Loss of voltage-gated hydrogen channel 1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T cells.
Voltage-gated hydrogen channel 1 (Hvcn1) is a voltage-gated proton channel, which reduces cytosol acidification and facilitates the production of ROS. The increased expression of this channel in some cancers has led to proposing Hvcn1 antagonists as potential therapeutics. While its role in most leukocytes has been studied in depth, the function of Hvcn1 in T cells remains poorly defined. We show that Hvcn1 plays a nonredundant role in protecting naive T cells from intracellular acidification during priming. Despite sharing overall functional impairment in vivo and in vitro, Hvcn1-deficient CD4+ and CD8+ T cells display profound differences during the transition from naive to primed T cells, including in the preservation of T cell receptor (TCR) signaling, cellular division, and death. These selective features result, at least in part, from a substantially different metabolic response to intracellular acidification associated with priming. While Hvcn1-deficient naive CD4+ T cells reprogram to rescue the glycolytic pathway, naive CD8+ T cells, which express high levels of this channel in the mitochondria, respond by metabolically compensating mitochondrial dysfunction, at least in part via AMPK activation. These observations imply heterogeneity between adaptation of naive CD4+ and CD8+ T cells to intracellular acidification during activation.


High- and low-inpatients' serum magnesium levels are associated with in-hospital mortality in elderly patients: a neglected marker?
Altered serum magnesium (Mg) level in the human body has been hypothesized to have a role in the prediction of hospitalization and mortality; however, the reported outcomes are not conclusive. The present study aimed to analyze the relationship between serum Mg and in-hospital mortality (IHM) in patients admitted to the medical ward of two hospitals in the Veneto region (Italy). Patients > 18 years hospitalized in the medical wards of the hospitals of Vittorio Veneto and Conegliano, Italy (from January 12, 2011, through December 27, 2016) with at least one measurement of serum Mg were included in the study. A logistic regression model was used to assess the unadjusted and adjusted (by age, gender, Charlson Comorbidity index, discharge diagnosis' class) association of serum Mg and IHM. In total 5024 patients were analyzed, corresponding to 6980 total admissions. The unadjusted analysis showed that IHM risk was significantly higher with 0.2 mg/dl incremental serum Mg level change from 2.4 mg/dl to 2.6, (OR 1.71 95% CI 1.55-1.89) and with 0.2 mg/dl change from serum Mg level of 1.4 mg/dl to 1.2 mg/dl, (OR 1.28 95% CI 1.17-1.40). Such results were confirmed at adjusted analysis. Present findings have relevant implications for the clinical management of patients suffering from medical conditions, highlighting the need for analyzing Mg concentration carefully. Serum Mg levels seem to be a good predictor of IHM.


Infectious spleen and kidney necrosis virus ORF48R functions as a new viral vascular endothelial growth factor.
Infectious spleen and kidney necrosis virus (ISKNV) causes a pandemic and serious disease in fish. Infection by ISKNV causes epidermal lesions, in which petechial hemorrhages and abdominal edema are prominent features. ISKNV ORF48R contains a domain similar to that of the platelet-derived growth factor and vascular endothelial growth factor (VEGF) families of proteins. ISKNV ORF48R showed higher similarity to the VEGFs encoded by Megalocytivirus and Parapoxvirus than to those encoded in fish and mammals. We used zebrafish as a model and constructed a recombinant plasmid containing the DNA sequence of ISKNV ORF48R to study ISKNV infection. The plasmid was microinjected into zebrafish embryos at the one-cell stage. Overexpression of the ISKNV ORF48R gene results in pericardial edema and dilation at the tail region of zebrafish embryos, suggesting that ISKNV ORF48R induces vascular permeability. ISKNV ORF48R is also able to stimulate a striking expression of flk1 in the zebrafish dorsal aorta and the axial vein. Furthermore, ISKNV ORF48R, while cooperating with zebrafish VEGF(121), can stimulate more striking expression of flk1 than can either ISKNV ORF48R or zebrafish VEGF(121) alone. However, decreased expression of FLK-1 by gene knockdown results in the disappearance of pericardial edema and dilation at the tail region of zebrafish embryos induced by overexpression of ISKNV ORF48R in the early stages of embryonic development.


Restoration of certain minimum benefits and other OASDI program changes: legislative history and summary of provisions.
The Omnibus Budget Reconciliation Act of 1981 (Public Law 97-35), enacted on August 13, 1981, contained a provision to eliminate the minimum-benefit provision under the Social Security program for both current and future beneficiaries. Although a large majority of the members of both Houses of Congress accepted the measure in the broad context of the Reconciliation Act, there was considerable reaction against it and the provision was reconsidered. On December 29, 1981, new legislation restored the minimum benefit for current, but not future, beneficiaries. To lessen the cash-flow problems of the Old-Age and Survivors Insurance (OASI) program, Public Law 97-123 also authorizes borrowing among the several trust funds and calls for the coverage, for Social Security tax and benefit purposes, of sick pay during the first 6 months of nonwork. In this article, the Commissioner of Social Security traces the legislative development of these and other provisions contained in the new law. He points out that, although the added expenditures for minimum benefits ultimately will be offset by the coverage of sick pay, the net short-term effect of the two provisions will be higher program costs. The interfund borrowing provision, however, could permit the payment of benefits on a timely basis throughout 1982 and the first 6 months of 1983.


Hepatitis and jaundice associated with measles in young adults. An analysis of 65 cases.
We analyzed the clinical course of 65 adult patients hospitalized because of measles during the years 1975 and 1981-1982. Liver involvement was found in 80% (52/65) of the patients, five patients had clinical jaundice. The disturbances of liver function tests reached their peak values between days 5 and 10 of the disease. In this study of measles in adulthood we have three observations of unusual interest: (1) hepatitis occurs commonly in the more severely ill patients and it may manifest clinically as jaundice; (2) long-term follow-up (up to seven years) shows a clear tendency to complete resolution of the liver damage; (3) there is a clear correlation between the severity of hepatic involvement and the occurrence of secondary bacterial infections.


Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia.
Dialysis patients suffer a manifold increase in cardiovascular mortality when compared to a nonuremic population, while this phenomenon is not sufficiently explained by an increased prevalence of traditional risk factors, such as hypercholesterolemia and hypertension. The presence of hyperphosphatemia, of an increased calcium x phosphate product, as well as the magnitude of vascular and valvular calcifications, were recently identified as specific major risk factors of cardiovascular mortality in the uremic population. Furthermore, hyperphosphatemia and an increased calcium x phosphate product could be quantitatively linked to the burden of coronary artery calcification in young dialysis patients, suggesting the correction of hyperphosphatemia as the central target for preventive therapeutic intervention. Recent studies in knockout mice, however, point to the alternative possibility that deficiencies in calcium-regulatory proteins may represent important pathomechanisms leading to extraosseous calcifications. alpha 2-Heremans Schmid glycoprotein (Ahsg/fetuin) and matrix Gla protein (MGP) are strong inhibitors of calcification in vivo. Novel evidence that deficiencies of such proteins may be involved in the pathogenesis of cardiovascular calcifications in dialysis patients will be discussed.


The brain-gut axis of fish: Rainbow trout with low and high cortisol response show innate differences in intestinal integrity and brain gene expression.
In fish, the stress hormone cortisol is released through the action of the hypothalamic pituitary interrenal axis (HPI-axis). The reactivity of this axis differs between individuals and previous studies have linked this to different behavioural characteristics and stress coping styles. In the current study, low and high responding (LR and HR) rainbow trout in terms of cortisol release during stress were identified, using a repeated confinements stress test. The expression of stress related genes in the forebrain and the integrity of the stress sensitive primary barrier of the intestine was examined. The HR trout displayed higher expression levels of mineralocorticoid and serotonergic receptors and serotonergic re-uptake pumps in the telencephalon during both basal and stressed conditions. This confirms that HPI-axis reactivity is linked also to other neuronal behavioural modulators, as both the serotonergic and the corticoid system in the telencephalon are involved in behavioural reactivity and cognitive processes. Involvement of the HPI-axis in the brain-gut-axis was also found. LR trout displayed a lower integrity in the primary barrier of the intestine during basal conditions compared to the HR trout. However, following stress exposure, LR trout showed an unexpected increase in intestinal integrity whereas the HR trout instead suffered a reduction. This could make the LR individuals more susceptible to pathogens during basal conditions where instead HR individuals would be more vulnerable during stressed conditions. We hypothesize that these barrier differences are caused by regulation/effects on tight junction proteins possibly controlled by secondary effects of cortisol on the intestinal immune barrier or differences in parasympathetic reactivity.


Dexmedetomidine: the new all-in-one drug in paediatric anaesthesia?
Dexmedetomidine is a drug with sedative, anxiolytic, sympatholytic and analgesic properties, which is finding widespread practice in paediatric anaesthesia and related practices. The present review summarizes its pharmacology and current experience with the drug. Dexmedetomidine is proving useful in many diverse areas in paediatric anaesthesia where its sedative properties are useful for premedication, fibreoptic intubation and radiologic procedures. Its use as an adjunct for balanced anaesthesia where it can decrease the use of other drugs, reduce emergence delirium, postoperative shivering and vomiting. Muted apoptotic neuroprotective effects may realize benefits in neonates. Cardiac conduction delay, an adverse effect, may prove beneficial for arrhythmias after congenital cardiac surgery. Most of the paediatric published studies concerning dexmedetomidine are observational in nature, with limited control groups or comparators. Adverse effects (e.g. bradycardia) still require greater scrutiny in the paediatric population and particularly with respect to different age groups. Dexmedetomidine currently has a firm position in the armamentarium of anaesthesia pharmacology. It is not the new all-in-one drug, but it is shaping up as a valuable adjunct for diverse indications within paediatric anaesthesia. VIDEO ABSTRACT: http://links.lww.com/COAN/A44.


