Anxiety dissociates the adaptive functions of sensory and motor response enhancements to social threats.
Efficient detection and reaction to negative signals in the environment is essential for survival. In social situations, these signals are often ambiguous and can imply different levels of threat for the observer, thereby making their recognition susceptible to contextual cues - such as gaze direction when judging facial displays of emotion. However, the mechanisms underlying such contextual effects remain poorly understood. By computational modeling of human behavior and electrical brain activity, we demonstrate that gaze direction enhances the perceptual sensitivity to threat-signaling emotions - anger paired with direct gaze, and fear paired with averted gaze. This effect arises simultaneously in ventral face-selective and dorsal motor cortices at 200 ms following face presentation, dissociates across individuals as a function of anxiety, and does not reflect increased attention to threat-signaling emotions. These findings reveal that threat tunes neural processing in fast, selective, yet attention-independent fashion in sensory and motor systems, for different adaptive purposes.


Mechanistic characterization of the HDV genomic ribozyme: a mutant of the C41 motif provides insight into the positioning and thermodynamic linkage of metal ions and protons.
Binding of two Mg2+ and two H+ ions influences the self-cleavage activity of the genomic HDV ribozyme. The positioning of these four ligands and their thermodynamic linkage are not fully resolved. Protonated C41 engages in a base triple, whereas protonated C75 has been implicated as an acid-base catalyst in bond cleavage. Prior studies led to the identification of one structural inner-sphere ion and one catalytic outer-sphere ion. In the present study, the contributions of the C41 base triple to the metal ion- and pH-dependence of the reaction are examined. Experiments were conducted on a CG to UA double mutant (DM), which changes the base triple to one involving an unprotonated C41. Below pH 6, the DM has a steeper dependence on pH than the wild-type (WT), consistent with a single protonation misfolding the core; this conclusion is also supported by thermal denaturation studies. Between pH 6 and 8, the WT and DM display nearly identical catalytic metal ion and H+ binding profiles. In contrast, over the same pH range, the WT and DM have distinct structural ion binding profiles; for the WT, binding is favored at lower pH, whereas the DM shows no pH dependence. These data localize the structural ion to the vicinity of the C41 motif. An overall model is presented that accommodates binding affinity, coupling, and positioning of the two metal ions and the two protons within the ribozyme. The data suggest that a protonated base triple allows the WT ribozyme to maintain appreciable activity at acidic pH, which could play an important role in the life cycle of the virus.


Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens.
Recent evidence suggests the intriguing possibility that midbrain dopaminergic (DAergic) neurons may use fast glutamatergic transmission to communicate with their postsynaptic targets. Because of technical limitations, direct demonstration of the existence of this signaling mechanism has been limited to experiments using cell culture preparations that often alter neuronal function including neurotransmitter phenotype. Consequently, it remains uncertain whether glutamatergic signaling between DAergic neurons and their postsynaptic targets exists under physiological conditions. Here, using an optogenetic approach, we provide the first conclusive demonstration that mesolimbic DAergic neurons in mice release glutamate and elicit excitatory postsynaptic responses in projection neurons of the nucleus accumbens. In addition, we describe the properties of the postsynaptic glutamatergic responses of these neurons during experimentally evoked burst firing of DAergic axons that reproduce the reward-related phasic population activity of the mesolimbic projection. These observations indicate that, in addition to DAergic mechanisms, mesolimbic reward signaling may involve glutamatergic transmission.


Challenges and strategies of the Genetics Home Reference.
This paper focuses on the first two years of operation of Genetics Home Reference (GHR), a Web-based resource <http://www.ghr.nlm.nih.gov> for the general public that helps to explain the health implications of findings from the Human Genome Project. Key challenges of Web-based consumer health communication encountered in the growth and maintenance of GHR are discussed: prioritizing topics for GHR, streamlining the development process while keeping genetic information accurate, and designing a system that helps consumers navigate complex genetic relationships. Various strategies are used to address these challenges. Tying content development to topics of national priority and addressing topics requested by users makes the site increasingly important for both consumers and health professionals. Informatics methods are essential for quality control, particularly for genetic information that changes frequently. Indexing and hierarchical browsing features help to facilitate navigation. GHR is a credible, dynamic Website that uses lay language to explain the effects of genetic variation on human health. Informatics strategies are key to effective management of a large and expanding body of genetics information. Feedback from formal and informal sources indicates increasing usage and favorable acceptance of GHR.


Sleep assessment in a population-based study of chronic fatigue syndrome.
Chronic fatigue syndrome (CFS) is a disabling condition that affects approximately 800,000 adult Americans. The pathophysiology remains unknown and there are no diagnostic markers or characteristic physical signs or laboratory abnormalities. Most CFS patients complain of unrefreshing sleep and many of the postulated etiologies of CFS affect sleep. Conversely, many sleep disorders present similarly to CFS. Few studies characterizing sleep in unselected CFS subjects have been published and none have been performed in cases identified from population-based studies. The study included 339 subjects (mean age 45.8 years, 77% female, 94.1% white) identified through telephone screen in a previously described population-based study of CFS in Wichita, Kansas. They completed questionnaires to assess fatigue and wellness and 2 self-administered sleep questionnaires. Scores for five of the six sleep factors (insomnia/hypersomnia, non-restorative sleep, excessive daytime somnolence, sleep apnea, and restlessness) in the Centre for Sleep and Chronobiology's Sleep Assessment Questionnaire (SAQ) were dichotomized based on threshold. The Epworth Sleepiness Scale score was used as a continuous variable. 81.4% of subjects had an abnormality in at least one SAQ sleep factor. Subjects with sleep factor abnormalities had significantly lower wellness scores but statistically unchanged fatigue severity scores compared to those without SAQ abnormality. CFS subjects had significantly increased risk of abnormal scores in the non-restorative (adjusted odds ratio [OR] = 28.1; 95% confidence interval [CI]= 7.4-107.0) and restlessness (OR = 16.0; 95% CI = 4.2-61.6) SAQ factors compared to non-fatigued, but not for factors of sleep apnea or excessive daytime somnolence. This is consistent with studies finding that, while fatigued, CFS subjects are not sleepy. A strong correlation (0.78) of Epworth score was found only for the excessive daytime somnolence factor. SAQ factors describe sleep abnormalities associated with CFS and provide more information than the Epworth score. Validation of these promising results will require formal polysomnographic sleep studies.


Antigen-specific B-cell unresponsiveness induced by chronic Mycobacterium avium subsp. paratuberculosis infection of cattle.
Mycobacterium avium subsp. paratuberculosis infection of cattle results in a chronic granulomatous enteritis. Clinical disease (i.e., cachexia, diarrhea, and high fecal bacterial counts) is preceded by a lengthy subclinical stage of disease. The immunologic mechanisms associated with the progression of infected cattle from subclinical to clinical disease are unclear. In this study, a cell proliferation assay was used in combination with flow cytometry to compare peripheral blood lymphocyte responses of cattle with subclinical paratuberculosis to responses of cattle with clinical paratuberculosis. B cells from cattle with subclinical disease proliferated vigorously upon stimulation with M. avium subsp. paratuberculosis antigen, with up to 12.4% of the total B cells responding. However, B cells from cattle with clinical disease did not proliferate upon antigen stimulation despite good proliferation in response to concanavalin A stimulation. In addition, these animals had high percentages of peripheral blood B cells. B cells from noninfected animals did not proliferate upon M. avium subsp. paratuberculosis antigen stimulation. Thus, it appears that B-cell proliferation is a sensitive indicator of subclinical Johne's disease. Furthermore, the immunologic mechanisms responsible for the antigen-specific unresponsiveness of peripheral blood B cells may be significant in the eventual progression from subclinical to clinical Johne's disease in cattle.


Drug repurposing screens identify Tubercidin as a potent antiviral agent against porcine nidovirus infections.
The emergence of new coronaviruses poses a significant threat to animal husbandry and human health. Porcine epidemic diarrhea virus (PEDV) is considered a re-emerging porcine enteric coronavirus, which causes fatal watery diarrhea in piglets. Currently, there are no effective drugs to combat PEDV. Drug repurposing screens have emerged as an attractive strategy to accelerate antiviral drug discovery and development. Here, we screened 206 natural products for antiviral activity using live PEDV infection in Vero cells and identified ten candidate antiviral agents. Among them, Tubercidin, a nucleoside analog derived from Streptomyces tubercidicus, showed promising antiviral activity against PEDV infection. Furthermore, we demonstrated that Tubercidin exhibited significant antiviral activity against both classical and variant PEDV. Time of addition assay showed that Tubercidin displayed a significant inhibitory effect on viral post-entry events but not during other periods. Molecular docking analysis indicated that Tubercidin had better docking efficiency and formed hydrophobic interactions with the active pocket of RNA-dependent RNA polymerase (RdRp) of PEDV and other nidoviruses. Additionally, Tubercidin can effectively suppress other porcine nidoviruses, such as SADS-CoV and PRRSV, demonstrating its broad-spectrum antiviral properties. In summary, our findings provide valuable evidence for the antiviral activity of Tubercidin and offer insights into the development of new strategies for the prevention and treatment of coronavirus infections.


Are large fracture trials possible?
Reliable clinical orthopaedic trauma research is important and necessary to guide orthopaedic surgeons and their patients to best practices and expected outcomes. Currently, most fracture care is guided by suboptimal clinical research. To address this need, large fracture trials are necessary to deliver Level I evidence and direct the orthopaedic trauma surgeon in the best treatments. Although trials of this nature have been rare, they have been completed successfully. Although each fracture trial comes with its own set of obstacles, the trial can be successful with proper expertise, study planning, and study design. The purpose of this article is to present the rationale, methodology, and implementation strategies to successfully complete a large fracture trial.


