into the structural finite element model successfully without significant loss of atomic information. The proposed method can predict the three-dimensional shape, equilibrium dynamic properties, and mechanical rigidities of monomeric to hierarchically assembled DNA structures at near-atomic resolution without adjusting any model parameters. The calculation takes less than only 15 min for most origami-scale DNA nanostructures consisting of 7000-8000 base-pairs. Hence, it is expected to be highly utilized in an iterative design-analysis-revision process for structured DNA assemblies.


p38 mitogen-activated protein kinase-dependent transactivation of ErbB receptor family: a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance.
Stress stimuli such as tumor necrosis factor (TNF) have been shown to induce insulin receptor substrate (IRS)-1 serine phosphorylation and insulin resistance by transactivation of ErbB receptors. We aimed at elucidating the potential role of p38 mitogen-activated protein kinase (p38MAPK) in mediating stress-induced ErbB receptors activation. p38MAPK effect on ErbBs transactivation and insulin signaling was assessed in Fao or HepG2 cells, exposed to stress stimuli, and on metabolic parameters in ob/ob and C57/BL6 mice. High-fat diet-fed mice and ob/ob mice exhibited elevated hepatic p38MAPK activation associated with glucose intolerance and hyperinsulinemia. Liver expression of dominant-negative (DN)-p38MAPKα in ob/ob mice reduced fasting insulin levels and improved glucose tolerance, whereas C57/BL6 mice overexpressing wild-type p38MAPKα exhibited enhanced IRS-1 serine phosphorylation and reduced insulin-stimulated IRS-1 tyrosine phosphorylation. Fao or HepG2 cells exposed to TNF, anisomycin, or sphingomyelinase demonstrated rapid transactivation of ErbB receptors leading to PI3-kinase/Akt activation and IRS-1 serine phosphorylation. p38MAPK inhibition either by SB203580, by small interfering RNA, or by DN-p38MAPKα decreased ErbB receptors transactivation and IRS-1 serine phosphorylation and partially restored insulin-stimulated IRS-1 tyrosine phosphorylation. When cells were incubated with specific ErbB receptors antagonists or in cells lacking ErbB receptors, anisomycin- and TNF-induced IRS-1 serine phosphorylation was attenuated, despite intact p38MAPK activation. The stress-induced p38MAPK activation leading to ErbB receptors transactivation was associated with intracellular reactive oxygen species generation and was attenuated by treatment with antioxidants. Hepatic p38MAPK is activated following various stress stimuli. This event is upstream to ErbB receptors transactivation and plays an important role in stress-induced IRS-1 serine phosphorylation and insulin resistance.


Carer psychoeducation in first-episode psychosis: evaluation outcomes from a structured group programme.
Carers play an important role in supporting client adjustment and relapse prevention following a first psychotic episode. The caring experience however is a stressful and demanding one, and carers require support to develop coping strategies and sustain themselves in their role. To evaluate a psychoeducation programme provided within a public adult mental health service, designed for the families of clients experiencing first-episode psychosis. A pre- and post-test questionnaire was administered to quantitatively measure the participants' changes in perceptions of their knowledge and understanding regarding mental illness and its treatment through attending the group. Qualitative items were included to ascertain other knowledge gained or benefits perceived and any critical feedback. The programme significantly improved carers' perceptions of their understanding of psychosis, recovery and relapse prevention. Additional feedback replicated previous findings that participants value support and feel less isolated through group attendance, gaining a sense of collective experience and the opportunity to share experiences and feel heard by peers. The evaluation demonstrates the efficacy of such a group and the importance of public mental health services in providing family interventions in first-episode psychosis care.


Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons.
We examined the cell proliferative, neurogenic, and behavioral effects of transforming growth factor alpha (TGFalpha) in a 6-OHDA Parkinson's disease model when compared with naive rats. Intrastriatal TGFalpha infusion induced significant proliferation, hyperplastic nodules, and substantial migratory waves of nestin-positive progenitor cells from the adult subventricular zone (SVZ) of dopamine-denervated rats. Interestingly, SVZ cells in naive rats displayed proliferation but minimal migration in response to the TGFalpha infusion. The cells in the expanded SVZ accumulated cytoplasmic beta-catenin, indicating activation of classical Wnt signaling. However, no evidence of any neuronal differentiation was found of these recruited progenitor cells anywhere examined in the brain. Consequently, no evidence of dopaminergic (DA) neurogenesis was found in the striatum or substantia nigra in any experimental group, and amphetamine-induced behavioral rotations did not improve. In summary, the cells in the TGFalpha-induced migratory cellular wave remain undifferentiated and do not differentiate into midbrain-like DA neurons.


Consequences of parental exposure to serum-free medium for progeny cell division.
Proliferating serum-dependent 3T3 cells prolong their intermitotic time by 9-10 h after exposure to serum-free medium for only 1 h. This delay was only observed in cells younger than 4 h, i.e. cells in the postmitotic G1 phase (G1pm), as defined by time elapsed since previous mitosis. These data confirm earlier findings that cells are very sensitive to growth factor or serum depletion during the first part of G1 and that only a short exposure to serum-free medium is sufficient for the cells to leave the cell cycle. However, such cells that have delayed their first cell cycle in response to a short exposure to serum-free medium in early G1 exhibit a reduced capacity to delay the subsequent cycle in response to a repeated exposure to serum-free medium. In contrast cells older than 4 h that are exposed for short periods to serum-free medium undergo cell division on schedule, but delay the subsequent cell cycle by several hours. This delay of the progeny cycle is mainly ascribable to the postmitotic part of G1 (G1pm). These data suggest that short exposures to serum-free medium exert an indirect effect on the progeny cell cycle and demonstrate that cycle times are not necessarily determined de novo in the lifetime of every cell, but may be influenced by events in the preceding cycle.


Extended Family Caregivers for Persons Living With Dementia.
Despite changes in the structure of contemporary families, little is known about extended family members-siblings, grandchildren, nieces/nephews, stepkin-who are primary caregivers for a relative living with dementia. Information about these caregivers is needed to help ensure their needs are understood by providers in health care and social service settings. The focus of this research was on the care situations of extended family caregivers and the impact of caregiving on their health and well-being. In Study 1, data from the National Study of Caregiving were used to describe the experiences of 107 extended family caregivers. In Study 2, case study techniques elicited additional information about the experiences of 10 extended family caregivers. Collectively, these caregivers provide care with little or no formal support and occasional help from a small informal network. Caregiving affected their physical and emotional health, depending on the strength of the relationship between the caregiver and the person living with dementia and the type of care provided. Findings contribute new knowledge about extended family caregivers and highlight the important role extended family dementia caregivers play and the challenges they face.


Grade and speed have greater influence on HR and RPE than ability, sex, and age in alpine skiing.
The purpose of this study was to investigate the influence of ski slope grade, skiing speed, skiing ability, sex, and age on HR, RPE, and energy expenditure responses during recreational alpine skiing. Thirty-eight participants were divided by age, sex, and skiing ability. Instructor- and self-paced skiing conditions were conducted on 10° and 19.8° slopes. Skiing HR was recorded, RPE collected at the end of each run, and energy expenditure calculated. The pertinent results of this study demonstrate that the interactions of grade × speed, speed × age, and grade × age and the main effects of speed and grade significantly influenced %HRmax, mean HR, RPE, and energy expenditure during skiing. When %HRmax is taken into account, the older skiers skied at a greater relative intensity than the young skiers. The sex, age, and skiing ability main effects did not have a significant influence on mean HR, RPE, and energy expenditure. These data demonstrates that increased speed and grade results in increased physiological stress. Using mean, HR data may not be the best option for assessing physiological stress during exercise in the older athlete as it does not account for the influence of the ageing process.


