Recent evidence indicates active roles for the cerebrospinal fluid (CSF) on body axis development and morphogenesis of the spine, implying CSF-contacting neurons (CSF-cNs) in the spinal cord. CSF-cNs ...project a ciliated apical extension into the central canal that is enriched in the channel PKD2L1 and enables the detection of spinal curvature in a directional manner. Dorsolateral CSF-cNs ipsilaterally respond to lateral bending although ventral CSF-cNs respond to longitudinal bending. Historically, the implication of the Reissner fiber (RF), a long extracellular thread in the CSF, to CSF-cN sensory functions has remained a subject of debate. Here, we reveal, using electron microscopy in zebrafish larvae, that the RF is in close vicinity with cilia and microvilli of ventral and dorsolateral CSF-cNs. We investigate in vivo the role of cilia and the RF in the mechanosensory functions of CSF-cNs by combining calcium imaging with patch-clamp recordings. We show that disruption of cilia motility affects CSF-cN sensory responses to passive and active curvature of the spinal cord without affecting the Pkd2l1 channel activity. Because ciliary defects alter the formation of the RF, we investigated whether the RF contributes to CSF-cN mechanosensitivity in vivo. Using a hypomorphic mutation in the scospondin gene that forbids the aggregation of SCO-spondin into a fiber, we demonstrate in vivo that the RF per se is critical for CSF-cN mechanosensory function. Our study uncovers that neurons contacting the cerebrospinal fluid functionally interact with the RF to detect spinal curvature in the vertebrate spinal cord.
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•Since its discovery in 1860, the role of the Reissner fiber has been debated•CSF-contacting neurons (CSF-cNs) are in close vicinity of the Reissner fiber•Mechanoreception in CSF-cNs requires the Reissner fiber•CSF-cNs together with the Reissner fiber detect spinal curvature in vivo
The role of the Reissner fiber, a long extracellular thread running in the cerebrospinal fluid (CSF), has been, since its discovery in 1860, a subject of debate. Orts-Del’Immagine et al. report that the Reissner fiber plays a critical role in the detection of spinal curvature by sensory neurons contacting the CSF.
An air and moisture stable 2‐hydroxypyridine based bifunctional ruthenium NNN‐pincer complex catalyzed efficient (TON=42840) N‐alkylation of amines under mild conditions. Surprisingly, with cyclic ...secondary amines this methodology selectively produced only amides. Notably, N‐methylation of several amines was achieved by using methanol as a green methylating agent. Furthermore, with lower catalyst loading (0.2 mol%) and shorter reaction time (6 h) numerous substituted quinolines were synthesized from 2‐aminobenzyl alcohols and secondary alcohols. The effectiveness of this protocol was further extended by successfully synthesizing 2‐alkylaminoquinolines in a one‐pot fashion from amino alcohol, aliphatic nitriles, and alcohols. Gram scale synthesis of various compounds was also investigated to demonstrate the synthetic applicability of this methodology.
Catalytic activities of a series of functional bipyridine-based Ru
complexes in β-alkylation of secondary alcohols using primary alcohols were investigated. Bifunctional Ru
complex (3 a) bearing ...6,6'-dihydroxy-2,2'-bipyridine (6DHBP) ligand exhibited the highest catalytic activity for this reaction. Using significantly lower catalyst loading (0.1 mol %) dehydrogenative carbon-carbon bond formation between numerous aromatic, aliphatic and heteroatom substituted alcohols were achieved with high selectivity. Notably, for the synthesis of β-alkylated secondary alcohols this protocol is a rare one-pot strategy using a metal-ligand cooperative Ru
system. Remarkably, complex 3 a demonstrated the highest reactivity compared to all the reported transition metal complexes in this reaction.