[Intrahepatic cholestasis induced by amoxicillin alone].
We present a young, female patient with clinical and biochemical manifestations of acute cholestasis who had undergone a 10-day course of 1,500 mg/day amoxicillin 3 weeks before the consultation. Diagnosis was based on the absence of alcohol consumption, negative viral markers and antibodies, normal biliary tract, clinical and biochemical improvement when amoxicillin was withdrawn and liver biopsy with histological changes compatible with amoxicillin-induced acute cholestasis. Because hepatotoxicity induced by amoxicillin alone is rare, we believe it important to communicate this new case and to warn of this possible complication. We also stress that simple cholestasis induced by amoxicillin alone, as presented in this case, has been described in only one report, published 10 years ago.


Bilateral multicanal benign paroxysmal positional vertigo coexisting with a vestibular schwannoma: case report.
We describe a rarely encountered case of coexisting bilateral multicanal benign paroxysmal positional vertigo (BPPV) and vestibular schwannoma in a 56-year-old woman. The patient had presented with a 10-year history of dizziness and imbalance, and her vestibular findings were perplexing. We decided on a working diagnosis of BPPV and began treatment. After several months of canalith repositioning maneuvers had failed to resolve her symptoms, we obtained magnetic resonance imaging, which revealed the presence of the vestibular schwannoma. This case serves as a reminder of the importance of differentiating between central and peripheral vestibular disorders, as well as central and anterior canal BPPV-induced down-beating nystagmus in order to establish the correct diagnosis and initiate appropriate treatment.


The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs.
Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ∼1 h. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03 and 0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.


The power of personal control: Task choice attenuates the effect of implicit sadness on sympathetically mediated cardiac response.
Implicitly processed pictures of facial expressions of emotions have been found to systematically influence sympathetically mediated cardiovascular reactivity during task performance. According to the Implicit-Affect-Primes-Effort model, this happens because different affect primes activate the concepts of performance ease versus performance difficulty. Grounded in a recent action shielding model, our laboratory experiment (N = 129 university students) tested whether engaging in action by personal choice can immunize against those implicit affective influences on effort. Participants worked on an objectively difficult cognitive task, which was either externally assigned or ostensibly personally chosen. As predicted, participants in the assigned task condition showed weaker cardiac pre-ejection period reactivity during task performance, reflecting disengagement, when they were primed with sadness than when they were exposed to anger primes. Most relevant, this affect prime effect disappeared when participants could ostensibly choose their task themselves. These findings replicate previous research on implicit affect's impact on sympathetically mediated cardiac response and extend the literature on action shielding by personal choice effects to implicit affective influences on action execution.


Skin flaps for the gynaecologist.
Skin flaps are becoming more frequently indicated in gynecologic surgical practice, especially in oncologic surgery. It is imperative that the gynecologic surgeon of today be well informed in the many physiologic processes of wound healing, also those factors that delay and those that promote wound healing. Knowledge of the detailed anatomy of abdomen, pelvis, vulva, peritoneum and ano-rectal area is essential. An appreciation of the specific muscular attachments, action, blood supply, collateral circulation and nerve supply are important prerequisites. Also, a working knowledge of the tissue dynamics associated with the transfer of skin, subcutaneous tissue and sometimes muscle to the required location. The important role played by vascular endothelial growth factor (VEGF), endothelial proginator cells, protein kinase C, and other factors being investigated in wound healing, is exciting. There are a number of procedures possible for most problems requiring tissue transfer. Tension free oxygenated areas for healing is essential. All the basic surgical rules for tissue handling and would healing must be carefully applied for optimum results.


Hyalomma (Hyalommina) arabica: nymphal and larval identity and spiny mouse hosts in Saudi Arabia (Acarina: Ixodoidea: Ixodidae).
Nymphal and larval Hyalomma (Hyalommina) arabica Pegram, Hoogstraal, and Wassef, 1982, described herein, closely resemble those of Hyalomma (Hyalommina) rhipicephaloides Neumann, differing chiefly in body size (both stages), nymphal basis capituli and scutal proportional dimensions, and distinctness of larval coxal spurs. Females of these species are also structurally similar but males differ in major critical characters. Nymphs and larvae of both species parasitize the spiny mouse (Acomys spp.), but immatures of the third African- Arabian species of this subgenus, Hyalomma (Hyalommina) punt Hoogstraal, Kaiser, and Pedersen, are unknown. Hyalomma (Hyalommina) arabica occurs in valleys and hills of western Saudi Arabia and western Yemen; H. (H.) rhipicephaloides in the Red Sea and Dead Sea areas; and H. (H.) punt in northeastern Somalia and eastern Ethiopia. The ibex (Capra ibex nubiana Cuvier) is probably the original host of adult H. (H.) arabica and H. (H.) rhipicephaloides; the related domestic goat is an important host of adults of the 3 species, which also parasitize domestic sheep. Gazelles are recorded hosts of adults of H. (H.) rhipicephaloides and H. (H.) punt and the latter is also recorded from goats, sheep, camels and cattle.


Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells.
Atherosclerotic cardiovascular disease is the number one cause of death for adults in Western society. Plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activators, has been implicated in both thrombogenesis and atherogenesis. Previous studies demonstrated that copper-oxidized low-density lipoprotein (C-oLDL) stimulated production of PAI-1 in vascular endothelial cells (EC). The present study examined the involvement of lectin-like oxidized LDL receptor-1 (LOX-1) and Ras/Raf-1/ERK1/2 pathway in the upregulation of PAI-1 in cultured EC induced by oxidized LDLs. The results demonstrated that C-oLDL or FeSO(4)-oxidized LDL (F-oLDL) increased the expression of PAI-1 or LOX-1 in human umbilical vein EC (HUVEC) or coronary artery EC (HCAEC). Treatment with C-oLDL significantly increased the levels of H-Ras mRNA, protein, and the translocation of H-Ras to membrane fraction in EC. LOX-1 blocking antibody, Ras farnesylation inhibitor (FTI-277), or small interference RNA against H-Ras significantly reduced C-oLDL or LDL-induced expression of H-Ras and PAI-1 in EC. Incubation with C-oLDL or F-oLDL increased the phosphorylation of Raf-1 and ERK1/2 in EC compared with LDL or vehicle. Treatment with Raf-1 inhibitor blocked Raf-1 phosphorylation and the elevation of PAI-1 mRNA level in EC induced by C-oLDL or LDL. Treatment with PD-98059, an ERK1/2 inhibitor, blocked C-oLDL or LDL-induced ERK1/2 phosphorylation or PAI-1 expression in EC. The results suggest that LOX-1, H-Ras, and Raf-1/ERK1/2 are implicated in PAI-1 expression induced by oxidized LDLs or LDL in cultured EC.


Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo.
The number and growth factor requirements of committed progenitor cells (colony-forming units-granulocyte/macrophage and burst-forming units-erythroid) in three patients with cyclic neutropenia (two congenital, one acquired) were studied before and during therapy with recombinant human granulocyte colony-stimulating factor (G-CSF; 3 to 10 micrograms/kg/d). When the patients with congenital disease were treated with G-CSF, the cycling of blood cells persisted, but the cycle length was shortened from 21 days to 14 days, and the amplitude of variations in blood counts increased. There was a parallel shortening of the cycle and increase of the amplitude of variations (from two- to three-fold to 10- to 100-fold) in the number of both types of circulating progenitor cells in these two patients. In the patient with acquired cyclic neutropenia, cycling of both blood cells and progenitors could not be seen. In cultures deprived of fetal bovine serum, erythroid and myeloid bone marrow progenitor cells from untreated patients and from normals differed in growth factor responsiveness. As examples, maximal growth of granulocyte/macrophage (GM) colonies was induced by granulocyte/macrophage (GM)-CSF plus G-CSF in the patients, whereas a combination of GM-CSF, G-CSF and interleukin-3 (IL-3) was required in the normals, and erythropoietin alone induced fourfold more erythroid bursts from cyclic neutropenic patients than from normal donors (46% versus 11% of the maximal colony number, respectively). The growth factor responsiveness of marrow progenitor cells slightly changed during the treatment toward the values observed with normal progenitors. These results indicate that treatment with G-CSF not only ameliorated the neutropenia, but also increased the amplitude and the frequency of oscillation of circulating progenitor cell numbers. These data are consistent with the hypothesis that G-CSF therapy affects the proliferation of the hematopoietic stem cell.


Temporal lobectomy in children with epilepsy.
The results of temporal lobectomy for medically refractory seizures are analyzed in 29 boys and 21 girls with a mean age of 15.8 years. The average age at onset of seizures was 7.5 years, and the time between onset and surgery averaged 8.3 years. Postoperatively, 27 patients (54%) were seizure-free, 12 patients (24%) had only occasional auras without loss of consciousness, five patients (10%) had fewer seizures, and six (12%) were unchanged. Therefore, 78% were essentially seizure-free and 88% benefited significantly from the operation. There was no significant change in the Wechsler Intelligence Scale scores before and after surgery; however, the shorter the time between seizure onset and surgery, the greater the likelihood of improvement in verbal and perceptual intelligence quotient. Social outcome was significantly improved, and a large percentage of patients were either in school or actively employed. Early consideration of temporal lobectomy in children with medically refractory seizures is recommended.


