Adult neurogenesis: a compensatory mechanism for neuronal damage.
It is now evident that the adult vertebrate brain including the human brain is efficiently and continuously generating new neurons. In the first part we describe the current view of how neurons are generated in the adult brain and the possible compensatory reactions to pathological situations in which neuronal damage might stimulate neural stem cell activity. In the second part, we discuss the current knowledge on the signals and cells involved in the process of neurogenesis. This knowledge is important because any neuronal replacement strategy depends on our ability to induce or modulate each step on the way to a new neuron: stem cell proliferation, cell fate determination, progenitor migration, and differentiation into specific neuronal phenotypes. Identification of the molecular signals that control these events are essential for the application of neural stem cell biology to develop repair strategies for neurodegenerative disorders.


Evaluation of acute toxicity and hepatoprotective activity of the methanolic extract of Dichrostachys cinerea (Wight and Arn.) leaves.
D. cinerea are the chief source of drug compounds that are active against various ailments such as jaundice, inflammations rheumatism, fever, asthma, body ache, chest problems, toothache, ulcers, wounds, eye diseases and have an aphrodisiac property. In present study, It was aimed to test the hepatoprotective activity of the plant. The methanolic extract of Dichrostachys cinerea (Mimoseae) leaves was subjected to evaluation of acute toxicity and hepatoprotective property, using albino mice and rats. The parameters for estimation of liver function, based on serum markers such as total bilirubin, total protein, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase with histopathological profile of the liver tissue, were studied consequently. The methanolic extract did not show any mortality up to a dose of 3500 mg/kg body weight. The methanolic extract showed significant hepatoprotectivity. The histopathological profile of the drug-treated liver tissue demonstrated similar morphology as that of controls. Methanolic extract of Dichrostachys cinerea was found to have significant hepatoprotective activity.


Patient involvement interventions for older adults in transitional care between hospital and primary care: a scoping review protocol.
The objective of this scoping review is to identify and map existing evidence of patient involvement interventions for older adults in transitional care between hospital and primary care.The questions of this review are.


A hyperelastic constitutive law for aortic valve tissue.
The objective of the present study was to perform biaxial testing and apply constitutive modeling to develop a strain energy function that accurately predicts the material behavior of the aortic valve leaflets. Ten leaflets from seven normal porcine aortic valves were biaxially stretched in a variety of protocols and the data combined to develop and fit a strain energy function to describe the material behavior. The results showed that the nonlinear anisotropic behavior of the aortic valve is well described by a strain energy function of two strain invariants, which uses only three coefficients to accurately predict the stress-strain behavior over a wide range of deformations. This structurally-motivated constitutive law has many applications, including computational modeling for clinical and engineering valve treatments.


Nuclear Respiratory Factor-1 (NRF-1) Regulates Transcription of the CXC Receptor 4 (CXCR4) in the Rat Retina.
The CXC receptor 4 (CXCR4) is required for various physiologic and pathologic processes in the eye, including stem cell trafficking, neuronal development, immune responses, and ocular neovascularization. Here, we used the rat retina models to determine the mechanisms driving CXCR4 transcription. The expression pattern of CXCR4 and nuclear respiratory factor-1 (NRF-1) were profiled in the rat retina during the course of development. Chromatin immunoprecipitation (CHiP) assay determined the transcriptional mechanism of CXCR4 in rat retina. A rat model of oxygen-induced retinopathy (OIR) that mimics retinal ischemia-reperfusion injury was established. Under either normoxic or hypoxic conditions, CXCR4 and NRF-1 expression in rat retinas was tracked by RT-PCR and Western analysis. Immunofluorescence staining localized CXCR4 and NRF-1. Both CXCR4 and NRF-1 were highly expressed in the neonatal rat retina, down-regulated in parallel, and silenced in fully developed retinas (1 month of age). ChIP assays revealed that NRF-1 was required for CXCR4 promoter activity in rat retinas. In the OIR rat model, retinal hypoxia induced up-regulation of CXCR4 and NRF-1 concurrently. Our findings suggest that NRF-1 regulates the expression of CXCR4 in normal retinal development and in pathologic processes of retinal hypoxia and neovascularization.


A collaborative platform for consensus sessions in pathology over Internet.
The design of valid databases in pathology faces the problem of diagnostic disagreement between pathologists. Organizing consensus sessions between experts to reduce the variability is a difficult task. The TRIDEM platform addresses the issue to organize consensus sessions in pathology over the Internet. In this paper, we present the basis to achieve such collaborative platform. On the one hand, the platform integrates the functionalities of the IDEM consensus module that alleviates the consensus task by presenting to pathologists preliminary computed consensus through ergonomic interfaces (automatic step). On the other hand, a set of lightweight interaction tools such as vocal annotations are implemented to ease the communication between experts as they discuss a case (interactive step). The architecture of the TRIDEM platform is based on a Java-Server-Page web server that communicate with the ObjectStore PSE/PRO database used for the object storage. The HTML pages generated by the web server run Java applets to perform the different steps (automatic and interactive) of the consensus. The current limitations of the platform is to only handle a synchronous process. Moreover, improvements like re-writing the consensus workflow with a protocol such as BPML are already forecast.


High IL-1α Production Was Induced in the WBN/Kob-Leprfa Type 2 Diabetes Mellitus Rat Model and Inhibited by Syphacia Muris Infection.
The novel WBN/Kob-Leprfa (fa/fa) congenic rat strain is considered a useful rat model of type 2 diabetes mellitus (T2DM). Accumulating findings suggest that low-grade inflammation is a causative factor in T2DM and that circulating levels of inflammatory cytokines are associated with insulin resistance. However, inflammatory cytokine profiles and their correlations with T2DM development/ progression in fa/fa rats have not been studied. In this study, we found that the fa/fa rats had considerably high plasma levels of interleukin (IL)-1α. Abundant cecal IL-1α mRNA expression and cecal inflammation with infiltrating IL-1α-producing macrophages was observed in fa/fa rats. Bone marrow derived macrophages from fa/fa rats expressed high levels of IL-1α upon lipopolysaccharide stimulation. Furthermore, Syphacia muris infection, which delays the onset of T2DM, reduced both plasma and cecal IL-1α levels in fa/fa rats. These results suggest that macrophage infiltration and IL-1α secretion comprise an important part of T2DM development and that S. muris infection inhibits pro-inflammatory cytokine expression in fa/fa rats.


Risk factors affecting Tests of Infant Motor Performance (TIMP) in pre-term infants at post-conceptional age of 40 weeks.
The purpose of this study is to correlate clinical factors with the Test of Infant Motor Performance (TIMP) in pre-term infants at a post-conceptional age of 40 weeks. The study enrolled 80 pre-term infants admitted to the Neonatal Intensive Care Unit (NICU). Data on birth weight, multiple birth, sex, delivery type, Apgar scores at 1 minute and 5 minutes, neonatal seizures and Intraventricular Haemorrhage (IVH) as assessed by echoencephalography were retrospectively analysed through a review of relevant medical records. IVH was the clinical factor most strongly correlated with the TIMP scores. Other clinical factors which significantly affected the TIMP scores were caesarean section, neonatal seizures, low birth weight and multiple births. When pre-term infants exhibit risk factors of developmental delay, it is suggestd that TIMP is performed early in life among pre-term infants and the results can be used to select infants for early interventions.


Computational analysis of the structural mechanism of inhibition of chemokine receptor CXCR4 by small molecule antagonists.
Understanding the structural mechanism of receptor-ligand interactions for the chemokine receptor CXCR4 is essential for determining its physiological and pathological functions and for developing new therapies targeted to CXCR4. We have recently reported a structural mechanism for CXCR4 antagonism by a novel synthetic CXCR4 antagonist RCP168 and compared its effectiveness against the natural agonist SDF-1α. In the present study, using molecular docking, we further investigate the binding modes of another seven small molecules known to act as CXCR4 antagonists. The predicted binding modes were compared with previously published mutagenesis data for two of these (AMD3100 and AMD11070). Four antagonists, including AMD3100, AMD11070, FC131 and KRH-1636, bound in a similar fashion to CXCR4. Two important acidic amino acid residues (Asp262 and Glu288) on CXCR4, previously found essential for AMD3100 binding, were also involved in binding of the other ligands. These four antagonists use a binding site in common with that used by RCP168, which is a novel synthetic derivative of vMIP-II in which the first 10 residues are replaced by D-amino acids. Comparison of binding modes suggested that this binding site is different from the binding region occupied by the N-terminus of SDF-1α, the only known natural ligand of CXCR4. These observations suggest the presence of a ligand-binding site (site A) that co-exists with the agonist (SDF-1α) binding site (site B). The other three antagonists, including MSX123, MSX202 and WZ811, are smaller in size and had very similar binding poses, but binding was quite different from that of AMD3100. These three antagonists bound at both sites A and B, thereby blocking both binding and signaling by SDF-1α.


Ultrathin, Ultra Narrow Band DMMA for Biosensing Applications.
A new ultrathin, ultra narrow band Dielectric based Metamaterial Absorber (DMMA) is designed for biosensing applications. The absorber provides dual-band response with perfect absorption with ultra-narrowband absorption characteristics with resonances at 5.98 THz and 6.72 THz. The absorber consists of a silicon based square split ring (SSSR) along with a graphene based circular split ring (GCSR) for the generation of perfect and ultra-narrow absorption characteristics. By varying the chemical potential of the graphene, the tunability and controllability is achieved for the proposed absorber. Due to its ultra narrow band absorption characteristics, the proposed absorber can be used for sensing cancer in various parts of the body, malaria, glucose in water and other chemicals. The unique features of the proposed absorber are its ultra-thin structure, simple design, tunability, polarization insensitivity, ultra narrow absorption bandwidth, high sensitivity, high Figure of Merit (FOM), and very high Quality factor (Q) values in a single device for detecting different diseases and chemicals.