Dietary Sources and Bioactivities of Melatonin.
Insomnia is a serious worldwide health threat, affecting nearly one third of the general population. Melatonin has been reported to improve sleep efficiency and it was found that eating melatonin-rich foods could assist sleep. During the last decades, melatonin has been widely identified and qualified in various foods from fungi to animals and plants. Eggs and fish are higher melatonin-containing food groups in animal foods, whereas in plant foods, nuts are with the highest content of melatonin. Some kinds of mushrooms, cereals and germinated legumes or seeds are also good dietary sources of melatonin. It has been proved that the melatonin concentration in human serum could significantly increase after the consumption of melatonin containing food. Furthermore, studies show that melatonin exhibits many bioactivities, such as antioxidant activity, anti-inflammatory characteristics, boosting immunity, anticancer activity, cardiovascular protection, anti-diabetic, anti-obese, neuroprotective and anti-aging activity. This review summaries the dietary sources and bioactivities of melatonin, with special attention paid to the mechanisms of action.


NCCN Clinical Practice Guidelines in Oncology: myelodysplastic syndromes.
These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.(116,119,120,128,129) Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials.


Integrated proteomic platforms for the comparative characterization of medulloblastoma and pilocytic astrocytoma pediatric brain tumors: a preliminary study.
A top-down/bottom-up integrated proteomic approach based on LC-MS and 2-DE analysis was applied for comparative characterization of medulloblastoma and pilocytic astrocytoma posterior cranial fossa pediatric brain tumor tissues. Although rare, primary brain tumors are the most frequent solid tumors in the pediatric age. Among them the medulloblastoma is the prevalent malignant tumor in childhood while pilocytic astrocytoma is the most common, rarely showing a malignant progression. Due to the limited availability of this kind of sample, the study was applied to pooled tumor tissues for a preliminary investigation. The results showed different proteomic profiles of the two tumors and evidenced interesting differential expression of several proteins and peptides. Top-down proteomics of acid-soluble fractions of brain tumor homogenates ascribed a potential biomarker role of malignancy to β- and α-thymosins and their truncated proteoforms and to C-terminal truncated (des-GG) ubiquitin, resulting exclusively detected or over-expressed in the highly malignant medulloblastoma. The bottom-up proteomics of the acid-soluble fraction identified several proteins, some of them in common with 2-DE analysis of acid-insoluble pellets. Peroxiredoxin-1, peptidyl-prolyl cis-trans isomerase A, triosephosphate isomerase, pyruvate kinase PKM, tubulin beta and alpha chains, heat shock protein HSP-90-beta and different histones characterized the medulloblastoma while the Ig kappa chain C region, serotransferrin, tubulin beta 2A chain and vimentin the pilocytic astrocytoma. The two proteomic strategies, with their pros and cons, well complemented each other in characterizing the proteome of brain tumor tissues and in disclosing potential disease biomarkers to be validated in a future study on individual samples of both tumor histotypes.


Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide.
Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic alternatives. Dermaseptin-B2, a natural multifunctional antimicrobial peptide isolated from Amazonian frog skin, has been reported to possess antitumor activity. To improve its pharmacological properties and to decrease its peripheral toxicity and lethality we developed a hormonotoxin molecule composed of dermaseptin-B2 combined with d-Lys6-LHRH to target the LHRH receptor. This hormonotoxin has a significant antiproliferative effect on the PC3 tumor cell line, with an IC50 value close to that of dermaseptin-B2. Its antitumor activity has been confirmed in vivo in a xenograft mouse model with PC3 tumors and appears to be better tolerated than dermaseptin-B2. Biophysical experiments showed that the addition of LHRH to dermaseptin-B2 did not alter its secondary structure or biological activity. The combination of different experimental approaches indicated that this hormonotoxin induces cell death by an apoptotic mechanism instead of necrosis, as observed for dermaseptin-B2. These results could explain the lower toxicity observed for this hormonotoxin compared to dermaseptin-B2 and may represent a promising targeting approach for cancer therapy.


The histone modifications governing TFF1 transcription mediated by estrogen receptor.
Transcription regulation by histone modifications is a major contributing factor to the structural and functional diversity in biology. These modifications are encrypted as histone codes or histone languages and function to establish and maintain heritable epigenetic codes that define the identity and the fate of the cell. Despite recent advances revealing numerous histone modifications associated with transcription regulation, how such modifications dictate the process of transcription is not fully understood. Here we describe spatial and temporal analyses of the histone modifications that are introduced during estrogen receptor α (ERα)-activated transcription. We demonstrated that aborting RNA polymerase II caused a disruption of the histone modifications that are associated with transcription elongation but had a minimal effect on modifications deposited during transcription initiation. We also found that the histone H3S10 phosphorylation mark is catalyzed by mitogen- and stress-activated protein kinase 1 (MSK1) and is recognized by a 14-3-3ζ/14-3-3ε heterodimer through its interaction with H3K4 trimethyltransferase SMYD3 and the p52 subunit of TFIIH. We showed that H3S10 phosphorylation is a prerequisite for H3K4 trimethylation. In addition, we demonstrated that SET8/PR-Set7/KMT5A is required for ERα-regulated transcription and its catalyzed H4K20 monomethylation is implicated in both transcription initiation and elongation. Our experiments provide a relatively comprehensive analysis of histone modifications associated with ERα-regulated transcription and define the biological meaning of several key components of the histone code that governs ERα-regulated transcription.


Llama single domain antibodies specific for the 7 botulinum neurotoxin serotypes as heptaplex immunoreagents.
There are currently 7 known serotypes of botulinum neurotoxin (BoNT) classified upon non-cross reactivity of neutralizing immunoglobulins. Non-neutralizing immunoglobulins, however, can exhibit cross-reactivities between 2 or more serotypes, particularly mosaic forms, which can hamper the development of highly specific immunoassays, especially if based on polyclonal antisera. Here we employ facile recombinant antibody technology to subtractively select ligands to each of the 7 BoNT serotypes, resulting in populations with very high specificity for their intended serotype. A single llama was immunized with a cocktail of 7 BoNT toxoids to generate a phage display library of single domain antibodies (sdAb, VHH or nanobodies) which were selected on live toxins. Resulting sdAb were capable of detecting both toxin and toxin complex with the best combinations able to detect 100s-10s of pg per 50 microL sample in a liquid bead array. The most sensitive sdAb were combined in a heptaplex assay to identify each of the BoNT serotypes in buffer and milk and to a lesser extent in carrot juice, orange juice and cola. Several anti-A(1) sdAb recognized A2 complex, showing that subtype cross-reactivity within a serotype was evident. Many of our sdAb could act as both captor and tracer for several toxin and toxin complexes suggesting sdAb can be used as architectural probes to indicate BoNT oligomerisation. Six of 14 anti-A clones exhibited inhibition of SNAP-25 cleavage in the neuro-2A assay indicating some sdAb had toxin neutralizing capabilities. Many sdAb were also shown to be refoldable after exposure to high temperatures in contrast to polyclonal antisera, as monitored by circular dichroism. Our panel of molecularly flexible antibodies should not only serve as a good starting point for ruggedizing assays and inhibitors, but enable the intricate architectures of BoNT toxins and complexes to be probed more extensively.


FOXSI-2 Solar Microflares. II. Hard X-ray Imaging Spectroscopy and Flare Energetics.
We study the nature of energy release and transfer for two sub-A class solar microflares observed during the second Focusing Optics X-ray Solar Imager (FOXSI-2) sounding rocket flight on 2014 December 11. FOXSI is the first solar-dedicated instrument to utilize focusing optics to image the Sun in the hard X-ray (HXR) regime, sensitive to energies of 4-20 keV. Through spectral analysis of the microflares using an optically thin isothermal plasma model, we find evidence for plasma heated to ~10 MK and emission measures down to ~1044 cm-3. Though nonthermal emission was not detected for the FOXSI-2 microflares, a study of the parameter space for possible hidden nonthermal components shows that there could be enough energy in nonthermal electrons to account for the thermal energy in microflare 1, indicating that this flare is plausibly consistent with the standard thick-target model. With a solar-optimized design and improvements in HXR focusing optics, FOXSI-2 offers approximately five times greater sensitivity at 10 keV than the Nuclear Spectroscopic Telescope Array for typical microflare observations and allows for the first direct imaging spectroscopy of solar HXRs with an angular resolution at scales relevant for microflares. Harnessing these improved capabilities to study small-scale events, we find evidence for spatial and temporal complexity during a sub-A class flare. This analysis, combined with contemporaneous observations by the Atmospheric Imaging Assembly on board the Solar Dynamics Observatory, indicates that these microflares are more similar to large flares in their evolution than to the single burst of energy expected for a nanoflare.


Vocal Identity Recognition in Autism Spectrum Disorder.
Voices can convey information about a speaker. When forming an abstract representation of a speaker, it is important to extract relevant features from acoustic signals that are invariant to the modulation of these signals. This study investigated the way in which individuals with autism spectrum disorder (ASD) recognize and memorize vocal identity. The ASD group and control group performed similarly in a task when asked to choose the name of the newly-learned speaker based on his or her voice, and the ASD group outperformed the control group in a subsequent familiarity test when asked to discriminate the previously trained voices and untrained voices. These findings suggest that individuals with ASD recognized and memorized voices as well as the neurotypical individuals did, but they categorized voices in a different way: individuals with ASD categorized voices quantitatively based on the exact acoustic features, while neurotypical individuals categorized voices qualitatively based on the acoustic patterns correlated to the speakers' physical and mental properties.


beta-lactam antibiotic production by Streptomyces clavuligerus mutants impaired in regulation of aspartokinase.
This work describes isolation and characterization of Streptomyces clavuligerus mutants resistant to the lysine analogue S-(2-aminoethyl)-L-cysteine (AEC). The mutation to AEC resistance was shown to affect the feedback regulation of aspartokinase; 70% of the mutants isolated had aspartokinase activity insensitive to concerted feedback inhibition by lysine plus threonine. Among these mutants, 70% (about 50% of the total AEC-resistant strains isolated) showed significant overproduction of beta-lactam antibiotics.