Relation between red cell distribution width and clinical outcomes after acute myocardial infarction.
Increased red blood cell distribution width (RDW) has been associated with adverse outcomes in heart failure and stable coronary disease. We studied the association between baseline RDW and changes in RDW during hospital course with clinical outcomes in patients with acute myocardial infarction (AMI). Baseline RDW and RDW change during hospital course were determined in 1,709 patients with AMI who were followed for a median of 27 months (range 6 to 48). The relation between RDW and clinical outcomes after hospital discharge were tested using Cox regression models, adjusting for clinical variables, baseline hemoglobin, mean corpuscular volume, and left ventricular ejection fraction. Compared to patients in the first RDW quintile, the adjusted hazard ratios for death progressively increased with higher quintiles of RDW (second quintile 1.1, 95% confidence interval [CI] 0.6 to 2.1; third quintile 1.8, 95% CI 1.0 to 3.2; fourth quintile 2.0, 95% CI 1.1 to 3.4; fifth quintile 2.8, 95% CI 1.6 to 4.7, p for trend <0.0001). An increase in RDW during hospital course was also associated with subsequent mortality (adjusted hazard ratio 1.13 for 1-SD increase in RDW, 95% CI 1.02 to 1.25). Similar results were obtained for the end point of heart failure. The association between increased RDW and worse outcome was evident in patients with and without anemia. In conclusion, there is a graded, independent association between increased RDW and mortality after AMI. An increase in RDW during hospitalization also portends adverse clinical outcome.


Necrotising lymphadenitis without granulocytic infiltration (Kikuchi's disease).
Kikuchi's disease (necrotising lymphadenitis) is characterised by cervical lymphadenopathy in young patients and may be mistaken for malignant disease both clinically and histologically. Microscopically, there is a varying degree of effacement of the lymph node architecture and necrosis with an infiltrate of "histiocytic" cells and absence of polymorphs. The disease is of unknown aetiology. It was originally described in Japan, and only 27 cases have been reported elsewhere (none in the United Kingdom), although it has probably been seen but not recognised. The clinical, histopathological, electron microscopic, and immunohistological findings in four cases of the disease were evaluated.


Contrast-enhanced power and color Doppler ultrasonography of the pancreas in healthy and diseased cats.
The diagnosis of feline pancreatic disease is difficult, because clinical abnormalities and routine noninvasive diagnostic tests are unreliable. The purpose of this study was to investigate by Doppler ultrasonography if vascularity and blood volume differs in the otherwise ultrasonographically normal and diseased feline pancreas. Thirty-six client owned cats. The pancreas was examined with B-mode and contrast-enhanced color and power Doppler ultrasonography. Doppler images were analyzed with a computer program: parameter fractional area represents a vascularity index and color-weighted fractional area assesses blood volume. Based on the B-mode findings, the pancreas was considered normal in 11 clinically healthy cats and diseased in 25 cats of which 4 were clinically healthy and 21 had clinical signs consistent with pancreatic disease. Histologic or cytologic samples were taken in all diseased pancreata. Fifteen samples were of diagnostic quality: purulent or mixed cellular inflammation (8), nodular hyperplasia (4), and neoplasia (3) were identified. Vascularity and blood volume for all Doppler methods was significantly higher in cats with pancreatic disease. Significantly higher Doppler values were detected with power Doppler than with color Doppler, and with postcontrast color and power Doppler than with precontrast Doppler technologies. Contrast-enhanced Doppler ultrasonography appears feasible in the feline pancreas. Significant differences were found between normal cats and those with evidence of pancreatic pathology. Further studies are needed to evaluate its use for the differentiation of pancreatic disorders and in cats suspected to have pancreatic disease but without B-mode ultrasonographic changes of the pancreas.


A label-free immunoassay based upon localized surface plasmon resonance of gold nanorods.
Robust gold nanorod substrates were fabricated for refractive index sensing based on localized surface plasmon resonance (LSPR). The substrate sensitivity was 170 nm/RIU with a figure of merit of 1.3. To monitor biomolecular interactions, the nanorod surfaces were covered with a self-assembled monolayer and conjugated to antibodies by carbodiimide cross-linking. Interactions with a specific secondary antibody were monitored through shifts in the LSPR spectral extinction peak. The resulting binding rates and equilibrium constant were in good agreement with literature values for an antibody-antigen system. The nanorod LSPR sensors were also shown to be sensitive and specific. These results demonstrate that given a sufficiently stable nanoparticle substrate with a well defined chemical interface, LSPR sensing yields similar results to the surface plasmon resonance technique, yet with much simpler instrumentation.


The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics.
What evidence is available regarding the emerging and investigational therapies for the treatment of metastatic brain tumors? These recommendations apply to adults with brain metastases. New radiation sensitizers Level 2 A subgroup analysis of a large prospective randomized controlled trial (RCT) suggested a prolongation of time to neurological progression with the early use of motexafin-gadolinium (MGd). Nonetheless this was not borne out in the overall study population and therefore an unequivocal recommendation to use the currently available radiation sensitizers, motexafin-gadolinium and efaproxiral (RSR 13) cannot be provided. Interstitial modalities There is no evidence to support the routine use of new or existing interstitial radiation, interstitial chemotherapy and or other interstitial modalities outside of approved clinical trials. New chemotherapeutic agents Level 2 Treatment of melanoma brain metastases with whole brain radiation therapy and temozolomide is reasonable based on one class II study. Level 3 Depending on individual circumstances there may be patients who benefit from the use of temozolomide or fotemustine in the therapy of their brain metastases. Molecular targeted agents Level 3 The use of epidermal growth factor receptor inhibitors may be of use in the management of brain metastases from non-small cell lung carcinoma.


Computed tomographic morphometry of thoracic pedicles: safety margin of transpedicular screw fixation in malaysian malay population.
A cross-sectional study of thoracic pedicle morphometry (T1-T12) of 180 Malaysian Malay patients obtained from computed tomographic scan. To determine the safety margin in the placement of thoracic transpedicular screw in the Malay population. Previous studies have shown a significantly smaller thoracic pedicular parameters in Asians compared with whites. The safety margin in the placement of thoracic transpedicular screw in our population therefore needs to be defined. T1-T12 vertebral pedicles were studied in 180 Malay ethnic patients (age range, 18-80 years). The following parameters were studied: transverse outer pedicle diameter, transverse inner pedicle diameter, transverse pedicle angle, chord length, pedicle length, and pedicle cortical thickness. The data obtained were statistically analyzed using Student's t test and ANOVA test. Female patients have significantly smaller dimensions in most of the parameters measured compared with male patients. However, no significant difference was found between age groups. Transverse outer pedicle diameter were widest at T1 (male, 8.42 mm; female, 7.56 mm) and narrowest at T4 (male, 4.56 mm; female, 3.95 mm). Pedicle diameters of less than 5.5 mm were commonly seen at T4 followed by T5, T6, T7, T8, and T9. A significant percentage of patients have an outer diameter of less than 4.5 mm from T4-T7. The medial cortices were 50% thicker than the lateral cortices at most levels. Chord lengths were maximum at T8 and minimum at T1. Transverse pedicle angle were widest at T1 and less than 5 degrees from T7-T12. The results suggest that the current pedicle screw system is not suitable for the majority of Malay population, especially at midthoracic level. The smaller pedicle measurements in Malays may be attributed to their shorter body built compared with whites.


Peer Consultation: An Enriching Necessity Rather Than a Luxury for Psychologists During and Beyond the Pandemic.
The pandemic increased professional and personal demands on psychologists, resulting in higher levels of burnout and clinician isolation (Aafjes-van Doorn et al., 2020; Shklarski et al., 2021). Meanwhile, professional consultation is less available due to remote work and social distancing (Sasangohar et al., 2020). Without adequate consultation, psychologists' burnout and isolation may impair their ability to provide quality clinical care (Maslach & Leiter, 2016). Limited literature focuses on how to support psychologists during this unprecedented time. We discuss assessment tools to identify needs for peer consultation and effective consultation group strategies. Our case example of a peer consultation group demonstrates how peer consultation can support psychologists and mitigate the unique challenges throughout the pandemic.


Palliative Care in SMA Type 1: A Prospective Multicenter French Study Based on Parents' Reports.
Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called "Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)" was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989-2009). In the latest period studied, median age at diagnosis was 3 months [0.6-10.4]. Seventy-seven patients died at a median 6 months of age[1-27]: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8).


Use of the Kleihauer test to detect fetal erythroblasts in the maternal circulation.
Non-invasive prenatal diagnosis of aneuploidies on fetal nucleated erythrocytes present in the maternal circulation is hampered by the extremely small cell number of uncertain origin (70% of erythroblasts circulating during pregnancy have a maternal origin). Therefore, a method allowing selection of the fetal cells among the maternal cells is indispensable after the erythroblast enrichment step. In the present study, after an erythroblast enrichment step on a ficoll gradient followed by a positive immuno-magnetic selection with anti-CD71 or anti-GPA antibodies, a rapid, simple and direct chemical staining method adapted from the classical Kleihauer test was developed to select fetal cells. Precise differentiation between fetal and maternal erythroblasts is based on the constitutional difference between fetal and adult haemoglobin (Hb). The fetal cells appear with an intense pink cytoplasmic staining while maternal cells with adult haemoglobin are colourless. Preservation of the cytoplasmic integrity allows one to distinguish morphological characteristics and to visualize simultaneously nuclear hybridization signal by FISH (fluorescent in situ hybridization). This approach was tested by FISH analysis using dual-colour X- and Y-specific DNA probes on blood samples from 15 pregnant women, with the results being compared to cytogenetic or sonographic sex determination. For 12 pregnancies fetal sex was determined successfully (5 XY/7 XX), in two cases in situ hybridization failed, and in one case no fetal erythroblast was observed after the Kleihauer test. The selection method was applied to a pregnancy at risk for cystic fibrosis (CF). After a Kleihauer test, fetal erythroblasts were collected by microdissection, whole genomic DNA was amplified by primer extension pre-amplification (PEP) followed by a nested CF PCR. The fetal genotype was successfully characterized and confirmed by conventional prenatal diagnosis.