Diagnosis and treatment of leptospirosis in the primary care setting.
Leptospirosis is an infectious illness that usually develops 1 to 2 weeks after indirect or direct exposure to the urine of infected animals. Infection occurs through open cuts, absorption through intact mucous membranes, and drinking contaminated water. The typical presentation is a flulike syndrome of sudden onset that tends to resolve within 2 weeks. A mild immunologic phase usually presents as an aseptic meningitis. A more severe immunologic phase (Well's syndrome) can result in jaundice, renal failure, adult respiratory distress syndrome, disseminated intravascular coagulation, and death. Laboratory tests take too long to replace clinical diagnosis, which is imperative so that antibiotic therapy can begin before the fourth day of illness. Although leptospirosis is more common in tropical climates, detection in the continental United States is increasing. Early, accurate detection and treatment in the primary care setting are vital for limiting life-threatening complications.


[Mineral content in the wild onion species and their nutritive value].
The accumulation of 11 microelements (Fe, Zn, Cu, Co, Mn, Ni, Pb, Cd, Sr, Cr, and Se) by 7 wild onion species of the genus Allium was studied. A. flavescens Bess possesses the higher accumulating capability; it accumulates five of eleven microelements (Cr, Ni, Cu, Zn, and Se) with biological accumulation coefficient (BAC) exceeding 1 and also contains high levels of Fe, Co, and Mn. These features enable this species to be the most promising for the nutrition adjustment of human commons with above-mentioned microelements primarily with Cr, which content in 100 g onion leaves achieves 84% of commons. A. fistulosum L., A. odorum L., and broad-leaved A. nutans form specifically accumulate Cu, Zn, and Se. A. montanum Schmidt is characterized by the accumulation of Zn. A. angulosum and A. schoenoprasum are xharacterized by the accumulation of Se. The broad-leaved forms of A. schoenoprasum L., A. nutans L., and A. odorum L. compared with their narrow-leaved forms accumulate more amounts of Zn and Cu.


Angiotensin II type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts.
Although polymorphic variations in genes of the RAS system have previously been associated with susceptibility to AAA, such studies have been significantly limited by small sample sizes. This study was undertaken, using the largest case series yet reported, to determine whether common genetic variants of the RAS are associated with either susceptibility or severity of AAA. The frequencies of 4 common genetic variants of genes related to the renin-angiotensin system were investigated in 3 geographically distinct, but ethnically similar, case-control cohorts, resulting in comparison of 1226 AAA cases with 1723 controls. In all 3 the AGTR1 1166C allele was significantly more common in AAA patients than controls (overall adjusted OR 1.60, 95% CI 1.32 to 1.93, P=1.1x10(-6)). Overall, the ACE ID genotype was associated with AAA (OR 1.33, 95% CI 1.06 to 1.67, P<0.02). The AGT 268T allele appeared to have an epistatic effect on large aneurysm size. This study has identified a strong and repeated association between the AGTR1 1166C allele and susceptibility to AAA, and a weaker effect associated with the ACE deletion allele, in 3 geographically distinct, but ethnically similar, case-control cohorts. This study highlights the key role of the RAS in AAA and emphasizes the need for replication and validation of results in suitable independent cohorts.


Trastuzumab Deruxtecan in Anti-Human Epidermal Growth Factor Receptor 2 Treatment-Naive Patients With Human Epidermal Growth Factor Receptor 2-Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial.
To investigate efficacy and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients with locally advanced or metastatic HER2-low (cohort 1, immunohistochemistry 2+/in situ hybridization-negative; cohort 2, immunohistochemistry 1+) gastric/GEJ adenocarcinoma treated with at least two prior regimens, including fluoropyrimidine and platinum, but anti-HER2 therapy naive, received T-DXd 6.4 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate by independent central review. Among 21 patients enrolled in cohort 1 and 24 enrolled in cohort 2, 19 and 21 patients, respectively, had central HER2 confirmation, received T-DXd, and had measurable tumors at baseline. The confirmed objective response rate was 26.3% (95% CI, 9.1 to 51.2) from five partial responses in cohort 1 and 9.5% (95% CI, 1.2 to 30.4) from two partial responses in cohort 2. Thirteen patients (68.4%) in cohort 1 and 12 (60.0%) in cohort 2 experienced reduced tumor size. The median overall survival was 7.8 months (95% CI, 4.7 to nonevaluable) in cohort 1 and 8.5 months (95% CI, 4.3 to 10.9) in cohort 2; the median progression-free survival was 4.4 months (95% CI, 2.7 to 7.1) and 2.8 months (95% CI, 1.5 to 4.3), respectively. The most common grade ≥ 3 treatment-emergent adverse events in cohorts 1 and 2 were anemia (30.0% and 29.2%), decreased neutrophil count (25.0% and 29.2%), and decreased appetite (20.0% and 20.8%). Drug-related interstitial lung disease/pneumonitis occurred in one patient in each cohort (grade 1 or 2). No drug-related deaths occurred. This study provides preliminary evidence that T-DXd has clinical activity in patients with heavily pretreated HER2-low gastric/GEJ adenocarcinoma.


Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat.
Systemic arterial hypertension has been previously suggested to develop as a compensatory condition when central nervous perfusion/oxygenation is compromised. Principal sympathoexcitatory C1 neurons of the rostral ventrolateral medulla oblongata (whose activation increases sympathetic drive and the arterial blood pressure) are highly sensitive to hypoxia, but the mechanisms of this O2 sensitivity remain unknown. Here, we investigated potential mechanisms linking brainstem hypoxia and high systemic arterial blood pressure in the spontaneously hypertensive rat. Brainstem parenchymal PO2 in the spontaneously hypertensive rat was found to be ≈15 mm Hg lower than in the normotensive Wistar rat at the same level of arterial oxygenation and systemic arterial blood pressure. Hypoxia-induced activation of rostral ventrolateral medulla oblongata neurons was suppressed in the presence of either an ATP receptor antagonist MRS2179 or a glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol, suggesting that sensitivity of these neurons to low PO2 is mediated by actions of extracellular ATP and lactate. Brainstem hypoxia triggers release of lactate and ATP which produce excitation of C1 neurons in vitro and increases sympathetic nerve activity and arterial blood pressure in vivo. Facilitated breakdown of extracellular ATP in the rostral ventrolateral medulla oblongata by virally-driven overexpression of a potent ectonucleotidase transmembrane prostatic acid phosphatase results in a significant reduction in the arterial blood pressure in the spontaneously hypertensive rats (but not in normotensive animals). These results suggest that in the spontaneously hypertensive rat, lower PO2 of brainstem parenchyma may be associated with higher levels of ambient ATP and l-lactate within the presympathetic circuits, leading to increased central sympathetic drive and concomitant sustained increases in systemic arterial blood pressure.


Reproductive responses to variation in temperature and food supply by house mice. I. Mating and pregnancy.
The effects of food restriction upon mating and pregnancy of female house mice were studied at a warm (21 degrees C) and a cold (5 degrees C) temperature to examine the hypothesis that the effects of temperature and food availability are not independent. Analyses of the data showed significant interaction between temperature and food availability for virtually all variables measured, supporting the initial hypothesis. Contingency analysis of mating, fertility, and litter survivorship showed that the interaction influenced not only the percentage of females successfully producing litters, but also the timing of abandonment of reproductive effort by those females that did not have surviving litters. The percentage of females who mated was reduced only in food-restricted females under cold conditions. Both low temperature and food restriction reduced the percentage of mated females that became pregnant. Food-restricted females under cold conditions who did become pregnant tended to kill their litters at birth. The net effect was an interaction between temperature and food restriction that resulted in females reducing or abandoning reproductive effort at progressively earlier stages of the reproductive cycle. The interaction between temperature and food restriction was further displayed in the growth curves of pregnant females, with the reduction of growth by food restriction being greater in the cold.