Cerebral sinovenous thrombosis after closed head injury.
Cerebral sinovenous thrombosis (CSVT) after closed head injury is an uncommon but potentially serious complication. The aim of this study was to determine whether diffusion weighted imaging (DWI) provide predictive information regarding prognosis. We retrospectively reviewed a series of 11 patients with CSVT after closed head injury. Each patient underwent computed tomography and magnetic resonance imaging within 24 hours of onset of symptoms, including DWI, magnetic resonance venography, and conventional sequences. Apparent diffusion coefficient (ADC) values were measured in seven regions of interest in 7 of 11 patients using DWI. Follow-up imaging and clinical outcome were assessed 6 months or later after initial presentation. The most affected sinus was the posterior portion of the superior sagittal sinus. There was a mean time interval of 4.1 days between subsequent venous stroke and the initial insult. Brain edema improved in 6 of 11 patients on follow-up imaging. Six of 11 patients recovered successfully, although high or mixed DWI intensity associated with moderately decreased ADC (0.53-0.57 x 10(-3) mm2/s). Two other patients with hematomas developed venous infarction, despite mixed DWI with heterogeneous ADC value (0.55-1.11 x 10(-3) mm2/s). The other three patients, with high DWI and strongly decreased ADC values (0.26-0.27 x 10(-3) mm2/s), developed severe brain atrophy after superior sagittal sinus thrombosis. The prospective cutoff point of ADC value may be higher in CSVT after head injury with traumatic hematoma. The territory of venous infarction was found to be larger in infants after treatment failure. In infants, CSVT can demonstrate initially cytotoxic brain edema, which is reversible with anticoagulation therapy.


Bacterial Cellulose-Based Bandages with Integrated Antibacteria and Electrical Stimulation for Advanced Wound Management.
Bandages for daily wounds are the most common medical supplies, but there are still ingrained defects in their appearance, comfort, functions, as well as environmental pollution. Here, novel bandages based on bacterial cellulose (BC) membrane for wound monitoring and advanced wound management are developed. The BC membrane is combined with silver nanowires (AgNWs) by using vacuum filtration method to achieve transparent, ultrathin (∼7 μm), breathable (389.98-547.79 g m-2 d-1 ), and sandwich-structured BC/AgNWs bandages with superior mechanical properties (108.45-202.35 MPa), antibacterial activities against E. coli and S. aureus, biocompatibility, and conductivity (9.8 × 103 -2.0 × 105 S m-1 ). Significantly, the BC/AgNWs bandage is used in the electrical stimulation (direct current, 600 microamperes for 1 h every other day) treatment of full-thickness skin defect in rats, which obviously promotes wound healing by increasing the secretion of vascular endothelial growth factor. The BC bandage is used for monitoring wounds and achieve a high accuracy of 94.7% in classifying wound healing stages of hemostasis, inflammation, proliferation, and remodeling, by using a convolutional neural network. The outcomes of this study not only provide two BC-based bandages as multifunctional wound management, but also demonstrate a new strategy for the development of the next generation of smart bandage. This article is protected by copyright. All rights reserved.


Clinical and molecular analysis of nine fetal cases with clinically significant variants causing nemaline myopathy.
To present the prenatal features and postnatal outcomes of pregnancies with fetal nemaline myopathy (NM). This was a retrospective study of nine cases with NM diagnosed by prenatal or postnatal clinical features and confirmed by genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, exome sequencing (ES) results, and pregnancy outcomes. All of the nine cases were detected to have NM-causing variants, involving NEB gene in 2 cases, ACTA1 in 3 cases, KLHL40 in 3 cases, and TPM2 in 1 case. Almost all (8/9) had normal first-trimester ultrasound scans except one who had an increased nuchal translucency. Seven (7/9) cases had second-trimester abnormal ultrasounds with fetal akinesia and/or extremity anomalies. Two (2/9) had only third-trimester abnormal ultrasounds with fetal akinesia and polyhydramnios, with one combined with fetal growth restriction. Four pregnancies with a positive prenatal ES were terminated, while five having not receiving prenatal ES continued to term. Only one infant survived 1 year old, and four passed away within 12 months. Prenatal ultrasound can detect clues that lead to the diagnosis of NM, such as reduced or absent fetal movements, polyhydramnios and extremity anomalies.


Resin-bonded fixed partial dentures: a recall study.
A clinical recall program was initiated at the University of Minnesota to evaluate the longevity and factors affecting longevity of resin-bonded fixed partial dentures (FPDs). Of the 49 resin-bonded FPDs evaluated in the clinic, 43 were acid-etched metal, resin-bonded FPDs, four were combinations of resin-bonded and conventional FPDs, and two were composite resin pontics. None of the combination FPDs and one of the two composite resin pontics were judged as failed at the examination. Of the 43 acid-etched metal resin-bonded FPDs, 15 were found to be debonded (failure rate = 34.9%). The average length of service for the 43 FPDs was 47.3 months. The average time of placement to debondment was 33 months for the 15 debonded FPDs. The failure rate for maxillary FPDs and FPDs with two retainers were significantly lower than the failure rate for mandibular FPDs and FPDs with more than two retainers (p greater than 0.05). The clinical significance of the present study was discussed.


Renal pathology at autopsy in patients who died after hematopoietic stem cell transplantation.
Acute and chronic renal dysfunction are common after hematopoietic stem cell transplantation (HSCT). Although the pathology of chronic HSCT nephropathy is well described, the histologic changes that accompany acute renal dysfunction after HSCT are less well known because renal biopsies are rarely undertaken in the peritransplantation period. Archival renal tissue from consecutive HSCT recipients who died and underwent autopsy at a single center during an 8-year period was studied. Abnormalities of renal pathology were described, and associations of histologic abnormalities with clinical events were systemically studied. Abnormalities of renal histology were common among the 26 patients in this study. The 3 most common histologic abnormalities were glomerular sclerosis (19/26; 73%), tubular epithelial atypia (19/26; 73%), and tubular calcification (18/26; 69%). Tubulitis (16/24; 67%) and interstitial fibrosis (16/26; 62%) were also frequently observed. Clinical veno-occlusive disease was not associated with histologic evidence of thrombotic microangiopathy in the kidney at autopsy. Also, clinical graft-versus-host disease was not associated with renal tubulitis. Unexpectedly, the proportion of patients with tubular atrophy (54%) or interstitial fibrosis (62%) was high, considering the young age of the patients at transplantation and their normal pretransplantation creatinine clearance. Well-recognized histologic abnormalities are common in the kidneys of patients who die after HSCT. Although we did not demonstrate associations of these histologic changes with clinical variables before death, larger studies with prospectively collected renal tissue are warranted.


Macro and microscopic examination of the ruptured surfaces of anterior cruciate ligaments of rabbits.
In a study combining tissue mechanics and fracture morphology for the first time, we examined the ruptured surfaces of anterior cruciate ligaments of rabbits and related their appearance to the initial loading conditions. Sixteen specimens were stretched to failure at rates of displacement of 10 and 500 mm/min. We used video images to study the changes which occurred during the fracture process and SEM to examine the appearance of the ruptured surfaces. The surfaces of ligaments tested at 10 mm/min had more pulled-out collagen fibres and the fibres had more pronounced waviness compared with those tested at 500 mm/min. We have shown that the macroscopic appearance of ruptured ligaments can be related to their microscopic appearance and that it is possible to deduce whether failure was by gradual tearing of the fibres or catastrophic failure.


Simultaneous recursive displacement estimation and restoration of noisy-blurred image sequences.
We develop a recursive model-based maximum a posteriori (MAP) estimator that simultaneously estimates the displacement vector field (DVF) and the intensity field from a noisy-blurred image sequence. Current motion-compensated spatio-temporal noise filters treat the estimation of the DVF as a preprocessing step. Generally, no attempt is made to verify the accuracy of these estimates prior to their use in the filter. By simultaneously estimating these two fields, we establish a link between the two estimators. It is through this link that the DVF estimate and its corresponding accuracy information are shared with the other intensity estimator, and vice versa. To model the DVF and the intensity field, we use coupled Gauss-Markov (CGM) models. A CGM model consists of two levels: an upper level, which is made up of several submodels with various characteristics, and a lower level or line field, which governs the transitions between the submodels. The CGM models are well suited for estimating the displacement and intensity fields since the resulting estimates preserve the boundaries between the stationary areas present in both fields. Detailed line fields are proposed for the modeling of these boundaries, which also take into account the correlations that exist between these two fields. A Kalman-type estimator results, followed by a decision criterion for choosing the appropriate set of line fields. Several experiments using noisy and noisy-blurred image sequences demonstrate the superior performance of the proposed algorithm with respect to prediction error and mean-square error.