Chronic effects assessment and plasma concentrations of the beta-blocker propranolol in fathead minnows (Pimephales promelas).
The presence of many human pharmaceuticals in the aquatic environment is now a worldwide concern, yet little is known of the chronic effects that these bioactive substances may be having on aquatic organisms. Propranolol, a non-specific beta adrenoreceptor blocker (beta-blocker), is used to treat high blood pressure and heart disease in humans. Propranolol has been found in surface waters worldwide at concentrations ranging from 12 to 590ng/L. To test the potential for ecologically relevant effects in fish in receiving waters, short-term (21 days) adult reproduction studies were conducted, in which fathead minnows were exposed to nominal concentrations of propranolol hydrochloride [CAS number 318-98-9] ranging from 0.001 to 10mg/L (measured concentrations typically from 78 to 130%). Exposure of fish to 3.4mg/L (measured) over 3 days caused 100% mortality or severe toxicity requiring euthanasia. The most sensitive endpoints from the studies were a decrease in hatchability (with regard to the number of days to hatch) and a concentration-related increase in female gonadal somatic index (GSI), giving LOEC(hatchability) and LOEC(female GSI) values of 0.1mg/L. Concentration-related decreases in weights of male fish were also observed, with LOEC(male wet weight value) of 1.0mg/L, and the LOEC(reproduction) value was 1.0mg/L. Collectively, these data do not suggest that propranolol was acting as a reproductive toxin. Plasma concentrations of propranolol in male fish exposed to nominal concentrations of 0.1 and 1.0mg/L were 0.34 and 15.00mg/L, respectively, which constitutes 436 and 1546% of measured water concentrations. These compare with predicted concentrations of 0.07 and 0.84mg/L, and thus to a degree support the use of partition coefficient models for predicting concentrations in plasma in fish. In addition, propranolol plasma concentrations in fish exposed to water concentrations of 0.1 and 1.0mg/L were greater than the human therapeutic plasma concentration and hence these data very strongly support the fish plasma model proposed by Huggett et al. [Huggett, D.B., Cook, J.C., Ericson, J.F., Williams, R.T., 2003a. A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish. Hum. Ecol. Risk Assess. 9, 1789-1799].


Noncovalent SUMO-1 binding activity of thymine DNA glycosylase (TDG) is required for its SUMO-1 modification and colocalization with the promyelocytic leukemia protein.
SUMO-1 is a member of a family of ubiquitin-like molecules that are post-translationally conjugated to various cellular proteins in a process that is mechanistically similar to ubiquitylation. To identify molecules that bind noncovalently to SUMO-1, we performed yeast two-hybrid screening with a SUMO-1 mutant that cannot be conjugated to target proteins as the bait. This screening resulted in the isolation of cDNAs encoding the b isoform of thymine DNA glycosylase (TDGb). A deletion mutant of TDGb (TDGb(Delta11)) that lacks a region shown to be required for noncovalent binding of SUMO-1 was also found not to be susceptible to SUMO-1 conjugation at an adjacent lysine residue, suggesting that such binding is required for covalent modification. In contrast, another mutant of TDGb (TDGb(KR)) in which the lysine residue targeted for SUMO-1 conjugation is replaced with arginine retained the ability to bind SUMO-1 non-covalently. TDGb was shown to interact with the promyelocytic leukemia protein (PML) in vitro as well as to colocalize with this protein to nuclear bodies in transfected cells. TDGb(KR) also colocalized with PML, whereas TDGb(Delta11) did not, indicating that the noncovalent SUMO-1 binding activity of TDGb is required for colocalization with PML. Furthermore, SUMO-1 modification of TDGb and PML enhanced the interaction between the two proteins. These results suggest that SUMO-1 functions to tether proteins to PML-containing nuclear bodies through post-translational modification and noncovalent protein-protein interaction.


Reappraising reappraisal: an expanded view.
Reappraisal is a frequently used and often successful emotion regulation strategy. However, its underlying cognitive mechanisms are not well understood. In this paper, we seek to clarify these mechanisms by expanding upon our recently proposed reAppraisal framework. According to this framework, reappraisal consists of appraisal shifts that arise from changes to the mental construal of a situation (reconstrual) or from changes to the goals that are used to evaluate the construal (repurposing). Here we propose that reappraisal can target both object-level construals and goals representing states in the environment as well as meta-level construals and goals about different states in the mind. We also propose that reappraisal can operate by facilitating decommitment from a dominant construal or goal as well as by facilitating commitment to alternative construals or goals. We demonstrate that the 2 × 2 × 2 matrix formed by crossing the three distinctions between reconstrual and repurposing, between object-level and meta-level representations, and between decommitment and commitment operations forms a useful map of different reappraisal tactics. We draw examples of each of the 8 reappraisal tactics from basic and clinical research. We conclude by considering future research inspired by the expanded reAppraisal framework.


Updates on the Management of Acute Myeloid Leukemia.
Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a disease with poor outcomes. They are more effective than standard chemotherapy with a good safety profile. For "fit patients" in first-line, the combination of gemtuzumab ozogamicin or midostaurin with intensive chemotherapy or Vyxeos is now considered the "standard of care" for selected patients. On the other hand, for "unfit patients", azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development. Nevertheless, global survival results, especially in relapsed or refractory patients, remain unfavorable. New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies ("triplets") and maintenance strategies guided by measurable residual disease.


Relative potency of lambdacyhalothrin and cypermethrin applied as thermal fogs for the control of houseflies (Musca domestica) and mosquitos (Aedes aegypti).
Two highly active synthetic pyrethroid insecticides, lambdacyhalothrin and cypermethrin, were evaluated as thermal fogs against houseflies (Musca domestica Linnaeus) and mosquitos (Aedes aegypti Linnaeus). Lambdacyhalothrin (OMS 3021) showed an average of 2.5 times more knockdown activity and over 5 times more adulticidal activity than cypermethrin against Musca domestica and Aedes aegypti. These results demonstrate that lambdacyhalothrin is highly effective at very low rates as a thermal fog against Ae. aegypti and M. domestica. Commercially available formulations of 2.5% and 5% lambdacyhalothrin can be diluted either with water for ULV cold aerosol space-spraying or with diesel/kerosene for thermal fogging at recommended application rates of 0.5-1 g ai/ha for mosquito control and 2 g ai/ha for housefly control. Due to the very low rates of application, formulated products of lambdacyhalothrin are unlikely to present any acute hazards in normal use. The low dosages required to bring about rapid control of houseflies and mosquitos make this new pyrethroid insecticide particularly cost-effective. Coupled with its good residual activity (Jutsum et al, 1984), lambdacyhalothrin can be adopted as a powerful tool in integrated pest management program for the control of medically important pests and vectors.


Living with systemic lupus erythematosus in South Africa: a bitter pill to swallow.
Systemic lupus erythematosus (SLE) often has a profound negative impact on health-related quality of life (HRQoL). In the absence of any qualitative studies in sub-Saharan Africa, we undertook a study to explore living experiences, perceptions and unmet needs of South African patients with SLE. Twenty-five women with SLE consented to participate in the study. They underwent individual in-depth interviews exploring their physical concerns, emotional health, sexual well-being and fertility. NVivo software was used for analysis. Participants were either of black ancestry or mixed racial ancestry, mainly indigent with only a quarter gainfully employed. Living with pain was the most common complaint, negatively impacting on activities of daily living (ADL), family expectations, social life, sleep and intimacy. Most participants expressed challenges of living with fatigue, and many felt their fatigue was misconstrued as being 'simply lazy'. This pernicious fatigue had negative consequences on many facets of ADL, including caring for dependants, job sustainability and sexual well-being. All participants experienced low emotional states, often associated with suicidal ideations. Many experienced difficulties with fertility and childbearing and these were exacerbated in many instances by the pessimism of health care providers, resulting in confusion and depression. Physical disfigurements resulting from lupus-associated alopecia and rashes and corticosteroid-induced weight fluctuations were a major concern. These changes often affected self-image and libido, leading to strained personal relationships. Coping mechanisms that participants adopted included intense spiritual beliefs, 'pushing through the difficult times' and use of alternative therapies to relief symptoms was common. A poor understanding of SLE on the part of participant's family and the community, coupled with the unpredictable course of the disease, exacerbated frustration and social exclusion. For most, limited income, lack of basic services, family dependencies, and comorbid diseases, such as human immune deficiency virus (HIV), exacerbated the daily negative SLE experiences. In this study of mainly indigent South African women, SLE is associated with complex, chronic and challenging life experiences. The chronic relapsing and unpredictable nature of the disease, poor understanding and acceptance of SLE, compounded by a background of poverty, inadequate social support structures, negatively impact on a range of personal, social and vocational daily life experiences. Improved access to psychosocial services and SLE education might result in better outcomes. (Ethics Project identification code: 275/2016 and M160633 registered 10 & 29 August 2016).


Inguinocrural dermolipectomy A retrospective study.
Inguinocrural dermolipectomy is a constantly increasing surgical procedure, especially for postbariatric patients with significant weight loss. The "crescent medial" and "vertical medial" thigh lifting techniques (CMTL/VMTL) are the most effective type of surgery to treat laxity and excess of skin and soft tissues in the medial region of the thighs Aim of this article is to suggest which patients may be eligible for a surgical thighplasty with an acceptable risk of postoperative complications. We performed a retrospective study with 30 female patients who underwent a surgical thighplasty between 2018 and 2008. Several parameters were evaluated such as age, patient weight and BMI before weight loss and before plastic surgery, the mode of weight loss (surgical vs. non-surgical), the type of technique performed ("crescent medial" vs. "vertical medial"), the association with other surgical procedures of size reduction plastic operation (ICD10 Procedure Code 8683), smoking at the time of the intervention. The correlations between these preoperative parameters and the development of postoperative complications were taken into consideration and different outcomes were evaluated, of which the modification of the size of the trousers after the thigh lifting operation, the days of hospitalization, the maintenance time drainage, the time needed to return to normal daily activities and improvement in the same, in walking and in physical activity after the execution of the procedure and the satisfaction in general of the patients. The association with other excisional surgeries such as brachioplasty, abdominoplasty or mastopexy, the BMI before thighplasty and weight loss modality condition significantly influence patient's post-operative outcomes. However, there is no clear correlation with age, smoking, the type of plastic surgery performed and its possible association with liposuction, and a drastic "drop" of BMI. In our opinion, even more than a single parameter predicts patients' post-operative complications. Acting on the significant findings of our investigation, surgeons could minimize post-operative risks as well as surgical minor complications. Therefore we advise to evaluate these factors before the intervention in order to select the patients more accurately and define the ideal candidate patient for inguinocrural dermolipectomy, so as obtain a reduction in postoperative complications. Body contouring, Massive weight loss, Thigh lift.


