Bridging for an isolated subtherapeutic INR: an evaluation of clinical practice patterns, outcomes, and costs from an anticoagulation clinic.
No formal recommendations support bridging patients taking warfarin for a subtherapeutic international normalized ratio (INR). This study aimed to: (1) characterize practices at one anticoagulation clinic, (2) evaluate adverse events, and (3) compare cost of bridging versus withholding bridging for subtherapeutic INR. A retrospective chart review of 320 patients having 546 isolated subtherapeutic INR episodes included patients with an INR below their therapeutic range, preceded by two INRs within or above range. Bridged episodes required more frequent follow-up visits to achieve therapeutic INR (2.5 ± 1.0 vs. 2.2 ± 0.6; P = 0.097), but fewer days until the INR returned to therapeutic range (6.8 ± 5.0 vs. 18.9 ± 16.0; P < 0.0001). The strongest predictor of bridging was the magnitude the INR fell below the therapeutic range, where those with a severely-low INR were 30-fold more likely to be bridged (P < 0.0001), and moderately-low INR episodes were 6-fold more likely to be bridged compared with mildly-low INR (P < 0.0001). Those at high thromboembolic risk were more likely to be bridged than at low-risk (OR 3.39 [1.50-7.68]; P = 0.0034). Increasing age reduced the likelihood of being bridged (OR 0.97 [0.95-0.99]; P = 0.0118). Adverse events were infrequent in both the bridged and non-bridged; thrombosis (2.0 vs. 0.7%), major bleeding (2.0 vs. 1.3%), minor bleeding (4.1 vs. 3.1%) and bruising (18.4 vs. 3.6%). Incremental cost difference of bridging was significantly greater for total cost ($967.13) and its components, direct medical ($951.32), transportation ($2.73) and productivity cost ($13.08). It is unclear if bridging for an isolated subtherapeutic INR reduces thrombosis risk, but it is associated with higher costs.


Thrombin regulates tissue factor and thrombomodulin mRNA levels and activities in human saphenous vein endothelial cells by distinct mechanisms.
The effects of thrombin, D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone (PPACK)-inhibited thrombin, and thrombin receptor agonist peptide, SFLLRNPNDKYEPF (SFLL, a portion of the receptor unmasked after thrombin cleavage), on the expression of tissue factor (TF) and thrombomodulin by human saphenous vein endothelial cells (HSVECs) in culture were studied. Unstimulated cells contained very low amounts of TF mRNA as measured by the reverse transcriptase-PCR method. Thrombin treatment increased TF mRNA to 8.0 +/- 1.9 (n = 3) times the control level. The increase was detectable within 2 h and declined to near basal level by 6 h. Induction of TF mRNA was not blocked by cycloheximide, treatment with cycloheximide alone also increased TF mRNA levels, and thrombin in combination with cycloheximide further enhanced the accumulation of TF mRNA. Thrombin caused a 14.5 +/- 1.5-fold (n = 5) increase in TF activity on the surface of HSVECs and a 20.5 +/- 1.4-fold (mean +/- S.D., n = 2) increase in the extracellular matrix. The thrombin-induced effects on TF synthesis could be fully reproduced by the thrombin receptor agonist peptide, SFLL, whereas PPACK-inhibited thrombin did not influence TF expression. Thrombin increased thrombomodulin mRNA to 190 +/- 39% (n = 5) of control levels, whereas PPACK-inhibited thrombin or SFLL did not influence thrombomodulin mRNA levels. In contrast, surface-bound thrombomodulin cofactor activity and thrombomodulin antigen in the cell lysates did not change over 24 h of incubation with thrombin. However, thrombin caused a 2-fold increase in thrombomodulin antigen released into the conditioned medium, and immunoelectron microscopy of HSVECs also demonstrated the presence of thrombomodulin vesicles close to the luminal cell surface in thrombin-treated cultures. The Western blot pattern thrombomodulin in the conditioned medium of untreated and thrombin-treated cells was found to be similar, and soluble thrombomodulin occurred mainly as fragments of the cell-associated form. We conclude that the transcriptional control by thrombin causes an increase in both TF and thrombomodulin mRNA. The increase in TF mRNA levels is also paralleled by an increase in surface expression, is dependent on the proteolytic activity of thrombin, and is mediated by the same receptor as the recently cloned thrombin receptor in platelets. Up-regulation of thrombomodulin mRNA levels by thrombin is distinct from this pathway and is associated with unchanged expression on the cell surface.


Factors affecting nutritional status of Anganwadi children: A cross-sectional study.
As per the National Family Health Survey (NFHS) 2015-16, 35.7% children below 5 years of age are underweight. In light of Malnutrition rates still remaining alarming in children, it becomes pertinent to elicit the factors that affect nutritional status of children. So, this study was undertaken. After obtaining ethical approval from institutional ethics committee, data were collected on a pretested questionnaire. Information from mothers of 1085 children attending Anganwadi center in an urban block of Patiala was collected and analyzed. Among females, 35.85% were underweight, whereas the proportion for males was 28.68%. The proportion among immunized children who were underweight was 31.34%, whereas the proportion among unimmunized children was 38.91%. Those who received supplementary nutrition were also in more in numbers in normal weight range than those who did not. Gender, birth order, and immunization status of child are significantly associated with nutritional status. This study showed that prevalence of malnutrition was less among those who received supplementary nutrition as compared to ones who did not.


Predictors of care seeking in women with urinary incontinence.
To determine predictors of health care utilization in women with urinary incontinence (UI) from the population to specialty care. The General Longitudinal Overactive Bladder Evaluation-UI is a population-based study on the natural history of UI in women ≥40 years of age. Prevalence of UI was estimated using the Bladder Health Survey (BHS). Survey data were linked with electronic health records (EHRs) to examine factors associated with a clinical UI diagnosis using logistic regression. Risk factors analyzed included: UI symptoms, subtypes, bother, severity, duration, and effect on quality of life, and demographic and other health characteristics. All statistical tests were two-sided with a P-value < 0.05 being significant. The overall prevalence of any UI based on responses to the BHS was 1,618/4,064 (40%). Of the 1,618 women with UI, there were only 398 (25%) women with EHR (clinical) diagnosis of UI. Women with UI versus those without UI were more likely to be have a BMI >25 kg/m(2) (70% vs. 58%), more likely to be parous (91% vs. 87%) and college educated (54% vs. 46%), P < 0.001. After adjusting for confounders in the model, variables significantly associated with clinical UI diagnosis included: older age (OR = 1.96), higher parity (> 1 birth) (OR = 1.76), higher urgency UI (OR = 1.08), adaptive behavior (OR = 1.2), and UI bother scores (OR = 1.01), as well as more frequent outpatient visits (OR = 1.03), P < 0.05. UI is a highly prevalent condition with only a minority of women seeking care. Factors associated with health care utilization include older age, parity (1+), number of doctor visits, urgency UI subtype, UI bother, and impact on behavior.


Sexual attitudes as correlates of sexual details in human figure drawing.
The hypothesis that sexual attitudes, as measured by the Sexual Opinion Survey, are related to the explicitness with which nude figures are drawn was examined. The presence or absence of various sexual and nonsexual anatomical features, as well as length and width measurements, were assessed in the drawing of nudes by 17 male and 23 female undergraduates. Individuals with relatively positive sexual attitudes (erotophiles), as compared with individuals with relatively negative attitudes (erotophobes), were more likely to include such details as a glans, a urinary meatus, and chest hair on male figures and pubic hair and nipples on female figures. Positive sexual attitudes were also associated with drawing figures with longer and wider penises, breasts, testicles, and mons. Relationships between sexual attitudes and the drawing of nonsexual body parts were generally not significant. The results are discussed in terms of the pervasive generality of sexual attitudes in influencing quite varied sex-related behaviors.


Rhythmic phrenic nerve activity and respiratory activity in spinal dogs.
The possibility of respiratory activity in adult spinal dogs was reinvestigasted with emphasis placed on the contribution of the phrenic nerves and diaphragm. Under chloroform anesthesia, the spinal cord was transected at either the C1 or C2 level. After spinal transection and occlusion of the blood flow to the head, anesthesia was discontinued. In 6 dogs spinal rhythmic respiratory activity was induced by administration of doxapram HCl, 3-5 mg/kg i.m., while in 2 dogs such activity occurred spontaneously. The observed cyclic changes in intrapleural pressure correlated with unilateral phrenic neurogram. The bursts frequency of the phrenic nerve activity was altered by the artificial positive-pressure respiration synchronizing the phrenic activity with the respirator. This suggests that afferent reflexes can modulate this spinal, cyclic phrenic nerve activity. This study demonstrates that the phrenic nerve and the diaphragm play a major role in spinal respiratory activity.


Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome.
Chronic prostatitis/chronic pelvic pain syndrome represents a wide range of clinical phenotypes and has traditionally been a diagnosis of exclusion with few proven remedies. Our structured, simplified approach to evaluation and management of this complex condition results in improved patient outcomes.


Industrial Enzymology: The Next Chapter.
This review focuses on recent developments in industrial enzymology, protein engineering, and the design and production of microorganisms. We highlight the latest recombinant DNA (rDNA) technology and tools of protein engineering. These advancements are delivering solutions that address the large unmet needs of customers and markets. To illustrate the progress made over the past three decades, several technological developments and applications are highlighted. High-throughput methods of cell and protein engineering have increased the pace of commercialization. Continuous innovations have impacted many areas of industrial biotechnology and its applications; for example, laundry and dish washing, textile processing, animal health, and human nutrition. The worldwide growth of this bioindustry reflects the potential of biotechnology, which in turn adds a new chapter to the field of industrial enzymology.


Expression of the adrenomedullin gene in adipose tissue.
Adrenomedullin (AM) is a potent vasodilating peptide originally isolated from human pheochromocytoma cells. This report concerns the expression and secretion of AM from adipose tissue. Northern blot analysis demonstrated marked expression of AM mRNA in mouse adipose tissue. Expression levels in adipose tissues were 2.5-3.2 times higher than in the kidney. AM mRNA level in mature adipocytes was 7.3 times higher than in the stroma-vascular fraction of adipose tissue. In mature adipocyte culture, time-dependent increase of AM peptide concentration in the culture medium was detected. AM expression was also detected in human subcutaneous adipose tissue. Adipose AM expression significantly increased in obesity mouse model, high-fat diet fed mice and ob/ob mice. These results suggest that adipose tissue, especially mature adipocytes, is major source of AM in the body, and that adipocyte-derived AM plays a pathophysiological role in obesity.