A case of ventricular septal rupture associated with major septal branch occlusion after percutaneous coronary intervention.
A 67-year-old man underwent elective percutaneous coronary intervention (PCI) of the left anterior descending artery. The major septal branch became occluded during coronary stenting. The patient developed dyspnea 19 days later. Chest radiography revealed lung congestion and a pleural effusion. Transthoracic echocardiography revealed a basal ventricular septal rupture. Emergency coronary angiography did not reveal any in-stent restenosis, and the major septal branch remained occluded. Therefore, the patient underwent closure of the ventricular septal rupture. The postoperative period was uneventful, and he was discharged 29 days after the operation. Septal branch occlusion due to coronary stenting occasionally occurs during routine PCI for which recanalization is sometimes not attempted. However, this case demonstrates that occluded septal branches, although rare, may cause serious complications. <Learning objective: Rupture of the ventricular septum, a complication of acute myocardial infarction, is usually observed in the setting of acute myocardial infarction associated with major coronary artery occlusion. However, ventricular septal rupture associated with side branch occlusion due to coronary stenting for stable angina pectoris is uncommon. Awareness of this rare complication is useful during routine percutaneous coronary intervention.>.


Cumulative reporting of chemical pathology.
A simple system for producing cumulative chemical pathology reports is described. Results of tests are transcribed onto the patient's laboratory record card and each time a new result is entered a copy is made by xerography and returned to the clinician as the laboratory report.A detailed account is given of the operation of the system and the design of the record card. The advantages of the system are enumerated and various problems that have been encountered are discussed.


Characterizing Delirium and Associated Risk Factors using the Cornell Assessment of Pediatric Delirium Score in Pediatric Burn Patients.
Delirium is a syndrome of acute brain dysfunction with disturbance in consciousness and cognition that is increasingly recognized in critically ill pediatric patients. The Cornell Assessment of Pediatric Delirium (CAPD) tool is used to detect delirium in children of all ages and developmental stages in various hospital settings. To date, the incidence of delirium in the pediatric burn population has been poorly defined. In order to describe the incidence as well as risk factors for delirium in this patient population, we retrospectively reviewed patients <18 years of age admitted to our American Burn Association-verified pediatric burn center from 3/2018-5/2021 who underwent delirium screening using the CAPD tool. Patient demographics, burn characteristics, hospitalization details, and date of first positive delirium screening were collected and χ2, Fisher's exact test, univariate, and multivariate analyses performed. Delirium was identified in 42 (10.8%) of 389 patients meeting inclusion criteria. Patients screening positive for delirium were older [4y (IQR: 2, 11) vs 2y (IQR: 1, 6), P<0.0005] and had larger total body surface area (TBSA) burns [21.63% (IQR: 9, 42) vs 3.5% (IQR: 1.75, 6), P<0.0001] than delirium-negative patients. Delirium-positive patients required a longer duration of mechanical ventilation [OR 4.23; 95% CI (1.16-15.39), P=0.0289] and had higher TBSA burns [OR 1.12; 95% CI (1.06-1.17), P<0.0001]. Delirium-positive patients had 1.6 day longer length-of-stay adjusted for TBSA burned [95% CI (0.81-2.41), P<0.0001]. Compared to delirium-negative patients, delirium-positive patients had a 5.4 day longer PICU admission [95% CI (2.93-10.3); P<0.0001]. Screening pediatric burn patients with risk factors known to be associated with delirium by using the CAPD score could improve delirium prevention and allow for early intervention.


