Mechanoreceptors observed in a ligamentous structure between the posterior horn of the lateral meniscus and the anterior cruciate ligament.

PURPOSE: A histological study of a structure between the posterior horn of the lateral meniscus and the anterior cruciate ligament. METHODS: Bilateral fresh-frozen cadaveric knees of two male donors (age 71 and 76 years) with no history of prior knee injury were examined. All dissections were performed by one experienced orthopaedic surgeon. Haematoxylin and Eosin staining was used to reveal tissue morphology. Goldner trichrome staining was used to evaluate the connective tissue. S100 and PGP 9.5 labelling were used for immunohistochemical analysis. RESULTS: In all cadaveric knees, a structure between the posterior horn of the lateral meniscus and the anterior cruciate ligament was identified. Histological analysis confirmed the ligamentous nature of this structure. Furthermore, Golgi tendon organs were observed within the ligamentous structure. CONCLUSION: This is the first study showing the presence of mechanoreceptors within the ligamentous structure between the posterior horn of the lateral meniscus and the anterior cruciate ligament. The ligamentous structure could contribute to stability of the knee by providing proprioceptive input, while preservation of the ligamentous structure might ensure a better functional outcome after surgery.

The antiviral protein viperin regulates chondrogenic differentiation via CXCL10 protein secretion.

Viperin (also known as radical SAM domain-containing 2 (RSAD2)) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RNase MRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RNase MRP snoRNA interfere with skeletal development, and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in chondrogenic differentiation. Using immunohistochemistry, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS proteomics, and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of chondrogenic differentiation by influencing transforming growth factor ß (TGF-ß)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-ß/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral protein viperin controls chondrogenic differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired chondrogenic differentiation of cells from individuals with CHH.

Innervation of the human spleen: A complete hilum-embedding approach.

INTRODUCTION: The spleen is hypothesized to play a role in the autonomic nervous system (ANS)-mediated control of host defence, but the neuroanatomical evidence for this assumption rests on a sparse number of studies, which mutually disagree with respect to the existence of cholinergic or vagal innervation. METHODS: We conducted an immuno- and enzyme-histochemical study of the innervation of the human spleen using a complete hilum-embedding approach to ensure that only nerves that entered or left the spleen were studied, and that all splenic nerves were included in the sampled area. Furthermore, a complete embedded spleen was serially sectioned to prepare a 3D reconstruction of the hilar nerve plexus. RESULTS: All detected nerves entering the spleen arise from the nerve plexus that surrounds branches of the splenic artery and are catecholaminergic. Inside the spleen these nerves continue within the adventitia of the white pulpal central arteries and red pulpal arterioles. Staining for either choline acetyltransferase or acetylcholinesterase did not reveal any evidence for cholinergic innervation of the human spleen, irrespective of the type of fixation (regularly fixed, fresh-frozen post-fixed or fresh-frozen cryoslides). Furthermore, no positive VIP staining was observed (VIP is often co-expressed in postganglionic parasympathetic nerves). CONCLUSION: Our comprehensive approach did not produce any evidence for a direct cholinergic (or VIP-ergic) innervation of the spleen. This finding does not rule out (indirect) vagal innervation via postganglionic non-cholinergic periarterial fibres.

Optical signature of nerve tissue-Exploratory ex vivo study comparing optical, histological, and molecular characteristics of different adipose and nerve tissues.