Multifocal hypopigmented retinal pigment epithelial lesions in incontinentia pigmenti.
Incontinentia pigmenti (IP) can manifest with retinal detachment in children and can simulate retinoblastoma. The authors report a clinicopathologic correlation of IP and illustrate the retinal pigment epithelium (RPE) alterations that may be useful in establishing the diagnosis. A 30-month-old reportedly healthy girl developed strabismus and was discovered to have total retinal detachment in the left eye. Intraocular calcification was found on ultrasonography and computed tomography, suggestive of retinoblastoma. Ophthalmoscopy of the right eye revealed sector distribution of approximately 70 elongated, linear hypopigmented lesions of the RPE located in the peripheral superotemporal, inferotemporal, and superonasal quadrants and measuring 300 microm or less in basal dimension. The left eye had a total retinal detachment, vitreous traction, perivascular exudation, and iris neovascularization. Despite the lack of medical history in this patient, skin examination revealed classic cutaneous findings of IP The enucleated left globe displayed tractional retinal detachment with vitreoretinal neovascularization and nonspecific RPE papillary proliferation. Scattered minor foci of intraretinal calcification were observed. There was no sign of retinoblastoma. IP can closely simulate retinoblastoma with retinal detachment and minor intraocular calcification. In this case, the classic cutaneous manifestations combined with the fine linear hypopigmented RPE foci were important in suggesting the diagnosis of IP.


Pre- and post-treatment computed tomographic findings of a primary intranasal transmissible venereal tumor in a canine patient.
A two-year-old, female intact, cross-breed dog presented with a two-month history of nasal discharge. Computed tomography (CT) demonstrated obliteration of both nasal cavities by soft tissue density, destruction of the nasal and ethmoidal turbinates, and lysis of the frontal and palatine bones and maxilla. Frontal sinuses and maxillary recesses were obscured by soft tissue/fluid density. Histopathological examination of the mass was diagnostic of transmissible venereal tumor. The dog was clinically normal 3 months after treatment initiation with vincristine sulphate and amoxicillin/clavulanate. Six months after the completion of treatment no mass-like lesion was demonstrated in CT sections. Nasal cavities, maxillary recesses and frontal sinuses were filled with air. The reticular turbinate nasal plexus appeared atrophic with focal loss of the nasal turbinates on both sides. The ethmoidal turbinates were well-defined; however, focal loss of turbinates was also seen. Lysis of the frontal and palatine bones were still evident.


A recurrent variant branch of the inferior alveolar nerve: is it unique?
The only named branch of the inferior alveolar nerve (IAN) before it enters the mandibular foramen is the mylohyoid nerve. However, several variations have been reported in the literature. In this study, a recurrent variant branch of the IAN arising just below the origin of the mylohyoid nerve was investigated in adult Indian cadavers allotted for dissection to the first year dental students of Government Dental College, Ahmedabad (India). The dissection was performed by the lateral approach to the infratemporal fossa. The nerve was found in 12 of 35 sides (34.3%) and 8 of 18 cadavers (44.4%). Thus, in our study it was not a rare variation of the IAN, where in most cases it innervated the lateral pterygoid muscle. In some cases, it terminated in the lateral pterygoid muscle. In others, it penetrated the muscle to join the anterior or posterior division of the mandibular nerve or its branches; thus, the variant nerve in such cases might be regarded as an additional root of the IAN. Because the concerned primordia of the nerves and muscles migrate extensively during development and growth, alternative routes of migration may bring about variants like the one under study. The variant appeared to be unique in some of its features. It may be a source of neuropathic and referred pain. Failure of the conventional inferior alveolar nerve block anesthesia and the peripheral neurectomy used for the treatment of trigeminal neuralgia may be partly due to the presence of this variation.


Preparation and electrical properties of Ca-doped La(2)NiO(4+δ) cathode materials for IT-SOFC.
Ca-doped La(2)NiO(4+δ) is synthesized via the nitrate-citrate route. The effects of Ca substitution for La on the sinterability, lattice structure and electrical properties of La(2)NiO(4+δ) are investigated. Ca-doping is unfavorable for the densification process of La(2-x)Ca(x)NiO(4+δ) materials. The introduction of Ca leads to the elongation of the La-O(2) bond length, which provides more space for the migration of oxygen ion in La(2)O(2) rock salt layers. The substitution of Ca increases remarkably the electronic conductivity of La(2-x)Ca(x)NiO(4+δ). With increasing Ca-doping level, both the excess oxygen concentration and the activation energy of oxygen ion migration decrease, resulting in an optimization where a highest ionic conductivity is presented. Ca-doping is charge compensated by the oxidation of Ni(2+) to Ni(3+) and the desorption of excess oxygen. The substitution of Ca enhances the structural stability of La(2)NiO(4+δ) material at high temperatures and renders the material a good thermal cycleability. La(1.7)Ca(0.3)NiO(4+δ) exhibits an excellent chemical compatibility with CGO electrolyte. La(2-x)Ca(x)NiO(4+δ) is a promising cathode alternative for solid oxide fuel cells.


Macromolecular crowding and protein stability.
An understanding of cellular chemistry requires knowledge of how crowded environments affect proteins. The influence of crowding on protein stability arises from two phenomena, hard-core repulsions and soft (i.e., chemical) interactions. Most efforts to understand crowding effects on protein stability, however, focus on hard-core repulsions, which are inherently entropic and stabilizing. We assessed these phenomena by measuring the temperature dependence of NMR-detected amide proton exchange and used these data to extract the entropic and enthalpic contributions of crowding to the stability of ubiquitin. Contrary to expectations, the contribution of chemical interactions is large and in many cases dominates the contribution from hardcore repulsions. Our results show that both chemical interactions and hard-core repulsions must be considered when assessing the effects of crowding and help explain previous observations about protein stability and dynamics in cells.


Physiologically-Based Pharmacokinetic Modeling to Support Determination of Bioequivalence for Dermatological Drug Products: Scientific and Regulatory Considerations.
Physiologically-based pharmacokinetic (PBPK) modeling and simulation provides mechanism-based predictions of the pharmacokinetics of an active ingredient following its administration in humans. Dermal PBPK models describe the skin permeation and disposition of the active ingredient following the application of a dermatological product on the skin of virtual healthy and diseased human subjects. These models take into account information on product quality attributes, physicochemical properties of the active ingredient and skin (patho)physiology, and their interplay with each other. Regulatory and product development decision makers can leverage these quantitative tools to identify factors impacting local and systemic exposure. In the realm of generic drug products, the number of US Food and Drug Administratioin (FDA) interactions that use dermal PBPK modeling to support alternative bioequivalence (BE) approaches is increasing. In this report, we share scientific considerations on the development, verification and validation (V&V), and application of PBPK models within the context of a virtual BE assessment for dermatological drug products. We discuss the challenges associated with model V&V for these drug products stemming from the fact that target-site active ingredient concentrations are typically not measurable. Additionally, there are no established relationships between local and systemic PK profiles, when the latter are quantifiable. To that end, we detail a multilevel model V&V approach involving validation for the model of the drug product of interest coupled with the overall assessment of the modeling platform in use while leveraging in vitro and in vivo data related to local and systemic bioavailability.


Evaluation of the exposure prediction component of Control of Substances Hazardous to Health Essentials.
The exposure prediction component of the Control of Substances Hazardous to Health (COSHH) Essentials model (paper version) was evaluated using field measurements from National Institute of Occupational Safety and Health (NIOSH) Health Hazard Evaluation (HHE) reports. Overall 757 measured exposures for 94 similar exposure groups (SEGs) were compared with the COSHH Essentials predicted exposure range (PER). The SEGs were stratified based on the magnitude of measured exposures (high, medium, or low) and physical state of the substance (vapor or particulate). The majority of measured exposures observed involved low-level exposure to vapors; thus, overall findings from the current study are limited to low-level vapor exposure scenarios. Overall, the exposure prediction component of COSHH Essentials vastly overestimated low-level exposures to vapors. This study went beyond the scope of previous studies and investigated which model components led to the overestimation. It was concluded that COSHH Essential's tendency to overestimate was due to multiple complex interactions among model components. Overall, the magnitude of overestimation seems to increase exponentially as values for predictor variables increase. This is likely due to the log-based scale used by the model to allocate concentration ranges. In addition, the current banding scheme used to allocate volatility appears to play a role in the overestimation of low-level exposures to vapors.


Efficient synthesis of 3,4-ethylenedioxythiophene (EDOT)-based functional π-conjugated molecules through direct C-H bond arylations.
A variety of 3,4-ethylenedioxythiophene (EDOT)-based π-conjugated molecules were efficiently synthesized in good yields through Pd-catalyzed direct C-H bond arylations, wherein a detailed synthetic investigation, including the screening of various kinds of palladium catalysts, ligands, additives, and solvents, was carried out. In addition, the spectroscopic and electrochemical properties of these EDOT-containing molecules were also investigated.


The liver part l: anatomy.
Understanding the anatomy of the hepatobiliary system provides the basis for the holistic care of patients with a liver disorder. In the second part of this series of articles, the functions of the liver will be examined.


Growth hormone releasing hormone receptor (GHRH-r) gene mutation in Indian children with familial isolated growth hormone deficiency: a study from western India.
Various mutations of the growth hormone releasing hormone receptor (GHRH-R) gene have been recently described to cause familial isolated growth hormone (GH) deficiency (FIGHD), with the GHRH-R nonsense mutation E72X reported in patients with FIGHD from South Asia. The molecular genetic basis of FIGHD in Indian children is not known. To look for the GHRH-R E72X non-sense mutation in our patients with FIGHD and describe its clinical phenotype. A total of 31 patients from 22 families diagnosed 4-20 years previously, 20 patients with familial IGHD-IB from 11 families and 11 patients with non-familial isolated GH deficiency (NFIGHD) (phenotypes IGHD-IB in eight patients and -IA in three) were included. Twenty-eight of 31 patients with IGHD-IB came from two states of Western India, 27 of them Hindus from 18 families (three consanguineous) and one from an inbred Moslem kindred. Twenty-two of the patients (71%) (18 FIGHD and four NFIGHD) had a homozygous G-->T transversion in exon 3, with this GHRH-R gene mutation E72X in 90% (18/20) of patients with FIGHD, 36% (4/11) of NFIGHD, altogether 78% (22/28) with phenotype IB. One parent pair with IGHD had homozygous E72X mutation, the rest were heterozygous carriers. Two siblings with IGHD due to homozygous E72X mutation were also heterozygous carriers for GH-1 gene 6.7 kb deletion, inherited from their mother, heterozygous for both GH-1 and GHRH-R mutations. Initial chronological age was 10.89 +/- 3.69 years, bone age 6.4 +/- 3.4 years, and mean height SDS was -5.83 +/- 1.41. The clinical phenotype, with sharp features, lean habitus, lack of frontal bossing or hypoglycemia, was characteristic. The mean peak GH was 1.25 +/- 0.75 ng/ml, IGF-I and IGFBP-3 below -2 SDS with no response to GHRH in those tested. MRI (n = 10) showed pituitary hypoplasia, mean vertical height 2.61 +/- 0.76 mm. Among the other 7/11 NFIGHD patients, four with phenotype IB were negative for genotypes tested in this study; of three patients with phenotype IA, two had the GH-1 gene 6.7 kb deletion, and one was a compound heterozygote with 6.7 and 7.6 kb deletions. The majority of patients with FIGHD from different communities belonged to non-consanguineous Hindu families from Western India. The GHRH-R gene E72X mutation was found in 71% of this series, in 90% of FIGHD, 36% of NFIGHD, and in 78% with phenotype IB. The characteristic phenotype helped in suspecting this mutation. GHRH-R gene mutations may be the most reasonable candidate for IGHD-IB with the E72X mutation predominating in the Indian subcontinent. More extensive studies need to be undertaken.