Acad. Prof. Yucel Kanpolat, Distinguished and Internationally Recognized Neurosurgeon and Friend of the Republic of Macedonia.
The sad news about the death of Acad. Yucel Kanpolat (September 17, 2016), a famous scholar, a pioneer in the field of neurosurgery, and a friend of the Republic of Macedonia, saddened the members of the Editorial Board of the journal PRILOZI of the Department of Medical Sciences of the Macedonian Academy of Sciences and Arts, of which he was a member, as well as the other members of the Academy. Yucel Kanpolat was an international figure, linking Turkey to almost every country in the world. Neurosurgery has lost a very special surgeon, scientist and humanitarian. During the visit to the Macedonian Academy of Sciences and Arts in 2011, we discussed the cooperation between the Turkish Academy of Sciences and the Macedonian Academy of Sciences and Arts, which he respected very much, as well as the role of the academies. He delivered a lecture on The Mission of Academia in the Age of Science, PRILOZI, MASA, XXXII, 2, p. 7-10 (2011), which we reprint in addition.


Effects of a phagocytosis-stimulating factor derived from polymorphonuclear neutrophils on the functions of macrophages.
The effects of phagocytosis-stimulating factor (PSF) derived from polymorphonuclear neutrophils on macrophage functions were studied. PSF enhanced the initial rate of phagocytosis of serum-opsonized zymosan particles by macrophages, whereas it did not affect the phagocytosis of immunoglobulin G-sensitized and inert zymosan particles. Kinetic studies showed that PSF accelerated the ingestion step, but not the attachment step, of phagocytosis by macrophages. On the other hand, PSF did not affect the other macrophage functions such as O2- generation, chemotaxis, adherence, and enzyme release. These results suggest that PSF may specifically modulate the complement receptor function of macrophages. Immunoblot assay showed the absence of components in macrophage which reacted with purified antibodies against polymorphonuclear neutrophil-derived PSF, and an extract from phagocytosing macrophages had no phagocytosis-stimulating activity, indicating that the macrophages did not produce PSF-like substances.


Whipple's disease presenting as sarcoidosis and valvular heart disease.
Whipple's disease is a rare systemic disorder that can present in a variety of ways and is often difficult to diagnose. It can involve almost any organ system and can mimic other diseases both in its symptoms and pathologic appearance. We present a case initially diagnosed as sarcoidosis that was found to be Whipple's disease after pathologic examination of the patient's mitral and aortic valves.


Compliance and psychological reactance in schizophrenia.
Non-compliance with neuroleptic medication in schizophrenia is a major cause of relapse. A number of sociodemographic variables, and illness, attitudinal and treatment variables, have been demonstrated to be associated with non-compliance. The present study examined a range of these variables and their predictive value in determining past and current compliance. Thirty-nine patients suffering from schizophrenia and three patients suffering from schizoaffective disorder completed a series of questionnaires assessing psychological reactance, insight, subjective response to medication, perceived threat to freedom of choice, and degree of current and past compliance. Logistic regression analyses were performed to determine which factors best predicted past and current compliance. Psychological reactance and age were found to be the best predictors of past compliance, with an interaction between reactance and perceived threat to freedom of choice posed by treatment provision also making a significant contribution. Past compliance behaviour and subjective response to medication predicted current compliance most significantly. Reactance is an important predictor of compliance history especially when patients perceive treatment to be a threat to freedom of choice. Subjective response to neuroleptics is most important in predicting current compliance. Implications for intervention are discussed.


Metabolism of L-fucose and L-rhamnose in Escherichia coli: differences in induction of propanediol oxidoreductase.
Escherichia coli is capable of growing on L-fucose or L-rhamnose as a sole source of carbon and energy. When grown under anaerobic conditions on either sugar, a nicotinamide adenine dinucleotide-linked L-lactaldehyde:propanediol oxidoreductase activity is induced. The functioning of this enzyme results in the regeneration of oxidized nicotinamide adenine dinucleotide. Conditions of induction of the enzyme activity were studied and were found to display different characteristics on each sugar. In the rhamnose-grown cells, the increase in enzyme activity detected under inducing conditions was accompanied by the synthesis of propanediol oxidoreductase, as measured by the appearance in the extracts of a protein that reacts with propanediol oxidoreductase antibodies. In contrast, in fucose-grown cells, the level of propanediol oxidoreductase as measured by enzyme antibody-reacting material was high under noninducing and inducing conditions. Thus, the increase in enzyme activity detected in going from noninducing to inducing conditions in fucose-grown cells did not depend on the appearance of the specific protein but on the activation of the propanediol oxidoreductase already present in the cells in an inactive form. The propanediol oxidoreductase of both homologous systems should consequently be regulated by different control mechanisms.


Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma.
Recent findings have shown that up to 60% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are caused by germline or somatic mutations in one of the 11 hitherto known susceptibility genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, HIF2A (EPAS1), RET, NF1, TMEM127 and MAX. This list of genes is constantly growing and the 11 genes together consist of 144 exons. A genetic screening test is extensively time consuming and expensive. Hence, we introduce next-generation sequencing (NGS) as a time-efficient and cost-effective alternative. Tumour lesions from three patients with apparently sporadic PCC were subjected to whole exome sequencing utilizing Agilent Sureselect target enrichment system and Illumina Hi seq platform. Bioinformatics analysis was performed in-house using commercially available software. Variants in PCC and PGL susceptibility genes were identified. We have identified 16 unique genetic variants in PCC susceptibility loci in three different PCC, spending less than a 30-min hands-on, in-house time. Two patients had one unique variant each that was classified as probably and possibly pathogenic: NF1 Arg304Ter and RET Tyr791Phe. The RET variant was verified by Sanger sequencing. NGS can serve as a fast and cost-effective method in the clinical genetic screening of PCC. The bioinformatics analysis may be performed without expert skills. We identified process optimization, characterization of unknown variants and determination of additive effects of multiple variants as key issues to be addressed by future studies.


A validated subjective rating of display quality: the Maryland Visual Comfort Scale.
Minimally invasive surgery requires high-quality imaging to provide effective visual displays to surgeons. Whereas objective measures--pixels, resolution, display size, contrast ratio--are used to compare imaging systems, there are no tools for assessing the perceptual impact of these physical measures. We developed the "Maryland Visual Comfort Scale" (MVCS) to measure perceptual qualities in relation to an imaging system. We theorize that what the surgeon perceives as a high-quality image can be summarized by a scoring of seven characteristics related to human perception, and that image quality is not homogenous across a video display such that object location impacts perception and display quality. We created a rating scale for seven dimensions of display characteristics (contrast, detail, brightness, lighting uniformity, focus uniformity, color, sharpness). For validation, 30 participants viewed test patterns and manipulated physiologic images, rating the image quality for all seven dimensions as well as giving an overall rating. Image ratings for contrast and detail dimensions were assessed across five locations on the video display. For ratings, two imaging systems were used, differing primarily in the 10-mm zero-degree scope's quality: a standard scope and one taken from service for quality degradation. The rating scale was sensitive to differences in scope quality for all seven items in the MVCS (all p values<0.01). Significant differences existed between quality ratings at central and peripheral locations (p<0.05). This seven-item rating scale for assessing visual comfort is reliable and sensitive to scope quality differences. The scale is sensitive to degradation of image quality at video display edges. These seven dimensions of display characteristics can be refined to create a psychometric to serve as a composite of perceptual quality in laparoscopy.


Managing faecal incontinence or leakage: the Peristeen Anal Plug.
Incontinence can be a devastating problem to many individuals. It is embarrassing and limiting socially, and prevents those with the problem from going about their day-to-day activities. People adopt coping strategies to manage the problem and those with urinary incontinence often look for containment products such as disposable pads or nappy-style products. These products have been developed using different absorbent materials and are accessible to sufferers in local supermarkets. Absorbency of the products has improved so that once wetted, they hold urine more easily. However, the same cannot be said for faecal incontinence management products and there are few that can be called upon to manage this devastating condition. The Peristeen Anal Plug, developed originally as the Conveen Anal Plug, stands alone in the search for a device to manage faecal incontinence or leakage.


Synthesis, surface characterization, and platelet reactivity evaluation for the self-assembled monolayer of alkanethiol with sulfonic acid functionality.
Owing to the capability of fabricating a well-defined chemical structure on the surface, self-assembled alkanethiols with a variety of terminal functionalities were prepared on the gold substrate for investigating the interactions between the biological environment and synthetic surface. In this study, we report the synthesis of the sulfonic acid terminated long-chain alkanethiol, 10-mercaptodecane-sulfonic acid, for direct preparation of a self-assembled monolayer (SAM) with -SO(3)H functionality. Nuclear magnetic resonance (NMR) and elemental analysis studies indicated that a high purity of sulfonic acid terminated alkanethiol was obtained. Surface characterization results showed that the -SO(3)H terminated SAM is hydrophilic and has a slightly higher hysteresis value, possibly because of the slower chain mobility of the bound sulfonic acid alkanethiol. Electron spectroscopy for chemical analysis (ESCA) analysis demonstrated that the -SO(3)H terminal group is situated in the outermost layer of the monolayer, as previous alkanethiol SAM structure models proposed. The platelet reactivity of the -SO(3)H SAM was higher than that of -OH SAM but less than the -CH(3) terminated one in vitro, whereas similar platelet reactivity was noticed between the -SO(3)H and -COOH SAMs. The higher platelet reactivity found on the -SO(3)H SAM could be caused by the higher surface functional group density inherent in the SAM structure and/or the composition and conformation state of the adsorbed protein layer.