OBJECTIVE To identify risk factors and outcomes associated with thrombocytopenia at sepsis onset in Staphylococcus aureus bacteremia. PATIENTS AND METHODS This single-center, retrospective, cohort ...study consists of all adult patients with a first episode of clinical S aureus bacteremia between April 1, 1988, and September 30, 1994, and between January 1, 1999, and December 31, 2007. Thrombocytopenia was defined as a platelet count less than 150 × 109 /L. The primary outcome was 30-day all-cause mortality. Risk factors for 30-day all-cause mortality were identified using univariate and multivariable analyses. Multivariable analysis was conducted using forward step logistic regression analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for risk of death. RESULTS A total of 1052 patients had clinical S aureus bacteremia. Thrombocytopenia at sepsis onset was present in 235 patients (22.3%). Thrombocytopenia was associated with community-acquired bacteremia, infections caused by methicillin-sensitive S aureus , high-magnitude bacteremia (defined as >4 positive blood cultures ≥3 separate positive blood culture sets), and endocarditis. Patients with thrombocytopenia presented more commonly with severe sepsis reflected by septic shock and acute renal failure. Thirty-day mortality was significantly higher among patients with thrombocytopenia (132/235 56.2%) vs those without thrombocytopenia (281/817 34.4%; P <.001). Higher mortality was associated with the degree of thrombocytopenia. In multivariable analysis, thrombocytopenia at baseline remained an independent risk factor for 30-day mortality (OR, 2.82; 95% CI, 1.87-4.24). The adjusted association between thrombocytopenia and death remained similar among the 917 patients with monomicrobial bacteremia (OR, 2.88; 95% CI, 1.83-4.53) and the 945 patients who did not die within the first 48 hours (OR, 2.88; 95% CI, 1.87-4.45.). CONCLUSION We observed a strong association between thrombocytopenia at sepsis onset and all-cause mortality in S aureus bacteremia, possibly related to mechanisms other than sepsis alone.
A Ru(II) NHC complex (loading down to 0.001 mol%) catalyzed cross coupling of a broad range of aromatic, aliphatic and heterocyclic alcohols is reported. This protocol also functioned efficiently ...under solvent‐free conditions. Remarkably, this catalytic system disclosed so far the highest TON of 288000 for the cross coupling of alcohols. Notably, this methodology was successfully applied for the one‐pot synthesis of a range of flavan derivatives. A detailed DFT studies and kinetic experiments were performed to understand the reaction mechanism as well as the high reactivity of this catalytic system.
Background
Several beta‐lactams are recommended as single agents for the treatment of febrile neutropenia.
Objectives
To compare the effectiveness of different anti‐pseudomonal beta‐lactams as single ...agents in the treatment of febrile neutropenia. To compare the development of bacterial resistance, bacterial and fungal superinfections during or following treatment with the different beta‐lactams.
Search methods
We searched the Cochane Register of Controlled Trials (CENTRAL), Issue 3, 2010. MEDLINE, EMBASE, LILACS, FDA drug applications, conference proceedings and ongoing clinical trial databases up to August 2010. References of included studies were scanned.
Selection criteria
Randomised controlled trials (RCTs) comparing an antipseudomonal beta‐lactam to another antipseudomonal beta‐lactam antibiotic, both given alone or with the addition of the same glycopeptide to both study arms, for the initial treatment of fever and neutropenia among cancer patients.
Data collection and analysis
Two review authors applied inclusion criteria and extracted the data independently. Missing data were sought. Risk ratios (RR) were calculated with 95% confidence intervals (CI), and pooled using the fixed effect model. The primary outcome was all‐cause mortality. Risk of bias was assessed using a domain‐based evaluation and its effect of results was assessed through sensitivity analyses.
Main results
Forty‐four trials were included. The antibiotics assessed were cefepime, ceftazidime, piperacillin‐tazobactam, imipenem and meropenem. Adequate allocation concealment and generation were reported in about half of the trials and only two trials were double‐blinded. The risk for all‐cause mortality was significantly higher with cefepime compared to other beta‐lactams (RR 1.39, 95% CI 1.04 to 1.86, 21 trials, 3471 participants), without heterogeneity and with higher RRs in trials at low risk for bias. There were no differences in secondary outcomes but for a non‐significantly higher rate of bacterial superinfections with cefepime. Mortality was significantly lower with piperacillin‐tazobactam compared to other antibiotics (RR 0.56, 95% CI 0.34 to 0.92, 8 trials, 1314 participants), without heterogeneity. Carbapenems resulted in similar all‐cause mortality and a lower rate of clinical failure and antibiotic modifications as compared to other antibiotics, but a higher rate of diarrhea caused by Clostridium difficile.