[Effect of hyperinsulinemia on liver insulin receptors of the growing rat subjected to energy restriction].
Two experiments (I and II) were carried out to study the interaction of insulin with amino acid metabolism in rats subjected to a restricted energy allowance (Grizard et al., 1975). 61 male rats, weighing 94 g at the beginning of the experiments, were divided into 4 groups and fed every 4 hrs. Group T was fed a balanced diet, and groups -E1, -E2 and -E3 were given a restricted energy allowance (table 1). The rats of group -E3 were injected with insulin at 11 a. m. every day, and those of group -E2 at that hour on the day they were killed. When the animals of a group had a mean body weight of 157 g, they were killed between 2 p. m. and 6 p. m., i. e. between two meals. Plasma insulin and insulin binding to liver plasma membranes were recorded. Reducing dietary energy intake resulted in a small decrease of postprandial plasma insulin and in a small increase of the plasma insulin clearance rate (table 2). It also augmented (125I) iodoinsulin binding to liver plasma membranes (fig. 1). This change could explain the increment of the liver protein synthesis observed in such animals (Arnal, Fauconneau and Pech, 1972). Exogenous insulin induced a resistance to insulin effects (Grizard, Prugnaud and Pion, 1977), and caused a large increase of plasma insulin and a small decline in (125I) iodoinsulin binding to liver plasma membranes for 3 to 5 h after the injection (fig. 1). A large increment in insulin binding was then noted (fig. 1). Increased insulin binding and decreased plasma insulin might be correlated. The enhanced insulin binding could not explain the resistance to the effects of insulin.


SNR-Adaptive OCT Angiography Enabled by Statistical Characterization of Intensity and Decorrelation With Multi-Variate Time Series Model.
In OCT angiography (OCTA), decorrelation computation has been widely used as a local motion index to identify dynamic flow from static tissues, but its dependence on SNR severely degrades the vascular visibility, particularly in low-SNR regions. To mathematically characterize the decorrelation-SNR dependence of OCT signals, we developed a multi-variate time series (MVTS) model. Based on the model, we derived a universal asymptotic linear relation of decorrelation to inverse SNR (iSNR), with the variance in static and noise regions determined by the average kernel size. Accordingly, with the population distribution of static and noise voxels being explicitly calculated in the iSNR and decorrelation (ID) space, a linear classifier is developed by removing static and noise voxels at all SNR, to generate a SNR-adaptive OCTA, termed as ID-OCTA. Then, flow phantom and human skin experiments were performed to validate the proposed ID-OCTA. Both qualitative and quantitative assessments demonstrated that the ID-OCTA offers a superior visibility of blood vessels, particularly in the deep layer. Finally, the implications of this work on both system design and hemodynamic quantification are further discussed.


Negative regulators of toll-like receptor 4-mediated macrophage inflammatory response.
Activation of macrophages through TLR4, the receptor for the bacterial endotoxin LPS, results in a potent inflammatory response aimed at eliminating the invading pathogen. Excessive production of inflammatory mediators is harmful to host tissue and in extreme cases can result in fatal outcomes. This inflammatory response is, therefore, tightly regulated by negative regulatory mechanisms that act to maintain homeostasis. This review will summarize recent advances in our current understanding of molecular mechanisms that regulate macrophage TLR4 signaling.


Amino-functionalized carbon nanotubes as solid basic catalysts for the transesterification of triglycerides.
Multiwalled carbon nanotubes grafted with various amino groups show high activity and stability when used as basic catalysts for the transesterification of triglycerides.


An ensemble framework for time delay synchronization.
Synchronization based state estimation tries to synchronize a model with the true evolution of a system via the observations. In practice, an extra term is added to the model equations which hampers growth of instabilities transversal to the synchronization manifold. Therefore, there is a very close connection between synchronization and data assimilation. Recently, synchronization with time-delayed observations has been proposed, in which observations at future times are used to help synchronize a system that does not synchronize using only present observations, with remarkable successes. Unfortunately, these schemes are limited to small-dimensional problems. In this article, we lift that restriction by proposing an ensemble-based synchronization scheme. Tests were performed using the Lorenz'96 model for 20-, 100- and 1000-dimension systems. Results show global synchronization errors stabilizing at values of at least an order of magnitude lower than the observation errors, suggesting that the scheme is a promising tool to steer model states to the truth. While this framework is not a complete data assimilation method, we develop this methodology as a potential choice for a proposal density in a more comprehensive data assimilation method, like a fully nonlinear particle filter.


Structural and Biochemical Features of Eimeria tenella Dihydroorotate Dehydrogenase, a Potential Drug Target.
Dihydroorotate dehydrogenase (DHODH) is a mitochondrial monotopic membrane protein that plays an essential role in the pyrimidine de novo biosynthesis and electron transport chain pathways. In Eimeria tenella, an intracellular apicomplexan parasite that causes the most severe form of chicken coccidiosis, the activity of pyrimidine salvage pathway at the intracellular stage is negligible and it relies on the pyrimidine de novo biosynthesis pathway. Therefore, the enzymes of the de novo pathway are considered potential drug target candidates for the design of compounds with activity against this parasite. Although, DHODHs from E. tenella (EtDHODH), Plasmodium falciparum (PfDHODH), and human (HsDHODH) show distinct sensitivities to classical DHODH inhibitors, in this paper, we identify ferulenol as a potent inhibitor of both EtDHODH and HsDHODH. Additionally, we report the crystal structures of EtDHODH and HsDHODH in the absence and presence of ferulenol. Comparison of these enzymes showed that despite similar overall structures, the EtDHODH has a long insertion in the N-terminal helix region that assumes a disordered configuration. In addition, the crystal structures revealed that the ferulenol binding pocket of EtDHODH is larger than that of HsDHODH. These differences can be explored to accelerate structure-based design of inhibitors specifically targeting EtDHODH.


The Genome of the Human Pathogen Candida albicans Is Shaped by Mutation and Cryptic Sexual Recombination.
The opportunistic fungal pathogen Candida albicans lacks a conventional sexual program and is thought to evolve, at least primarily, through the clonal acquisition of genetic changes. Here, we performed an analysis of heterozygous diploid genomes from 21 clinical isolates to determine the natural evolutionary processes acting on the C. albicans genome. Mutation and recombination shaped the genomic landscape among the C. albicans isolates. Strain-specific single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) clustered across the genome. Additionally, loss-of-heterozygosity (LOH) events contributed substantially to genotypic variation, with most long-tract LOH events extending to the ends of the chromosomes suggestive of repair via break-induced replication. Consistent with a model of inheritance by descent, most polymorphisms were shared between closely related strains. However, some isolates contained highly mosaic genomes consistent with strains having experienced interclade recombination during their evolutionary history. A detailed examination of mitochondrial genomes also revealed clear examples of interclade recombination among sequenced strains. These analyses therefore establish that both (para)sexual recombination and mitotic mutational processes drive evolution of this important pathogen. To further facilitate the study of C. albicans genomes, we also introduce an online platform, SNPMap, to examine SNP patterns in sequenced isolates.IMPORTANCE Mutations introduce variation into the genome upon which selection can act. Defining the nature of these changes is critical for determining species evolution, as well as for understanding the genetic changes driving important cellular processes. The heterozygous diploid fungus Candida albicans is both a frequent commensal organism and a prevalent opportunistic pathogen. A prevailing theory is that C. albicans evolves primarily through the gradual buildup of mitotic mutations, and a pressing issue is whether sexual or parasexual processes also operate within natural populations. Here, we establish that the C. albicans genome evolves by a combination of localized mutation and both short-tract and long-tract loss-of-heterozygosity (LOH) events within the sequenced isolates. Mutations are more prevalent within noncoding and heterozygous regions and LOH increases towards chromosome ends. Furthermore, we provide evidence for genetic exchange between isolates, establishing that sexual or parasexual processes have contributed to the diversity of both nuclear and mitochondrial genomes.


Frameshift mutation in PRKDC, the gene for DNA-PKcs, in the DNA repair-defective, human, glioma-derived cell line M059J.
Anderson, C. W., Dunn, J. J., Freimuth, P. I., Galloway, A. M. and Allalunis-Turner, M. J. Frameshift Mutation in PRKDC, the Gene for DNA-PKcs, in the DNA Repair-Defective, Human, Glioma-Derived Cell Line M059J. Radiat. Res. 156, 2-9 (2001). The glioma-derived cell line M059J is hypersensitive to ionizing radiation, lacks DNA-PK activity, and fails to express protein for the catalytic subunit, DNA-PKcs, while a sister cell line, M059K, derived from the same tumor, has normal DNA-PK activity. Both cell lines are near pentaploid and have multiple copies of chromosome 8, the chromosome on which the DNA-PKcs gene, PRKDC, is located. Sequence analysis of PCR-amplified exons revealed the loss in M059J cells of a single "A" nucleotide in exon 32, corresponding to the first nucleotide of codon 1351 (ACC, Thr) of PRKDC. Loss of the "A" nucleotide would terminate the DNA-PKcs reading frame early in exon 33. DNA from M059K cells had only the wild-type sequence. An analysis of sequences surrounding PRKDC exon 32 from 87 unrelated individuals revealed no polymorphic nucleotides except for a triplet repeat near the 3' end of this exon; no individual had a frameshift mutation in exon 32. No other sequence differences in PRKDC between M059J and M059K cells were observed in approximately 15,000 bp of genomic sequence including the sequences of exons 5 through 38 and surrounding intron sequence, suggesting a possible reduction to homozygosity at this locus prior to acquisition of the mutation leading to the M059J cell line.