BACKGROUND: During several anesthesiological procedures, needles are inserted through the skin of a patient to target nerves. In most cases, the needle traverses several tissues-skin, subcutaneous adipose tissue, muscles, nerves, and blood vessels-to reach the target nerve. A clear identification of the target nerve can improve the success of the nerve block and reduce the rate of complications. This may be accomplished with diffuse reflectance spectroscopy (DRS) which can provide a quantitative measure of the tissue composition. The goal of the current study was to further explore the morphological, biological, chemical, and optical characteristics of the tissues encountered during needle insertion to improve future DRS classification algorithms. METHODS: To compare characteristics of nerve tissue (sciatic nerve) and adipose tissues, the following techniques were used: histology, DRS, absorption spectrophotometry, high-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy, and solution 2D 13 C-1 H heteronuclear single-quantum coherence spectroscopy. Tissues from five human freshly frozen cadavers were examined. RESULTS: Histology clearly highlights a higher density of cellular nuclei, collagen, and cytoplasm in fascicular nerve tissue (IFAS). IFAS showed lower absorption of light around 1200 nm and 1750 nm, higher absorption around 1500 nm and 2000 nm, and a shift in the peak observed around 1000 nm. DRS measurements showed a higher water percentage and collagen concentration in IFAS and a lower fat percentage compared to all other tissues. The scattering parameter (b) was highest in IFAS. The HR-MAS NMR data showed three extra chemical peak shifts in IFAS tissue. CONCLUSION: Collagen, water, and cellular nuclei concentration are clearly different between nerve fascicular tissue and other adipose tissue and explain some of the differences observed in the optical absorption, DRS, and HR-NMR spectra of these tissues. Some differences observed between fascicular nerve tissue and adipose tissues cannot yet be explained but may be helpful in improving the discriminatory capabilities of DRS in anesthesiology procedures. Lasers Surg. Med. 50:948-960, 2018. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

"It breaks your soul": An in-depth exploration of workplace injustice in nursing.

AIM(S): To understand nurses' experiences of injustice in the workplace and to identify the impact of injustice on well-being. BACKGROUND: Little is known about how nurses view injustice or its effects on their well-being, although research indicates that such perceptions are central to workplace practices such as performance management and outcomes such as employee well-being. METHOD(S): A qualitative study was conducted with semi-structured interviews for nurses employed in Australian public hospitals. Data were analysed using content analysis. RESULTS: Experiences of injustice and unfairness negatively impacted on performance and the personal health of nurses. Unfair treatment was met with reduced effort and commitment. CONCLUSION(S): This study provides valuable insights into how nurses perceive and experience injustice at work and supports the link between injustice and nurses' decreased well-being and effectiveness. IMPLICATIONS FOR NURSING MANAGEMENT: Implications for nurse managers include the need for managers to engage in regular conversations regarding systemic barriers to performance and implementing performance management as an ongoing dialogue designed for employee voice and relationship management. This process also suggests a need for leadership development in nursing management. Using such steps and strategies would significantly enhance best practice in nursing management.

Arginase 1 deletion in myeloid cells affects the inflammatory response in allergic asthma, but not lung mechanics, in female mice.

BACKGROUND: (Over-)expression of arginase may limit local availability of arginine for nitric oxide synthesis. We investigated the significance of arginase1 (ARG1) for the development of airway hyperresponsiveness (AHR) and lung inflammation in female mice with ovalbumin (OVA)-induced allergic asthma. METHODS: Arg1 was ablated in the lung by crossing Arg1 fl/fl and Tie2Cre tg/- mice. OVA sensitization and challenge were conducted, and AHR to methacholine was determined using the Flexivent system. Changes in gene expression, chemokine and cytokine secretion, plasma IgE, and lung histology were quantified using RT-qPCR, ELISA, and immunohistochemistry, respectively. RESULTS: Arg1 ablation had no influence on the development of OVA-induced AHR, but attenuated OVA-induced increases in expression of Arg2 and Nos2, Slc7a1, Slc7a2, and Slc7a7 (arginine transporters), Il4, Il5 and Il13 (TH2-type cytokines), Ccl2 and Ccl11 (chemokines), Ifng (TH1-type cytokine), Clca3 and Muc5ac (goblet cell markers), and OVA-specific IgE. Pulmonary IL-10 protein content increased, but IL-4, IL-5, IL-13, TNFα and IFNγ content, and lung histopathology, were not affected. Arg1 elimination also decreased number and tightness of correlations between adaptive changes in lung function and inflammatory parameters in OVA/OVA-treated female mice. OVA/OVA-treated female mice mounted a higher OVA-IgE response than males, but the correlation between lung function and inflammation was lower. Arg1-deficient OVA/OVA-treated females differed from males in a more pronounced decline of arginine-metabolizing and -transporting genes, higher plasma arginine levels, a smaller OVA-specific IgE response, and no improvement of peripheral lung function. CONCLUSION: Complete ablation of Arg1 in the lung affects mRNA abundance of arginine-transporting and -metabolizing genes, and pro-inflammatory genes, but not methacholine responsiveness or accumulation of inflammatory cells.

Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice.

Asthma is a chronic inflammatory disease of the small airways, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. Recent studies suggest a role for arginase in asthma pathogenesis, possibly because arginine is the substrate for both arginase and NO synthase and because NO modulates bronchial tone and inflammation. Our objective was to investigate the importance of increased pulmonary arginase 1 expression on methacholine-induced AHR and lung inflammation in a mouse model of allergic asthma. Arginase 1 expression in the lung was ablated by crossing Arg1(fl/fl) with Tie2Cre(tg/-) mice. Mice were sensitized and then challenged with ovalbumin. Lung function was measured with the Flexivent. Adaptive changes in gene expression, chemokine and cytokine secretion, and lung histology were quantified with quantitative PCR, ELISA, and immunohistochemistry. Arg1 deficiency did not affect the allergic response in lungs and large-airway resistance, but it improved peripheral lung function (tissue elastance and resistance) and attenuated adaptive increases in mRNA expression of arginine-catabolizing enzymes Arg2 and Nos2, arginine transporters Slc7a1 and Slc7a7, chemokines Ccl2 and Ccl11, cytokines Tnfa and Ifng, mucus-associated epithelial markers Clca3 and Muc5ac, and lung content of IL-13 and CCL11. However, expression of Il4, Il5, Il10, and Il13 mRNA; lung content of IL-4, IL-5, IL-10, TNF-α, and IFN-γ protein; and lung pathology were not affected. Correlation analysis showed that Arg1 ablation disturbed the coordinated pulmonary response to ovalbumin challenges, suggesting arginine (metabolite) dependence of this response. Arg1 ablation in the lung improved peripheral lung function and affected arginine metabolism but had little effect on airway inflammation.

An indicator to assess risks on water and air of pesticide spraying in crop fields.

Stakeholders involved in actions to reduce the use and the impacts on the environment or human health of pesticides need operational tools to assess crop protection strategies in regard to these impacts. I-Phy3 brings together all improvements introduced since the first version of the indicator to better meet user's needs and requirements of integrating processes. I-Phy3 was deeply modified to ensure its predictive quality. I-Phy 3 is structured in three levels of aggregation in form of hierarchical fuzzy decision trees designed with the CONTRA method. At the 1st level, five basic subindicators assess the risk of contamination (RC) for the different transfer pathways involved in surface water, ground water and atmosphere contamination: leaching, runoff, drainage, drift, volatilization. At the 2nd level, RC subindicators are aggregated with a toxicity variable (human or aquatic) in a risk indicator. At the 3rd level, the global indicator I-Phy3 results from the aggregation of three risk indicators for groundwater, surface waters and air. I-Phy3 yielded better validation results than its previous versions. This effort to assess the predictive quality of the indicator should be pursued and completed by a feasibility and utility test by end-users. A subindicator on risk of soil contamination is a gap which remains to fill.

Arginine deficiency causes runting in the suckling period by selectively activating the stress kinase GCN2.

Suckling "F/A2" mice, which overexpress arginase-I in their enterocytes, develop a syndrome (hypoargininemia, reduced hair and muscle growth, impaired B-cell maturation) that resembles IGF1 deficiency. The syndrome may result from an impaired function of the GH-IGF1 axis, activation of the stress-kinase GCN2, and/or blocking of the mTORC1-signaling pathway. Arginine deficiency inhibited GH secretion and decreased liver Igf1 mRNA and plasma IGF1 concentration, but did not change muscle IGF1 concentration. GH supplementation induced Igf1 mRNA synthesis, but did not restore growth, ruling out direct involvement of the GH-IGF1 axis. In C2C12 muscle cells, arginine withdrawal activated GCN2 signaling, without impacting mTORC1 signaling. In F/A2 mice, the reduction of plasma and tissue arginine concentrations to ∼25% of wild-type values activated GCN2 signaling, but mTORC1-mediated signaling remained unaffected. Gcn2-deficient F/A2 mice suffered from hypoglycemia and died shortly after birth. Because common targets of all stress kinases (eIF2α phosphorylation, Chop mRNA expression) were not increased in these mice, the effects of arginine deficiency were solely mediated by GCN2.