Alcohol, tobacco, and mammographic density: a population-based study.
Mammographic density (MD), or the proportion of the breast with respect to its overall area that is composed of dense tissue, is a strong risk factor for breast cancer. Studies support a positive association of mammographic density and alcohol drinking. This was a cross-sectional multicenter study based on 3584 women, aged 45-68 years, recruited from seven screening centers within the Spanish breast cancer screening program network. The association between MD, alcohol consumption and tobacco use was evaluated by using ordinal logistic models with random center-specific intercepts. We found a weak positive association between current alcohol intake and higher MD, with current alcohol consumption increasing the odds of high MD by 13% (OR = 1.13; 95% CI 0.99-1.28) and high daily grams of alcohol being positively associated with increased MD (P for trend = 0.045). There were no statistically significant differences in MD between smokers and non-smokers. Nevertheless, increased number of daily cigarettes and increased number of accumulated lifetime cigarettes were negatively associated with high MD (P for trend 0.017 and 0.021). The effect of alcohol on MD was modified by menopausal status and tobacco smoking: whereas, alcohol consumption and daily grams of alcohol were positively associated with higher MD in postmenopausal women and in women who were not currently smoking, alcohol consumption had no effect on MD in premenopausal women and current smokers. Our results support an association between recent alcohol consumption and high MD, characterized by a modest increase in risk at low levels of current consumption and a decrease in risk among heavier drinkers. Our study also shows how the effects of alcohol in the breast can be modified by other factors, such as smoking.


Stress, burnout and doctors' attitudes to work are determined by personality and learning style: a twelve year longitudinal study of UK medical graduates.
The study investigated the extent to which approaches to work, workplace climate, stress, burnout and satisfaction with medicine as a career in doctors aged about thirty are predicted by measures of learning style and personality measured five to twelve years earlier when the doctors were applicants to medical school or were medical students. Prospective study of a large cohort of doctors. The participants were first studied when they applied to any of five UK medical schools in 1990. Postal questionnaires were sent to all doctors with a traceable address on the current or a previous Medical Register. The current questionnaire included measures of Approaches to Work, Workplace Climate, stress (General Health Questionnaire), burnout (Maslach Burnout Inventory), and satisfaction with medicine as a career and personality (Big Five). Previous questionnaires had included measures of learning style (Study Process Questionnaire) and personality. Doctors' approaches to work were predicted by study habits and learning styles, both at application to medical school and in the final year. How doctors perceive their workplace climate and workload is predicted both by approaches to work and by measures of stress, burnout and satisfaction with medicine. These characteristics are partially predicted by trait measures of personality taken five years earlier. Stress, burnout and satisfaction also correlate with trait measures of personality taken five years earlier. Differences in approach to work and perceived workplace climate seem mainly to reflect stable, long-term individual differences in doctors themselves, reflected in measures of personality and learning style.


Kidney shape statistical analysis: associations with disease and anthropometric factors.
Organ measurements derived from magnetic resonance imaging (MRI) have the potential to enhance our understanding of the precise phenotypic variations underlying many clinical conditions. We applied morphometric methods to study the kidneys by constructing surface meshes from kidney segmentations from abdominal MRI data in 38,868 participants in the UK Biobank. Using mesh-based analysis techniques based on statistical parametric maps (SPMs), we were able to detect variations in specific regions of the kidney and associate those with anthropometric traits as well as disease states including chronic kidney disease (CKD), type-2 diabetes (T2D), and hypertension. Statistical shape analysis (SSA) based on principal component analysis was also used within the disease population and the principal component scores were used to assess the risk of disease events. We show that CKD, T2D and hypertension were associated with kidney shape. Age was associated with kidney shape consistently across disease groups. Body mass index (BMI) and waist-to-hip ratio (WHR) were also associated with kidney shape for the participants with T2D. Using SSA, we were able to capture kidney shape variations, relative to size, angle, straightness, width, length, and thickness of the kidneys, within disease populations. We identified significant associations between both left and right kidney length and width and incidence of CKD (hazard ratio (HR): 0.74, 95% CI: 0.61-0.90, p < 0.05, in the left kidney; HR: 0.76, 95% CI: 0.63-0.92, p < 0.05, in the right kidney) and hypertension (HR: 1.16, 95% CI: 1.03-1.29, p < 0.05, in the left kidney; HR: 0.87, 95% CI: 0.79-0.96, p < 0.05, in the right kidney). The results suggest that shape-based analysis of the kidneys can augment studies aiming at the better categorisation of pathologies associated with chronic kidney conditions.


Relationship between infiltrating cells and adhesion molecules in the nasal mucosa of patients with allergic rhinitis.
Antigen-induced changes of cell adhesion molecules and their relationships to infiltrating cells were investigated immunohistochemically in nasal mucosa of perennial allergic rhinitis patients. An increased expression of E-selectin and VCAM-1 was noted on the vascular endothelium of the nasal mucosa 15-25 h after the topical antigen challenge. Although there was no increased expression of ICAM-1, we noted a positive correlation between the expression of E-selectin and ICAM-1. The expression of E-selectin and VCAM-1 as well as ICAM-1 was revealed to be correlated with the number of EG2-positive cells and CD4-positive cells, but not with elastase-positive cells. These findings suggest that all these adhesion molecules play a role in the topical influxes of eosinophils and CD4-positive cells in allergic nasal mucosa.


The Roscommon Family Study. IV. Affective illness, anxiety disorders, and alcoholism in relatives.
This report seeks to evaluate the specificity of the familial liability to schizophrenia by examining in the relatives of the various proband groups the risk for affective illness (AI), anxiety disorders, and alcoholism. A case-controlled epidemiologic family study using DSM-III-R criteria. Three hundred eighty-four index probands from a psychiatric case register, 150 unselected control probands from an electoral register and 2043 of their living and traceable relatives, of whom 1753 were personally interviewed. In personally interviewed relatives of schizophrenic probands, the lifetime risk for all AI (24.9% +/- 3.8%) or just bipolar AI (1.2% +/- 0.7%) was very similar to that found in interviewed relatives of controls (22.8% +/- 4.0% and 1.4% +/- 0.7%, respectively). However, the risk for all AI (49.7% +/- 12.9%) or bipolar AI (4.8% +/- 3.2%) was substantially increased in relatives of schizoaffective probands. A substantially higher proportion of relatives of schizophrenic vs control probands who had AI demonstrated psychotic--and specially mood-incongruent psychotic--symptoms when affectively ill. Neither the risk for anxiety disorders nor that for alcoholism was increased in relatives of schizophrenic vs control probands. The familial liability to schizophrenia possesses some specificity and does not substantially increase the risk to AI, anxiety disorders, or alcoholism. Even when narrowly defined, schizoaffective disorder has a substantial familial link to classic AI. The familial liability to schizophrenia predisposes to psychosis, and especially mood-incongruent psychosis, when affectively ill. Finally, these results do not support the hypothesis that, from a familial perspective, schizophrenia and AI are on a single etiologic continuum.


Inhibition of ion conductances by osmotic shrinkage of Madin-Darby canine kidney cells.
Osmotic swelling of Madin-Darby canine kidney (MDCK) cells enhances the ion conductances of the cell membrane, which allows release of cellular ions and subsequent regulatory cell volume decrease. The present study has been performed to test whether cell shrinkage similarly affects the ion conductances of MDCK cell membranes. Increase of extracellular osmolarity by addition of 50 mM NaCl or 100 mM mannitol leads within 3 min to a hyperpolarization of the cell membrane, a marked increase of cell membrane resistance [by 223 +/- 38% (n = 8) and 228 +/- 21% (n = 5), respectively], as well as a moderate increase of the K+ selectivity of the cell membrane (by 37 +/- 13%, n = 9). Thus exposure to hypertonic extracellular fluid decreases the cell membrane conductances including the K+ conductance. Cell volume measurements reveal a regulatory cell volume increase, which is sensitive to both furosemide and dimethylamiloride. Extracellular ATP (10 microM), which activates calcium-sensitive K+ channels, hyperpolarizes the cell membrane close to the K+ equilibrium potential. The respective values are -69.9 +/- 3.1 mV (n = 9) in isotonic fluid, -79.4 +/- 1.8 mV (n = 9) within 3 min, and -76.4 +/- 1.8 mV (n = 7) within 16-h exposure to hypertonic extracellular fluid. This observation points to a sustained increase of intracellular K+ activity after exposure to hypertonic extracellular fluid.


Activities of some enzymes of pyrimidine and DNA synthesis in a rat transplantable hepatoma and human primary hepatomas, in cell lines derived from these tissues, and in human fetal liver.
Activites of the enzymes DNA polymerase, thymidine kinase, thymidylate kinase, thymidylate synthase, and deoxycytidylate deaminase have been measured in rat and human normal and neoplastic liver, in human fetal liver, and in cell lines derived from human hepatomas and rat transplantable hepatomas. The activities of these enzymes were increased in rat transplantable hepatomas, relative to rat normal or host liver, to a degree corresponding to the rapid growth rate of these tumors. With the exception of thymidine kinase, which did not change, the activities of these enzymes increased in human hepatomas relative to the corresponding host liver (apparently normal liver tissue from the same patient) and to human normal liver. The increases in enzyme activity observed in human hepatomas were small in comparison with those found in the rapidly growing rat hepatomas. The activities of deoxycytidylate deaminase in both human and rat liver tissues were 2 to 3 orders of magnitude higher than those of the other enzymes assayed. Activities of the enzymes of DNA synthesis in a slow-growing cell line derived from a human hepatoma were similar to those in human hepatoma tissues. In the case of rapidly growing cell lines derived from rat and human hepatomas, enzyme activities were higher than those in the corresponding tissues.