Coordinated cellular and humoral immune responses after two-dose SARS-CoV2 mRNA vaccination in liver transplant recipients.
Limited data are available on risks and benefits of anti-SARS-CoV2 vaccination in solid organ transplant recipients, and weaker responses have been described. At the Italian National Institute for Infectious Diseases, 61 liver transplant recipients underwent testing to describe the dynamics of humoral and cell-mediated immune response after two doses of anti-SARS-CoV2 mRNA vaccines and compared with 51 healthy controls. Humoral response was measured by quantifying both anti-spike and neutralizing antibodies; cell-mediated response was measured by PBMC proliferation assay with IFN-γ and IL-2 production. Liver transplant recipients showed lower response rates compared with controls in both humoral and cellular arms; shorter time since transplantation and multi-drug immunosuppressive regimen containing mycophenolate mofetil were predictive of reduced response to vaccination. Specific antibody and cytokine production, though reduced, were highly correlated in transplant recipients.


Relevance of in vitro studies for aging of the organism. A review.
Cell culture in vitro has been widely used to study aging at a cellular level. The criticisms that have been raised to the use of this experimental system are due to incorrect interpretations of the results obtained, and to ignorance of the physiological development of the human organism through its life span. The cell culture methodology has yielded fundamental knowledge concerning how a cell is modified through division, how this creates a change in cell function, and the consequences it has on cell interactions.


Desiccation- and abscisic acid-responsive genes encoding major intrinsic proteins (MIPs) from the resurrection plant Craterostigma plantagineum.
Major intrinsic proteins (MIPs) are a family of channel proteins that are mainly represented by aquaporins in plants. These are divided into TIPs (tonoplast intrinsic proteins) and PIPs (plasma membrane intrinsic proteins) according to their subcellular localization. Homologues to PIPs and TIPs were isolated from the desiccation-tolerant resurrection plant Craterostigma plantagineum by two approaches: firstly, a cDNA library constructed from RNA of dehydrated C. plantagineum leaves was screened with an Arabidopsis thaliana Ath-PIP1b cDNA probe and, secondly, a cDNA library was screened differentially to isolate early drought-induced transcripts. According to sequence homologies the isolated cDNA clones were grouped as follows: Cp-PIPa, Cp-PIPb, Cp-PIPc and Cp-TIP. Cp-PIPa, Cp-PIPc and Cp-TIP transcript accumulation was regulated by dehydration and abscisic acid (ABA). Within the Cp-PIPa group transcripts were regulated either by drought only or by drought and ABA, indicating that ABA-dependent and -independent signal transduction pathways lead to Cp-PIPa expression. Comparison of Cp-PIPa expression in detached leaves and in whole plants suggested the involvement of a signal transmitted in the whole plant in response to drought. Cp-PIPb transcript levels were constitutive in all organs tested. Antibodies raised against a Cp-PIPA protein recognized a polypeptide with an apparent molecular mass of 28 kDa. Using these antibodies it was shown that both Cp-PIPA and Cp-PIPB proteins were localized to the plasma membrane. The role of different members of the MIP group in the dehydration response is discussed.


Cells with stemness features are generated from in vitro transformed human fibroblasts.
Cancer stem cells (CSCs) have been involved in the maintenance, progression and relapse of several tumors, but their origin is still elusive. Here, in vitro transformed human fibroblasts (cen3tel cells) and the tumorsphere assay were used to search for and possibly characterize CSCs in transformed somatic cells. Cen3tel cells formed spheres showing self-renewal capacity and Sox2 overexpression, suggesting that they contained a subset of cells with CSC-like features. Sphere cells displayed deregulation of a c-MYC/miR-34a circuitry, likely associated with cell protection from apoptosis. Gene expression profiles of sphere cells revealed an extensive transcriptional reprogramming. Genes up-regulated in tumorspheres identified processes related to tumorigenesis and stemness, as cholesterol biosynthesis, apoptosis suppression, interferon and cytokine mediated signalling pathways. Sphere cells engrafted into NSG mice more rapidly than adherent cells, but both cell populations were tumorigenic. These results indicate that, during transformation, human somatic cells can acquire CSC properties, confirming the high plasticity of tumor cells. However, CSC-like cells are not the only tumorigenic population in transformed cells, indicating that the CSC phenotype and tumorigenicity can be uncoupled.


Neural tuning in the granite spiny lizard.
Scanning electron microscopy was used to examine the basilar papilla of the granite spiny lizard. The papilla contains three distinct hair cell populations: an apical and a basal population with free-standing cilia, and a central population with a tectorial membrane. In the free-standing populations, stereocilium length decreases towards the ends of the papilla. Ciliary tuft morphology differs in the free-standing and the tectorial membrane populations, except that several of the free-standing hair cells with the shortest stereocilia have a tuft morphology like the hair cells in the tectorial membrane population. On the basis of single-fiber physiology, auditory nerve fibers can be divided into a low characteristic frequency (CF) and a high CF population. Mappings of the tonotopic organization of the nerve demonstrated two groups of high CF fibers that correspond to the two free-standing hair cell populations. The low CF fibers are associated with the tectorial membrane hair cell population. Fiber CF correlated with hair cell cilium length, not position on basilar membrane, for hair cells with free-standing cilia. Tonotopic organization of high CF fibers could be predicted reasonably well from the histogram of fiber CFs.


Soil acidification and vegetation changes in deciduous forest in southern Sweden.
Thirtyfour deciduous forest sites in southern Sweden, originally studied in 1949-1970, were resampled in 1984/85. The average pH change in the humus layer was-0.78 and-0.23 in soils originally studied 30-35 and 15-20 years ago, respectively. Cover changes in the field layer were measured and related to pH changes. The number of species had increased in spite of pH decreases, reaching a maximum at pH 4.0-5.0, while the total cover of the field layer was unchanged.Two groups of species showed no correlation with pH decreases in the humus layer. A large number of species had increased in cover on a majority of sites over the entire species specific pH interval, including nitrophilic species (Rubus idaeus, Chamaenerium angustifolium, Aegopodium podagraria, Stellaria nemorum). A few species had decreased in cover on a majority of sites (Polygonatum multiflorum, Pulmonaria officinalis, Dentaria bulbifera). Some species showed a covariation with pH changes, decreasing in cover in sites in the acidic part of the pH interval (Mercurialis perennis, Lamium galeobdolon, Galium odoratum, Oxalis acetosella, Luzula pilosa). Without excluding other factors, this paper suggests that the increased nitrogen deposition and the increased acidity in the humus layer might cause some of the cover changes in the presented species.


Changes in the serum level of hepatitis B virus (HBV) surface antigen over the natural course of HBV infection.
Despite its status as a potential biomarker of hepatitis B virus (HBV) response to interferon treatment, the changes in hepatitis B surface antigen (HBsAg) levels over the natural course of HBV carriers have not been analyzed sufficiently. A total of 101 HBV carriers were followed prospectively from 1999 to 2009. HBsAg level was measured yearly during the followed period. HBsAg levels at baseline ranged from -1.4 to 5.32 log IU/ml, with a median value of 3.2 log IU/ml. Lower HBsAg levels were significantly associated with higher age and lower HBV replication status. The rate of change of HBsAg levels showed two peaks, with a cut-off value of -0.4 log IU/year. Based on this, patients were tentatively classified into rapid decrease (rate of change <-0.4 log IU/year) and non-rapid decrease groups. All baseline levels of HBsAg, HB core-related Ag, and HBV DNA were lower in the rapid decrease group than in the non-rapid decrease group. Patients with persistently positive HBeAg were all classified into the non-rapid decrease group. In patients with persistently negative HBeAg, HBV DNA levels were significantly (P = 0.028) lower in the rapid decrease group than in the non-rapid decrease group. Lower baseline HBsAg levels were significantly associated with older age and lower viral activity. Both a loss of HBeAg detection as well as inactive replication of HBV are suggested to be fundamental factors contributing to a rapid decrease in HBsAg over the natural course of HBV infection.


HIV Prevention Programs for Racial and Ethnic Minority Communities: Do The Right Thing 4LIFE: An African American Prevention/Outreach Program Utilizing Barbershops and Beauty Salons.
Using the Popular Opinion Leader Model to develop and implement new creative, innovative, and effective programs reaching the African American community.


Excess iron aggravates the severity of COVID-19 infection.
Coronavirus disease-19 (COVID-19) can induce severe inflammation of the lungs and respiratory system. Severe COVID-19 is frequently associated with hyper inflammation and hyper-ferritinemia. High iron levels are known to trigger pro-inflammatory effects. Cumulative iron loading negatively impacts on a patients innate immune effector functions and increases the risk for infection related complications. Prognosis of severe acute respiratory SARS-CoV-2 patients may be impacted by iron excess. Iron is an essential co-factor for numerous essential cellular enzymes and vital cellular operations. Viruses hijack cells in order to replicate, and efficient replication requires an iron-replete host. Utilizing iron loaded cells in culture we evaluated their susceptibility to infection by pseudovirus expressing the SARS-CoV-2 spike protein and resultant cellular inflammatory response. We observed that, high levels of iron enhanced host cell ACE2 receptor expression contributing to higher infectivity of pseudovirus. In vitro Cellular iron overload also synergistically enhanced the levels of; reactive oxygen species, reactive nitrogen species, pro-inflammatory cytokines (IL-1β, IL-6, IL-8 & TNF-α) and chemokine (CXCL-1&CCL-4) production in response to inflammatory stimulation of cells with spike protein. These results were confirmed using an in vivo mouse model. In future, limiting iron levels may be a promising adjuvant strategy in treating viral infection.


Acute aortic regurgitation due to aortic dissection confined to the sinus of Valsalva.
A 34-year-old man with severe heart failure was diagnosed with acute aortic regurgitation (AR) by transthoracic echocardiography (TTE). However, this differential diagnosis was incomplete. Only transesophageal echocardiography (TEE) revealed an intimal flap, leading to a diagnosis of Stanford type A aortic dissection. No abnormal findings were observed in the ascending aorta by contrast-enhanced computed tomography (CT). Aortic dissection confined to the sinus of Valsalva has rarely been reported; however, TEE should still be considered for the differential diagnosis of acute AR, even if there is no evidence of dissection by TTE or contrast-enhanced CT.