Authors' conclusions
Current evidence supports the use of piperacillin‐tazobactam in locations where antibiotic resistance profiles do not mandate empirical use of carbapenems. Carbapenems result in a higher rate of antibiotic‐associated and Clostridium difficile‐associated diarrhea. There is a high level of evidence that all‐cause mortality is higher with cefepime compared to other beta‐lactams and it should not be used as monotherapy for patients with febrile neutropenia.
Background
Aprepitant, a neurokinin-1 receptor antagonist, in combination with 5 HT-3 antagonist and dexamethasone is recommended in adults receiving moderately and highly emetogenic chemotherapy to ...reduce chemotherapy-induced vomiting (CIV). Data for use of aprepitant in children is limited and hence aprepitant is not recommended by Pediatric Oncology Group of Ontario guidelines for prevention of CIV in children <12 years.
Methods
A randomized, double-blind, placebo-controlled trial was conducted at a single center in chemotherapy naïve children (5–18 years) receiving highly emetogenic chemotherapy. All patients received intravenous ondansetron (0.15 mg/kg) and dexamethasone (0.15 mg/kg) prior to chemotherapy followed by oral ondansetron and dexamethasone. Patients randomly assigned to aprepitant arm received oral aprepitant (15–40 kg = days 1–3, 80 mg; 41–65 kg = day 1, 125 mg and days 2–3, 80 mg) 1 h before chemotherapy. Control group received placebo as add-on therapy. Primary outcome measure was the incidence of acute moderate to severe vomiting, which was defined as more than two vomiting episodes within 24 h after the administration of the first chemotherapy dose until 24 h after the last chemotherapy dose in the block. Complete response (CR) was defined as absence of vomiting and retching during the specified phase.
Results
Of the 96 randomized patients, three were excluded from analysis; 93 patients were analyzed (50 in aprepitant arm and 43 in placebo arm). Acute moderate and severe vomiting was reported in 72 % patients receiving placebo and 38 % patients receiving aprepitant (
p
= 0.001). Complete response rates during acute phase were significantly higher in aprepitant arm (48 vs. 12 %,
p
< 0.001). No major adverse effects were reported by patients/guardians.
Conclusions
This double-blind, randomized, placebo-controlled trial shows that aprepitant significantly decreases the incidence of CIV during acute phase when used as an add-on drug with ondansetron and dexamethasone in children receiving highly emetogenic chemotherapy.
Catalytic activities of a series of functional bipyridine‐based RuII complexes in β‐alkylation of secondary alcohols using primary alcohols were investigated. Bifunctional RuII complex (3 a) bearing ...6,6’‐dihydroxy‐2,2’‐bipyridine (6DHBP) ligand exhibited the highest catalytic activity for this reaction. Using significantly lower catalyst loading (0.1 mol %) dehydrogenative carbon−carbon bond formation between numerous aromatic, aliphatic and heteroatom substituted alcohols were achieved with high selectivity. Notably, for the synthesis of β‐alkylated secondary alcohols this protocol is a rare one‐pot strategy using a metal–ligand cooperative RuII system. Remarkably, complex 3 a demonstrated the highest reactivity compared to all the reported transition metal complexes in this reaction.
Alcohols as alkylating agents: A rare example of highly efficient, atom economical and a greener strategy for the synthesis of a variety of β‐alkylated secondary alcohols with high selectivity is presented.
Catalytic activities of a series of functional bipyridine-based Ru super(II) complexes in beta -alkylation of secondary alcohols using primary alcohols were investigated. Bifunctional Ru super(II) ...complex (3a) bearing 6,6'-dihydroxy-2,2'-bipyridine (6DHBP) ligand exhibited the highest catalytic activity for this reaction. Using significantly lower catalyst loading (0.1mol%) dehydrogenative carbon-carbon bond formation between numerous aromatic, aliphatic and heteroatom substituted alcohols were achieved with high selectivity. Notably, for the synthesis of beta -alkylated secondary alcohols this protocol is a rare one-pot strategy using a metal-ligand cooperative Ru super(II) system. Remarkably, complex 3a demonstrated the highest reactivity compared to all the reported transition metal complexes in this reaction. Alcohols as alkylating agents: A rare example of highly efficient, atom economical and a greener strategy for the synthesis of a variety of beta -alkylated secondary alcohols with high selectivity is presented.
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