Using the Mus musculus hybrid zone to assess covariation and genetic architecture of limb bone lengths.
Two subspecies of the house mouse, Mus musculus domesticus and Mus musculus musculus, meet in a narrow contact zone across Europe. Mice in the hybrid zone are highly admixed, representing the full range of mixed ancestry from the two subspecies. Given the distinct morphologies of these subspecies, these natural hybrids can be used for genomewide association mapping at sufficiently high resolution to directly infer candidate genes. We focus here on limb bone length differences, which is of special interest for understanding the evolution of developmentally correlated traits. We used 172 first-generation descendants of wild-caught mice from the hybrid zone to measure the length of stylopod (humerus/femur), zeugopod (ulna/tibia) and autopod (metacarpal/metatarsal) elements in skeletal CT scans. We find phenotypic covariation between limb elements in the hybrids similar to patterns previously described in Mus musculus domesticus inbred strains, suggesting that the hybrid genotypes do not influence the covariation pattern in a major way. Mapping was performed using 143,592 SNPs and identified several genomic regions associated with length differences in each bone. Bone length was found to be highly polygenic. None of the candidate regions include the canonical genes known to control embryonic limb development. Instead, we are able to identify candidate genes with known roles in osteoblast differentiation and bone structure determination, as well as recently evolved genes of, as yet, unknown function.


Utilization and charges for terminal cancer patients in Rhode Island.
A population-based sample of 2,104 terminal cancer patients who died in Rhode Island during 1980-1981 was created by merging death certificates, the claims of Medicare and non-Medicare health insurance beneficiaries served by Blue Cross and Blue Shield of Rhode Island, and records of the state's only hospice. The data collected included utilization and charges for services rendered by hospitals, nursing homes, home health agencies, physicians, and outpatient clinics. Regression analysis of charges during the last month and six months revealed significant differences for age and hospice: Six-month charges were found to be inversely related to age (+151 for each year of age), and the charges for the last month of care for decedents who received hospice care were 43.5% lower than the charges for conventional care.


Increased cognitive complexity reveals abnormal brain network activity in individuals with corpus callosum dysgenesis.
Cognitive reasoning is thought to require functional interactions between whole-brain networks. Such networks rely on both cerebral hemispheres, with the corpus callosum providing cross-hemispheric communication. Here we used high-field functional magnetic resonance imaging (7 T fMRI), a well validated cognitive task, and brain network analyses to investigate the functional networks underlying cognitive reasoning in individuals with corpus callosum dysgenesis (CCD), an anatomical abnormality that affects the corpus callosum. Participants with CCD were asked to solve cognitive reasoning problems while their brain activity was measured using fMRI. The complexity of these problems was parametrically varied by changing the complexity of relations that needed to be established between shapes within each problem matrix. Behaviorally, participants showed a typical reduction in task performance as problem complexity increased. Task-evoked neural activity was observed in brain regions known to constitute two key cognitive control systems: the fronto-parietal and cingulo-opercular networks. Under low complexity demands, network topology and the patterns of local neural activity in the CCD group closely resembled those observed in neurotypical controls. By contrast, when asked to solve more complex problems, participants with CCD showed a reduction in neural activity and connectivity within the fronto-parietal network. These complexity-induced, as opposed to resting-state, differences in functional network activity help resolve the apparent paradox between preserved network architecture found at rest in CCD individuals, and the heterogeneous deficits they display in response to cognitive task demands [preprint: https://doi.org/10.1101/312629].


[Solitary pulmonary arteriovenous fistula in infancy and childhood (author's transl)].
Pulmonary arteriovenous fistula is not a rare congenital malformation, but obviously most often it is a very late diagnosis. Moreover the disease is associated with a high risk of serious complications, namely cerebrovascular accidents. Two patients, an one month old infant and an 8 years old boy with typical symptoms and signs are presented. Both of them were operated upon successfully. It is concluded, that the diagnosis of solitary pulmonary arteriovenous fistula should lead to immediate operation, which is technically easy and of low risk only, even in infancy. Conservative surgery is recommended without sacrifice of healthy lung tissue, i.e. local excision or segmental resection in subpleural lesions and lobectomy for deep-seated fistulas.


[CT arthrography of the shoulder after surgical repair for ventral instability].
25 patients who had undergone a modified Lange repair were examined postoperatively after about four years, both clinically and by CT arthrography. Ventral redislocation was no longer seen postoperatively. As regards residual ventral instability, there was agreement between CT arthrography and the clinical findings in 20/25 patients (90%). Newly developed or residual dorsal instability could be accurately demonstrated by the presence of pathological changes of the dorsal labrum and by the observation of a wide dorsal joint recess. CT arthrography did not provide reliable evidence concerning loss of function and mobility of the treated shoulder. However, the presence of marked capsular folding suggests a poor clinical result.


Systematic comparison of two methods to measure parasite density from malaria blood smears.
This study was designed to directly compare the accuracy, reproducibility, and efficiency of three methods commonly used to measure blood-stage malaria parasite density from Giemsa-stained blood films. Parasites and white blood cells (WBCs) were counted in 154 thick films by two independent microscopists. Forty-six slides were read by counting parasitized red blood cells (RBCs) in the thin film. Using these same slides, parasites were again counted by two independent microscopists using an ocular grid. Overall, parasite densities were significantly lower and discrepancy between readers was higher when using the grid method compared to the WBC method, but there was no difference when compared to the RBC method. When one reader who had difficulty with the grid method was excluded, the discrepancy between readers was equivalent for the three methods. Densities and discrepancy between readers were indistinguishable when parasites were counted until 200 or 500 WBCs. Counting beyond 200 WBCs may not significantly improve parasite density measurements. Using an ocular grid directly measures parasites per volume rather than using a WBC per microliter conversion factor and eliminates the need to switch from the thick film to the thin film for high parasitemias. However, significant differences in densities measured by the grid method and the WBC method need to be evaluated.


Effect of long-chain polyunsaturated fatty acid supplementation during pregnancy or lactation on infant and child body composition: a systematic review.
n-3 (omega-3) Long-chain polyunsaturated fatty acids (LC-PUFAs) inhibit fat cell differentiation and fat storage in adults, and this has led to the hypothesis that maternal n-3 LC-PUFA supplementation may reduce fat mass in children. The objective of this systematic review was to evaluate the effect of n-3 LC-PUFA supplementation in pregnancy or lactation on infant and child body composition in randomized controlled trials. MEDLINE and EMBASE databases were searched for relevant articles. Human trials that supplemented the maternal diet with n-3 LC-PUFAs during pregnancy or lactation and assessed either body fat mass or body mass index in children were included. Trials had to be randomized in design. The quality of all included studies was assessed against set criteria, and results of eligible trials were compared. There were only 3 human trials (4 publications) that met our inclusion criteria. There was considerable disparity in study design and trial quality. The results were variable and showed positive, negative, or neutral effects of maternal n-3 LC-PUFA supplementation on body fat mass in children. This systematic review highlights the paucity of robust data from human studies to evaluate the effect of increased n-3 LC-PUFA exposure during the perinatal period on body fat mass in offspring. Further studies are required in which the intervention is confined to the perinatal period and that are sufficiently powered, have appropriate controls, have adequate blinding of participants and investigators, and have high retention rates.


N-terminal domain of soluble epoxide hydrolase negatively regulates the VEGF-mediated activation of endothelial nitric oxide synthase.
The mammalian soluble epoxide hydrolase (sEH) has both an epoxide hydrolase and a phosphatase domain. The role of sEH hydrolase activity in the metabolism of epoxyeicosatrienoic acids (EETs) and the activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) has been well defined. However, far less is known about the role of sEH phosphatase activity in eNOS activation. In the present study, we investigated whether the phosphatase domain of sEH was involved in the eNOS activation in ECs. The level of eNOS phosphorylation in aortas is higher in the sEH knockout (sEH(-/-)) mice than in wild-type mice. In ECs, pharmacological inhibition of sEH phosphatase or overexpressing sEH with an inactive phosphatase domain enhanced vascular endothelial growth factor (VEGF)-induced NO production and eNOS phosphorylation. In contrast, overexpressing the phosphatase domain of sEH prevented the VEGF-mediated NO production and eNOS phosphorylation at Ser617, Ser635, and Ser1179. Additionally, treatment with VEGF induced a c-Src kinase-dependent increase in transient tyrosine phosphorylation of sEH and the formation of a sEH-eNOS complex, which was abolished by treatment with a c-Src kinase inhibitor, PP1, or the c-Src dominant-negative mutant K298M. We also demonstrated that the phosphatase domain of sEH played a key role in VEGF-induced angiogenesis by detecting the tube formation in ECs and neovascularization in Matrigel plugs in mice. In addition to epoxide hydrolase activity, phosphatase activity of sEH plays a pivotal role in the regulation of eNOS activity and NO-mediated EC functions.


Effects of alkyl gallates on P-glycoprotein function.
In this study, we examined the effects of the food antioxidants, alkyl gallates, on the function of P-glycoprotein (P-gp) and elucidated the importance of alkyl chains and gallic acid moieties on the activity of P-gp. We examined the effects of three alkyl (n-butyl, n-octyl and n-dodecyl) gallates and their related compounds on the cellular accumulation and efflux of rhodamine 123 and daunorubicin in P-gp overexpressing KB-C2 cells. Alkyl gallates increased the cellular accumulation of these P-gp substrates dependent on their alkyl chain lengths by inhibiting the efflux of the substrates. n-Dodecylresorcinol also increased the accumulation, but its effect was less than that of n-dodecyl gallate. However, either lauric acid or n-dodecyl-beta-d-maltoside, which does not have a phenol group, did not increase the accumulation. The results indicated that both the gallic acid moiety and a long alkyl chain play important roles in the modification of P-gp function. The cytotoxicity of daunorubicin was recovered in the presence of alkyl gallates possibly due to their inhibition of P-gp function.