Bardet-Biedl syndrome highlights the major role of the primary cilium in efficient water reabsorption.

Studies of the primary cilium, now known to be present in all cells, have undergone a revolution, in part, because mutation of many of its proteins causes a large number of diseases, including cystic kidney disease. Bardet-Biedl syndrome (BBS) is an inherited ciliopathy characterized, among other dysfunctions, by renal defects for which the precise role of the cilia in kidney function remains unclear. We studied a cohort of patients with BBS where we found that these patients had a urinary concentration defect even when kidney function was near normal and in the absence of major cyst formation. Subsequent in vitro analysis showed that renal cells in which a BBS gene was knocked down were unciliated, but did not exhibit cell cycle defects. As the vasopressin receptor 2 is located in the primary cilium, we studied BBS-derived unciliated renal epithelial cells and found that they were unable to respond to luminal arginine vasopressin treatment and activate their luminal aquaporin 2. The ability to reabsorb water was restored by treating these unciliated renal epithelial cells with forskolin, a receptor-independent adenylate cyclase activator, showing that the intracellular machinery for water absorption was present but not activated. These findings suggest that the luminal receptor located on the primary cilium may be important for efficient transepithelial water absorption.

Cardiovascular and noncardiovascular mortality among patients starting dialysis.

CONTEXT: Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. OBJECTIVE: To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. DESIGN, SETTING, AND PATIENTS: Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123,407]) was compared with the European general population (Eurostat). MAIN OUTCOME MEASURES: Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. RESULTS: Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and 10,183,322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43). CONCLUSION: Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality.

The human neonatal small intestine has the potential for arginine synthesis; developmental changes in the expression of arginine-synthesizing and -catabolizing enzymes.

BACKGROUND: Milk contains too little arginine for normal growth, but its precursors proline and glutamine are abundant; the small intestine of rodents and piglets produces arginine from proline during the suckling period; and parenterally fed premature human neonates frequently suffer from hypoargininemia. These findings raise the question whether the neonatal human small intestine also expresses the enzymes that enable the synthesis of arginine from proline and/or glutamine. Carbamoylphosphate synthetase (CPS), ornithine aminotransferase (OAT), argininosuccinate synthetase (ASS), arginase-1 (ARG1), arginase-2 (ARG2), and nitric-oxide synthase (NOS) were visualized by semiquantitative immunohistochemistry in 89 small-intestinal specimens. RESULTS: Between 23 weeks of gestation and 3 years after birth, CPS- and ASS-protein content in enterocytes was high and then declined to reach adult levels at 5 years. OAT levels declined more gradually, whereas ARG-1 was not expressed. ARG-2 expression increased neonatally to adult levels. Neurons in the enteric plexus strongly expressed ASS, OAT, NOS1 and ARG2, while varicose nerve fibers in the circular layer of the muscularis propria stained for ASS and NOS1 only. The endothelium of small arterioles expressed ASS and NOS3, while their smooth-muscle layer expressed OAT and ARG2. CONCLUSION: The human small intestine acquires the potential to produce arginine well before fetuses become viable outside the uterus. The perinatal human intestine therefore resembles that of rodents and pigs. Enteral ASS behaves as a typical suckling enzyme because its expression all but disappears in the putative weaning period of human infants.

The analysis of survival data: the Kaplan-Meier method.