The Gbetagamma dimer drives the interaction of heterotrimeric Gi proteins with nonlamellar membrane structures.
Heterotrimeric G proteins are peripheral membrane proteins that propagate signals from membrane receptors to regulatory proteins localized in distinct cellular compartments. To facilitate signal amplification, G proteins are in molar excess with respect to G protein-coupled receptors. Because G proteins are capable of translocating from membrane to cytosol, protein-lipid interactions play a crucial role in signal transduction. Here, we studied the binding of heterotrimeric G proteins (Galphabetagamma) to model membranes (liposomes) and that of the entities formed upon receptor-mediated activation (Galpha and Gbetagamma). The model membranes used were composed of defined membrane lipids capable of organizing into either lamellar or nonlamellar (hexagonal H(II)) membrane structures. We demonstrated that although heterotrimeric G(i) proteins and Gbetagamma dimers can bind to lipid bilayers of phosphatidylcholine, their binding to membranes was markedly and significantly enhanced by the presence of nonlamellar phases of phosphatidylethanolamine. Conversely, activated G protein alpha subunits showed an opposite membrane binding behavior with a marked preference for lamellar membranes. These results have important consequences in cell signaling. First, the binding characteristics of the Gbetagamma dimer account for the lipid binding behavior and the cellular localization of heterotrimeric G proteins. Second, the distinct protein-lipid interactions of heterotrimeric G proteins, Gbetagamma dimers, and Galpha subunits with membrane lipids explain, in part, their different cellular mobilizations during signaling upon receptor activation. Finally, their differential interactions with lipids suggest an active role of the membrane lipid secondary structure in the propagation of signals through G protein-coupled receptors.


High-Resolution Respirometry for Mitochondrial Characterization of Ex Vivo Mouse Tissues.
This article describes methodologies to examine mitochondrial respiration in fresh preparations of mouse tissues, including skeletal muscle, heart, liver, white and brown adipose tissue, and brain. Reference values and tips to maximize experimental efficiencies are also provided. Finally, correction methods and complementary techniques to properly interpret the results are presented and contrasted.


Array-based analysis on tobacco plastid transcripts: preparation of a genomic microarray containing all genes and all intergenic regions.
The plastid genome of higher plants includes about 120 genes. We adopted genomic array technologies to the tobacco plastid genome. A microarray was constructed, consisting of 220 DNA fragments that cover the whole genome sequence. Each DNA fragment corresponds to a single known gene or an intergenic region. We evaluated reliability of this microarray by comparing the plastid RNA level in light- or dark-grown tobacco seedlings. The transcripts encoding photosynthetic subunits increased significantly in light-grown tissues as expected. Furthermore, we found unexpected signals in several intergenic regions, suggesting the existence of novel transcripts in tobacco plastids.


Extraction of species-specific glycan substructures.
Glycans, which are carbohydrate sugar chains attached to some lipids or proteins, have a huge variety of structures and play a key role in cell communication, protein interaction and immunity. The availability of a number of glycan structures stored in the KEGG/GLYCAN database makes it possible for us to conduct a large-scale comparative research of glycans. In this paper, we present a novel approach to compare glycan structures and extract characteristic glycan substructures of certain organisms. In the algorithm we developed a new similarity measure of glycan structures taking into account of several biological aspects of glycan synthesis and glycosyltransferases, and we confirmed the validity of our similarity measure by conducting experiments on its ability to classify glycans between organisms in the framework of a support vector machine. Finally, our method successfully extracted a set of candidates of substructrues which are characteristic to human, rat, mouse, bovine, pig, chicken, yeast, wheat and sycamore, respectively. We confirmed that the characteristic substructures extracted by our method correspond to the substructures which are known as the species-specific sugar chain of gamma-glutamyltranspeptidases in the kidney.


The Gettier Problem in informed consent.
The duty to procure informed consent (IC) from patients before any significant intervention is among the pillars of medical and research ethics. The provision by the doctor of relevant information about treatment and free decision-making by the patient are essential elements of IC. The paper presents cases of IC where the free decision about treatment is not causally related to the information provided, and claims that such cases pose a difficulty parallel to that presented by the Gettier Problem in epistemology. In analogy to the original problem with the concept of knowledge, these Gettier-type cases show an indeterminacy in the concept of IC: we either need to add some explicit additional condition of causal connection between information and consent, or else we should understand the concept in a new way-specifically, since the practice of autonomy necessarily involves some consideration of the relevant information, we must understand free consent in a way that no longer refers to patient autonomy.


A fast method for computing the centroid of a type-2 fuzzy set.
Type reduction does the work of computing the centroid of a type-2 fuzzy set. The result is a type-1 fuzzy set from which a corresponding crisp number can then be obtained through defuzzification. Type reduction is one of the major operations involved in type-2 fuzzy inference. Therefore, making type reduction efficient is a significant task in the application of type-2 fuzzy systems. Liu introduced a horizontal slice representation, called the α-plane representation, and proposed a type-reduction method for a type-2 fuzzy set. By exploring some useful properties of the α-plane representation and of the type reduction for interval type-2 fuzzy sets, a fast method is developed for computing the centroid of a type-2 fuzzy set. The number of computations and comparisons involved is greatly reduced. Convergence in each iteration can then speed up, and type reduction can be done much more efficiently. The effectiveness of the proposed method is analyzed mathematically and demonstrated by experimental results.


Cancer biomarkers defined by autoantibody signatures to aberrant O-glycopeptide epitopes.
Autoantibodies to cancer antigens hold promise as biomarkers for early detection of cancer. Proteins that are aberrantly processed in cancer cells are likely to present autoantibody targets. The extracellular mucin MUC1 is overexpressed and aberrantly glycosylated in many cancers; thus, we evaluated whether autoantibodies generated to aberrant O-glycoforms of MUC1 might serve as sensitive diagnostic biomarkers for cancer. Using an antibody-based glycoprofiling ELISA assay, we documented that aberrant truncated glycoforms were not detected in sera of cancer patients. An O-glycopeptide microarray was developed that detected IgG antibodies to aberrant O-glycopeptide epitopes in patients vaccinated with a keyhole limpet hemocyanin-conjugated truncated MUC1 peptide. We detected cancer-associated IgG autoantibodies in sera from breast, ovarian, and prostate cancer patients against different aberrent O-glycopeptide epitopes derived from MUC1. These autoantibodies represent a previously unaddressed source of sensitive biomarkers for early detection of cancer. The methods we have developed for chemoenzymatic synthesis of O-glycopeptides on microarrays may allow for broader mining of the entire cancer O-glycopeptidome.


Gluten-Free Diet Only during Pregnancy Efficiently Prevents Diabetes in NOD Mouse Offspring.
Studies have documented that the pathogenesis of autoimmune diabetes is influenced by the intake of gluten. Aims. To investigate the importance of gluten exposure during pregnancy and the subsequent development of autoimmune diabetes in offspring. Methods. Nonobese diabetic mice were divided into 7 groups to receive combinations of gluten-free and standard diet before, during, or after pregnancy. Diabetes incidence in offspring was followed in each group (n = 16-27) for 310 days. Insulitis score and intestinal expression of T-cell transcription factors (RT-QPCR) were evaluated in animals from the different diet groups. Results. If mothers were fed a gluten-free diet only during pregnancy, the development of autoimmune diabetes in offspring was almost completely prevented with an incidence reduction from 62.5% in gluten-consuming mice to 8.3% (p < 0.0001) in the gluten-free group. The islets of Langerhans were less infiltrated (p < 0.001) and the intestinal expression of RORγt (Th17) (p < 0.0001) reduced in mice whose mothers were Gluten-free during pregnancy. Conclusion. A gluten-free diet exclusively during pregnancy efficiently prevents autoimmune diabetes development in offspring and reduces insulitis and intestinal expression of RORγt (Th17).


[Angiotensin II receptor antagonists: candesartan cilexetil].
Blockade of the action of angiotensin II (AII) has long been a target for the development of novel antihypertensive agents. We recently discovered a novel class of potent nonpeptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is a highly potent and insurmountable AII type-1 receptor (AT1)-selective antagonist. Structure-activity relationship (SAR) studies revealed that the adjacent arrangement of a lipophilic substituent, a tetrazolylbiphenylmethyl moiety and a carboxyl group was the important structural requirement for potent AII antagonistic activity. Especially, the presence of a carboxyl group at the 7-position was found to be essential for insurmountable antagonism. To improve bioavailability of candesartan, chemical modification was examined to yield candesartan cilexetil, a prodrug of candesartan. Candesartan cilexetil is a potent and long-acting blocker that, when given once a day to patients, provides effective 24 hr blood pressure control.


Comparison of cytolytic and proliferative activities of human gamma delta and alpha beta T cells from peripheral blood against various human tumor cell lines.
Peripheral blood lymphocytes (PBLs) from healthy donors were more than 95% enriched for gamma delta T cells. V gamma 9/V delta 2 was the predominant T-cell subset and represented more than two thirds of the isolated gamma delta T cells. When activated by surface-immobilized anti-TCR delta 1 monoclonal antibody (MoAb) during 5 days of culture, gamma delta T cells demonstrated a significant fourfold to 15-fold stronger cytolytic activity against various tumor cell lines than did PBL polyclonal alpha beta T cells analogously activated by surface-immobilized anti-CD3 MoAbs. Blocking experiments with specific MoAbs demonstrated that the cytolytic activity of gamma delta T cells was non-major histocompatibility complex (MHC) restricted and did not involve the gamma delta T-cell antigen receptor (TCR) but that cytolytic activity was dependent on LFA-1 beta/ICAM1 interaction. The proliferative responses of gamma delta and alpha beta T cells to Ovcar-3 tumor cells and irradiated allogeneic PBLs were inhibited by anti-HLA-A,B,C MoAb. Our findings suggest that gamma delta T cells activated via the TCR have a significant advantage in non-MHC-restricted lysis of various tumor cell lines over PBL alpha beta T cells stimulated analogously with anti-CD3, which may be important in terms of applicability of activated gamma delta cells for adoptive immunotherapy of metastatic cancers.