Lacerations and ruptures of the flexor or extensor hallucis longus tendons.
Lacerations and ruptures of the flexor hallucis longus or extensor hallucis longus tendon are frequently managed with operative repair. Tendon injuries of the hallux are not all alike; careful consideration should be given to the mechanism and site of injury, the timing of presentation, and the presence of other injuries. Not all tendon injuries of the hallux require repair. The effectiveness of a repair will depend on the goals of surgery, which may include pain relief, active joint motion, or correction of deformity. When goals are clearly defined, a satisfactory result can be expected in most patients.


Strongly anisotropic in-plane thermal transport in single-layer black phosphorene.
Using first principles calculations, we predict the thermal conductivity of the two-dimensional materials black phosphorene and blue phosphorene. Black phosphorene has an unprecedented thermal conductivity anisotropy ratio of three, with predicted values of 110 W/m-K and 36 W/m-K along its armchair and zigzag directions at a temperature of 300 K. For blue phosphorene, which is isotropic with a zigzag structure, the predicted value is 78 W/m-K. The two allotropes show strikingly different thermal conductivity accumulation, with phonons of mean free paths between 10 nm and 1 μm dominating in black phosphorene, while a much narrower band of mean free paths (50-200 nm) dominate in blue phosphorene. Black phosphorene shows intriguing potential for strain-tuning of its thermal conductivity tensor.


Antigenic modulation and down regulation-their similarities suggest they may have a common origin.
Antigenic modulation, the antibody-induced disappearance of membrane-associated determinants of neoplastic cells, has a fundamental similarity to the down regulation of receptors for hormones and other ligands affecting the physiology of various nonneoplastic cell types. After hormone stimulation, cells previously responsive become refractory to further stimulation. Diminution in responsiveness correlates with a quantitative reduction in the numbers of specific complementary hormone receptors present. Murine leukemia cells, as one example "escape" antibody-mediated destruction through the mechanism of antigenic modulation. Resistance of the cells correlates with a reduction of the numbers of specific antigens present. In both down regulation and modulation, continued cellular metabolism in the absence of ligand leads to a re-expression of the hormone receptor/membrane antigen involved. It is postulated that the two phenomena have evolved from similar underlying cellular mechanisms.


Salmeterol and fluticasone propionate given as a combination. Lack of systemic pharmacodynamic and pharmacokinetic interactions.
To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects. Twenty-eight healthy subjects received salmeterol 100 microg, salmeterol 100 microg/fluticasone propionate 500 microg and fluticasone propionate 500 microg via a Diskus dry powder inhaler twice daily for 11 days according to a randomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 microg on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and glucose levels] and fluticasone propionate (on 24-h urinary cortisol and morning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta2-adrenoceptors and beta2-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10. Dosing continued on the evening of day 10 and on day 11, and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol (up to a total dosage of 3,200 microg) was evaluated. All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences between the single-dose and repeat-dose salmeterol groups. The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate. Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary cortisol excretion (22.4 microg compared with 48.6 microg with placebo), but this was unaffected by the co-administration of salmeterol. Morning plasma cortisol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta2-adrenoceptors and no correlation of beta2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only during the first half-hour after dosing. Co-administration of fluticasone propionate did not affect the peak plasma concentration (Cmax) of salmeterol. For fluticasone propionate, there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax, plasma concentration at the end of the dosing interval (Ct), terminal elimination half-life (t1/2) or time to Cmax (tmax). The area under the concentration-time curve within a dosing interval (AUCt) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher (about 8%) than after inhalation of fluticasone propionate alone (P=0.0135). However, the 90% confidence intervals (CIs) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.


Dementia Attributable Healthcare Utilizations in the Caribbean versus United States.
Despite the high burden of Alzheimer's disease and other dementias among the Hispanic population worldwide, little is known about how dementia affects healthcare utilizations among this population outside of the US, in particular among those in the Caribbean region. This study examines healthcare utilization associated with Alzheimer's disease and other dementias among older adults in the Caribbean as compared to the US. We conducted harmonized analyses of two population-based surveys, the 10/66 Dementia Group Research data collected in Dominican Republic, Cuba, and Puerto Rico, and the US-based Health and Retirement Study. We examined changes in hospital nights and physician visits in response to incident and ongoing dementias. Incident dementia significantly increased the risk of hospitalization and number of hospital nights in both populations. Ongoing dementia increased the risk of hospitalization and hospital nights in the US, with imprecise estimates for the Caribbean. The number of physician visits was elevated in the US but not in the Caribbean. The concentration of increased healthcare utilization on hospital care and among patients with incident dementia suggests an opportunity for improved outpatient management of new and existing dementia patients in the Caribbean.


EEG analysis with nonlinear deterministic and stochastic methods: a combined strategy.
We describe nonlinear deterministic versus stochastic methodology, their applications to EEG research and the neurophysiological background underlying both approaches. Nonlinear methods are based on the concept of attractors in phase space. This concept on the one hand incorporates the idea of an autonomous (stationary) system, on the other hand implicates the investigation of a long time evolution. It is an unresolved problem in nonlinear EEG research that nonlinear methods per se give no feedback about the stationarity aspect. Hence, we introduce a combined strategy utilizing both stochastic and nonlinear deterministic methods. We propose, in a first step to segment the EEG time series into piecewise quasi-stationary epochs by means of nonparametric change point analysis. Subsequently, nonlinear measures can be estimated with higher confidence for the segmented epochs fulfilling the stationarity condition.


Cigarette smoke decreases MARCO expression in macrophages: implication in Mycoplasma pneumoniae infection.
Bacterial infections including Mycoplasma pneumoniae (Mp) are a major cause of exacerbations in chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) is the leading cause of COPD, and affects the function of alveolar macrophages that act as the first line of defense against the invading respiratory pathogens. Macrophages express a transmembrane receptor called macrophage receptor with collagenous structure (MARCO) that is involved in the clearance of microorganisms. Whether CS down-regulates MARCO and eventually decreases the clearance of Mp has not been investigated. We utilized human monocytic cell line (THP-1)-derived macrophages to examine the effects of CS extract (CSE) on MARCO expression and Mp growth. Specifically, macrophages were pre-exposed to CSE for 6 h, and then infected with or without Mp for 2 h. MARCO was examined at both mRNA and protein levels by using real-time PCR and immunofluorescent staining, respectively. Mp in the supernatants was quantified by quantitative culture. In addition, a neutralizing MARCO antibody was added to macrophages to test if blockade of MARCO impaired Mp clearance. We found that CSE significantly decreased MARCO expression in a dose-dependant manner at 6 h post-CSE. Mp levels in CSE-treated cells were higher than those in non-CSE-treated cells, indicating a decreased pathogen clearance. Additionally, neutralizing MARCO in macrophages markedly increased Mp levels. Our results indicate that cigarette smoke exposure down-regulates MARCO expression in macrophages, which may be in part responsible for impaired bacterial (e.g., Mp) clearance.


The effect of short intermittent light exposures on the melatonin circadian rhythm and NMU-induced breast cancer in female F344/N rats.
We investigated the effects of altered endogenous nighttime melatonin concentrations on mammary tumor production in an N-nitroso-N-methylurea (NMU)-induced breast cancer model in female Fischer 344 (F344)/N rats. Experiments were designed 1) to evaluate whether short-duration intermittent exposures to light at night would affect the nocturnal rise of melatonin, resulting in a decrease in nighttime serum melatonin concentrations, 2) to evaluate whether any suppression of nighttime serum melatonin concentrations could be maintained for a period of weeks, and 3) to determine the effects of suppressed serum melatonin concentrations on the incidence and progression of NMU-induced breast cancer. In vivo studies were used to assess serum melatonin concentrations after 1 day and 2 and 10 weeks of nightly administration of short-duration intermittent light exposure at night and incidence of NMU-induced tumors. Five 1-minute exposures to incandescent light every 2 hours after the start of the dark phase of the light: dark cycle decreased the magnitude of the nocturnal rise of serum melatonin concentrations in rats by approximately 65%. After 2 weeks of nightly intermittent light exposures, an average decrease of the peak nighttime serum melatonin concentrations of approximately 35% occurred. The amelioration continued and, at 10 weeks, peak nighttime serum melatonin concentrations were still decreased, by approximately 25%. Because peak endogenous nighttime serum melatonin values could be moderately suppressed for at least 10 weeks, a 26-week NMU mammary tumor study was conducted. Serum melatonin concentrations and incidence, multiplicity, and weight of NMU-induced mammary tumors were assessed. A group of pinealectomized (Px) animals was also included in the tumor study. No effect on the development of mammary tumors in an NMU-induced tumor model in rats occurred when endogenous nighttime serum melatonin concentrations were moderately suppressed by short-duration intermittent light exposures at night. At necropsy, there were no alterations in mammary tumor incidence (28/40 NMU controls, 28/40 NMU + light, 31/40 NMU + Px), multiplicity (2.18 tumors/tumor-bearing NMU control, 1.89 NMU + light, 2.39 NMU + Px), or average tumor weight (1.20 g NMU control, 1.19 g NMU + light, 0.74 g NMU + Px). Tumor burden had no effect on the serum melatonin cycle. At 26 weeks, however, animals exposed to intermittent light at night exhibited approximately 3-fold higher serum melatonin concentrations as compared with controls. Additionally, rats that had been pinealectomized at 4 weeks of age had serum melatonin concentrations that were markedly higher than the expected baseline concentrations for pinealectomized rats (<15 pg/ml), suggesting the reestablishment of a melatonin cycle. This finding was unexpected and suggests that melatonin can be produced by an organ or tissue other than the pineal gland.