What is this patient's prognosis regarding graft rejection? Do patients using a particular drug live longer than those not using it? How does this co-morbidity affect access to transplantation? To answer this type of questions one needs to perform survival analysis. This paper focuses on the Kaplan-Meier method, the most popular method used for survival analysis. It makes it possible to calculate the incidence rate of events like recovery of renal function, myocardial infarction or death by using information from all subjects at risk for these events. It explains how the method works, how survival probabilities are calculated, survival data can be summarized and survival in groups can be compared using the logrank test for hypothesis testing. In addition, it provides some guidance regarding the presentation of survival plots. Finally, it discusses the limitations of the Kaplan-Meier method and refers to other methods that better serve additional purposes.

Survival analysis: time-dependent effects and time-varying risk factors.

In traditional Kaplan-Meier or Cox regression analysis, usually a risk factor measured at baseline is related to mortality thereafter. During follow-up, however, things may change: either the effect of a fixed baseline risk factor may vary over time, resulting in a weakening or strengthening of associations over time, or the risk factor itself may vary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of a fixed baseline risk factor are addressed. An example is presented showing that underweight is a strong risk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a risk factor for mortality, which is stronger in the long run than in the short run. In addition, the analysis of how time-varying risk factors (so-called time-dependent risk factors) are related to mortality is demonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effects over time should be driven by a clear research question. Both kinds of research questions, that is those of time-dependent effects as well those of time-dependent risk factors, can be analyzed with time-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usually implies focusing on short-term effects only.

The analysis of survival data in nephrology: basic concepts and methods of Cox regression.

How much does the survival of one group differ from the survival of another group? How do differences in age in these two groups affect such a comparison? To obtain a quantity to compare the survival of different patient groups and to account for confounding effects, a multiple regression technique for survival data is needed. Cox regression is perhaps the most popular regression technique for survival analysis. This paper explains how Cox regression works, what the proportionality assumption means and how to interpret the results of univariate and multiple Cox regression models.

A protocol improves GP recording of long-term sickness absence risk factors.

BACKGROUND: If general practitioners (GPs) were better informed about patients' risks of long-term sickness absence (LTSA), they could incorporate these risk assessments into their patient management plans and cooperate more with occupational physicians to prevent LTSA. AIM: To evaluate the effectiveness of a protocol helping GPs in recording risks of LTSA and in co-operating with occupational physicians (OPs). METHODS: Twenty-six GPs (co-operating in four groups) in Amsterdam, The Netherlands, participated in a controlled intervention study. Fourteen GPs were the protocol-supported intervention group and twelve GPs were the reference group. Outcome measures were consultations containing work-related information, information about two risk factors for LTSA, referrals to OPs and contacts of OPs with GPs and patients. Outcomes were identified through an electronic search in the GPs' information systems. Entries containing information were independently scored by two investigators. The proportions of patients with consultations documenting LTSA-pertinent items were compared between the groups, accounting for differences at baseline. RESULTS: There was no increase in consultations containing work-related information. Recording of risk factor information increased in the intervention group; the difference was 4.5% [95% CI 1.5-7.6] and 1.8% (95% CI -0.8 to 4.4) for the two risk factors. The referral rate to the OP increased by 2.9% (95% CI 1.2-4.5). There was no effect on contacts of OPs with GPs or with patients. CONCLUSION: Protocol-supported consultations may lead to a modest increase in information regarding two risk factors for LTSA in GPs' electronic records and to more referrals to OPs.

The human phrenic nerve serves as a morphological conduit for autonomic nerves and innervates the caval body of the diaphragm.

Communicating fibres between the phrenic nerve and sympathetic nervous system may exist, but have not been characterized histologically and immunohistochemically, even though increased sympathetic activity due to phrenic nerve stimulation for central sleep apnoea may entail morbidity and mortality. We, therefore, conducted a histological study of the phrenic nerve to establish the presence of catecholaminergic fibres throughout their course. The entire phrenic nerves of 35 formalin-fixed human cadavers were analysed morphometrically and immunohistochemically. Furthermore, the right abdominal phrenic nerve was serially sectioned and reconstructed. The phrenic nerve contained 3 ± 2 fascicles in the neck that merged to form a single fascicle in the thorax and split again into 3 ± 3 fascicles above the diaphragm. All phrenic nerves contained catecholaminergic fibres, which were distributed homogenously or present as distinct areas within a fascicle or as separate fascicles. The phrenicoabdominal branch of the right phrenic nerve is a branch of the celiac plexus and, therefore, better termed the "phrenic branch of the celiac plexus". The wall of the inferior caval vein in the diaphragm contained longitudinal strands of myocardium and atrial natriuretic peptide-positive paraganglia ("caval bodies") that where innervated by the right phrenic nerve.