Long-term outcomes in patients treated with tissue-sparing posterior cervical fusion to revise a 1-level pseudarthrosis following ACDF.
Observational Study BACKGROUND: Symptomatic pseudarthrosis is one long-term complication in patients treated with anterior discectomy and fusion (ACDF). When revising a pseudarthrosis, a surgeon must decide to intervene posteriorly and/or anteriorly. Open posterior cervical fusion (PCF) is attractive for high rates of arthrodesis, however this technique introduces risks of added complications resulting from extensive soft tissue dissection. The purpose of this study was to assess long-term outcomes in patients undergoing tissue-sparing PCF with facet instrumentation to treat a single level pseudarthrosis. Forty-five subjects were recruited from six participating sites. All subjects had a history of ACDF that was subsequently revised with tissue-sparing PCF to treat symptomatic pseudarthrosis at one level. Long-term radiographic assessments included flexion and extension X-ray and multi-planar CT. Subjects additionally completed a patient satisfaction questionnaire. Radiographs were assessed by investigators and an independent core imaging lab to diagnose implant integrity and arthrodesis at the revised levels. The revision procedure required a median 49 min to complete with an estimated blood loss of 10 cc. Subjects were discharged a median 1 day following treatment. There were no instances of hospital re-admission nor subsequent surgical interventions. Study follow-up assessments were performed a median 39 months from revision. Surgeons diagnosed complete fusion in 91 % of cases. The core imaging lab identified bridging bone across the revised segment in 80 % of cases. Range of motion was < 2° in 93 % of cases. Seventy-four percent of subjects reported being satisfied with their outcomes. This study summarizes long-term radiographic outcomes in a cohort of patients receiving tissue-sparing PCF for the treatment of pseudarthrosis. Assessed years after revision, patients achieved rates of arthrodesis similar to open PCF without the soft tissue dissection responsible for perioperative morbidity and long-term soft tissue pain.


Minimally invasive direct pars repair with cannulated screws and recombinant human bone morphogenetic protein: case series and review of the literature.
OBJECTIVE The objective of this study was to describe the use of a minimally invasive surgical treatment of lumbar spondylolysis in athletes by a fluoroscopically guided direct pars screw placement with recombinant human bone morphogenetic protein-2 (rhBMP-2) and to report on clinical and radiographic outcomes. METHODS A retrospective review was conducted of all patients treated surgically for lumbar spondylolysis via a minimally invasive direct pars repair with cannulated screws. Demographic information, clinical features of presentation, perioperative and intraoperative radiographic imaging, and postoperative data were collected. A 1-cm midline incision was performed for the placement of bilateral pars screws utilizing biplanar fluoroscopy, followed by placement of a fully threaded 4.0-mm-diameter titanium cannulated screw. A tubular table-mounted retractor was utilized for direct pars fracture visualization and debridement through a separate incision. The now-visualized pars fracture could then be decorticated, with care taken not to damage the titanium screw when using a high-speed drill. Local bone obtained from the curettage was then placed in the defect with 1.05 mg rhBMP-2 divided equally between the bilateral pars defects. RESULTS Nine patients were identified (mean age 17.7 ± 3.42 years, range 14-25 years; 6 male and 3 female). All patients had bilateral pars fractures of L-4 (n = 4) or L-5 (n = 5). The mean duration of preoperative symptoms was 17.22 ± 13.2 months (range 9-48 months). The mean operative duration was 189 ± 29 minutes (range 151-228 minutes). The mean intraoperative blood loss was 17.5 ± 10 ml (range 10-30 ml). Radiographic follow-up was available in all cases; the mean length of time from surgery to the most recent imaging study was 30.8 ± 23.3 months (range 3-59 months). The mean hospital length of stay was 1.13 ± 0.35 days (range 1-2 days). There were no intraoperative complications. CONCLUSIONS Lumbar spondylolysis treatment with a minimally invasive direct pars repair is a safe and technically feasible option that minimizes muscle and soft-tissue dissection, which may particularly benefit adolescent patients with a desire to return to a high level of physical activity.


Oxidant mechanisms in toxic acute renal failure.
Over the last decade, there has been accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown in both in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, the results of recent studies suggest that cytochrome P-450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Cyclosporine A has been shown to enhance the generation of hydrogen peroxide in vitro and lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.