Ileoileal intussusception as initial manifestation of Crohn's disease.
Intussusception is usually considered a childhood condition, but it may also be present in adults, where it is more often associated with an underlying pathology. There is no agreement upon the correct treatment of adult intussusception, although surgical intervention is considered necessary. Resection without prior reduction has been the traditional treatment of choice due to the significant risk for malignancy found in most series. We describe an unusual case of intestinal necrosis secondary to ileoileal intussusception caused by Crohn's disease. A long intestinal resection was necessary and the patient was discharged without major complications. Based on the details of this case, the authors emphasize the potential importance of considering individualized treatment of adult intussusception. The practical benefit for reduction of viable bowel in Crohn's patients is the preservation of bowel length.


Complementary Features of Attention Bias Modification Therapy and Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders.
In the treatment of anxiety disorders, attention bias modification therapy (ABMT) and cognitive-behavioral therapy (CBT) may have complementary effects by targeting different aspects of perturbed threat responses and behaviors. ABMT may target rapid, implicit threat reactions, whereas CBT may target slowly deployed threat responses. The authors used amygdala-based connectivity during a threat-attention task and a randomized controlled trial design to evaluate potential complementary features of these treatments in pediatric anxiety disorders. Prior to treatment, youths (8-17 years old) with anxiety disorders (N=54), as well as healthy comparison youths (N=51), performed a threat-attention task during functional MRI acquisition. Task-related amygdala-based functional connectivity was assessed. Patients with and without imaging data (N=85) were then randomly assigned to receive CBT paired with either active or placebo ABMT. Clinical response was evaluated, and pretreatment amygdala-based connectivity profiles were compared among patients with varying levels of clinical response. Compared with the CBT plus placebo ABMT group, the CBT plus active ABMT group exhibited less severe anxiety after treatment. The patient and healthy comparison groups differed in amygdala-insula connectivity during the threat-attention task. Patients whose connectivity profiles were most different from those of the healthy comparison group exhibited the poorest response to treatment, particularly those who received CBT plus placebo ABMT. The study provides evidence of enhanced clinical effects for patients receiving active ABMT. Moreover, ABMT appears to be most effective for patients with abnormal amygdala-insula connectivity. ABMT may target specific threat processes associated with dysfunctional amygdala-insula connectivity that are not targeted by CBT alone. This may explain the observation of enhanced clinical response to CBT plus active ABMT.


Mycobacterium chelonae bacteraemia in a patient with myasthenia gravis receiving long-term steroid therapy.
Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms found in soil and water. Infections caused by NTM are increasing with conditions ranging from harmless colonization to invasive infections, the latter being more common in immunocompromised hosts. In this report, we present a case of bacteraemia caused by Mycobacterium chelonae , a rapidly growing NTM belonging to Class IV in the Runyon classification, in a 71-year-old male with ocular myasthenia gravis undergoing treatment with oral prednisolone. Gram staining of these organisms from blood culture can be easily overlooked or confused with diptheroids. Detection of Gram-positive bacilli should prompt Ziehl-Neelsen staining to distinguish diphtheroids from rapidly growing mycobacteria in immunosuppressed patients. In addition, speciation and antimicrobial susceptibility testing are of paramount importance in such cases as there is considerable variation in the resistance patterns between different species of NTM. Line probe assay provides a rapid and reliable method for identification of NTM to the species level, which can guide treatment with appropriate antibiotics. This case report highlights the importance of early detection of such cases so as to optimize management and improve patient outcomes.


Nodal promotes growth and invasion in human gliomas.
Uncontrolled growth and diffused invasion are major causes of mortality in patients with malignant gliomas. Nodal has been shown to have a central role in the tumorigenic signaling pathways of malignant melanoma. In this study, we show that grade IV human glioma cell lines expressed different levels of Nodal, paralleled to the potential for cell invasiveness. Treatment of glioma cell lines with recombinant Nodal (rNodal) increased matrix metalloproteinase 2 (MMP-2) secretion and cell invasiveness. The ectopic expression of Nodal in GBM glioma cells that expressed Nodal at low level resulted in increased MMP-2 secretion, enhanced cell invasiveness, raised cell proliferation rates in vitro, increased tumor growth in vivo, and was associated with poor survival in a mice xenograft model. In contrast, the knockdown of Nodal expression in U87MG glioma cells with high Nodal expression level had reduced MMP-2 secretion, less cell invasiveness, lower tumor growth in vivo and longer lifespan in mice with U87MG/shNodal cell xenografts. In addition, Nodal knockdown promoted the reversion of malignant glioma cells toward a differentiated astrocytic phenotype. Furthermore, our data support the notion that Nodal may regulate glioma progression through the induction of the leukemia inhibitory factor (LIF) and Cripto-1 through activated Smad.


Postoperative pain associated with orthopedic shoulder and elbow surgery: a prospective study.
In the last 2 decades, extensive research in postoperative pain management has been undertaken to decrease morbidity. Orthopedic procedures tend to have increased pain compared with other procedures, but further research must be done to manage pain more efficiently. Postoperative pain morbidities and analgesic dependence continue to adversely affect health care. The study assessed the pain of 78 elbow and shoulder surgery patients preoperatively and postoperatively using the Short-Form McGill Pain Questionnaire (SF-MPQ). Preoperatively, each patient scored their preoperative pain (PP) and anticipated postoperative pain (APP). Postoperatively, they scored their 3-day (3dpp) and 6-week postoperative pain (6wpp). The pain intensities at these 4 intervals were then compared and analyzed using Pearson coefficients. APP and PP were strong predictors of postoperative pain. The average APP was higher than the average postoperative pain. The 6wpp was significantly lower than the 3dpp. Sex, chronicity, and type of surgery were not significant factors; however, the group aged 18 to 39 years had a significant correlation with postoperative pain. PP and APP were both independent predictors of increased postoperative pain. PP was also predictive of APP. Although, overall postoperative pain was lower than APP or PP due to pain management techniques, postoperative pain was still significantly higher in patients with increased APP or PP than their counterparts. Therefore, surgeons should factor patient's APP and PP to better manage their patient's postoperative pain to decrease comorbidities.


Cellular synthesis of macromolecular glycogen and its deposition.
The largest macromolecules of glycogen synthesized histochemically in tissue cells were spherical branching bodies composed of several large branches with many smaller branches, presumably containing a Meyer structure of alpha-1,4-1,6-glucosidic linkages. The synthesized macromolecules of glycogen were variable in size and structure, and were closely related to the activities of enzymes, phosphorylase, branching glycosyltransferase, and glycogen synthetase. The glycogen molecules appeared to be individually free in the cytoplasmic matrices. It is possible that they are synthesized there, and not related to the membrane system.


[Medial posteroventral pallidotomy for the treatment of Parkinson's disease].
Stereotactic medial posteroventral pallidotomy for treatment of Parkinson's disease attracts increasing attention. We report on the preliminary results of 12 patients at 1 year after microelectrode-guided unilateral pallidotomy. The primary indications were severe bradykinesia and levodopa-induced dyskinesias. After radiofrequency lesioning all patients had immediate improvement of contralateral parkinsonian signs. Postoperative magnetic resonance imaging confirmed the localization of the lesions. At the 1-year follow-up, all patients had sustained benefit. The global improvement was rated as moderate in six cases, and as marked in six other cases. The mean values of various subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) showed highly significant changes in the "off" state (pre/postoperatively): UPDRS Motor score (60.3/31). UPDRS Activities of Daily Living (ADL) score (33.2/18.3), gait/postural stability score (13.8/7.0), and subscores for contralateral rigidity (4.9/2.1), tremor (7.1/1.4) and bradykinesia (11.6/5.3). There was also significant improvement of ipsilateral bradykinesia and rigidity. Furthermore, we found significant changes of the mean values of the UPDRS ADL and motor "on" scores, an increase of the percentage of "on" time with reduced on-off fluctuations, and a decrease of the percentage of levodopa-induced dyskinesias, with marked improvement or complete abolition of contralateral dyskinesias in particular. The preoperative levodopa regimen was maintained, in general, or only slightly modified, if necessary. Two patients had transient complications: one patient suffered postoperative pneumonia and altered mental status; another patient displayed mild Broca's aphasia secondary to a small stroke involving the dorsal thalamus and the adjacent white matter. There were no persistent side effects at the 1-year follow-up. Contemporary unilateral pallidotomy is an effective and promising therapeutical option for surgical treatment of advanced Parkinson's disease.


Electrical and morphological factors influencing the depolarizing after-potential in rat and lizard myelinated axons.
1. Intra-axonal recording and electron microscopy were applied to intramuscular myelinated axons in lizards and rats to investigate factors that influence the amplitude and time course of the depolarizing after-potential. 2. Depolarizing after-potentials in lizard axons had larger peak amplitudes and longer half-decay times than those recorded in rat axons (mean values 10 mV, 35 ms in lizard; 3 mV, 11 ms in rat). These differences were not due to differences in temperature, resting potential or action potential amplitude or duration. 3. For a given axon diameter, the myelin sheath in lizard fibres was thinner and had fewer wraps than in rat fibres. There was no significant difference in myelin periodicity. Calculations suggest that the thinner myelin sheath accounts for < 30% of the difference between depolarizing after-potential amplitudes recorded in lizard and rat axons. 4. Consistent with a passive charging model for the depolarizing after-potential, the half-time of the passive voltage transient following intra-axonal injection of current was shorter in rat than in lizard axons. 5. Aminopyridines prolonged the falling phase of the action potential and increased the amplitude of the depolarizing after-potential in both types of axon. 6. During repetitive stimulation the depolarizing after-potentials following successive action potentials exhibited little or no summation. Axonal input conductance in the interspike interval increased during the train. 7. These findings suggest that the amplitude and time course of the depolarizing after-potential are influenced not only by the passive properties of the axon and myelin sheath, but also by persisting activation of axolemmal K+ channels following action potentials.


Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia.
Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.


Choroid Plexus Papilloma Arising From the Temporal Horn With a Bilateral Hypersecretory Hydrocephalus: A Case Report and Review of Literature.
Cerebrospinal fluid (CSF) within the cerebral ventricular system is secreted by a neuroepithelial tissue which is called as the choroid plexus. Tumors arising from these tissues are rare. Choroid plexus papillomas (CPPs) have been denoted as WHO grade I of the choroid plexus tumors. Among the intracranial tumors, neoplasms of the choroid plexus constitute around 0.36-0.6%. CPPs are mostly slow growing and cause symptoms due to mass effect and obstructive hydrocephalus, resulting in increased intracranial pressure. We report a case of CPP arising from the temporal horn in a 7-year-old girl presenting with progressive head enlargement since birth due to bilateral massive hydrocephalus without any obstruction, making it purely a hypersecretory hydrocephalus. A drainage procedure followed by complete tumor resection was carried out in our case and the patient showed marked relief from her symptoms.


Propagating Neural Source Revealed by Doppler Shift of Population Spiking Frequency.
Electrical activity in the brain during normal and abnormal function is associated with propagating waves of various speeds and directions. It is unclear how both fast and slow traveling waves with sometime opposite directions can coexist in the same neural tissue. By recording population spikes simultaneously throughout the unfolded rodent hippocampus with a penetrating microelectrode array, we have shown that fast and slow waves are causally related, so a slowly moving neural source generates fast-propagating waves at ∼0.12 m/s. The source of the fast population spikes is limited in space and moving at ∼0.016 m/s based on both direct and Doppler measurements among 36 different spiking trains among eight different hippocampi. The fact that the source is itself moving can account for the surprising direction reversal of the wave. Therefore, these results indicate that a small neural focus can move and that this phenomenon could explain the apparent wave reflection at tissue edges or multiple foci observed at different locations in neural tissue. The use of novel techniques with an unfolded hippocampus and penetrating microelectrode array to record and analyze neural activity has revealed the existence of a source of neural signals that propagates throughout the hippocampus. The source itself is electrically silent, but its location can be inferred by building isochrone maps of population spikes that the source generates. The movement of the source can also be tracked by observing the Doppler frequency shift of these spikes. These results have general implications for how neural signals are generated and propagated in the hippocampus; moreover, they have important implications for the understanding of seizure generation and foci localization.


Phosphate homeostasis and root development in Arabidopsis are synchronized by the zinc finger transcription factor ZAT6.
Phosphorus availability is limited in many natural ecosystems. Plants adapt to phosphate (Pi) deficiency by complex molecular processes. There is growing evidence suggesting that transcription factors are key components in the regulation of these processes. In this study, we characterized the function of ZAT6 (zinc finger of Arabidopsis 6), a cysteine-2/histidine-2 zinc finger transcription factor that is responsive to Pi stress. ZAT6 is induced during Pi starvation and localizes to the nucleus. While the RNAi suppression of ZAT6 appeared to be lethal, its overexpression affects root development and retards seedling growth as a result of decreased Pi acquisition. The ZAT6 overexpression also resulted in altered root architecture of older plants, with consequent changes in Pi acquisition. These results indicate that ZAT6 regulates root development independent of the Pi status of the plant, thereby influencing Pi acquisition and homeostasis. In addition, the expression of several Pi starvation-responsive genes was decreased in ZAT6 overexpressing plants, thereby confirming the role of ZAT6 in regulating Pi homeostasis. This study thus indicates that ZAT6 is a repressor of primary root growth and regulates Pi homeostasis through the control of root architecture. To our knowledge, ZAT6 is the first cysteine-2/histidine-2 zinc finger transcription factor reported to regulate root development and nutrient stress responses.


Comparative efficacy of cefadroxil and cefaclor in the treatment of skin and soft-tissue infections.
A ten-day, randomized, open-label study was conducted to compare the efficacy of 1,000 mg of cefadroxil once daily and 250 mg of cefaclor TID in 200 black patients with skin and soft-tissue infections caused by microorganisms sensitive to these cephalosporins. Statistically, the clinical results with each drug were not significantly different: 91% efficacy with cefadroxil and 95% efficacy with cefaclor. The important difference between cefadroxil and cefaclor is the remarkably longer half-life of cefadroxil, which makes once-a-day dosing possible and offers greater patient convenience and the likelihood of better compliance. In an analysis of compliance, only 2% of the patients in the cefadroxil group (20 capsules given to each patient) returned unused capsules; 77% in the cefaclor group (30 capsules given to each patient) returned unused capsules.


Potential therapeutic use of the ketogenic diet in autism spectrum disorders.
The ketogenic diet (KGD) has been recognized as an effective treatment for individuals with glucose transporter 1 (GLUT1) and pyruvate dehydrogenase (PDH) deficiencies as well as with epilepsy. More recently, its use has been advocated in a number of neurological disorders prompting a newfound interest in its possible therapeutic use in autism spectrum disorders (ASD). One study and one case report indicated that children with ASD treated with a KGD showed decreased seizure frequencies and exhibited behavioral improvements (i.e., improved learning abilities and social skills). The KGD could benefit individuals with ASD affected with epileptic episodes as well as those with either PDH or mild respiratory chain (RC) complex deficiencies. Given that the mechanism of action of the KGD is not fully understood, caution should be exercised in ASD cases lacking a careful biochemical and metabolic characterization to avoid deleterious side effects or refractory outcomes.


Terrorism preparedness training for nonclinical hospital workers: empowering them to take action.
While aspects of the national response to the last years' terrorist attacks have included preparedness training for health care institutions, much of the focus has been on clinician recognition of biologic exposures. However, many hospital workers have nonclinical responsibilities (such as housekeepers and mailroom workers) and many more, though active in clinical care, are para-professionals with limited medical training (such as nursing assistants). These workers are critical to the achievement of our institution's mission to provide competent and compassionate medical care, even during an emergency. In recognition of this, and to understand their attitudes and concerns, we conducted focus groups. The process provided a forum to receive immediate feedback from the workers, and will be used to design customized knowledge and skills training sessions that empower them to take proper responsive action should a terrorist attack occur. Our experience may be useful to others who are planning terrorism preparedness training programs.


"End-stage" neurofibrillary tangle pathology in preclinical Alzheimer's disease: fact or fiction?
Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical 'dementia' status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition.


Tuberculin activity of mycobacterial fractions obtained by chromatography.
Commercial purified protein derivatives (PPD), old tuberculin (OT), the bacillary extract, and the culture filtrate of Mycobacterium tuberculosis H37Ra were submitted to Sephadex G-25 and diethylaminoethyl (DEAE)-cellulose chromatography. The ability of the fractions obtained to elicit delayed dermal hypersensitivity in M. tuberculosis H37Ra-infected guinea pigs was studied. Skin tests with Sephadex fractions in M. tuberculosis H37Ra-infected guinea pigs showed that the tuberculin activity was localized in the first fraction. All other Sephadex fractions were nonessential and nonspecifically irritating. Fractions from chromatography of Sephadex G-25 fraction 1 on DEAE-cellulose columns showed that all but the first were able to elicit delayed hypersensitivity reactions. There was a variability in the capacity to elicit the tuberculin reaction according to the fraction injected and the stage of tuberculous infection in guinea pigs. Compared to the others, the seven lots of commercial PPD were variable in composition and content. They contained both essential and nonessential materials for the tuberculin reaction. Sephadex fraction 1 would appear to be a better tuberculin as it excludes nonessential nonspecifically irritating elements and contains the complement able to elicit the tuberculin reaction. Its methodological simplicity would be economically advantageous.


Plerixafor, a CXCR4 antagonist, mitigates skin radiation-induced injury in mice.
Even with modern 3D conformal treatments skin radiation injury can be an inadvertent complication associated with clinical radiotherapy particularly at tissue folds. It is also of concern in the context of a radiological terrorism incident or accident, since skin irradiation lowers the lethal dose of whole body radiation. We hypothesize that radiation-induced skin injury originates from a loss of stem and progenitor cells, accompanied by excessive ROS production and proinflammatory cytokines. Plerixafor, a CXCR-4 antagonist, is one of the most efficient bone marrow stem cell mobilizers and these studies were designed to experimentally assess the potential of Plerixafor to reduce skin radiation injury. The right hind legs of groups of C57BL/6 mice were exposed to radiation alone or in combination with Plerixafor. Plerixafor was administered intraperitoneally at a dose of 5 mg/kg given in two doses separated by two days and started either on day 0, 4, 7, 15 or 24 after irradiation. The primary end point was skin injury, which was assessed three times a week for at least 2 months using a semi-quantitative scale. Secondary end points measured at selected time points included histology (primarily H&E) and cytokine levels (TGF-β and TNF-α). The acute and late skin injury in mice receiving Plerixafor was highly dependent on the timing of administration of the drug. The maximum benefit was observed when the drug was started 1 week after radiation exposure, and earlier or later administration of the drug decreased its efficacy. Secondary damage end points (cytokine levels and histologically assessed tissue thickness) provided confirmatory observations. In an attempt to gain insight into the effect of timing of administration of the agent on the mitigation effect, the ligand to CXCR4, stromal derived factor, SDF-1, was measured as a function of time after radiation exposure. Expression of SDF-1 monitored in skin as a function of time after a 30 Gy radiation exposure suggested a strong correlation between timing of administration of Plerixafor and expression of SDF-1 in irradiated skin: optimum drug administration timing coincided with maximal SDF-1 expression in the skin of irradiated mice. This report presents the first observation that CXCR4 antagonist improves both acute and late skin response to radiation exposure.