Deletion of endothelial arginase 1 does not improve vasomotor function in diabetic mice.

Endothelial arginase 1 was ablated to assess whether this prevents hyperglycemia-induced endothelial dysfunction by improving arginine availability for nitric oxide production. Endothelial Arg1-deficient mice (Arg1-KOTie2 ) were generated by crossing Arg1fl/fl (controls) with Tie2Cretg/- mice and analyzed by immunohistochemistry, measurements of hemodynamics, and wire myography. Ablation was confirmed by immunohistochemistry. Mean arterial blood pressure was similar in conscious male control and Arg1-KOTie2 mice. Depletion of circulating arginine by intravenous infusion of arginase 1 or inhibition of nitric oxide synthase activity with L-NG -nitro-arginine methyl ester increased mean arterial pressure similarly in control (9 ± 2 and 34 ± 2 mmHg, respectively) and Arg1-KOTie2 mice (11 ± 3 and 38 ± 4 mmHg, respectively). Vasomotor responses were studied in isolated saphenous arteries of 12- and 34-week-old Arg1-KOTie2 and control animals by wire myography. Diabetes was induced in 10-week-old control and Arg1-KOTie2 mice with streptozotocin, and vasomotor responses were studied 10 weeks later. Optimal arterial diameter, contractile responses to phenylephrine, and relaxing responses to acetylcholine and sodium nitroprusside were similar in normoglycemic control and Arg1-KOTie2 mice. The relaxing response to acetylcholine was dependent on the availability of extracellular l-arginine. In the diabetic mice, arterial relaxation responses to endothelium-dependent hyperpolarization and to exogenous nitric oxide were impaired. The data show that endothelial ablation of arginase 1 in mice does not markedly modify smooth muscle and endothelial functions of a resistance artery under normo- and hyperglycemic conditions.

Cost issues in new disease-modifying treatments for advanced cancer: in-depth interviews with physicians.

BACKGROUND: The high costs of new disease-modifying, but non-curative, treatments in advanced cancer are increasingly regarded as problematic. Little is known about oncologists' beliefs regarding their ethical obligations for cost considerations about these types of treatments. PARTICIPANTS AND METHODS: This study used in-depth interviews to explore how physicians in The Netherlands view their role regarding the cost of potentially beneficial but expensive drugs, especially for new disease-modifying treatments in advanced cancer. Thirty-six physicians, 19 physicians caring for patients with advanced cancer and 17 physicians participating in four national oncology guideline committees, were interviewed. RESULTS: Physicians identified cost considerations on three levels: individual patient care, hospital policies and national guideline development. Generally, physicians were reluctant to consider costs in individual patient care, believing this compromised their ethical obligations. They did consider costs relevant at the level of hospital policies regarding coverage for drugs. They were divided regarding the role of cost considerations in national practice guideline development. CONCLUSIONS: The distinctive levels of decision-making were understood to be morally relevant as physicians separated their role as direct care provider from that of taking part in decisions about coverage. Because of the fundamental tension between the physician obligation to act in the best interest of the individual patient, the vulnerability of having a life-threatening illness and the inevitability of sharing resources in modern health care, cost considerations will always be problematic for physicians. The roles physicians play at different levels, especially at the levels of hospital policies and national practice guidelines, should further be developed and explicated.

Densely integrated microring resonator based photonic devices for use in access networks.

Two reconfigurable optical add-drop multiplexers, operating in the second or third telecom window, as well as a 1x4x4 reconfigurable lambda-router operating in the second telecom window, are demonstrated. The devices have a footprint less than 2 mm(2) and are based on thermally tunable vertically coupled microring resonators fabricated in Si(3)N(4)/SiO(2).