Application of a volar static splint in poststroke spasticity of the upper limb.
To evaluate clinical and neurophysiologic effects of 3-month reflex inhibitory splinting (RIS) for poststroke upper-limb spasticity. Pretest-posttest trial. Outpatient rehabilitation center. Forty consecutive patients with hemiplegia and upper-limb spasticity after stroke that had occurred at least 4 months before. Patients wore an immobilizing hand splint custom-fitted in the functional position for at least 90 minutes daily for 3 months. Patients underwent measurement of (1) spasticity at the elbow and wrist according to Modified Ashworth Scale; (2) passive range of motion (PROM) at the wrist and elbow; (3) pain at the shoulder, elbow, and wrist using a visual analog scale; (4) spasms; and (5) comfort and time of splint application. The instrumental measure of spasticity was the ratio between the maximum amplitude of the H-reflex and the maximum amplitude of the M response (Hmax/Mmax ratio). A significant improvement of wrist PROM (F=8.92, P=.001) with greater changes in extension than in flexion, and a reduction of elbow spasticity (F=5.39, P=.002), wrist pain (F=2.89, P=.04), and spasms (F=4.33, P=.008) were observed. The flexor carpi radialis Hmax/Mmax ratio decreased significantly (F=4.2, P=.007). RIS was well tolerated. RIS may be used as an integrative treatment of poststroke upper-limb spasticity. It can be used comfortably at home, in selected patients without functional hand movements, and in cases of poor response or tolerance to antispastic drugs.


Obesity and the aging adult: ideas for promoting patient safety and preventing caregiver injury.
Some experts contend that the increasing prevalence of obesity among patients and caregivers leads to more frequent and serious musculoskeletal injuries among caregivers. Others believe that failure to ensure safe, appropriate equipment and supporting policies leads to the increasing prevalence of caregiver injuries. Health facilities best serve residents, caregivers, and institutions when there is preplanning for extra care and resources; size-appropriate equipment; larger, heavier furniture; and adequate space to accomplish tasks. The challenge to stakeholders is to find ways to prevent injuries that pose direct and indirect cost liabilities to caregivers, institutions, policy makers, and others. Several strategies are available to reduce or prevent caregiver injury and to promote patient safety. Physical environment, equipment, lift team, and necessary policy changes are discussed as possible strategies.


Critical behavior in vacuum gravitational collapse in 4 + 1 dimensions.
We show that the (4 + 1)-dimensional vacuum Einstein equations admit gravitational waves with radial symmetry. The dynamical degrees of freedom correspond to deformations of the three-sphere orthogonal to the (t,r) plane. Gravitational collapse of such waves is studied numerically and shown to exhibit discretely self-similar type II critical behavior at the threshold of black hole formation.


Seronegative Mediastinal Coccidioidomycosis as a Novel Presentation of CTPS1 Combined Immunodeficiency.
Inborn errors of immunity may present with susceptibility to coccidioidomycosis. This is especially so in disorders impairing the interferon-γ and interleukin 12 signaling axis. We describe the first case of cytidine nucleotide triphosphate synthetase 1 (CTPS1) deficiency, a combined immunodeficiency impairing lymphocyte proliferation, presenting with coccidioidomycosis.


Evidence for proctolin-like substances in the central nervous system of the leech Hirudo medicinalis.
The distribution of proctolin-like immunoreactive (PLI) cells was mapped in the central nervous system of the leech Hirudo medicinalis. In segmental ganglia, PLI cells can be divided into two groups: cells that stain repeatedly in every successive ganglion, and cells that stain only in specific segmental ganglia. The number of PLI cells, therefore, ranged from eight to 20 cells per ganglion. One bilateral pair of PLI cells (cells PLI-1) was further characterized morphologically by Lucifer yellow and horseradish peroxidase cell injections. Cell PLI-1 conforms in soma position, morphology, and physiological properties with cell 101, which has been previously classified as an inhibitory motoneuron to the flattener muscles. A locust bioassay (O'Shea and Adams, Science 213:567-569, 1981) was used to detect the presence of proctolin-like bioactivity. Extracts of leech ganglia when applied to the extensor tibialis muscle of the locust leg induced a proctolin-like response similar to the responses induced by proctolin standards. This work extends the finding of proctolin-like substances to the annelid phylum.


Modulation of immune response by interleukin-10 in systemic Corynebacterium kutscheri infection in mice.
Interleukin (IL)-10 is an anti-inflammatory cytokine that modulates sepsis by decreasing pro-inflammatory cytokine production and chemokine expression. In this study, IL-10-deficient and wild-type (WT) mice were infected with Corynebacterium kutscheri to determine if the absence of IL-10 altered the protective immunity and pathogenesis. After infection, IL-10 knockout (KO) mice had a higher survival rate than WT mice. The decrease of body weight and the increased weight of organs such as liver and spleen were greater in WT mice. Bacterial counts were significantly increased after inoculation in WT mice over those in IL-10 KO mice. WT mice had more granulomatous inflammation and coagulative necrosis in the liver and spleen, lymphocyte depletion in lymphoid follicles, and apoptosis of immune cells in the spleen. WT mice had significantly higher plasma concentrations of aspartate aminotransferase and alanine aminotransferase. Furthermore, more upregulation of tumor necrosis factor-α and IL-4 in the plasma, macrophage inflammatory protein-2, keratinocyte-derived chemokine, inducible nitric oxide synthase, and interferon-inducible protein 10 mRNA in the spleen were observed in WT mice after inoculation. These results suggest that the lack of IL-10 contributes to an increase in the systemic clearance of C. kutscheri, and that IL-10 plays a detrimental role in controlling systemic C. kutscheri infection.


The origin of the protein synthesis mechanism.
The origin and development of the protein synthesis mechanism is considered in four successive steps. The genetic code is supposed to be controlled by the relative amount (availability) of various amino acids and nucleotides on the one hand, and utility on each amino acid in the polypeptide. on the other hand. Thus, more simple (inutile) and abundant amino acids tended to correspond to codons which were rich in the less frequent base species, G and C. Features of primitive tRNA in the discrimination of amino acid are discussed. Primitive tRNA is proposed to have a discriminator site for amino acid and, separated from it, an anticodon site for interaction with nucleotides. A hypothetical course of subdivision of various nucleic acid species is proposed. In the scheme, mRNA and ribosomal RNA (rRNA) were derived from more primitive insoluble RNA. DNA appeared in the late, not first, step of the development. Several other aspects of evolutionary development of the whole protein synthesis mechanism, e.g., role of the discriminator site on primitive tRNA, modification and subdivision of code catalogue into a more precise specification of amino acids, and possible primordial interactions between tRNA and tRNA-binding sites on insoluble rRNA, are discussed.


Mechanisms of insulin resistance caused by nutrient toxicity.
Insulin resistance, the impaired action of insulin, has been linked to many important consequences, including Type 2 diabetes, hypertension, dyslipidemia, acanthosis nigricans and polycystic ovarian syndrome. Although there are some genetic causes for insulin resistance, the most common cause is an excess of nutrition a condition called "Nutrient Toxicity". Both excess glucose and excess fat can cause insulin resistance in muscle and fat tissues and excess fat can cause insulin resistance in the liver. High fat feeding and fat infusion rapidly lead to the development of insulin resistance caused by impairment in glucose transport. Other studies have shown defects in insulin signaling possibly secondary to activation of Protein Kinase C resulting from the accumulation of active fatty acyl CoA's. Glucose toxicity has been studied both in vivo and in vitro. In vivo it has been shown that rats over-expressing the gluconeogenic enzyme Phosphoenol Pyruvate Carboxykinase (PEPCK) develop insulin resistance in fat and muscle tissues and some features of the metabolic syndrome including mild obesity and dyslipidemia. Excess glucose entry in fat cells results in increased flux through the hexosamine biosynthesis pathway leading to activation of protein kinase C and impairment of glucose transport. Obesity resulting from excess nutrient intake can also cause insulin resistance by an increase in the production of agents that impair insulin action such as TNFalpha and resistin and a decrease in the production of an insulin sensitizing compound adiponectin. Both glucose and free fatty acids acutely stimulate insulin secretion but chronic exposure to high levels of either nutrient leads to impairment of beta cell function. The combination of insulin resistance and beta cell failure leads to diabetes. Nutrient toxicity is thus the driving cause of the diabetes epidemic that is being recorded around the world.


An Invariant Protein That Colocalizes With VAR2CSA on Plasmodium falciparum-Infected Red Cells Binds to Chondroitin Sulfate A.
Plasmodium falciparum-infected red blood cells (iRBCs) bind and sequester in deep vascular beds, causing malaria-related disease and death. In pregnant women, VAR2CSA binds to chondroitin sulfate A (CSA) and mediates placental sequestration, making it the major placental malaria (PM) vaccine target. In this study, we characterize an invariant protein associated with PM called P falciparum chondroitin sulfate A ligand (PfCSA-L). Recombinant PfCSA-L binds both placental CSA and VAR2CSA with nanomolar affinity, and it is coexpressed on the iRBC surface with VAR2CSA. Unlike VAR2CSA, which is anchored by a transmembrane domain, PfCSA-L is peripherally associated with the outer surface of knobs through high-affinity protein-protein interactions with VAR2CSA. This suggests that iRBC sequestration involves complexes of invariant and variant surface proteins, allowing parasites to maintain both diversity and function at the iRBC surface. The PfCSA-L is a promising target for intervention because it is well conserved, exposed on infected cells, and expressed and localized with VAR2CSA.


Visual outcome of cataract extraction and lens implantation complicated by vitreous loss.
A retrospective study of 62 cases of planned extracapsular cataract extraction with intraocular lens implantation complicated by vitreous loss revealed a visual outcome of 20/20 to 20/40 in 34 eyes (54.8%), 20/50 to 20/80 in 16 eyes (25.8%), 20/100 to 20/400 in six eyes (9.7%), and worse than 20/400 in six eyes (9.7%). If preexisting ocular diseases such as glaucoma and macular degeneration are eliminated, 77.3% achieved a visual acuity of 20/40 or better.


Oligodontia in the primary dentition: report of a case.
Congenital absence of primary teeth is relatively rare. The prevalence, possible etiological factors and management of oligodontia was briefly reviewed. This paper reports a rare case of multiple missing (n=18) primary teeth in a 4-year-old male of Asian origin.


Polyacrylamide gel electrophoresis separation and detection of polyamidoamine dendrimers possessing various cores and terminal groups.
Detection and separation of polyamidoamine dendrimers possessing various cores and surface groups was studied by polyacrylamide gel electrophoresis. Although many dyes and staining techniques were able to detect dendrimers on polyacrylamide gels, Coomassie Blue was found to be the most sensitive and convenient. Amine and hydroxyl terminated dendrimers were best separated under acidic conditions, while dendrimers with carboxyl surfaces required alkaline buffers. Some dendrimers were very susceptible to diffusion that could occur during their separation, staining or destaining steps. In the absence of an appropriate fixation step, dendrimers could be resolved by using small pore size gels and low voltage or current. Increasing core lengths did not significantly affect migration of a given dendrimer generation but exhibited improved separation and staining characteristics. Polyacrylamide gel electrophoresis was found to be a rapid, inexpensive, and reliable procedure to characterize many different water-soluble dendritic macromolecules.