Motion Analysis of the Mandible during Low-Speed, Rear-End Impacts using High-Speed X-rays.
There has been much debate over "whiplash"-induced temporomandibular joint (TMJ) dysfunction following low-speed, rear-end automobile collisions. While several authors have reported TMJ injury based on case studies post collision, there has been little biomechanical evidence showing that rear-end impact was the primary cause of such injury. The purpose of this study was to measure the relative translation between the upper and lower incisors in cadavers subjected to low-speed, rearend impacts. High-speed x-ray images used for this analysis were reported previously for the analysis of cadaveric cervical spine kinematics during low-speed, rear-end impacts. The cadavers were positioned at various seatback angles and body postures, producing an overall picture of various seating scenarios. Of the 38 tests conducted using 10 cadavers, there were seven tests from three cadavers in which the positions of the upper and lower incisors could be tracked with precision using imageprocessing software. The relative protrusion, retrusion, and mouth opening were computed from these seven sets of data, providing a better understanding of TMJ motion. Based on this limited data, the average maximum protrusion, retrusion and mouth opening were 1.6+/-1.8, 1.1+/-0.7, and 1.2+/-1.2 mm, respectively. These values appear to fall within normal physiological limits experienced during daily activities such as mastication. It is concluded that low-speed, rear-end automobile collisions do not appear to create the motion required to initiate injury to the TMJ.


Treatment of severe weight loss in anorexia nervosa with hyperalimentation and psychotherapy.
Hyperalimentation is a feeding technique in which all essential nutrients are infused intravenously to sustain patients who cannot eat. Although no panacea for anorexia nervosa, hyperalimentation can provide calories for intractable, malnourished patients. The authors describe the psychiatric and hyperalimentation treatment for four severely anorectic patients who had lost up to 44% of their body weight before entering the study. With treatment their percentage of ideal weight rose from a mean of 59% to a mean of 81% during hospitalization, and to a mean of 94% on outpatient follow-up of 5--16 months. The authors discuss the indications, limitations, and need for interdisciplinary collaboration in this treatment.


EBV LMP1 in Gingival Epithelium Potentially Contributes to Human Chronic Periodontitis via Inducible IL8 Production.
Human chronic periodontitis is a major health problem. Although some oral bacteria have been reported to be putative pathogens, Epstein-Barr virus (EBV) is reported to be associated with the progression of periodontitis. However, the role of EBV in the aetiology of periodontitis is unknown. Therefore, we investigated periodontal pathogenesis of EBV to confirm whether EBV-encoded latent membrane protein 1 (LMP1) induces Interleukin-8 (IL8) production in human gingival cells. Real-time polymerase chain reaction, luciferase assay, enzyme-linked immunosorbent assay (ELISA), and western blotting were performed for determining IL8 mRNA expression, nuclear factor kappa B (NF-ĸB) transcription, IL8 production, and the phosphorylation of NF-ĸB p65 and Inhibitor of kappa B alpha (IĸBα), respectively, in Ca9-22 human gingival epithelial cells. Two LMP1 mutants lacking C-terminal activating region (CATR) domains responsible for activating NF-ĸB were used. Extremely high IL8 production was induced by LMP1 in time- and dose-dependent manner, where simultaneous phosphorylation of NF-κB p65 and IĸBα and transcription of NF-ĸB were observed. On the contrary, IL8 production and NF-ĸB transcription were drastically inhibited by dominant negative mutant of IĸBα. Moreover, the LMP1 mutants failed to induce IL8 production. Our findings suggest that due to CATR domains, LMP1 contributes to the progression of periodontitis via IL8 production attributable to NF-ĸB activation.


Whole antilymphocyte serum: a potent safe immunosuppressive agent for intravenous use in man.
Fifty-one renal and marrow graft recipients have been treated with whole, absorbed rabbit anti-human-lymphocyte serum. Such sera are potent nontoxic immunosuppressive agents. Preexisting sensitivity can be erased, and early rejection episodes are essentially eliminated. Prolonged treatment is necessary and safe, and it ensures a sustained depression in circulating T cells. Adaptation between kidney graft and host then occurs, so that the combination of prednisone and Imuran alone can sustain graft viability.


Excision and grafting of palmoplantar keratoderma.
Palmoplantar keratodermas may present to the clinician with an extremely broad series of clinical findings. Management has also taken on a wide variety of medical and surgical modalities. The literature seems to provide evidence that optimum management consists of surgical excision with skin grafting. It is believed that this will eliminate all of the underlying tissue and associated skin appendages, which are believed to be the source of this abnormal skin entity. We present a case of a patient in which tangential excision with delayed split-thickness skin grafting was performed after initial application of an acellular dermal matrix (Integra). Unfortunately, there was nearly immediate recurrence of this disease, and we, therefore, suggest a more aggressive approach to the initial excision.


Antibiotic susceptibility patterns of Helicobacter pylori strains isolated from northeastern Mexico.
There are reports of increased antibiotic resistance rates in Helicobacter pylori strains around the world. The aim of this study was to determine the susceptibility patterns in H. pylori strains isolated in Monterrey, Mexico. We studied 62 strains isolated from the same number of symptomatic adult patients. Metronidazole (Mtz), clarithromycin (Cla), amoxicillin (Amx) and tetracycline (Tet) were tested by the E-test method. We observed that 37.1% of the strains were resistant to Mtz (MIC > or = 8 mg/L), and 8.1% to Cla (MIC > or = 8 mg/L), but we did not observe resistance to Amx (MIC > or = 2 mg/L) or Tet (MIC > or = 4 mg/L). In northeastern Mexico, the percentage of resistant strains was similar to that observed in developed countries. These results confirm that it is necessary to evaluate the susceptibility patterns of H. pylori strains by geographic area.


Fabrication of removable palatal augmentation prosthesis on a complete denture to reduce weight and maintain hygiene.
A removable veneer-type palatal augmentation prosthesis (PAP) was attached to a complete denture to reduce weight and maintain good hygiene. As a result, the weight of the PAP was reduced from 27.1 g at the time of palatal augmentation, by using the tissue conditioner, to 16.6 g, with the definitive removable veneer-type prosthesis. This method can also be applied to removable partial dentures when the impression of the palatal augmentation is properly positioned on the definitive cast after the removal of the tissue conditioner.


Towards Evaluating Pitch-Related Phonation Function in Speech Communication Using High-Density Surface Electromyography.
Pitch, as a sensation of the sound frequency, is a crucial attribute toward constructing a natural voice for communication. Producing intelligible sounds with normal pitches depend on substantive interdependencies among facial and neck muscles. Clarifying the interrelations between the pitches and the corresponding muscular activities would be helpful for evaluating the pitch-related phonating functions, which would play a significant role both in training pronunciation and in assessing dysphonia. In this study, the speech signals and the high-density surface electromyography (HD sEMG) signals were synchronously acquired when phonating [a:], [i:], and [ә:] vowels with increasing pitches, respectively. The HD sEMG energy maps were constructed based on the root mean square values to visualize spatiotemporal characteristics of facial and neck muscle activities. Normalized median frequency (nMF) and root-mean square (nRMS) were correspondingly extracted from the speech and sEMG recordings to quantitatively investigate the correlations between sound frequencies and myoelectric characteristics. The results showed that the frame-wise energy maps built from sEMG recordings presented that the muscle contraction strength increased monotonously across pitch-rising, with left-right symmetrical distribution for the face/neck. Furthermore, the nRMS increased at a similar rate to the nMF when there were rising pitches, and the two parameters had a significant correlation across different vowel tasks [(a:) (0.88 ± 0.04), (i:) (0.89 ± 0.04), and (ә:) (0.87 ± 0.05)]. These findings suggested the possibility of utilizing muscle contraction patterns as a reference for evaluating pitch-related phonation functions. The proposed method could open a new window for developing a clinical approach for assessing the muscular functions of dysphonia.


Impact of air pollution on running performance.
Air pollution exposures during training may impact race preformances. We aggregated data on 334 collegiate male track & field athletes from 46 universities across the United States over 2010-2014. Using distributed lag non-linear models, we analyzed the relationship between race time and PM2.5, ozone, and two versions of the Air Quality Index (AQI) exposures up to 21 days prior to the race. We observed a 12.8 (95% CI: 1.3, 24.2) second and 11.5 (95% CI: 0.8, 22.1) second increase in race times from 21 days of PM2.5 exposure (10.0 versus 5.0 μg/m3) and ozone exposure (54.9 versus 36.9 ppm), respectively. Exposure measured by the two-pollutant threshold (PM2.5 and ozone) AQI was not significantly associated with race time; however, the association for summed two-pollutant AQI (PM2.5 plus ozone) was similar to associations observed for the individual pollutants (12.4, 95% CI: 1.8, 23.0 s). Training and competing at elevated air pollution levels, even at exposures within AQI's good-to-moderate classifications, was associated with slower race times. This work provides an initial characterization of the effect of air pollution on running performance and a justification for why coaches should consider approaches to reduce air pollution exposures while training.


Advanced non-small cell lung cancer treated with palliative systemic therapy complicated by calvarial metastasis: a case report.
Bony metastases are often seen in advanced cancers and lead to deterioration in patient quality of life with common complications of pain, bone fractures, and hypercalcemia. While most sites of metastasis to bone are observed in the axial skeleton from patients with a primary lung, breast or prostate cancer, metastases to the calvarium from lung cancer are less common, and thus less likely to be identified and managed. A 69-year-old Caucasian female with advanced non-small cell lung cancer (NSCLC) presented with worsening symptoms of widespread body pain, fatigue, and weight loss. Physical examination was remarkable for a palpable protrusion on the patient's head. Imaging revealed a parieto-occipital calvarial lesion, a likely metastasis from her lung cancer. A previously performed CT-guided lung biopsy was evaluated for actionable tumor markers to allow for more specific and efficacious line of treatments; the patient's tumor had lacked any notable gene mutations. The treatment plan included radiotherapy, combined immunotherapy and chemotherapy consisting of pembrolizumab, pemetrexed, and carboplatin. Despite the treatment, the patient's skull lesion had continued to grow, and her overall condition deteriorated to the point where she required hospice. Given the unique location of calvarial metastases, early detection appears to correlate with improving patient outcomes and quality of life. A multimodal approach with a high index of suspicion is essential for diagnosing and managing rare presentations of metastatic disease.


Data centric sensor stream reduction for real-time applications in wireless sensor networks.
This work presents a data-centric strategy to meet deadlines in soft real-time applications in wireless sensor networks. This strategy considers three main aspects: (i) The design of real-time application to obtain the minimum deadlines; (ii) An analytic model to estimate the ideal sample size used by data-reduction algorithms; and (iii) Two data-centric stream-based sampling algorithms to perform data reduction whenever necessary. Simulation results show that our data-centric strategies meet deadlines without loosing data representativeness.