Salinimonas iocasae sp. nov., a halophilic bacterium isolated from a polychaete tube in a hydrothermal field.
A moderately halophilic bacterium, designated strain KX18D6T, was isolated from the tube of the polychaete Paralvinella hessleri collected from a hydrothermal field located in the Okinawa Trough. Strain KX18D6T was Gram-stain-negative, rod-shaped, facultatively anaerobic, motile, oxidase- and catalase-positive, and grew optimally at 30-35 °C, pH 7.0 and in the presence of 3-5 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain KX18D6T grouped with the members of the genus Salinimonas, including Salinimonas chungwhensis BH030046T (97.7 % sequence similarity), Salinimonas lutimaris DPSR-4T (97.2 %) and Salinimonas sediminis N102T (96.4 %). Genome sequencing of strain KX18D6T revealed a genome size of 4.16 Mb and a DNA G+C content of 47.3 mol%. Genomic average nucleotide identity (orthoANI) values of strain KX18D6T with S. chungwhensis DSM 16280T, S. lutimaris KCTC 23464T and S. sediminis N102T were 76.2, 73.1 and 73.2 %, respectively, while the in silico DNA-DNA hybridization (GGDC) values for strain KX18D6T with these strains were 25.3, 17.7 and 18.0 %, respectively. The major fatty acids were summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c), C16 : 0 and summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c). The predominant respiratory quinone was ubiquinone 8, and the predominant polar lipids were phosphatidylethanolamine and phosphatidylglycerol. On the basis of comparative analysis of phylogenetic, phylogenomic, phenotypic and chemotaxonomic characteristics, strain KX18D6T (=KCTC 72464T=MCCC 1K03884T) is clearly distinguishable from the type strains of species of the genus Salinimonas and is considered to represent a novel species of the genus Salinimonas, for which the name Salinimonas iocasae sp. nov. is proposed.


NMR monitoring of intracellular sodium in dog and rabbit kidney-tubules.
23Na-nuclear magnetic resonance (NMR) was used to monitor intra- and extracellular sodium in suspensions of dog cortical tubules, rabbit cortical tubules, and dog thick ascending limbs. The NMR visibility of the intracellular sodium was determined by comparing the NMR and flame photometry results and by redistributing the sodium ions between the intra- and extracellular compartments using the ionophore nystatin (influx) or sodium substitution for choline in the extracellular fluid (efflux). The intracellular sodium visibility was approximately 30% for the total sodium and 58% for the transportable sodium. Addition of sodium to sodium-depleted homogenates of dog renal cortex also showed a loss of visibility. The values of the relaxation times T1 and T2 were determined but could not be correlated with the visibility measurements. The intracellular sodium concentration in dog cortical tubules incubated in optimal biochemical conditions was estimated at 51 mM and was dependent on the extracellular sodium concentration.


Tandem constructs to mitigate transgene persistence: tobacco as a model.
Some transgenic crops can introgress genes into other varieties of the crop, to related weeds or themselves remain as 'volunteer' weeds, potentially enhancing the invasiveness or weediness of the resulting offspring. The presently suggested mechanisms for transgene containment allow low frequency of gene release (leakage), requiring the mitigation of continued spread. Transgenic mitigation (TM), where a desired primary gene is tandemly coupled with mitigating genes that are positive or neutral to the crop but deleterious to hybrids and their progeny, was tested as a mechanism to mitigate transgene introgression. Dwarfism, which typically increases crop yield while decreasing the ability to compete, was used as a mitigator. A construct of a dominant ahasR (acetohydroxy acid synthase) gene conferring herbicide resistance in tandem with the semidominant mitigator dwarfing Delta gai (gibberellic acid-insensitive) gene was transformed into tobacco (Nicotiana tabacum). The integration and the phenotypic stability of the tandemly linked ahasR and Delta gai genomic inserts in later generations were confirmed by polymerase chain reaction. The hemizygous semidwarf imazapyr-resistant TM T1 (= BC1) transgenic plants were weak competitors when cocultivated with wild type segregants under greenhouse conditions and without using the herbicide. The competition was most intense at close spacings typical of weed offspring. Most dwarf plants interspersed with wild type died at 1-cm, > 70% at 2.5-cm and 45% at 5-cm spacing, and the dwarf survivors formed no flowers. At 10-cm spacing, where few TM plants died, only those TM plants growing at the periphery of the large cultivation containers formed flowers, after the wild type plants terminated growth. The highest reproductive TM fitness relative to the wild type was 17%. The results demonstrate the suppression of crop-weed hybrids when competing with wild type weeds, or such crops as volunteer weeds, in seasons when the selector (herbicide) is not used. The linked unfitness would be continuously manifested in future generations, keeping the transgene at a low frequency.


Use of nonsteroidal antiinflammatory drugs and non-Hodgkin lymphoma: a population-based case-control study.
The association between long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) and non-Hodgkin lymphoma (NHL) was examined using data collected between October 2001 and May 2004 in an ongoing population-based case-control study in the San Francisco Bay Area. NHL cases were identified using rapid case ascertainment and Surveillance, Epidemiology, and End Results registry data. Control participants were frequency-matched to cases by age, sex, and county of residence. Participants completed in-person interviews designed to measure potential NHL risk factors. Questions were asked regarding use during the past 20 years of aspirin, prescription and over-the-counter nonselective NSAIDs, and cyclooxygenase-2 (COX-2) inhibitors. A total of 1,000 cases and 1,060 controls contributed data for these interim analyses. Analyses were carried out for men and women and for both sexes combined. After adjustment for age and sex, there was no consistent association between long-term use and NHL for all NSAIDs combined, aspirin, nonselective NSAIDs, and COX-2 inhibitors. For women, long-term aspirin use may be associated with a decreased risk of NHL (for 3-<9 years of use, odds ratio=0.41, 95% confidence interval: 0.18, 0.94). Conversely, although the confidence intervals were wide, the adjusted odds ratios for COX-2 inhibitor use were nearly twofold for women, indicating a possible increase in NHL risk associated with regular use of COX-2 inhibitors.


Co-producing active lifestyles as whole-system-approach: theory, intervention and knowledge-to-action implications.
Population health interventions tend to lack links to the emerging discourse on interactive knowledge production and exchange. This situation may limit both a better understanding of mechanisms that impact health lifestyles and the development of strategies for population level change. This paper introduces an integrated approach based on structure-agency theory in the context of 'social practice'. It investigates the mechanisms of co-production of active lifestyles by population groups, professionals, policymakers and researchers. It combines a whole system approach with an interactive knowledge-to-action strategy for developing and implementing active lifestyle interventions. A system model is outlined to describe and explain how social practices of selected groups co-produce active lifestyles. Four intervention models for promoting the co-production of active lifestyles through an interactive-knowledge-to-action approach are discussed. Examples from case studies of the German research network Capital4Health are used to illustrate, how intervention models might be operationalized in a real-world intervention. Five subprojects develop, implement and evaluate interventions across the life-course. Although subprojects differ with regard to settings and population groups involved, they all focus on the four key components of the system model. The paper contributes new strategies to address the intervention research challenge of sustainable change of inactive lifestyles. The interactive approach presented allows consideration of the specificities of settings and scientific contexts for manifold purposes. Further research remains needed on what a co-produced knowledge-to-action agenda would look like and what impact it might have for whole system change.


Chronic activation of a designer G(q)-coupled receptor improves β cell function.
Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of β cell G(q) signaling greatly improve β cell function and glucose homeostasis in mice. These beneficial metabolic effects were accompanied by the enhanced expression of many genes critical for β cell function, maintenance, and differentiation. By employing a combination of in vivo and in vitro approaches, we identified a novel β cell pathway through which receptor-activated G(q) leads to the sequential activation of ERK1/2 and IRS2 signaling, thus triggering a series of events that greatly improve β cell function. Importantly, we found that chronic stimulation of a designer G(q)-coupled receptor selectively expressed in β cells prevented both streptozotocin-induced diabetes and the metabolic deficits associated with the consumption of a high-fat diet in mice. Since β cells are endowed with numerous receptors that mediate their cellular effects via activation of G(q)-type G proteins, our findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.


Prevention of progression of nephropathy.
Several factors have been implicated in progressive nephropathy. In a recent clinical trial, the Modification of Diet in Renal Disease (MDRD) study, six factors out of 41 examined were found to be predictors of progression of renal disease: proteinuria, mean arterial pressure, black race, diagnosis of polycystic kidney disease, serum transferin levels, and serum high density lipoprotein (HDL) cholesterol. Hypertension as a factor in progressive renal disease has been documented in both animal and human studies. Patients in the MDRD study were randomly assigned to two levels of blood pressure control: usual (mean arterial pressure of 107 mmHg) or low (mean arterial pressure of 92 mmHg). Patients with proteinuria > 1 g/day assigned to the low blood pressure goal had a slower mean decline in GFR as compared to patients assigned to the usual blood pressure goal. Recommendations derived from the results of the MDRD study specify that in patients with proteinuria > 1 g/day, a mean arterial pressure goal of 92 mmHg or less (equivalent to a blood pressure of 125/75 mmHg) should be the target. Several studies have suggested that dietary protein restriction benefits patients with chronic renal disease. The MDRD study found that dietary protein restriction slowed disease progression in patients with more advanced renal disease (GFR 13-24 ml/min) at the onset of the trial. In summary, current evidence indicates that a decrease in proteinuria, lowering of systemic blood pressure, and a decreased intake of protein ameliorate the rate of progression (loss of GFR) in patients with chronic renal disease.


[Nephrogenic adenoma in intestinal mucosa. A case in urethro-sigmoid anastomosis].
To describe a case of nephrogenic adenoma occurring in the intestinal mucosa of the neobladder urethro-sigmoid anastomosis in a patient who had undergone cystectomy for a bladder carcinoma. Of 14 cases of nephrogenic adenoma in 11 patients, one involved the lamina propria of large bowel mucosa. A 67-year-old patient submitted to radical cystoprostatectomy and orthotopic bladder substitution using a detubulized sigmoid neobladder due to multicentric G3 pTa, pTis urothelial bladder carcinoma had two episodes of stricture of the distal anastomosis. After the second episode, endoscopic resection of the area was performed. Histological examination of the specimen disclosed nephrogenic adenoma of the intestinal mucosa. Nephrogenic metaplasia has been observed in the intestinal mucosa of patients undergoing different urological procedures. To our knowledge, our patient is the third case involving large bowel mucosa reported in the literature. These three cases suggest that nephrogenic adenoma might not be a metaplastic process specific to the urothelium.