Multitargeted therapy: can promiscuity be praised in an era of political correctness?
The rapidly expanding knowledge of the pathogenesis of cancer at the molecular level is providing new targets for drug discovery and development. However, cancer is a complex disease characterized by multiple genetic and molecular alterations affecting cell proliferation, survival, differentiation and invasion among others. Many of these alterations represent potential targets for the development of new anticancer therapeutics. Because of the enormous biological diversity of cancer, it is unlikely that attacking only one of these targets will eliminate a malignant cell. Rather, strategic combination of agents targeted against the most critical of those alterations will be needed. Another approach that is rendering promising clinical results is the use of more unspecific agents that inhibit or modulate several relevant targets simultaneously. A deep biologic understanding of the relative relevance of each target in different cancer types will be key to efficiently direct those drugs to diseases more likely to benefit from its particular modulation profile.


Fabrication of MOF-derivated CuOx-C electrode for electrochemical degradation of ceftazidime from aqueous solution.
Antibiotic contamination has already been one of hazards to aquatic environment due to the abuse of antibiotics. Metal-organic frameworks (MOFs) are known as a kind of promising porous material for solving the environmental deterioration. In this article, the physicochemical and electrochemical properties of a series of porous copper oxide carbon materials (CuOx-C) synthesized by carbonizing Cu-BTC were compared. Due to the suitable carbonization temperature, CuOx-C-550 N, whose geometric structure was similar to Cu-BTC, possessed a multiscale pore structure containing many mesopores and partial macropores in accordance with the pore size distribution curves. More copper/copper oxides were introduced toimproving the electrochemical ability, evidence by XRD, XPS, CV and EIS characterization. Moreover, the degradation of ceftazidime (CAZ) through anodic oxidation was discussed. In AO/CuOx-C-550 N system, the effects of current, solution pH, initial CAZ concentration and Na2SO4 concentration were analyzed. CAZ removal rate reached 100% within 20 min under the optimal condition and a good electrocatalytic ability with 90% CAZ removal after 20 runs indicated a good electrochemical stability of CuOx-C-550 N. Furthermore, the degradation mechanism and pathway of CAZ were proposed. The Cu(II)/Cu(I) oxidation-reduction couples on the anodic surface contribute to the efficiently selective degradation of cephalosporins for CuOx-C-550 N. Overall, this study shows a good method to design and prepare a new MOF derivative for the remediation of aquatic contamination.


Diagnosing pregnancy in free-ranging dugongs using fecal progesterone metabolite concentrations and body morphometrics: a population application.
Assessing reproductive status and monitoring reproductive rates is important in the effective management of vulnerable marine mammal species such as the dugong (Dugong dugon). Knowledge of the reproductive physiology of this species is limited, and determining reproductive parameters (e.g., sexual maturation, pregnancy, and reproductive senescence) has been restricted by a lack of non-lethal methods for assessing reproductive status in free-ranging individuals. The aim of this study was to develop a method to identify pregnant individuals in a wild dugong population. Using an enzymeimmunoassay, we quantified concentrations of fecal progesterone metabolites (fP) in 322 dugongs, including confirmed pregnant females (n=10), presumed non-pregnant adult females (n=25), juvenile females (n=24), subadult females (n=41), adult females of unknown pregnancy state (n=63), and males of all sizes (n=159). External body morphometrics of each dugong were measured, and confirmation of pregnancy in adult female dugongs was determined by ultrasonography or observation of subsequent neonates. Concentrations of fP were different between sexes and reproductive size classes (P<0.001), and ∼30-fold higher in confirmed pregnant dugongs (2017-7760 ng/g) compared to presumed non-pregnant females (30-221 ng/g), juvenile females (29-195 ng/g), and males (24-261 ng/g) (P<0.001). Body measures of maximum and anal girths, and teat length were all greater in confirmed pregnant females than presumed non-pregnant females (all P<0.05). We evaluated a Discriminant Function Analysis (DFA) to provide a model for predicting pregnant and non-pregnant dugongs. Cross-validated results showed that the DFA correctly classified 100% of pregnant and non-pregnant females using fP concentrations, body length, fineness ratio (an index of body shape), and teat length (a female reproductive trait). Using the DFA model, we classified the pregnancy status of all female dugongs and identified a total of 30 females as pregnant and 133 females as non-pregnant from the sampled population over the sample period. Pregnant dugongs in the Moreton Bay population are characterized by fecal progesterone metabolite concentrations > 1000 ng/g, body length ≥ 260 cm, maximum girth ≥ 215 cm, anal girth ≥ 126 cm, and teat length ≥ 5 cm long. In summary, analysis of fP concentrations in combination with body morphometrics may be used to diagnose pregnancy in free-ranging dugongs, and provides a new tool to monitor breeding rates of wild sirenian populations.


Activation of the complement system at the interface between blood and artificial surfaces.
The interaction between blood and the artificial devices used in haemodialysis results in the activation of the immune system. Complement activation is known to play a key role in the production of inflammatory mediators. This article describes the complement system and the way in which it is triggered in the patient undergoing haemodialysis. It highlights those factors thought to be of particular importance in the pathogenesis of adverse reactions and targets them as obstacles to be overcome in the future design of biocompatible materials.


New technique of right heart bypass in congenital heart surgery with autologous lung as oxygenator.
Modifications have been made in cardiopulmonary circuit to reduce the inflammatory deleterious effects and cost. We present our experience of one such right heart bypass (RHB) circuit utilizing autologus lung as oxygenator. From September 2001 to December 2002, 15 patients underwent congenital heart surgery with this technique. Bypass circuit consisted of a reservoir and a roller pump along with a cardiotomy sucker. The left pulmonary artery and main pulmonary artery were used for arterial return, and venous drainage was achieved with innominate vein cannulation. Inferior vena cava cannulation was performed when needed. Thirteen patients underwent bidirectional Glenn shunt surgery (12 to 24 months, 6 to 10 kg). One patient (26 years old) underwent central shunt with enlargement of confluence and left pulmonary artery. Another patient (18 months old) underwent 1.5 ventricle repair. There were no hospital deaths. Mean flow achieved on RHB was 0.57 +/- 0.3 L/min/m(2), central venous pressure was 3.3 +/- 1.8 mm Hg (0 to 7 mm Hg), and mean arterial pressure could be maintained satisfactorily in all patients (54 +/- 14 mm Hg). Mean RHB time was 54 +/- 14 min. Mean central venous pressure was 10.1 +/- 2.4 mm Hg after procedure and saturation was similar to that on (RHB 88% +/- 8%). The mean amount of drainage was 9.1 +/- 4.2 mL/kg per 24 hours. Avoiding an oxygenator and reducing the number of tubings achieved a combined cost savings of 40% for all procedures. Right heart bypass is a simple, safer, and less expensive alternative to conventional cardiopulmonary bypass. This technique allows effective decompression of superior vena cava, adequate oxygenation, and predicts saturation after Glenn shunt. It can also be applied for central shunts and pulmonary artery reconstructions with cost containment.


[Laryngeal apnea].
The apneic laryngeal chemoreflex (QRL), elicited by water on the vocal cords and the reflex by mechanical stimulation (MRL) has been compared in dog. The response decrease with naloxone at a 400 micrograms.kg-1, suggesting that the reflex inhibition depends on endogenous opioids of the respiratory centre.


Local anesthetic intolerance due to metabisulfite.
The case of a 40-year-old woman with severe edema of the face and neck after the injection of a local dental anesthetic is presented. The reaction is attributed to the presence of sodium metabisulfite, and antioxidant, in the local anesthetic. Both the anesthetic and the sodium metabisulfite gave a delayed positive patch-test response.


CB1 receptors in the paraventricular nucleus of the hypothalamus modulate the release of 5-HT and GABA to stimulate food intake in rats.
Endocannabinoids and their receptors not only contribute to the control of natural processes of appetite regulation and energy balance but also have an important role in the pathogenesis of obesity. CB1 receptors (CB1R) are expressed in several hypothalamic nuclei, including the paraventricular nucleus (PVN), where induce potent orexigenic responses. Activation of CB1R in the PVN induces hyperphagia by modulating directly or indirectly orexigenic and anorexigenic signals; however, interaction among these mediators has not been clearly defined. CB1R mRNA is expressed in serotonergic neurons that innervate the PVN, and activation of 5-HT receptors in the PVN constitutes an important satiety signal. Some GABAergic terminals are negatively influenced by 5-HT, suggesting that the hyperphagic effect of CB1R activation could involve changes in serotonergic and GABAergic signaling in the PVN. Accordingly, the present study was aimed to characterize the neurochemical mechanisms related to the hyperphagic effects induced by activation of CB1R in the PVN, studying in vitro and in vivo changes induced by direct activation these receptors. Here, we have found that the neurochemical mechanisms activated by stimulation of CB1 receptors in the PVN involve inhibition of 5-HT release, resulting in a decrease of serotonergic activity mediated by 5-HT1A and 5-HT1B receptors and inducing disinhibition of GABA release to stimulate food intake. In conclusion, these neurochemical changes in the PVN are determinant to the cannabinoid-induced stimulation of food intake. Our findings provide evidence of a functional connection among CB1R and serotonergic and GABAergic systems on the control of appetite regulation mediated by endocannabinoids.


Acute renal insufficiency due to renal infarctions in a patient with neurofibromatosis.
Manifestations of neurofibromatosis in the skin, the eye, and the skeletal and nervous systems have been well documented since the disease was first described in 1882. Stenosing vascular lesions as complications of neurofibromatosis were first reported in 1945. They are being increasingly recognized and most commonly involve the renal artery. Renal artery stenosis (usually proximal), intraparenchymal renal arterial abnormalities, and coarctation of the abdominal aorta often lead to hypertension. However, despite reports of bilateral and severe renal artery disease, renal infarction and resulting renal insufficiency have not been described. We present the case of a 35-year-old woman with neurofibromatosis and chronic hypertension associated with narrowing of right intrarenal arteries. The patient had two separate episodes of left renal infarction documented clinically and radiographically. The second infarct resulted in renal insufficieny. There was no hypercoagulopathy or source for embolism. This case suggests that renal infarction and renal insufficiency are additional complications of neurofibromatosis.