Prognostic value of metabolic tumor volume and total lesion glycolysis in esophageal carcinoma patients treated with definitive chemoradiotherapy.
The aim of this study was to evaluate the prognostic importance metabolic tumor volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) in patients with esophageal cancer treated with definitive chemoradiotherapy. Seventy-two esophageal cancer patients treated with definitive chemoradiotherapy [57 (79%) patients] or definitive radiotherapy [15 (21%) patients] were retrospectively analyzed. The regions equal to or greater than SUV of 2.5 were selected to delineate MTV and TLG was calculated by multiplying the mean SUV by the MTV of the primary lesions. The overall survival (OS) and disease-free survival (DFS) were evaluated for all patients and also patients with squamous cell carcinoma. The median survival time was 13.4 months (range: 1.8-119.3 months) for all patients. Maximum SUV, mean SUV, MTV, and TLG values were significantly higher in patients with extensive T-stage (T3-T4) compared with patients with T1-T2 disease. Patients with regional lymph node metastasis had significantly higher MTV and TLG values compared with patients with no lymph node metastasis. On multivariate analysis, MTV, TLG, presence of lymph node metastasis, and lack of concurrent chemotherapy were negative significant prognostic factors for OS and DFS for the entire cohort and for patients with squamous cell carcinoma esophageal cancer. Metabolic volumes (MTV and TLG), regional lymph node metastasis, and concurrent chemotherapy are major prognostic factors for DFS and OS in patients with esophageal carcinoma. In addition, MTV and TLG are important in predicting nodal metastasis, and together with metabolic volumes, SUV are associated significantly with local tumor invasion.


Novel gene rearrangement in the mitochondrial genome of Coenobita brevimanus (Anomura: Coenobitidae) and phylogenetic implications for Anomura.
The complete mitochondrial genomes (mitogenomes) can indicate phylogenetic relationships among organisms, as well as useful information about the process of molecular evolution and gene rearrangement mechanisms. However, knowledge on the complete mitogenome of Coenobitidae (Decapoda: Anomura) is quite scarce. Here, we describe in detail the complete mitogenome of Coenobita brevimanus, which is 16,393 bp in length, and contains 13 protein-coding genes, two ribosomal RNA, 22 transfer RNA genes, as well as a putative control region. The genome composition shows a moderate A + T bias (65.0%), and exhibited a negative AT-skew (-0.148) and a positive GC-skew (0.183). Five gene clusters (or genes) involving eleven tRNAs and two PCGs were found to have rearranged with respect to the pancrustacean ground pattern gene order. Duplication-random loss and recombination models were determined as most likely to explain the observed large-scale gene rearrangements. Phylogenetic analysis placed all Coenobitidae species into one clade. The polyphyly of Paguroidea was well supported, whereas the non-monophyly of Galatheoidea was inconsistence with previous findings on Anomura. Taken together, our results help to better understand gene rearrangement process and the evolutionary status of C. brevimanus and lay a foundation for further phylogenetic studies of Anomura.


Genetic Variants in KIR/HLA-C Genes Are Associated With the Susceptibility to HCV Infection in a High-Risk Chinese Population.
KIR/HLA-C signaling pathway influences the innate immune response which is the first defense to hepatitis C virus (HCV) infection. The aim of this study was to determine the association between the genetic polymorphisms of KIR/HLA-C genes and the outcomes of HCV infection in a high-risk Chinese population. In this case-control study, four single nucleotide polymorphisms (SNPs) of KIR/HLA-C genes (KIR2DS4/KIR2DS1/KIR2DL1 rs35440472, HLA-C rs2308557, HLA-C rs1130838, and HLA-C rs2524094) were genotyped by TaqMan assay among drug users and hemodialysis (HD) patients including 1,378 uninfected control cases, 307 subjects with spontaneous viral clearance, and 217 patients with persistent HCV infection. Bioinformatics analysis was used to functionally annotate the SNPs. After logistic regression analysis, the rs35440472-A and rs1130838-A alleles were found to be associated with a significantly elevated risk of HCV infection (OR = 1.562, 95% CI: 1.229-1.987, P < 0.001; OR = 2.134, 95% CI: 1.180-3.858, P = 0.012, respectively), which remained significant after Bonferroni correction (0.05/4). The combined effect of their risk alleles and risk genotypes (rs35440472-AA and rs1130838-AA) were linked to the increased risk of HCV infection in a locus-dosage manner (all Ptrend < 0.001). Based on the SNPinfo web server, rs35440472 was predicted to be a transcription factor binding site (TFBS) while rs1130838 was predicted to have a splicing (ESE or ESS) function. KIR2DS4/KIR2DS1/KIR2DL1 rs35440472-A and HLA-C rs1130838-A variants are associated with increased susceptibility to HCV infection in a high-risk Chinese population.


Uranium-series constraints on radionuclide transport and groundwater flow at the Nopal I uranium deposit, Sierra Pena Blanca, Mexico.
Uranium-series data for groundwater samples from the Nopal I uranium ore deposit were obtained to place constraints on radionuclide transport and hydrologic processes for a nuclear waste repository located in fractured, unsaturated volcanic tuff. Decreasing uranium concentrations for wells drilled in 2003 are consistent with a simple physical mixing model that indicates that groundwater velocities are low ( approximately 10 m/y). Uranium isotopic constraints, well productivities, and radon systematics also suggest limited groundwater mixing and slow flow in the saturated zone. Uranium isotopic systematics for seepage water collected in the mine adit show a spatial dependence which is consistent with longer water-rock interaction times and higher uranium dissolution inputs at the front adit where the deposit is located. Uranium-series disequilibria measurements for mostly unsaturated zone samples indicate that (230)Th/(238)U activity ratios range from 0.005 to 0.48 and (226)Ra/(238)U activity ratios range from 0.006 to 113. (239)Pu/(238)U mass ratios for the saturated zone are <2 x 10(-14), and Pu mobility in the saturated zone is >1000 times lower than the U mobility. Saturated zone mobility decreases in the order (238)U approximately (226)Ra > (230)Th approximately (239)Pu. Radium and thorium appear to have higher mobility in the unsaturated zone based on U-series data from fractures and seepage water near the deposit.


Chronic hepatitis C virus in the state of Piauí, northeastern Brazil.
Knowledge of genotype distribution of hepatitis C virus (HCV) has clinical importance due to genotype 1 lower response to treatment compared with genotypes 2 and 3. The goal of this survey was to describe clinical and laboratorial profiles of patients with chronic hepatitis C (CHC) in the State of Piauí, as well as to expand the overall awareness of the distribution of HCV genotyping in Northeast of Brazil. A retrospective cross-sectional study was carried out between April 1999 and August 2005. A total of 153 patients were included, 119 (77.8%) males and 34 (22.2%) females; mean age = 48.01 +/- 9.11 years. We observed a homogeneous distribution between genotypes 1 (50.0%) and 3 (49.0%), while the most frequent subtype noticed was 3a (49.0%). The mean viral load among patients with subtype 1b (1,232,476 UI/mL) was significantly superior to the subtype 1a (391,204 UI/mL; p = 0.010) and to the subtype 3a (594,228 UI/mL; p = 0.047). The average levels of gamma-glutamiltransferase of genotype 1 (144 mg/dL) had statistical differences when compared to genotype 3 (74 mg/dL; p = 0.014). Most patients showed mild to moderate degrees of histopathological necroinflammatory activity and hepatic fibrosis (79.0% and 56.2%, respectively). We concluded that most candidates to treatment of CHC in the State of Piauí presented with clinically stable hepatic illness; the distribution of genotypes 1 and 3 was virtually homogeneous; and there was no significant demographic or clinical differences among genotypes or subtypes of HCV.


Prediction of cardiovascular events by central blood pressure using radial tonometry in type 2 diabetes mellitus patients.
High blood pressure (BP) and type 2 diabetes mellitus (T2DM) are major causes of atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Central blood pressure (CBP) is more predictive of ASCVD than is brachial BP; however, an association of CBP with ASCVD has not been found in T2DM patients. We evaluated the impact of CBP and the association between optimal level of noninvasively measured CBP and office BP in T2DM patients based on composite outcome of ASCVD, HF, and complications of hypertension. Patients were enrolled from June 2011 to December 2015 and were followed up through December 2019. CBP was measured using radial tonometry. The primary endpoints were composite outcome of ASCVD, HF, and hypertension-induced complications such as left ventricular hypertrophy, retinopathy, and proteinuria. During the 6.5-year follow-up period, 515 patients were enrolled in the study. A total of 92 patients (17.9%) developed primary endpoints. The mean age of subjects was 61.3 ± 12.1 years and 55% (n = 283) were male. Patients who developed primary endpoints were older (65.3 ± 9.5 years vs. 60.5 ± 12.4 years) and had lower high-density lipoprotein (36.6 ± 9.4 mg/dL vs. 41.8 ± 11.1 mg/dL), higher CBP (123.6 ± 20.6 mmHg vs. 118.0 ± 20.6 mmHg), and higher pulse pressure (61.3 ± 16.6 mmHg vs. 56.5 ± 15.1 mmHg) than subjects without primary endpoint development. After adjustment for various risk factors, CBP was an independent predictor for primary endpoints (hazard ratio, 1.14; 95% confidence interval, 1.02-1.27; P = 0.016). In addition, the association of CBP and primary endpoints showed a U-shaped curve with the lowest incidence at CBP 118 mmHg and systolic BP about 128 mmHg. We show the importance of CBP measurements in T2DM patients and present a cutoff value for ASCVD events and hypertension-induced complications.


Application of microwave tissue coagulation in partial nephrectomy.
Microwave tissue coagulation was used during partial nephrectomy in 10 mongrel dogs, without clamping the renal artery. There were no major complications, such as retroperitoneal hematoma, abscess formation, or macroscopic infarction of the kidney tissue related to this new procedure. The advantages of microwave coagulation are reduced blood loss, shorter operative time, and minimal risk of vascular injury.


Evolutionary origins and specialisation of membrane transport.
From unicellular protists to the largest megafauna and flora, all eukaryotes depend upon the organelles and processes of the intracellular membrane trafficking system. Well-defined machinery selectively packages and delivers material between endomembrane organelles and imports and exports material from the cell surface. This process underlies intracellular compartmentalization and facilitates myriad processes that define eukaryotic biology. Membrane trafficking is a landmark in the origins of the eukaryotic cell and recent work has begun to unravel how the revolution in cellular structure occurred.