Cellulose nanocrystal assisted trace silver nitrate to synthesize green silver nanocomposites with antibacterial activity.
Cellulose nanocrystals (CNCs) with silver nanoparticles (AgNPs) are used for applications ranging from chemical catalysis to environmental remediation, and generation of smart electronics and biological medicine such as antibacterial agents. To reduce the synthesis cost of AgNPs and environmental pollution, microwave-assisted generation of AgNPs on the CNC surface (AgNPs@CNC) has been found to be useful, because microwave reaction has the advantages of simple reaction conditions, short reaction time and high reaction efficiency. The silver ions (Ag+) could be added to the CNC suspension and placed in the microwave reactor for a few minutes to produce AgNPs. AgNP generation was affected by factors such as the concentrations of Ag+ and CNC, and the power of the microwave, as well as the time of reaction. In this study, we used trace amounts of AgNO3 to rapidly synthesize AgNPs using a green microwave-based method instead of Tollen's reagent, and the antibacterial activity of the T1 sample showed that only using 0.03 mM (∼0.01 wt%) AgNO3 to synthesize AgNPs@CNC could achieve good antibacterial properties.


Structural characterization of the lipids A of three Bordetella bronchiseptica strains: variability of fatty acid substitution.
The structures of lipids A isolated from the lipopolysaccharides (LPSs; endotoxins) of three different pathogenic Bordetella bronchiseptica strains were investigated by chemical composition and methylation analysis, gas chromatography-mass spectrometry, nuclear magnetic resonance, and plasma desorption mass spectrometry (PDMS). The analyses revealed that the LPSs contain the classical lipid A bisphosphorylated beta-(1-->6)-linked D-glucosamine disaccharide with hydroxytetradecanoic acid in amide linkages. Their structures differ from that of the lipid A of Bordetella pertussis endotoxin by the replacement of hydroxydecanoic acid on the C-3 position with hydroxydodecanoic acid or dodecanoic acid and the presence of variable amounts of hexadecanoic acid. The dodecanoic acid is the first nonhydroxylated fatty acid to be found directly linked to a lipid A glucosamine. The lipids A were heterogeneous and composed of one to three major and several minor molecular species. The fatty acids in ester linkage were localized by PDMS of chemically modified lipids A. B. pertussis lipids A are usually hypoacylated with respect to those of enterobacterial lipids A. However, one of the three B. bronchiseptica strains had a major hexaacylated molecular species. C-4 and C-6' hydroxyl groups of the backbone disaccharide were unsubstituted, the latter being the proposed attachment site of the polysaccharide. The structural variability seen in these three lipids A was unusual for a single species and may have consequences for the pathogenicity of this Bordetella species.


Pupillary response to cognitive workload during saccadic tasks in Parkinson's disease.
The relationship between cognitive workload and cognitive impairments in Parkinson's disease (PD) is currently not well known. This study compared cognitive workload during saccadic tasks between patients with PD and controls. Sixteen controls, 11 patients with no obvious cognitive impairment (PD-NCI) (MOCA score≥26), and 10 PD patients with cognitive impairment (PD-CI) (MOCA score<26) performed prosaccade and antisaccade tasks. Cognitive workload, extracted via pupil recording, and other eye metrics were compared between the three groups. PD-NCI patients exhibited greater cognitive workload than controls in the prosaccade task. PD-CI patients also showed more cognitive workload in the prosaccade task than PD-NCI patients and controls. No other differences in eye metrics were found between the three groups. Cognitive workload could be used to differentiate between different cognitive states in PD. The causal relationship between increased cognitive workload and cognitive decline in PD-NCI should be the focus of future studies.


How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia.
Acute myeloid leukemia (AML) is associated with poor outcomes, especially in older patients in whom the disease is most common. B-cell lymphoma 2 (BCL-2) is an antiapoptotic protein involved in the survival and maintenance of AML, and it is overexpressed in the leukemia stem cell population. Venetoclax is an oral BCL-2 protein inhibitor recently approved by the United States Food and Drug Administration (FDA) for use in combination with a hypomethylating agent (HMA) (azacitidine or decitabine) or low-dose cytarabine for front-line treatment of AML in older patients or those unfit for induction chemotherapy. Given that its mechanism of action is unique, it is not surprising that this widely effective therapy presents unique challenges, including but not limited to the rapidity of responses, the rate and depth of cytopenias, and issues related to drug-drug interactions. With the recent FDA approval and increasingly widespread use, we aim here to summarize, based on evidence and experience, emerging management strategies for the combination of HMAs and venetoclax in the treatment of AML.