Age-driven modulation of tRNA-derived fragments in Drosophila and their potential targets.
Development of sequencing technologies and supporting computation enable discovery of small RNA molecules that previously escaped detection or were ignored due to low count numbers. While the focus in the analysis of small RNA libraries has been primarily on microRNAs (miRNAs), recent studies have reported findings of fragments of transfer RNAs (tRFs) across a range of organisms. Here we describe Drosophila melanogaster tRFs, which appear to have a number of structural and functional features similar to those of miRNAs but are less abundant. As is the case with miRNAs, (i) tRFs seem to have distinct isoforms preferentially originating from 5' or 3' end of a precursor molecule (in this case, tRNA), (ii) ends of tRFs appear to contain short "seed" sequences matching conserved regions across 12 Drosophila genomes, preferentially in 3' UTRs but also in introns and exons; (iii) tRFs display specific isoform loading into Ago1 and Ago2 and thus likely function in RISC complexes; (iii) levels of loading in Ago1 and Ago2 differ considerably; and (iv) both tRF expression and loading appear to be age-dependent, indicating potential regulatory changes from young to adult organisms. We found that Drosophila tRF reads mapped to both nuclear and mitochondrial tRNA genes for all 20 amino acids, while previous studies have usually reported fragments from only a few tRNAs. These tRFs show a number of similarities with miRNAs, including seed sequences. Based on complementarity with conserved Drosophila regions we identified such seed sequences and their possible targets with matches in the 3'UTR regions. Strikingly, the potential target genes of the most abundant tRFs show significant Gene Ontology enrichment in development and neuronal function. The latter suggests that involvement of tRFs in the RNA interfering pathway may play a role in brain activity or brain changes with age.


Delirium Development After Lung Transplantation: An Intraoperative Assessment.
This study aimed to evaluate the relationship between intraoperative hemodynamic and laboratory parameters with postoperative delirium development after lung transplantation. A total of 77 patients who underwent lung transplantation in a single center were included in the study. Demographic and clinical data recorded at critical intraoperative stages (after induction [T1], after bilateral lungs are dissected [T2], while the patient is ventilated for 1 lung [T3], while the unilateral transplanted lung is ventilated [T4], while bilateral transplanted lungs are ventilated [T5], and after the thorax is closed [T6]), postoperative complications, mechanical ventilation duration, intensive care, and hospitalization durations and mortality rates were recorded. A total of 83.1% of the 77 patients were male, and the mean (SD) age was 47.56 (12.95) years. The mean body mass index (calculated as weight in kilograms divided by height in meters squared) was 23.30 (3.99), and the median Charles Comorbidity Index (CCI) was 1. The diagnosis of 36.4% of the patients was chronic obstructive pulmonary disease. Delirium was seen in 51.9% of the patients. Age, CCI, intraoperative mean arterial pressure changes, lactate levels, mechanical ventilation duration, and hospital stay were all associated with delirium development. Age, CCI, duration of mechanical ventilation, and hospital stay were independent predictors of postoperative delirium development. We believe that our study will be a guide for future prospective randomized controlled studies.


Relationship Between TSH Levels and Cognition in the Young Adult: An Analysis of the Human Connectome Project Data.
The nature of the relationship between serum thyrotropin (TSH) levels and higher cognitive abilities is unclear, especially within the normal reference range and in the younger population. To assess the relationship between serum TSH levels and mental health and sleep quality parameters (fluid intelligence [Gf], MMSE (Mini-Mental State Examination), depression scores, and, finally, Pittsburgh Sleep Quality Index (PSQI) scores (working memory, processing speed, and executive function) in young adults. This was a retrospective analysis of the data from the Human Connectome Project (HCP). The HCP consortium is seeking to map human brain circuits systematically and identify their relationship to behavior in healthy adults. Included were 391 female and 412 male healthy participants aged 22-35 years at the time of the screening interview. We excluded persons with serum TSH levels outside the reference range (0.4-4.5 mU/L). TSH was transformed logarithmically (log TSH). All the key variables were normalized and then linear regression analysis was performed to assess the relationship between log TSH as a cofactor and Gf as the dependent variable. Finally, a machine learning method, random forest regression, predicted Gf from the dependent variables (including alcohol and tobacco use). The main outcome was normalized Gf (nGf) and Gf scores. Log TSH was a significant co-predictor of nGF in females (β = 0.31(±0.1), P < .01) but not in males. Random forest analysis showed that the model(s) had a better predictive value for females (r = 0.39, mean absolute error [MAE] = 0.81) than males (r = 0.24, MAE = 0.77). Higher serum TSH levels might be associated with higher Gf scores in young women.


Recording epileptic activity with MEG in a light-weight magnetic shield.
Ten patients with focal epilepsy were studied with magnetoencephalography (MEG) to determine if a new light-weight magnetically shielded room (lMSR) provides sufficient attenuation of magnetic interference to detect and localize the magnetic correlates of epileptic activity. Interictal MEG epileptic events co-localizing with the presumed location of the epileptogenic zone were found in all patients. MEG measurements performed in the lMSR provide an adequate signal-to-noise ratio for non-invasive localization of epileptic foci.


Estradiol-induced accumulation of vitellogenin mRNA and secretion of vitellogenin in liver cultures of Xenopus.
Explants of male Xenopus liver maintained in a serum-free culture medium respond to stimulation by 2 X 10(-8) M 17beta-estradiol with an increasing rate of accumulation of vitellogenin mRNA, as revealed by hybridization of cDNA to the total cytoplasmic RNA extracted from the cultures. A similar response is observed for secretion of 32PO4-labeled vitellogenin into the culture medium. The in vitro response is improved in liver tissue of prestimulated animals, and by adaptation of liver explants to the culture medium prior to hormone treatment, but attains only about 10% of the in vivo response. Since essential features of the in vivo response are maintained in liver explants, organ culture appears suitable for investigating initial events of estradiol action leading to enhanced synthesis of vitellogenin.


Trunk flexibility using a sit-and-reach test after surgery for adolescent idiopathic scoliosis.
Spinal fusion reduces flexibility, but we do not have detailed knowledge that accounts for growth or sex differences. We sought to determine trunk flexibility pre- and postoperatively in patients with adolescent idiopathic scoliosis (AIS). We included data from 109 patients with AIS in this retrospective, single-center observational study. Patients had performed a sit-and-reach (SR) test preoperatively, and 1 and 2 years postoperatively, and measurements were standardized to Z scores according to age and sex. The patient data were divided into three groups according to the level of lower instrumented vertebra (LIV): (1) Group A (fusion above L2); (2) Group B (fusion to L2), and (3) Group C (fusion to L3 or L4). The change in the Z score for various levels was determined and compared. The preoperative Z score for all patients was -0.622. At 2 years postoperatively, the Z score in Groups A and B was not significantly different from the preoperative score; in Group C, the Z score decreased by 1 year postoperatively, improved during the second year, but remained significantly lower than the preoperative score. Our study was the first to assess trunk flexibility using the SR test in patients with scoliosis. Preoperatively, patients with AIS had lower SR test Z-scores than the general population, indicating a lower trunk flexibility in these patients. At 2 years after surgery in these patients, trunk flexibility had returned to preoperative levels when LIV was at L2 or above, but when LIV was at L3 or L4, trunk flexibility was less than it was preoperatively. Prognostic Level II: retrospective study.


The induction of systemic and mucosal immunity to protein vaccines delivered through skin sites exposed to UVB.
It has been reported that common mucosal immunity can be efficiently induced in mice following immunization through the skin with vaccine formulations containing either the active form of vitamin D, or chemical agents capable of locally enhancing cyclic adenosine monophosphate levels. Herein, we report that exposure of skin to ultraviolet radiation B (UVB) can be employed as a means to alter systemic humoral immune responses and to promote the induction of mucosal immunity to protein antigens delivered into UVB-exposed skin sites. Our data indicates that the skin, as a vaccination site, can be manipulated to allow efficient induction of common mucosal and systemic immune responses.


Polymeric nanoparticles for hemoglobin-based oxygen carriers.
This article reports on the current status of the research on blood substitutes with particular attention on hemoglobin-based oxygen carriers (HBOCs). Insights on the physiological role of hemoglobin are reported in the view of the development of both acellular and cellular hemoglobin-based oxygen carriers. Attention is then focused on biocompatible polymeric materials that find application as matrices for cellular based HBOCs and on the strategies employed to avoid methemoglobin formation. Results are reported regarding the use of bioerodible polymeric matrices based on hemiesters of alternating copolymer (maleic anhydride-co-butyl vinyl ether) for the preparation of hemoglobin loaded nanoparticles.


Experiences of learning, development and preparedness for clinical practice among undergraduate paramedicine students, graduate/intern paramedics and their preceptors: a systematic review protocol.
What are the barriers and facilitators related to learning, development, and preparedness for practice from the perspective of undergraduate paramedicine students, graduate/intern paramedics and the preceptors/trainers that facilitate learning?


Determining Objective Parameters to Assess Gait Quality in Franches-Montagnes Horses for Ground Coverage and Over-Tracking - Part 1: At Walk.
Ground coverage and over-tracking are two gait quality traits describing the forward movement of the front respectively the hind limbs in relation to stride length and over-tracking distance. To investigate the complex interplay of different movement patterns in ground coverage and over-tracking, limb and body kinematics of 24 Franches-Montagnes (FM) stallions were measured with 3D optical motion capture (OMC) on a treadmill during an incremental speed test at the walk (1.4-2.0 m/s). The significance and amount of explained variance of kinematic parameters on stride length and over-tracking distance were estimated using linear mixed-effect models, with speed and horse as random effects. Two separate models were tested: a full model with all parameters measurable by OMC, and a reduced model with a subset of parameters also measurable with inertial measurement units (IMUs). The kinematic parameters were correlated to the subjective scores from six breeding experts to interpret their external validity. The parameter for ground coverage at the walk, explaining most of the variance in stride length, were the maximal forelimb retraction angle (11%) measured with OMC, and the range of pelvis pitch (10%) if measuring with IMUs. The latter was also the most relevant for quantifying over-tracking, explaining 24% to 33% of the variance in the over-tracking distance. The scores from most breeding experts were significantly correlated (r ≥ |0.41|) with the fore- and hind limb protraction angles, which reflect the textual definition of ground coverage and over-tracking. Both gait quality traits can be objectively quantified using either OMC or IMUs.


Application of a self-organizing map and positive matrix factorization to investigate the spatial distributions and sources of polycyclic aromatic hydrocarbons in soils from Xiangfen County, northern China.
The concentrations of 16 priority polycyclic aromatic hydrocarbons (PAHs) were measured in 128 surface soil samples from Xiangfen County, northern China. The total mass concentration of these PAHs ranged from 52 to 10,524ng/g, with a mean of 723ng/g. Four-ring PAHs contributed almost 50% of the total PAH burden. A self-organizing map and positive matrix factorization were applied to investigate the spatial distribution and source apportionment of PAHs. Three emission sources of PAHs were identified, namely, coking ovens (21.9%), coal/biomass combustion (60.1%), and anthracene oil (18.0%). High concentrations of low-molecular-weight PAHs were particularly apparent in the coking plant zone in the region around Gucheng Town. High-molecular-weight PAHs mainly originated from coal/biomass combustion around Gucheng Town, Xincheng Town, and Taosi Town. PAHs in the soil of Xiangfen County are unlikely to pose a significant cancer risk for the population.