Spatio-temporal development of cuticular ridges on leaf surfaces of Hevea brasiliensis alters insect attachment.
Cuticular ridges on plant surfaces can control insect adhesion and wetting behaviour and might also offer stability to underlying cells during growth. The growth of the plant cuticle and its underlying cells possibly results in changes in the morphology of cuticular ridges and may also affect their function. We present spatial and temporal patterns in cuticular ridge development on the leaf surfaces of the model plant, Hevea brasiliensis. We have identified, by confocal laser scanning microscopy of polymer leaf replicas, an acropetally directed progression of ridges during the ontogeny of Hevea brasiliensis leaf surfaces. The use of Colorado potato beetles (Leptinotarsa decemlineata) as a model insect species has shown that the changing dimensions of cuticular ridges on plant leaves during ontogeny have a significant impact on insect traction forces and act as an effective indirect defence mechanism. The traction forces of walking insects are significantly lower on mature leaf surfaces compared with young leaf surfaces. The measured walking traction forces exhibit a strong negative correlation with the dimensions of the cuticular ridges.


The neonatal lupus syndrome.
The neonatal lupus syndrome and congenital heart block are strongly associated with the presence of antibodies to the ribonucleoprotein antigen Ro. The study of these conditions has given insight into possible pathogenetic mechanisms operating in connective tissue diseases.


Epithelial Xbp1 is required for cellular proliferation and differentiation during mammary gland development.
Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1α-mediated splicing, which results in a frameshift to encode a protein with transcriptional activity. However, the direct function of Xbp1 in epithelial cells during mammary gland development is unknown. Here we report that the loss of Xbp1 in the mammary epithelium through targeted deletion leads to poor branching morphogenesis, impaired terminal end bud formation, and spontaneous stromal fibrosis during the adult virgin period. Additionally, epithelial Xbp1 deletion induces endoplasmic reticulum (ER) stress in the epithelium and dramatically inhibits epithelial proliferation and differentiation during lactation. The synthesis of milk and its major components, α/β-casein and whey acidic protein (WAP), is significantly reduced due to decreased prolactin receptor (Prlr) and ErbB4 expression in Xbp1-deficient mammary epithelium. Reduction of Prlr and ErbB4 expression and their diminished availability at the cell surface lead to reduced phosphorylated Stat5, an essential regulator of cell proliferation and differentiation during lactation. As a result, lactating mammary glands in these mice produce less milk protein, leading to poor pup growth and postnatal death. These findings suggest that the loss of Xbp1 induces a terminal UPR which blocks proliferation and differentiation during mammary gland development.


Contributing factors to medial tibial stress syndrome: a prospective investigation.
To conduct a prospective, multisite, cohort study investigating the possible risk factors for medial tibial stress syndrome (MTSS) in college athletes. One hundred and forty-six healthy, collegiate athletes from NCAA Division I and Division II institutions participated in the study. Subjects first completed a health history questionnaire to establish previous history of injury and underwent a physical examination to assess their ankle/foot strength, ankle/foot range of motion, tibial varum, and navicular drop before the start of their respective athletic season. Athletes were instructed to report to a certified athletic trainer if they developed pain on their tibia. If MTSS was present, subjects were then placed into the symptomatic group. Independent t-tests and chi-square analyses were used to determine whether differences existed between MTSS and healthy athletes for the continuous and the discrete dependent variables, respectively. The significant dependent variables were then used in the discriminant function analysis. Twenty-nine subjects developed MTSS during this study. Athletes that had been participating in athletic activity for fewer than 5 yr were significantly more likely to develop MTSS (P = 0.002). Additionally, athletes with a previous history of MTSS (P = 0.0001), a previous history of stress fracture (P = 0.039), and the use of orthotics (P = 0.031) were more likely to develop MTSS compared with those who did not develop MTSS. This study established that the factors most influencing MTSS development were previous history of MTSS and stress fracture, years of running experience, and orthotic use. These data demonstrate the importance of establishing a thorough history before the start of the season so that athletes who might be at risk for MTSS development can be identified.


Quantifying the contribution of VA service-connected disability pensions to the "check effect".
The study attempted to quantify the effect of receiving a disability pension check at the beginning of the month on the timing of substance-related hospitalizations in Department of Veterans Affairs (VA) facilities. All substance-related hospitalizations during fiscal year 2005 were identified in the VA National Psychosis Registry (13,402 hospitalizations among 8,813 individuals) and in a random sample of VA patients without serious mental illness (689 hospitalizations among 508 individuals). Multivariable logistic regression examined the impact of pension check receipt on timing of hospitalizations while controlling for other predictors of substance-related hospitalizations. Receipt of a service-connected pension was associated with an increased risk of admission during the first two weeks of the month (odds ratio=1.08; 95% confidence interval=1.01-1.16). Staggering the disbursement of VA disability pensions (sending half the checks at the beginning and half in the middle of the month) might modestly reduce peak demand for substance-related inpatient services.


Do guidelines for treating chest disease in children use Cochrane Reviews effectively? A systematic review.
Cochrane Reviews summarise best evidence and should inform guidelines. We assessed the use of Cochrane Reviews in the UK guidelines for paediatric respiratory disease. We found 21 guidelines which made 1025 recommendations, of which 96 could be informed by a Cochrane Review. In 38/96 recommendations (40%), some or all of the relevant Cochrane Reviews were not cited. We linked recommendations to 140 Cochrane Reviews. In 37/140 (26%) cases, the guideline recommendation did not fully agree with the Cochrane Review. Guideline developers may fail to use Cochrane Reviews or may make recommendations which are not in line with best evidence.


Bismuth-catalyzed and doped silicon nanowires for one-pump-down fabrication of radial junction solar cells.
Silicon nanowires (SiNWs) are becoming a popular choice to develop a new generation of radial junction solar cells. We here explore a bismuth- (Bi-) catalyzed growth and doping of SiNWs, via vapor-liquid-solid (VLS) mode, to fabricate amorphous Si radial n-i-p junction solar cells in a one-pump-down and low-temperature process in a single chamber plasma deposition system. We provide the first evidence that catalyst doping in the SiNW cores, caused by incorporating Bi catalyst atoms as n-type dopant, can be utilized to fabricate radial junction solar cells, with a record open circuit voltage of V(oc) = 0.76 V and an enhanced light trapping effect that boosts the short circuit current to J(sc) = 11.23 mA/cm(2). More importantly, this bi-catalyzed SiNW growth and doping strategy exempts the use of extremely toxic phosphine gas, leading to significant procedure simplification and cost reduction for building radial junction thin film solar cells.


Silica-dust-exposed mine workers with scleroderma (systemic sclerosis).
The incidence of scleroderma (systemic sclerosis) was found to be increased in a population of black men who were gold miners. Ten men with scleroderma were detected during a five-year period. The annual incidence of the disease in this population in the group aged 33 to 57 years was estimated to be 81.8 per million. All of the men with scleroderma had disturbances of pulmonary function which were not present in a control group of silica-dust-exposed men without scleroderma. Not all of the subjects with scleroderma had silicosis, but all had been occupationally exposed to silica dust. There was a significant increase in the prevalence of tuberculosis in the past in the group with scleroderma, compared with a group of men with silicosis from the same population. The nature of the association of tuberculosis with scleroderma has not been defined.


Simultaneous generation of sub-20 fs deep and vacuum ultraviolet pulses in a single filamentation cell and application to time-resolved photoelectron imaging.
Sub-20 fs pulses of the third, fourth, and fifth harmonics of a Ti:sapphire laser are simultaneously generated using cascaded four-wave mixing in filamentation propagation of the fundamental frequency and the second harmonic pulses in Ne gas. Reflective optics under vacuum are employed after the four-wave mixing to minimize material dispersion of the optical pulses. The cross-correlation between 198 and 159 nm pulses of 18 fs is achieved without dispersion compensation. This new light source is applied to time-resolved photoelectron imaging of carbon disulfide (CS₂).


Boosting hydrogen evolution by using covalent frameworks of fluorinated cobalt porphyrins supported on carbon nanotubes.
A cobalt(ii) tetrakis(2,3,5,6-tetrafluoro-4-ethynylphenyl)porphyrin (FCoP-H) was designed and synthesized. With carbon-nanotube-templated polymerization, covalent porphyrin frameworks using FCoP-H can be synthesized via the Hay-coupling. The resulting FCoP@CNT is efficient to catalyze the hydrogen evolution reaction (HER) in aqueous media, and its performance is superior, in terms of both lower overpotentials and larger catalytic currents, to covalent porphyrin frameworks using non-fluorinated cobalt porphyrin analogues and also monomeric fluorinated cobalt porphyrins simply adsorbed on CNTs. This work combines the merits of CNT-templated covalent frameworks and fluorinated cobalt porphyrins to significantly improve the HER performance. This strategy is valuable to be explored in other electrocatalytic systems using molecule-engineered carbon materials.


Resonance strategies used in Bulgarian women's singing style: a pilot study.
Are the characteristic timbre and loudness of Bulgarian women's singing related to tuning of resonances of the vocal tract? We studied an Australian female singer, who practises and teaches Bulgarian singing technique. Two different vocal qualities of this style were studied. The louder teshka is characterized by a sonorous voice production. The less loud leka has a smoother timbre that is closer to that of the head voice register. Six vowels in each of teshka, leka and the subject's 'normal' (i.e. Western rather than Bulgarian) style were studied. The acoustic resonances of the singer's vocal tract were measured directly during singing by injecting a synthesized, broad-band acoustic current. This singer does not use resonance tuning consistently in her classical Western style. However, in both teshka and leka, she tunes the first tract resonance close to the second harmonic of the voice for most vowels. This tuning boosts the power output in the radiation field for that harmonic. This tuning also contributes to the very strong second harmonic which is a characteristic of the timbre identified as the Bulgarian style.


Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study.
Autism spectrum disorders (ASDs) are heterogeneous complex neurodevelopmental pathologies defined by behavioral symptoms, but which have well-characterized genetic, immunological, and physiological comorbidities. Despite extensive research efforts, there are presently no agreed upon therapeutic approaches for either the core behaviors or the associated comorbidities. In particular, the known autoimmune disorders associated with autism are appealing targets for potential stem cell therapeutics. Of the various stem cell populations, fetal stem cells (FSCs) offer the potent immunoregulatory functions found in primordial mesenchymal stem cells, while exhibiting rapid expansion capacity and recognized plasticity. These properties enhance their potential for clinical use. Furthermore, FSCs are potent and implantable "biopharmacies" capable of delivering trophic signals to the host, which could influence brain development. This study investigated the safety and efficacy of FSC transplantations in treating children diagnosed with ASDs. Subjects were monitored at pre, and then 6 and 12 months following the transplantations, which consisted of two doses of intravenously and subcutaneously administered FSCs. The Autism Treatment Evaluation Checklist (ATEC) test and Aberrant Behavior Checklist (ABC) scores were performed. Laboratory examinations and clinical assessment of adverse effects were performed in order to evaluate treatment safety. No adverse events of significance were observed in ASD children treated with FSCs, including no transmitted infections or immunological complications. Statistically significant differences (p < 0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores when compared to pretreatment values. We recognize that the use of FSCs remains controversial for the present. The results of this study, however, warrant additional investigations into the mechanisms of cell therapies for ASDs, while prompting the exploration of FSCs as "biopharmacies" capable of manufacturing the full array of cell-signaling chemistry. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.


The role of nitrogen defects in graphitic carbon nitride for visible-light-driven hydrogen evolution.
The introduction of nitrogen (N) defects (N vacancies labeled as Vns and cyano groups) has been demonstrated as one of the promising strategies to extend the light absorption range of graphitic carbon nitride (CN), thus improving the photocatalytic activity for hydrogen (H2) evolution. However, the photocatalysis mechanism of such N-deficient CN (DCN) has not been fully understood. In this study, N defects are introduced into CN by a KOH-assisted thermal polymerization method. On the basis of experimental investigations and density functional theory (DFT) calculations, it is found that the extension of the absorption range of DCN is attributed to both the valence band (VB) tailing induced by Vns and bandgap narrowing induced by cyano groups. Moreover, the conduction band (CB) is lowered by the N defects, indicating a reduced driving force for H2 evolution. Transient absorption (TA) spectroscopy reveals that when the electrons in the intrinsic VB of DCN are excited to the CB, the separation efficiency of these electrons and as-generated holes is seriously restricted by their low mobility. While when the electrons in VB tail states (Vn states) are excited to the CB, the separation efficiency of these electrons and as-generated holes could be almost maintained thanks to the improved mobility of the holes. As a result, DCN shows a limited enhancement of the H2 evolution rate compared with CN under visible light irradiation. This work points out that extending the light absorption range of a given photocatalyst by doping (or self-doping) may be accompanied by some negative factors, which restrict the overall photocatalytic activity.


N-Acetyl-beta-D-glucopyranosylamine 6-phosphate is a specific inhibitor of glycogen-bound protein phosphatase 1.
Previous work has shown that the C-1-substituted glucose-analogue N-acetyl-beta-D-glucopyranosylamine (1-GlcNAc) is a competitive inhibitor of glycogen phosphorylase (GP) and stimulates the inactivation of this enzyme by GP phosphatase. In addition to its effects on GP, 1-GlcNAc also prevents the glucose-led activation of glycogen synthase (GS) in whole hepatocytes. Such an effect on GS was thought to be due to the formation of 1-GlcNAc-6-P by the action of glucokinase within the hepatocyte [Board, Bollen, Stalmans, Kim, Fleet and Johnson (1995) Biochem. J. 311, 845-852]. To investigate this possibility further, a pure preparation of 1-GlcNAc-6-P was synthesized. The effects of the phosphorylated glucose analogue on the activity of protein phosphatase 1 (PP1), the enzyme responsible for dephosphorylation and activation of GS, are reported. During the present study, 1-GlcNAc-6-P inhibited the activity of the glycogen-bound form of PP1, affecting both the GSb phosphatase and GPa phosphatase activities. A level of 50% inhibition of GSb phosphatase activity was achieved with 85 microM 1-GlcNAc-6-P in the absence of Glc-6-P and with 135 microM in the presence of 10 mM Glc-6-P. At either Glc-6-P concentration, 500 microM 1-GlcNAc-6-P completely inhibited activity. The Glc-6-P stimulation of the GPa phosphatase activity of PP1 was negated by 1-GlcNAc-6-P but there was no inhibition of the basal rate in the absence of Glc-6-P. 1-GlcNAc-6-P inhibition was specific for the glycogen-bound form of PP1 and did not inhibit the GSb phosphatase activity of the cytosolic form of the enzyme. The present work explains our previous observations on the inactivating effects on GS of incubating whole hepatocytes with 1-GlcNAc. These observations have their basis in the inhibition of glycogen-bound PP1 by 1-GlcNAc-6-P. A novel inhibitor of PP1, specific for the glycogen-bound form of the enzyme, is presented.


A self-assembled amphiphilic imidazolium-based ATP probe.
A novel amphiphilic imidazolium-based probe containing a dansyl fluorophore and a long cetyl chain has been developed for ATP recognition. The probe forms self-assembled micelle-like aggregates at low concentration in its aqueous solution and can selectively recognize ATP among other bioactive anions with a significant enhancement in fluorescence emission.


Decreases in plasma MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in uremic patients during hemodialysis.
Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) play important roles in the pathophysiology of renal diseases. Imbalanced MMPs/TIMPs are implicated in the vascular alterations of uremic patients on hemodialysis (HD). We have investigated the plasma levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in uremic patients and the effects of a course of HD on the changes in these factors. There were 382 uremic patients on regular HD treatment and 50 healthy controls enrolled in this study. The plasma MMP-2 and MMP-9 levels were detected by gelatin zymography, and TIMP-1 and TIMP-2 concentrations were determined by ELISA assay. Significantly higher plasma MMP-2 and MMP-9 and decreased TIMP-1 in the uremic patients were detected compared with those in the controls. Therefore, there were markedly higher MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in the uremic patients. In the course of a single HD session, the plasma MMP-2 level was significantly decreased from pre-HD to post-HD. TIMP-1 concentration was significantly increased from pre-HD to post-HD. Although the HD session did not have a significant effect on the levels of plasma MMP-9 and TIMP-2, both plasma MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios were significantly decreased from pre-HD to post-HD levels. HD session could decrease MMP-2 and increase TIMP-1 level in the circulation of uremic patients. The physiological significance of reduced MMPs/TIMPs ratio due to a single HD session is required to further validate.


Quantitative ischemia detection during cardiac magnetic resonance stress testing by use of FastHARP.
Because ECG alterations caused by ischemia cannot be reliably detected in the high-field MRI environment, detection of wall motion abnormalities is often used to ensure patient safety during stress testing. However, an experienced observer is needed to detect these abnormalities. In this study, we investigate the use of fast harmonic phase (FastHARP) MRI for the quantitative, operator-independent detection of the onset of ischemia during acute coronary occlusion. Eight mongrel dogs underwent an acute 2-minute closed-chest coronary artery occlusion while continuous FastHARP images were acquired. Full regional wall strain was determined every other heartbeat in a single short-axis imaging slice. After 5 minutes of reperfusion, a second 2-minute ischemic episode was induced during the acquisition of conventional cine wall-motion images. The time at which ECG alterations were observed during the first ischemic period was recorded. The time from occlusion to the detection of ischemia, based on a consensus of 2 blinded observers, was determined for MRI. No significant ischemia was present in 2 animals. In the remaining animals, the onset of ischemia was detected significantly earlier by FastHARP than by cine MRI (9.5+/-5 versus 33+/-14 seconds, P<0.01). HARP ischemia detection preceded ECG changes, on average, by 54 seconds. The rapid acquisition and detection of induced ischemia with FastHARP MRI shows promise as a nonsubjective method to diagnose significant coronary lesions during MR stress testing.


Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains.
The increasing ineffectiveness of traditional antibiotics and the rise of multidrug resistant (MDR) bacteria have necessitated the revival of bacteriophage (phage) therapy. However, bacteria might also evolve resistance against phages. Phages and their bacterial hosts coexist in nature, resulting in a continuous coevolutionary competition for survival. We have isolated several clinical strains of Pseudomonas aeruginosa and phages that infect them. Among these, the PIAS (Phage Induced Antibiotic Sensitivity) phage belonging to the Myoviridae family can induce multistep genomic deletion in drug-resistant clinical strains of P. aeruginosa, producing a compromised drug efflux system in the bacterial host. We identified two types of mutant lines in the process: green mutants with SNPs (single nucleotide polymorphisms) and smaller deletions and brown mutants with large (∼250 kbp) genomic deletion. We demonstrated that PIAS used the MexXY-OprM system to initiate the infection. P. aeruginosa clogged PIAS phage infection by either modifying or deleting these receptors. The green mutant gaining phage resistance by SNPs could be overcome by evolved PIASs (E-PIASs) with a mutation in its tail-fiber protein. Characterization of the mutant phages will provide a deeper understanding of phage-host interaction. The coevolutionary process continued with large deletions in the same regions of the bacterial genomes to block the (E-)PIAS infection. These mutants gained phage resistance via either complete loss or substantial modifications of the phage receptor, MexXY-OprM, negating its essential role in antibiotic resistance. In vitro and in vivo studies indicated that combined use of PIAS and antibiotics could effectively inhibit P. aeruginosa growth. The phage can either eradicate bacteria or induce antibiotic sensitivity in MDR-resistant clinical strains. We have explored the potential use of combination therapy as an alternative approach against MDR P. aeruginosa infection.