Comparative anatomy of rabbit and human achilles tendons with magnetic resonance and ultrasound imaging.
We sought to describe the comparative anatomy of the Achilles tendon in rabbits and humans by using macroscopic observation, magnetic resonance imaging, and ultrasonography. The calcaneus-Achilles tendon-gastrocnemius-soleus complexes from 18 New Zealand white rabbits underwent ultrasound (US) and magnetic resonance (MR) imaging and gross anatomic sectioning; these results were compared with those from a cadaveric gastrocnemius-soleus-Achilles tendon-calcaneus specimen from a 68-y-old human male. The medial and lateral gastrocnemius muscle tendons merged 5.2 +/- 0.6 mm proximal to the calcaneal insertion macroscopically, at 93% of their course, different from the gastrocnemius human tendons, which merged at 23% of their overall course. The rabbit flexor digitorum superficialis tendon, corresponding to the flexor digitorum longus tendon in human and comparable in size with the gastrocnemius tendons, was located medial and anterior to the medial gastrocnemius tendon proximally and rotated dorsally and laterally to run posterior to the Achilles tendon-calcaneus insertion. In humans, the flexor digitorum longus tendon tracks posteriorly to the medial malleolus. The soleus muscle and tendon are negligible in the rabbit; these particular comparative anatomic features in the rabbit were confirmed on the MR images. Therefore the rabbit Achilles tendon shows distinctive gross anatomical and MR imaging features that must be considered when using the rabbit as a research model, especially for mechanical testing, or when generalizing results from rabbits to humans.


[An information system on live births and the use of its data in epidemiology and health statistics].
The Brazilian Ministry of Health implemented, in 1990, a System of Information of Live Births (SINASC) which introduced a Birth Certificate with a view to obtaining the total number of these events and their distribution according to epidemiological, demographic and clinical characteristics. It was decided to evaluate the System according to its coverage and the quality of information obtained, two years after its initial implementation. The population of this study consists of 15,142 hospital live births which occurred in five cities of the State of São Paulo, Brazil, in 1992. Birth Certificates and the corresponding maternal and child hospital records were examined visually with a view to checking data recorded on the Birth Certificate. It was seen that the system achieved a high degree of completeness (99.5%) and obtained a very accurate report for most of the items, though rather poor reporting for Apgar Score, length of gestation, mother's schooling, parity and father's name. This study allows suggestions to be made for the reformulation of some items and regarding the necessity for retraining the hospital personnel involved in the filling in of the certificates. Overall this study confirms that the Birth Certificate data are adequate for a valid analysis of aspects of maternal and child health research. The data showed high percentages of adolescent mothers (17.5%) and deliveries by cesarian section (48.4%). The percentage of low birth weight was 8.5%.


Nutritional and Medicinal Value of Specialty Mushrooms.
Although the button mushroom ( Agaricus bisporus ) accounts for slightly over half of total world mushroom production, specialty mushrooms, e.g., shiitake ( Lentinula edodes ), straw ( Volvariella volvacea ), oyster ( Pleurotus spp.), and enokitake ( Flammulina velutipes ), are increasing in popularity. These species contain moderate quantities of good quality protein and are good sources of dietary fiber, vitamin C, B vitamins, and minerals. Lipid levels are low, but unsaturated to saturated fatty acid ratios are high (about 2.0 - 4.5:1). Some species (e.g., shiitake) accumulate cadmium and selenium and other heavy metals, and some may contain toxic substances such as the heat labile cardiotoxic proteins volvatoxin in the straw mushroom and flammutoxin in enokitake. Extensive clinical studies, primarily in Japan, have clearly demonstrated that a number of species have medicinal and therapeutic value, by injection or oral administration, in the prevention/treatment of cancer, viral diseases (influenza, polio), hypercholesterolemia, blood platelet aggregation, and hypertension. Most of the studies have focused on shiitake, enokitake, Pleurotus spp., and on the generally nonculinary Ganoderma spp. Many of the active substances which include polysaccharides (e.g., β-glucans), nucleic acid derivatives (the hypocholesterolemic eritadenine), lipids, peptides, proteins, and glycoproteins, have been isolated and identified. Some of the mechanisms of activity have been elucidated, e.g., antiviral activity via stimulation of interferon production in the host. Additional medical claims less well documented may nonetheless have some validity and merit further study.


Intra-urethral ultrasound in women with stress incontinence.
To investigate whether the sphincter area in women can be seen and quantified with intra-urethral ultrasound (IUUS). Currently, sphincter capacity in women is determined by clinical tests, vaginal palpation, urodynamics and urethral pressure profile. A pilot study using IUUS was carried out in 32 stress incontinent and 12 healthy women to enable the urethra and para-urethral tissue to be visualized. Round-tipped miniature transducer-containing (20 MHz) catheters (6 and 9 F) were tested. Both provided 15 frames per second. Real-time 360 degrees cross-sectional ultrasound images were obtained by using a standard intraluminal ultrasound system. The external urethral sphincter was visualized and its circumference and area were measured. IUUS provided high resolution imaging of the urethra and surrounding tissues. The whole length of the urethra was visualized. The external sphincter was easily recognized as an oval-shaped, hypoechoic structure. Examination of 44 stress incontinent and healthy women revealed a negative correlation between the external urethral sphincter (area and circumference) and the grade of stress incontinence (P < 0.01). In no patient with normal urinary continence was the sphincter reduced in size (< 2.8 cm circumference). IUUS is a useful technique in the diagnosis of incontinence, as conventional methods provide little information on the sphincter itself. The evaluation of sphincter size and morphology could help in the choice of therapy.


Secondary syphilis presenting as tonsillitis in three patients.
We describe three homosexual men presenting to the ear, nose and throat clinic with severe tonsillitis. All were subsequently diagnosed with secondary syphilis of the tonsil. Syphilis should be considered as a diagnosis in high risk patients presenting with tonsillar lesions, even in the absence of other classical features of the disease.


Perfusion reduction in the absence of structural differences in cognitively impaired versus unimpaired RRMS patients.
Cognitive impairment affects 40%-68% of relapsing-remitting multiple sclerosis (RRMS) patients. Gray matter (GM) demyelination is complicit in cognitive impairment, yet cortical lesions are challenging to image clinically. We wanted to determine whether cortical cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) differences exist between cognitively impaired (CI) and unimpaired (NI) RRMS. Prospective study of healthy controls (n = 19), CI (n = 20), and NI (n = 19) undergoing magnetic resonance imaging (MRI) and cognitive testing <1 week apart. White matter (WM) T2 hyperintense lesions and T1 black holes were traced. General linear regression assessed the relationship between lobar WM volume and cortical and WM CBF, CBV, and MTT. Relationship between global and lobar cortical CBF, CBV, and MTT and cognitive impairment was tested using a generalized linear model. Adjusted Bonferroni p < 0.005 was considered significant. No significant differences for age, gender, disease duration, and any fractional brain or lesion volume were demonstrated for RRMS subgroups. Expanded Disability Status Scale (EDSS) and Hospital Anxiety and Depression Scale-Depression (HADS-D) were higher in CI. Lobar cortical CBF and CBV were associated with cognitive impairment (p < 0.0001) after controlling for confounders. Cortical CBV accounted for 7.2% of cognitive impairment increasing to 8.7% with cortical CBF (p = 0.06), while WM and cortical CBF accounted for 8.2% of variance (p = 0.04). Significant cortical CBF and CBV reduction was present in CI compared to NI in the absence of structural differences.


Neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic adenocarcinoma: feasibility, efficacy, and survival.
We evaluated the feasibility and efficacy of neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic cancer. From October 2000 to August 2006, 245 patients with pancreatic adenocarcinoma underwent surgical exploration at our institution. Of these, 78 patients (32%) had undergone neoadjuvant therapy for initially unresectable disease, whereas the remaining patients (serving as the control group) were explored at presentation (n=167). All neoadjuvant patients received gemcitabine-based chemotherapy, often in conjunction with docetaxal and capecitabine in a regimen called GTX (81%). Seventy-five percent of neoadjuvant patients also received preoperative abdominal radiation (5,040 rad). Neoadjuvant patients were younger than control-group patients (60.8 vs 66.2 years, respectively, p<0.002). Seventy-six percent of neoadjuvant patients were resected as compared to 83% of control patients (NS). Concomitant vascular resection was required in 76% of neoadjuvant patients but only 20% of NS (p<0.01). Complications were more frequent in the neoadjuvant group (44.1 vs 30.9%, p<0.05), and mortality was higher (10.2 vs 2.9%, p<0.03). Among the neoadjuvant patients, all but one of the deaths were in patients that underwent arterial reconstruction. Mortality for patients undergoing a standard pancreatectomy without vascular resection was 0.8% in this series. Of patients resected, negative margins were achieved in 84.7% of neoadjuvant patients and 72.7% of NS. Within the cohort of neoadjuvant patients, radiation significantly increased the complication rate (13.3 vs 54.6%, p<0.006), but did not affect median survival (512 vs 729 days, NS). Median survival for patients who received neoadjuvant therapy (503 days) was longer than NS that were found to be unresectable at surgery (192 days, p<0.001) and equivalent to NS that were resected (498 days). Resection rate, margin status, and median survivals were equivalent when neoadjuvant patients were compared to patients considered resectable by traditional criteria, demonstrating equal efficacy. Surgical resection with venous reconstruction following neoadjuvant therapy for patients with locally advanced pancreatic cancer can be performed with acceptable morbidity and mortality. This approach extended the boundaries of surgical resection and greatly increased median survival for the "inoperable" patient with advanced pancreatic cancer.


Cloning of two genes encoding Rab7 in Paramecium.
Rab7 is a small GTPase that plays a crucial role in the regulation of transport from early to late endosomes and lysosomes, phagosome maturation and in lysosomal biogenesis in mammalian cells. It contains conserved and unique sequence elements that mediate its function. Two Rab7 genes, Rab7a (703 bp) and Rab7b (707 bp) were identified in the unicellular eukaryote Paramecium by PCR amplification. They contain three short introns of different lengths (28-32 bp) and sequence located at identical positions in both genes. The presence of two Rab7 genes in the Paramecium genome was confirmed by Southern hybridization analysis performed with six different restriction enzymes. Expression of both genes was assessed by Northern blot and RT-PCR. Two transcripts of 1.8 and 2.2 kb were identified by hybridization analysis. The cloned complementary DNAs, both of 618 nucleotides in length, encode polypeptides of 206 amino acids that are 97.6% identical and differ in their C-termini. The predicted protein sequences of Rab7a and Rab7b contain all characteristic domains essential for Rab function: the effector domain (YRATVGADF) and four GTP-binding consensus sequences (GDSGVGKT, WDTAGQ, NKLD, SAK) as well as the prenylation motif (-CC) at the C-terminus indispensable for Rab binding to the membrane. Similarity searches revealed 81.6-82.1% homology of Paramecium Rab7 isoforms to human Rab7 and a lack of an insert typical for the Kinetoplastida - the species that appeared earlier in evolution. Paramecium is the first free-living lower eukaryote in which homologues of Rab7 have been identified that exhibit features similar to those of mammalian Rab7.


Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism.
The insulin-like growth factor (IGF) signaling pathway plays a crucial role in the regulation of cell growth, differentiation, apoptosis, and aging. IGF-binding proteins (IGFBPs) are important members of the IGF axis. IGFBP-5 is up-regulated during cellular senescence in human dermal fibroblasts and endothelial cells, but the function of IGFBP-5 in cellular senescence is unknown. Here we show that IGFBP-5 plays important roles in the regulation of cellular senescence. Knockdown of IGFBP-5 in old human umbilical endothelial cells (HUVECs) with IGFBP-5 micro-RNA lentivirus caused partial reduction of a variety of senescent phenotypes, such as changes in cell morphology, increases in cell proliferation, and decreases in senescence-associated beta-galactosidase (SA-beta-gal) staining. In addition, treatment with IGFBP-5 protein or up-regulation of IGFBP-5 in young cells accelerates cellular senescence, as confirmed by cell proliferation and SA-beta-gal staining. Premature senescence induced by IGFBP-5 up-regulation in young cells was rescued by knockdown of p53, but not by knockdown of p16. Furthermore, atherosclerotic arteries exhibited strong IGFBP-5-positive staining along intimal plaques. These results suggest that IGFBP-5 plays a role in the regulation of cellular senescence via a p53-dependent pathway and in aging-associated vascular diseases.


The "Loma Linda stent": a screw-retained resin stent.
This article describes a technique in which an acellular dermal allograft is used in combination with a photopolymerized acrylic resin stent to increase the zone of keratinized tissue around osseointegrated dental implants. During the second-stage surgery, a split thickness labial flap is reflected and apically repositioned by being sutured onto the periosteum and connective tissue. The acellular dermal allograft is then sutured onto the recipient site. The acrylic resin is trimmed and secured with temporary abutments to the implants, fitting passively over the graft and then photopolymerized intraorally. The stent is left for 1 week to secure the graft in place. This technique offers an alternative mucogingival procedure for increasing the zone of keratinized tissue around osseointegrated dental implants.


Cross-correlation analysis of mechanomyographic signals detected in two axes.
The purpose of this study was to use laser displacement sensors to examine the cross-correlation of surface mechanomyographic (MMG) signals detected from the rectus femoris muscle in perpendicular and transverse axes during isometric muscle actions of the leg extensors. Ten healthy men (mean +/- SD age = 22.1 +/- 1.6 years) and ten healthy women (age = 24.4 +/- 2.8 years) volunteered to perform submaximal to maximal isometric muscle actions of the dominant leg extensors. During each muscle action, two separate MMG signals were detected from the rectus femoris with laser displacement sensors. One MMG sensor was oriented in an axis that was perpendicular (PERP) to the muscle surface, and the second sensor was oriented in an axis that was transverse (TRAN) to the muscle surface. For each subject and force level, the MMG signals from the PERP and TRAN sensors were cross-correlated. The results showed maximum cross-correlation coefficients that ranged from R(x)(,y) = 0.273 to 0.989, but all subjects demonstrated at least one coefficient greater than 0.89. These findings showed a high level of association between the MMG signals detected in the perpendicular and transverse axes. Thus, it may not be necessary to detect MMG signals in multiple axes.


Beyond migration-Chemokines in lymphocyte priming, differentiation, and modulating effector functions.
Chemokines and their receptors coordinate the positioning of leukocytes, and lymphocytes in particular, in space and time. Discrete lymphocyte subsets, depending on their activation and differentiation status, express various sets of chemokine receptors to be recruited to distinct tissues. Thus, the network of chemokines and their receptors ensures the correct localization of specialized lymphocyte subsets within the appropriate microenvironment enabling them to search for cognate antigens, to become activated, and to fulfill their effector functions. The chemokine system therefore is vital for the initiation as well as the regulation of immune responses to protect the body from pathogens while maintaining tolerance towards self. Besides the well investigated function of orchestrating directed cell migration, chemokines additionally act on lymphocytes in multiple ways to shape immune responses. In this review, we highlight and discuss the role of chemokines and chemokine receptors in controlling cell-to-cell contacts required for lymphocyte arrest on endothelial cells and immunological synapse formation, in lymphocyte priming and differentiation, survival, as well as in modulating effector functions.


Long-Term Outcomes of Active Surveillance and Immediate Surgery for Adult Patients with Low-Risk Papillary Thyroid Microcarcinoma: 30-Year Experience.
Background: It has been 30 years since the initiation of active surveillance (AS) for adult patients with low-risk papillary thyroid microcarcinoma (PTMC). This study compared the long-term oncological outcomes of patients who underwent AS or immediate surgery (IS). Methods: This is a retrospective review of extended follow-up data from patients enrolled in a single-center, prospective observational study in Japan. In total, 5646 patients diagnosed with low-risk PTMC at Kuma Hospital between 1993 and 2019 were enrolled in this study. Of these, 3222 patients underwent AS (AS group), whereas 2424 underwent IS (IS group). The patients were followed up regularly, at least once per year. Descriptive outcome data were presented according to the treatment group. Results: In the AS group, 124 patients (3.8%) had tumor enlargement of ≥3 mm, and the 10- and 20-year enlargement rates were 4.7% and 6.6%, respectively. Novel lymph node metastases occurred in 27 patients (0.8%), and the 10- and 20-year nodal metastasis occurrence rates were 1.0% and 1.6%, respectively. In the IS group, 13 patients (0.5%) experienced lymph node recurrence postoperatively, and the 10- and 20-year nodal recurrence rates were 0.4% and 0.7%, respectively. Eighteen (1.4%) of the 1327 patients who underwent hemithyroidectomy experienced recurrence in the residual thyroid. The rate of lymph node metastasis was significantly higher in the AS group than in the IS group (1.1% vs. 0.4% and 1.7% vs. 0.7% at 10 and 20 years, respectively; p = 0.009), but the differences were small. However, the proportion of patients who underwent one or more and two or more surgeries was significantly higher in the IS group than in the AS group (100% vs. 12.3% and 1.07% vs. 0.09%, p < 0.01). Distant metastatic recurrence was observed in one patient after AS and conversion surgery and another after IS; however, they were alive (18.4 and 18.8 years after diagnosis, respectively). None of the patients in this study died of thyroid carcinoma. Conclusions: Long-term oncological outcomes of patients with PTMC generally did not differ clinically significantly between those undergoing AS and IS. AS is a viable initial management option for patients with low-risk PTMC.


Health-related quality of life among children with acute lymphoblastic leukemia.
The objective was to quantify the health-related quality of life (HRQL) of children treated for acute lymphoblastic leukemia (ALL) and identify specific disabilities for remediation. Two types of subjects were included: ALL patients 5 plus years old in a multi-center clinical trial and general population control groups. Patients were assessed during all four major phases of active treatment and approximately 2 years after treatment. Health status and HRQL were measured using HEALTH UTILITIES INDEX® (HUI®) Mark 2 (HUI2) and Mark 3 (HUI3). HRQL scores were used to calculate quality-adjusted life years (QALYs). Excess disability rates identified attributes for remediation. HUI assessments (n = 749) were collected during the five phases. Mean HRQL increased from induction through the post-treatment phase (P < 0.001). There were no significant demographic or treatment effects on HRQL, except for type of asparaginase during continuation therapy (P = 0.005 for HUI2 and P = 0.007 for HUI3). Differences in mean HRQL scores between patients and controls were important (P < 0.001) during the active treatment phases but not during the post-treatment phase. Relative to controls, patients lost approximately 0.2 QALYs during active treatment. Disability was evident in mobility/ambulation, emotion, self-care and pain, and declined over time. Patients with ALL experienced important but declining deficits in HRQL during active treatment phases: Equivalent to losing approximately 2 months of life in perfect health. HRQL within the 2-years post-treatment phase was similar to controls. The policy challenge is to develop new treatment protocols producing fewer disabilities in mobility/ambulation, emotion, self-care, and pain without compromising survival.


[Value-based medicine in ophthalmology].
Value-based medicine (VBM) unifies costs and patient-perceived value (improvement in quality of life, length of life, or both) of an intervention. Value-based ophthalmology is of increasing importance for decisions in eye care. The methods of VBM are explained and definitions for a specific terminology in this field are given. The cost-utility analysis as part of health care economic analyses is explained. VBM exceeds evidence-based medicine by incorporating parameters of cost and benefits from an ophthalmological intervention. The benefit of the intervention is defined as an increase or maintenance of visual quality of life and can be determined by utility analysis. The time trade-off method is valid and reliable for utility analysis. The resources expended for the value gained in VBM are measured with cost-utility analysis in terms of cost per quality-adjusted life years gained (euros/QALY). Numerous cost-utility analyses of different ophthalmological interventions have been published. The fundamental instrument of VBM is cost-utility analysis. The results in cost per QALY allow estimation of cost effectiveness of an ophthalmological intervention. Using the time trade-off method for utility analysis allows the comparison of ophthalmological cost-utility analyses with those of other medical interventions. VBM is important for individual medical decision making and for general health care.


A mathematical model to describe the risk of infection from sharing injection equipment.
A mathematical model is presented that describes the probability of a subject becoming infected as a result of sharing equipment used for percutaneous injections. This risk is a function of (a) the number of syringes shared by the subject, (b) the probability of a syringe becoming contaminated after being used once by an infective person, (c) the probability of a person becoming infected after using a contaminated syringe once, (d) the number of persons who have previously used each syringe shared by the subject, (e) the prevalence of infectivity in the group from which these previous users are drawn, (f) the number of times each syringe has been used by each previous user, and (g) the number of times the subject uses it. Simulations with the model suggest mainly that (i) when each shared syringe has been used previously by only one person, the number of persons with whom syringes are shared is more important than the number of syringes; (ii) the reverse is true when each shared syringe has previously been used by many persons; and (iii) for an equal number of injections, the "shooting gallery" type of sharing can be much more risky than other kinds of sharing, but this difference decreases as the infections becomes more prevalent.