Early local steroid therapy of infantile eyelid hemangiomas (local steroid therapy of lid hemangiomas).
Two cases of upper eyelid capillary hemangiomas were successfully treated by local injection of steroids. Both cases required two injections, performed between 11 and 20 weeks of age. No untoward side effects occurred. This treatment would appear to be valuable in preventing the development of ophthalmic sequelae commonly associated with benign observation.


Circulation of spotted fever group rickettsiae among dogs seropositive for Leishmania spp. in an urban area of Brazil.
Dogs play an epidemiological role in several vector-borne diseases that affect human and animal health worldwide. We aimed to identify rickettsial circulation among dogs with canine visceral leishmaniasis (CVL) from a region endemic for both diseases. CVL-seropositive dogs were screened for spotted fever group rickettsiae using an indirect immunofluorescence assay. Among the CVL-positive dogs, anti-Rickettsia rickettsii antibodies were identified in one asymptomatic and one oligosymptomatic dog. This study shows low circulation of antibodies to R. rickettsii in CVL-seropositive dogs. It is recommended that surveillance studies in dogs should continue in order to monitor this scenario.


Treatment with convalescent plasma in solid organ transplant recipients with COVID-19: Experience at large transplant center in New York City.
Solid organ transplant (SOT) recipients may be at higher risk for poor outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Convalescent plasma is an investigational therapy that may benefit immunosuppressed patients by providing passive immunity. Convalescent plasma was administered to hospitalized patients with coronavirus disease-2019 (COVID-19) at an academic transplant center in New York City. Eligible patients were hospitalized and required to have positive nasopharyngeal polymerase chain reaction (PCR) diagnosis of SARS-CoV-2 infection, be at least 18 years old, and have either dyspnea, blood oxygen saturation ≤ 93% on ambient air, respiratory frequency ≥ 30 breaths/min, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, or lung infiltrates > 50%. Thirteen SOT recipients received convalescent plasma from April 9, 2020, to May 17, 2020. The median time from symptom onset to plasma infusion was 8 days. Eight of 13 patients (62%) had de-escalating oxygenation support by day 7 post-convalescent plasma. Nine (69%) patients were discharged, 1 (7%) patients remain hospitalized, and 3 (23%) patients died. This series supports the need for additional studies on convalescent plasma use in SOT recipients with COVID-19 to better determine efficacy and identify patients who are likely to benefit.


Differential patient travel distance and time to psoriasis clinical trial sites.
Considering the known disparities in racial representation in psoriasis clinical trials, this study sought to characterize travel distance and time to reach a psoriasis clinical trial site as a potential barrier to trial participation for multiple demographic and geographic variables. We determined travel distance and time from every census tract population center in the United States to the nearest psoriasis clinical trial site using ArcGIS and linked travel estimates to demographic characteristics in each census tract based on 2020 American Community Survey. The average distance and time traveled to reach a psoriasis clinical trial site nationally were 45.6 miles and 51.8 min, respectively. Urban residence and Northeast location had significantly lower travel distance and time relative to their geographic counterparts. Travel burden was significantly greater among Native American and Black races, individuals without college education and Veterans Affairs beneficiaries relative to their counterparts. These findings reveal disparate access regarding rurality, race, education and insurance type, which may encourage investigators to increase travel funding for underrepresented groups and diversity recruitment efforts to promote access to psoriasis clinical trials.


Understanding the self-assembly of the polymeric drug solubilizer Soluplus®.
Soluplus® is one of the most widely used amphiphilic copolymers in drug delivery and has been reported to strongly enhance the adsorption of model drugs. However, there is still a limited understanding of its micellar behavior as it responds to the different routes of administration, which involve important changes in concentration. The microstructure of Soluplus aqueous solutions has been investigated at a wide range of polymer concentrations (2 × 10-6 - 0.2 g/mL) by a combination of diffusion NMR (dNMR), small angle X-ray scattering (SAXS), static (SLS) dynamic (DLS) light scattering and viscosity measurements. These techniques have been coupled with surface tension measurements to frame the polymer's critical micellar concentration (cmc). We demonstrate the presence at all tested concentrations of two forms of Soluplus, with hydrodynamic radii of 3 and 26 nm, where the fraction of smaller objects accounts for as much as 60-70%. dNMR, SAXS, DLS and SLS indicate that Soluplus spontaneously self-assembles into large spherical particles with a core-shell structure. However, self-assembly takes place three orders of magnitude above the cmc evaluated via surface tension measurements. Instead of the traditional cooperative micellization process, we propose a thermal-activated isodesmic self-assembly of the small aggregates into core-shell micelles.


Diabetic state-induced modifications of succinylcholine binding mode in the microsomal fractions of mouse skeletal muscles.
The skeletal muscles of alloxan-induced diabetic mice and genetically diabetic KK-CAY mice are hypersensitive to a depolarizing blocker, succinylcholine (SuCh) but not to the competitive antagonist, d-tubocurarine (d-TC). The mechanism by which the action of the depolarizing blocker is modified in the diabetic state was investigated on the binding of 14C-SuCh to the microsomal fraction isolated from mouse skeletal muscles. The Scatchard plot of microsomal preparations from normal ddY mice showed positive cooperativity in SuCh binding, whereas that of the preparations from alloxan-induced diabetic mice as well as genetically diabetic KK-CAY mice lost the positive cooperative interactions. The dissociation constant (Kd) of high affinity site in diabetic muscles was significantly lower than that in non-diabetic ddY muscle. The microsomal fractions from denervated muscles of normal ddY mice maintained weakly positive cooperativity in SuCh binding, and the affinity of SuCh binding in denervated muscles was lower than that of non-denervated muscles. In conclusion, the diabetic state selectively altered the SuCh binding mode. This alteration seems to be closely correlated with the pharmacological hypersensitivity to SuCh.


Immunoglobulin gene rearrangement and its implications for the study of B-cell neoplasia.
Molecular biologic investigation of the process of immunoglobulin gene rearrangement has elucidated the mechanism of immunologic diversification and has provided essential tools for the study of B-cell neoplasia. The use of immunoglobulin gene probes has permitted a clearer understanding of B-cell malignancies, but has also raised new questions and pointed out new directions for ultimately clarifying the mechanism of B-cell transformation. Thus, we have a difficult challenge ahead, but with our present knowledge, we are in a better position than ever to address critical issues relating to the genesis of lymphoid neoplasia.


A cross-sectional study on sarcopenia using different methods: reference values for healthy Saudi young men.
The aim of this study was to determine reference values for sarcopenia indices using different methods in healthy Saudi young men. Participants included 232 Saudi men aged between 20 and 35 years. The study measured anthropometric indices, blood pressure, hand grip strength, and lean muscle mass using dual-energy X-ray absorptiometry (DXA), and bioelectrical impedance analysis (BIA) was performed using Inbody 770 and Tanita 980 devices. Using DXA, the mean value of appendicular lean mass divided by the height squared (ALM/ht2) was found to be 8.97 ± 1.23 kg/m2; hand grip strength measured 42.8 ± 7.6 kg. While the differences between DXA and BIA (Tanita) were significant for all parameters, the differences between DXA and Inbody values were significant only for ALM parameters. Inbody sensitivity and specificity values were 73% and 95.9%, respectively. The kappa (P = 0.80) and p values (P < 0.001) showed good agreement between Inbody and DXA, whereas Tanita sensitivity and specificity values were 54.2% and 98.3%, respectively. Bland-Altman plots for differences in lean mass values between Tanita, Inbody, and DXA methods showed very high bias for Tanita and DXA, with significant differences (P < 0.001). The cut-off values for sarcopenia indices for Saudi young men are different from those of other ethnicities. The use of tailored cut-off reference values instead of a general cut-off for BIA devices is recommended.


The Early Years of 2,2'-Bipyridine-A Ligand in Its Own Lifetime.
The first fifty years of the chemistry of 2,2'-bipyridine are reviewed from its first discovery in 1888 to the outbreak of the second global conflict in 1939. The coordination chemistry and analytical applications are described and placed in the context of the increasingly sophisticated methods of characterization which became available to the chemist in this time period. Many of the "simple" complexes of 2,2'-bipyridine reported in the early literature have been subsequently shown to have more complex structures.


Quantitative Correction of Cervical Sagittal Deformity in Atlanto-Axial Dislocation.
A mechanism-based reasoning and retrospective cohort study. To establish a quantitative relationship between the change of clivo-axial angle (CXA) and the change of subaxial cervical lordosis (CL) in correction surgery of atlantoaxial dislocation (AAD). The evolving understanding of mechanism has dramatically improved the treatment modality of AAD. Cervical sagittal alignment is another important aspect of the surgery, in addition to reduction of odontoid process. However, a quantitative reference for correction surgery has not been established. Frankfort-axial angle (FXA) was introduced. Based on two assumptions, (1) sagittal alignment of the spine aims at keeping horizontal gaze and (2) deformities at craniovertebral junction make little impact on slope of T1 vertebra, we deduced that the change of CXA equaled change of CL (ΔCXA = -ΔCL). We retrospectively reviewed our case cohort to validate this finding with linear regression analysis. Sixteen cases (eight male and eight female, mean age 40.4±12.5 yr old) were included. Liner fitting equation for ΔFXA and ΔCXA is y=1.005x (coefficient of determination, R=0.966; significance of the estimated coefficients P<0.001, t-statistics) and that for ΔCL and ΔCXA is y=-1.023x (R=0.976, P<0.001). These results support our deduction that ΔCXA = -ΔCL, which can be used as a guidance of quantitative correction of sagittal deformity in AAD. Correction of CXA will influence the subaxial cervical lordosis (ΔCXA = -ΔCL) of AAD patients. This equation can serve as a quantitative reference for preoperative planning and intraoperative refining of the correction of cervical sagittal deformity in AAD. 4.


Correlation between iron mobilization and emergence of benzene in leachate at old landfills.
Leachate monitoring data from a closed municipal solid waste (MSW) landfill with negligible gas production showed increasing iron, alkalinity and benzene levels over time. Due to significant rain water infiltration, concentration data alone was not adequate to analyze the possible correlations between the leachate quality parameters monitored. When quantities (kg/d) present in leachate rather than concentrations (mg/L) of benzene, bicarbonate and iron were analyzed; there were significant correlations between benzene and iron as well as biocarbonate and iron quantities. Increasing iron quantity in leachate was accompanied by increasing quantities of benzene and bicarbonate which are indicative of transformation reactions of polymeric organic compounds present in MSW. The results indicate that biotransformation mechanisms in landfills are similar to those in anaerobic sediments due to lack of electron acceptors with higher energy yields.


[Home care and its relationship to the work environment in health].
This paper discusses home care as a service that has expanded in the public and private health system, while arguing for the possibility that such care can leverage a significant impact on the population's quality of life and health. The article presents home care as a strategic possibility for reorganizing the health system, by means of integration between health workers and health institutions, and considers its possible political, economic, and technical impacts on the health system, health workers, and users of the service.


Postmortem examinations in patients of a geriatric hospital.
The rate of postmortem examinations (PME) especially in elderly patients is continuously declining, mostly due to the low interest of the medical staff and the reluctance of relatives. We surveyed PME performed over a 20-year period in patients of a geriatric hospital in Israel. The 93 autopsies represent a rate of 2.8% in the first five years which went down to 0.25% in the later years. In 58% of the cases, clinical cause of death was confirmed by the PME. Pulmonary embolism had the lowest confirmation rate, and was more frequently found in females (28%) than in males (10%) (p<0.03). Undiagnosed conditions in the elderly present a clinical challenge that increases with the patient's age. However, despite progress in diagnostic technology, confirmation rates of death causes have not changed much. Therefore, as the age of death rises, it is important to preserve and foster PMEs, the most reliable source of medical evidence.


Anatomical pitfalls during encircling cryoablation of the left atrium for atrial fibrillation therapy in the pig.
We previously published encircling endocardial cryo-isolation of the pulmonary vein (PV) region. This study documented mechanisms of isolation failure using CARTO mapping. Cryo-isolation used a modified Surgifrost introduced via a Universal Cardiac Introducer on the left atrial appendage. Of five pigs, two had incomplete isolation and repeat mapping: Activation was over Bachmann's bundle (BB) in one and the coronary sinus (CS) in the other. Repeat cryoablation failed to eliminate gaps. Histologically, the BB gap had nonlesioned sub-epicardial fibres and thick fat covering the cryolesioned BB: fat protecting the epicardium from cryoablation. The inferior gap had a large CS, and a thick myocardium bridging the isthmus: myocardial thickness and CS thermal sink preventing transmural cryolesions. CARTO mapping localized gaps. Although the CS is known to cause failure, its protective mechanism is not well documented. The BB gap is novel. These findings have important clinical implications for isolation of the PV region.


Reduced field of view single-shot spiral perfusion imaging.
To develop a single-shot spiral perfusion pulse sequence with outer-volume suppression (OVS) to achieve whole-heart coverage with a short temporal footprint of 10 ms per slice location. A highly accelerated single-shot variable density spiral pulse sequence with an integrated OVS module for reduced field of view (rFOV) perfusion imaging with 2 mm spatial resolution was developed and evaluated in simulations, phantom experiments and in clinical patients with (n = 8) or without (n = 8) OVS. Images were reconstructed by block low-rank sparsity with motion guidance (BLOSM) and graded by two cardiologists on a 5-point scale (1, excellent; 5, poor). Simulation and phantom results showed that OVS effectively suppressed the signal outside the desired field of view (FOV). Clinical patient data demonstrated high quality perfusion images with rFOV. The average image quality scores of full FOV cases and rFOV cases were 3.1 ± 0.64 and 2.3 ± 0.46, respectively, (P = 0.02) from cardiologist 1 and 2.5 ± 0.54 and 1.8 ± 0.47, respectively, (P = 0.04) from cardiologist 2, showing superior image quality for the rFOV images compared with the full FOV images. A single-shot spiral perfusion sequence that uses OVS and BLOSM performs perfusion imaging with a very short temporal footprint per image supporting whole-heart coverage with good image quality. Magn Reson Med 79:208-216, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Pseudomonas aeruginosa: a pathogen making itself at home.
Upon bacterial infection, mounting the appropriate immune response is paramount to effective pathogen clearance. In a recent study, Agaronyan et al. show how Pseudomonas aeruginosa can divert host immunity to boost type 2 responses and drive mucus production, which can then act as a nutrient source for bacteria.


Determinants of negative white-coat effect in treated hypertensive patients: the Jichi Morning Hypertension Research (J-MORE) study.
The negative white-coat effect (WCE), a phenomenon in which out-of-office blood pressure (BP) is higher than clinic BP, has not been well examined, unlike the WCE. As part of the Jichi Morning Hypertension Research study, in which clinic and home BP were measured in 969 hypertensive outpatients, 405 patients with normal clinic BP were separately analyzed. Clinic BP was measured on two different occasions, and home BP was measured twice in the morning and twice in the evening for three consecutive days. Clinic and home BP were each averaged from all readings, and negative WCE was defined as clinic systolic BP (SBP) lower than home SBP. Negative WCE was observed in 324 (33%) of the patients overall and in 173 (42%) of the patients with controlled BP (clinic BP < 140/90 mm Hg). In multiple logistic regression analysis adjusting for covariates including home SBP and pulse rate, negative WCE was correlated with older age (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06) and male gender (OR 1.08, 95% CI 1.01-1.14) in overall subjects. Among patients with well-controlled clinic BP, negative WCE was significantly correlated with the presence of ischemic heart disease (OR 1.17, 95% CI 1.04-1.31). The association of negative WCE with age and male gender remained significant under stringent criteria (negative WCE < -10.2 mm Hg (the mean -1 s.d.)). Negative WCE remaining even after clinic BP is controlled may be related to cardiovascular risk factors such as older age, male gender, and a history of ischemic heart disease.


Electrophysiologic Changes in the Human Heart Produced by Enalaprilat (Angiotensin-Converting Enzyme Inhibitor).
Several trials have showed that angiotensin-converting enzyme inhibitors possess some extent of antiarrhythmic properties. To evaluate the effects of Enalaprilat on His bundle recording, patients undergoing diagnostic coronary angiogram due to angina pectoris and a positive thallium exercise test subsequently underwent His bundle electrogram. A double-blind crossover protocol was used with conduction velocity measurements at baseline and after saline (placebo) and Enalaprilat 2.5 mg intravenously. There were no significant changes in heart rate (64 plus minus 9 versus 65 plus minus 11 versus 65 plus minus to beats min(minus sign1)) at baseline, after saline and enalaprilat infusion, respectively, mean blood pressure (97 plus minus 11 versus 94 plus minus 10 versus 94 plus minus 7 mm Hg, respectively), atrioventricular conduction time (100 plus minus 20 versus 100 plus minus versus 100 plus minus 20 versus 100 plus minus ms), and His--Purkinje (HV) conduction time (40 plus minus 12 versus 40 plus minus 13 versus 40 plus minus 12 ms). Ventricular activity duration was 110 plus minus 11 ms at baseline, 110 plus minus 10 ms after saline infusion (p = NS), and 88 plus minus 13 ms after Enalaprilat administration (p < 0.001). Angiotensin-converting enzyme inhibition appears to produce significant reduction in ventricular activity duration (increase in intraventricular conduction velocity).


Isolation of a rare Escherichia coli O157:H7 strain from farm animals in Greece.
A strain of Escherichia coli O157:H7 was isolated from goat faeces during a surveillance study on the prevalence of this serotype of E. coli in farm animals in Greece. Three hundred and fifty one faecal samples were collected from goat, sheep and cattle breeding farms in the area of Epirus, Northwestern Greece. The E. coli O157:H7 isolate was nonsorbitol-fermenter, produced only VT2 and showed a beta-glucuronidase positive activity, a rather unusual biochemical feature for the E. coli O157:H7 serotype. No other strain of E. coli O157:H7 was isolated from the faecal samples of the rest farm animals examined, thus the overall prevalence of animal carriage was found to be 0.2%. The findings also indicate that goats can be a reservoir of E. coli O157:H7 and goat milk, dairy products and meat may serve as a vehicle for the pathogen transmission to humans.


The Effect of Sagittal Plane Deformities after Tibial Plateau Fractures to Functions and Instability of Knee Joint.
The objective of this study is to evaluate the effect of posterior tibial slope after fracture healing on antero-posterior knee laxity, functional outcome and patient satisfaction. 126 patients who were treated for tibial plateau fractures between 2008-2013 in the orthopedics and traumatology department of our institution were evaluated for the study. Patients were treated with open reduction and internal fixation, arthroscopy assisted minimally invasive osteosynthesis or conservative treatment. Mean posterior tibial slope after the treatment was 6.91 ± 5.11 and there was no significant difference when compared to the uninvolved side 6.42 ± 4,21 (p = 0.794). Knee laxity in anterior-posterior plane was 6.14 ± 2.11 and 5.95 ± 2.25 respectively on healthy and injured side. The difference of mean laxity in anterior-posterior plane between two sides was statistically significant. In this study we found no difference in laxity between the injured and healthy knees. However Tegner score decreased significantly in patients who had greater laxity difference between the knees. We did not find significant difference between fracture type and laxity, IKDC functional scores independent of the ligamentous injury. In conclusion despite coronal alignment is taken into consideration in treatment of tibial plateau fractures, sagittal alignment is reasonably important for stability and should not be ignored.


K-means clustering of overweight and obese population using quantile-transformed metabolic data.
Use of K-means clustering for big data technology to cluster an overweight and obese population metabolically. K-means clustering with the help of quantile transformation of attribute values was applied to overcome the impact of the considerable variation in the values of obesity attributes involving outliers and skewed distribution. Overall, 447 subjects were categorized into six clusters; metabolically normal, mild, and severe categories. There were clearly separated metabolically normal Cluster 1 and severe Cluster 2, as well as intermediate Cluster 3, 4, and 5 that had profiles of fewer attributes with abnormal values. Cluster 3 was characteristic of sole hypertension. Cluster 3 and 4 exhibited contrasting HDL-C and LDL-C levels despite similarly elevated total cholesterol. Cluster 6 with slightly elevated triglyceride was closest to the normal group. Four- and 10-quantile-transformations yielded consistent clustering results. Compared with the original data, the quantile-transformed data produced more regular and spherical clusters and evenly distributed clusters in terms of object numbers. This big data analysis strategy makes use of quantile-transformation of data to overcome the issue of outliers and the irregular distribution and applies to the analysis of other non-communicable diseases.


Regulation of the expression and processing of caspase-12.
Phylogenetic analysis clusters caspase-12 with the inflammatory caspases 1 and 11. We analyzed the expression of caspase-12 in mouse embryos, adult organs, and different cell types and tested the effect of interferons (IFNs) and other proinflammatory stimuli. Constitutive expression of the caspase-12 protein was restricted to certain cell types, such as epithelial cells, primary fibroblasts, and L929 fibrosarcoma cells. In fibroblasts and B16/B16 melanoma cells, caspase-12 expression is stimulated by IFN-gamma but not by IFN-alpha or -beta. The effect is increased further when IFN-gamma is combined with TNF, lipopolysaccharide (LPS), or dsRNA. These stimuli also induce caspase-1 and -11 but inhibit the expression of caspase-3 and -9. In contrast to caspase-1 and -11, no caspase-12 protein was detected in macrophages in any of these treatments. Transient overexpression of full-length caspase-12 leads to proteolytic processing of the enzyme and apoptosis. Similar processing occurs in TNF-, LPS-, Fas ligand-, and thapsigargin (Tg)-induced apoptosis. However, B16/B16 melanoma cells die when treated with the ER stress-inducing agent Tg whether they express caspase-12 or not.


T-cell activation by recombinant immunoreceptors: impact of the intracellular signalling domain on the stability of receptor expression and antigen-specific activation of grafted T cells.
Recombinant immunoreceptors are modularily composed of extracellular antigen binding and intracellular signalling domains that are preferentially derived from CD3zeta or Fc epsilon RIgamma. The impact of the signalling domain on the stability of immunoreceptor expression and function is not completely understood. To address this issue, we generated and expressed a panel of recombinant zeta- and gamma-chain immunoreceptors, respectively, in human peripheral blood T cells. The expression level of zeta-chain immunoreceptors in human T cells is significantly lower than those of the homologous gamma-chain receptors. Low zeta-chain receptor expression in peripheral T cells is because of the intracellular signalling domain and independent of the Fc epsilon RIgamma or CD3zeta transmembrane region. Expression of both receptors decreases upon prolonged cultivation. Shortly after receptor engraftment, target cell lysis and induction of IFN-gamma secretion are mediated with similar efficiency by zeta- and gamma-chain immunoreceptors. Upon prolonged propagation, however, T-cell activation mediated by zeta-chain immunoreceptors is more efficient than by gamma-chain receptors, indicating that the initial high expression level of gamma-chain immunoreceptors compensates its lower activation capacity. Consequently, gamma-chain immunoreceptors exhibit a higher threshold value for specific activation and are more pronouncedly inhibited by soluble ligand antigen compared to the homologous zeta-chain receptor. These findings have substantial consequences for the design of recombinant immunoreceptors for use in adoptive immunotherapy.


Terrestrial nitrogen and noble gases in lunar soils.
The nitrogen in lunar soils is correlated to the surface and therefore clearly implanted from outside. The straightforward interpretation is that the nitrogen is implanted by the solar wind, but this explanation has difficulties accounting for both the abundance of nitrogen and a variation of the order of 30 per cent in the 15N/14N ratio. Here we propose that most of the nitrogen and some of the other volatile elements in lunar soils may actually have come from the Earth's atmosphere rather than the solar wind. We infer that this hypothesis is quantitatively reasonable if the escape of atmospheric gases, and implantation into lunar soil grains, occurred at a time when the Earth had essentially no geomagnetic field. Thus, evidence preserved in lunar soils might be useful in constraining when the geomagnetic field first appeared. This hypothesis could be tested by examination of lunar farside soils, which should lack the terrestrial component.


Pulmonary delivery of peptide drugs: effect of particle size on bioavailability of leuprolide acetate in healthy male volunteers.
Leuprolide acetate, a nonapeptide with potent luteinizing hormone releasing hormone (LHRH) agonist activity, has low oral bioavailability. Unique aerosols of leuprolide acetate were developed and particle size distribution studies were carried out. A light scattering method (Malvern Model 2600c) was compared to the impaction method (Andersen Sampler) for measuring size distribution. Results showed the Malvern method to be comparable to the impaction method with the Malvern being faster and easier to use. Absolute bioavailability of leuprolide acetate in healthy human male volunteers ranged from 4% to 18% and agreed well with particle size data. Bioavailability corrected for respirable fraction ranged from 35% to 55%, indicating that the pulmonary route may have high potential for systemic delivery of this peptide.


Family study of common fragile sites.
The frequency of folate-sensitive common fragile sites (1p31, 1q44, 3p14, 3q26.2, 6q26, 16q23, Xp22.3) was determined in 19 healthy individuals from four families. The individuals consisted of 12 males and 7 females from 1 to 59 years of age. The frequency showed intrafamilial variation, but we were unable to demonstrate that the frequency was inherited in a Mendelian codominant fashion. In eight subjects whose chromosome 3 homologues could be distinguished by Q-band polymorphism, breakages at 3p14 occurred with equal frequencies on the homologues. Our study suggests that common fragile sites are a part of normal chromosome structure, and the frequency of their expression largely depends on environmental factors.


The rate of electrical energy dissipation (power) and the RC constant unify all electroporation parameters.
Electroporation parameters can be optimized by coupling RC constant values with the amount of electrical power dissipation in the electroporation medium. Electroporation efficiency increases more steeply with power at low power values.


Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway.
Oral helminthic mebendazole (MBZ) has been reported to cause liver injury with inflammatory responses. However, the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether MBZ and other helminthic drugs increase the release of pro-inflammatory cytokines and chemokines using human monocytic cells. The release of interleukin (IL)-8 and tumor necrosis factor (TNF) α from human monocytic THP-1 cells was significantly increased by treatment with MBZ, albendazole (ABZ), fenbendazole (FBZ), or oxibendazole (OBZ), but not by albendazole sulfoxide or praziquantel, suggesting that MBZ and structurally similar drugs can stimulate monocytes and increase the release of pro-inflammatory cytokines. MBZ also significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 in THP-1 cells. Pretreatment with the MAP kinase/ERK kinase 1/2 inhibitor U0126 significantly suppressed the increase of IL-8 and TNFα levels by MBZ, ABZ, FBZ, or OBZ treatment in THP-1 cells, but the p38 mitogen-activated protein kinase inhibitor SB203580 or JNK1/2 inhibitor SP600125 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFα in THP-1 cells treated with MBZ and structurally similar drugs. In conclusion, the release of inflammatory mediators by MBZ might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to hepatotoxicity.


A Uromodulin Mutation Drives Autoimmunity and Kidney Mononuclear Phagocyte Endoplasmic Reticulum Stress.
We identified a family with a UMOD gene mutation (C106F) resulting in glomerular inflammation and complement deposition. To determine if the observed phenotype is due to immune system activation by mutant uromodulin, a mouse strain with a homologous cysteine to phenylalanine mutation (C105F) in the UMOD gene was generated using CRISPR-Cas9 gene editing and the effect of this mutation on mononuclear phagocytic cells was examined. Mutant mice developed high levels of intracellular and secreted aggregated uromodulin, resulting in anti-uromodulin antibodies and circulating uromodulin containing immune complexes with glomerular deposition and kidney fibrosis with aging. F4/80+ and CD11c+ kidney cells phagocytize uromodulin. Differential gene expression analysis by RNA sequencing of F4/80+ phagocytic cells revealed activation of the activating transcription factor 5 (ATF5)-mediated stress response pathway in mutant mice. Phagocytosis of mutant uromodulin by cultured dendritic cells resulted in activation of the endoplasmic reticulum stress response pathway and markers of cell inactivation, an effect not seen with wild-type protein. Mutant mice demonstrate a twofold increase in T-regulatory cells, consistent with induction of immune tolerance, resulting in decreased inflammatory response and improved tissue repair following ischemia-reperfusion injury. The C105F mutation results in autoantibodies against aggregated misfolded protein with immune complex formation and kidney fibrosis. Aggregated uromodulin may induce dendritic cell tolerance following phagocytosis through an unfolded protein/endoplasmic reticulum stress response pathway, resulting in decreased inflammation following tissue injury.


Acute aortic dissection in blacks: insights from the International Registry of Acute Aortic Dissection.
Few data exist on race-related differences in acute aortic dissection patients. We evaluated black (n = 189, 14%) or white (n = 1165, 86%) patients (mean age 62.8 ± 15.3 years; 36.4% women) enrolled in 13 US centers participating in the International Registry of Acute Aortic Dissection. We excluded patients of other racial descent. Type B acute aortic dissection was more frequent in the black cohort (52.4% vs 39.3%, P = .001). Black patients were younger (mean age 54.6 ± 12.8 years vs 64.2 ± 15.2 years, P <.001) and more likely to have a history of cocaine abuse (12% vs 1.6%, P <.001), hypertension (89.7% vs 73.9%, P <.001), and diabetes (13.2% vs 6.4%, P = .001). Conversely, they were less likely to have bicuspid aortic valve (1.8% vs 5.8%, P = .029), iatrogenic dissection (0.5% vs 4.5%, P = .010), and prior aortic dissection repair (7.7% vs 12.8%, P = .047). Presenting features were similar except for more abdominal pain (44.6% vs 30.6%, P <.001) and left ventricular hypertrophy on echocardiogram (44.2% vs 20.1%, P <.001) in blacks. Management was similar. Hypotension/shock/tamponade was less common (7.6% vs 20.1%, P <.001), whereas acute kidney failure was more common (41.0% vs 21.7%, P <.001) in blacks. Mortality was similar in-hospital (14.3% vs 19.1%, P = .110, odds ratio 0.704, 95% confidence interval 0.457-1.085) and at 3 years postdischarge, as evaluated by Kaplan-Meier survival analysis (22.0% vs 14.3%, P = .224, SE = 0.062 and 0.018). Our study shows differences in type, etiology, and presentation of blacks and whites with acute aortic dissection, yet similar mortality for these cohorts.


[Shear strength measurements for the clinical evaluation of bonded ceramic systems].
The shear bond strength of dental ceramic (Dicor, Optec) and luting composite (Dicor, Optec, Dual-cement) bonded to dentin and to etched enamel was evaluated. The mean bond strength was 23.8 N/mm2 to enamel and 0.60 N/mm2 to dentin. Using the Optec dentinal bonding agents increased these values to 2.00 N/mm2.


In vitro and in vivo studies of a novel nanohydroxyapatite/superhydrophilic vertically aligned carbon nanotube nanocomposites.
An association between in vitro and in vivo studies has been demonstrated for the first time, using a novel nanohydroxyapatite/superhydrophilic vertically aligned multiwalled carbon nanotube (nHAp/VAMWCNT-O2) nanocomposites. Human osteoblast cell culture and bone defects were used to evaluate the in vitro extracellular matrix (ECM) calcification process and bone regeneration, respectively. The in vitro ECM calcification process of nHAp/VAMWCNT-O2 nanocomposites were investigated using alkaline phosphatase assay. The in vivo biomineralization studies were carried out on bone defects of C57BL/6/JUnib mice. Scanning electron microscopy, micro-energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and X-ray difractometry analyses confirmed the presence of the nHAp crystals. nHAp/VAMWCNT-O2 nanocomposites induced in vitro calcification of the ECM of human osteoblast cells in culture after only 24 h. Bone regeneration with lamellar bone formation after 9 weeks was found in the in vivo studies. Our findings make these new nanocomposites very attractive for application in bone tissue regeneration.