Respiration resolved imaging with continuous stable state 2D acquisition using linear frequency SWEEP.

PURPOSE: To investigate the potential of continuous radiofrequency (RF) shifting (SWEEP) as a technique for creating densely sampled data while maintaining a stable signal state for dynamic imaging. METHODS: We present a method where a continuous stable state of magnetization is swept smoothly across the anatomy of interest, creating an efficient approach to dense multiple 2D slice imaging. This is achieved by introducing a linear frequency offset to successive RF pulses shifting the excited slice by a fraction of the slice thickness with each successive repeat times (TR). Simulations and in vivo imaging were performed to assess how this affects the measured signal. Free breathing, respiration resolved 4D volumes in fetal/placental imaging is explored as potential application of this method. RESULTS: The SWEEP method maintained a stable signal state over a full acquisition reducing artifacts from unstable magnetization. Simulations demonstrated that the effects of SWEEP on slice profiles was of the same order as that produced by physiological motion observed with conventional methods. Respiration resolved 4D data acquired with this method shows reduced respiration artifacts and resilience to non-rigid and non-cyclic motion. CONCLUSIONS: The SWEEP method is presented as a technique for improved acquisition efficiency of densely sampled short-TR 2D sequences. Using conventional slice excitation the number of RF pulses required to enter a true steady state is excessively high when using short-TR 2D acquisitions, SWEEP circumvents this limitation by creating a stable signal state that is preserved between slices.

Molecular signatures of cortical expansion in the human fetal brain.

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. A growing catalogue of cells in the prenatal brain has revealed remarkable molecular diversity across cortical areas.1,2 Despite this, little is known about how this translates into the patterns of differential cortical expansion observed in humans during the latter stages of gestation. Here we present a new resource, µBrain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal developing brain. Built using generative artificial intelligence, µBrain is a three-dimensional cellular-resolution digital atlas combining publicly-available serial sections of the postmortem human brain at 21 weeks gestation3 with bulk tissue microarray data, sampled across 29 cortical regions and 5 transient tissue zones.4 Using µBrain, we evaluate the molecular signatures of preferentially-expanded cortical regions during human gestation, quantified in utero using magnetic resonance imaging (MRI). We find that differences in the rates of expansion across cortical areas during gestation respect anatomical and evolutionary boundaries between cortical types5 and are founded upon extended periods of upper-layer cortical neuron migration that continue beyond mid-gestation. We identify a set of genes that are upregulated from mid-gestation and highly expressed in rapidly expanding neocortex, which are implicated in genetic disorders with cognitive sequelae. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of expansion across the neocortical sheet during the prenatal epoch. The µBrain atlas is available from: https://garedaba.github.io/micro-brain/ and provides a new tool to comprehensively map early brain development across domains, model systems and resolution scales.

[Oesophageal GIST at the left tracheobronchial angle: resection with right-sided VATS]. / GIST des Ösophagus im linken tracheobronchialen Winkel: Resektion mittels rechtsthorakaler VATS.

OBJECTIVE: The vast majority of submucosal oesophageal tumours are leiomyomas. Gastrointestinal stromal tumours (GIST) account for only one percent of all gastrointestinal malignancies, whereby an oesophageal location represents a medical rarity. Although surgical resection is the gold standard, the optimal procedure remains a matter of debate. Conventional oesophageal resection is the most common therapeutic choice to ensure complete removal with an appropriate safety margin and avoid dissemination of neoplastic cells. Anyhow, occasional case reports about enucleation of oesophageal GIST have been published. This video paper for the first time describes the use of right-sided video-assisted thoracoscopic surgery (VATS) as a technique to enucleate an oesophageal GIST within the left tracheobronchial angle. INDICATION: A 68-year-old male patient was evaluated for recurrent haemoptysis and dysphagia and diagnosed with a 1.4 cm sized oesophageal tumour at the left tracheobronchial angle. CT scan showed a submucosal location without signs of invasive growth. After conducting endosonography we suspected a leiomyoma and performed minimally invasive enucleation with right-sided VATS. METHOD: Employing independent lung ventilation the patient was put into a left lateral position. Four trocars were applied. After incision of the mediastinal pleura the tumour was localised with intraoperative gastroscopy and diaphanoscopy. By mobilisation of the oesophagus and transection of the azygous vein it was possible to bluntly dissect the mass from surrounding oesophageal muscular fibres and safely extract it with a specimen bag. After removal of the thoracic drainage on the first postoperative day the patient was discharged the day after. The further course was uneventful. Histological work-up showed a GIST pT1cN0M0 R0 with a Ki-67 index less than 1 % (UICC I). After 10 months of follow-up the patient is recurrence-free and shows no symptoms. CONCLUSION: Enucleation of a locally limited oesophageal GIST by right-sided VATS is a feasible and safe surgical procedure with dramatically reduced invasiveness compared to conventional open oesophageal resections.

αvß8 integrin-expression by BATF3-dependent dendritic cells facilitates early IgA responses to Rotavirus.

Secretory intestinal IgA can protect from re-infection with rotavirus (RV), but very little is known about the mechanisms that induce IgA production during intestinal virus infections. Classical dendritic cells (cDCs) in the intestine can facilitate both T cell-dependent and -independent secretory IgA. Here, we show that BATF3-dependent cDC1, but not cDC2, are critical for the optimal induction of RV-specific IgA responses in the mesenteric lymph nodes. This depends on the selective expression of the TGFß-activating integrin αvß8 by cDC1. In contrast, αvß8 on cDC1 is dispensible for steady state immune homeostasis. Given that cDC2 are crucial in driving IgA during steady state but are dispensable for RV-specific IgA responses, we propose that the capacity of DC subsets to induce intestinal IgA responses reflects the context, as opposed to an intrinsic property of individual DC subsets.

Autoionization in liquid water.

The dissociation of a water molecule in liquid water is the fundamental event in acid-base chemistry, determining the pH of water. Because of the short time scales and microscopic length scales involved, the dynamics of this autoionization have not been directly probed by experiment. Here, the autoionization mechanism is revealed by sampling and analyzing ab initio molecular dynamics trajectories. We identify the rare fluctuations in solvation energies that destabilize an oxygen-hydrogen bond. Through the transfer of protons along a hydrogen bond "wire," the nascent ions separate by three or more neighbors. If the hydrogen bond wire connecting the two ions is subsequently broken, a metastable charge-separated state is visited. The ions may then diffuse to large separations. If, however, the hydrogen bond wire remains unbroken, the ions recombine rapidly. Because of their concomitant large electric fields, the transient ionic species produced in this case may provide an experimentally detectable signal of the dynamics we report.

The use of antenatal fetal magnetic resonance imaging in the assessment of patients at high risk of preterm birth.

Preterm birth, defined as birth occurring prior to 37 weeks gestation is a common obstetric complication affecting 8% of pregnancies and is associated with significant morbidity and mortality. Infection/inflammation has been implicated in both the aetiology of preterm birth itself and associated neonatal pulmonary and neurological morbidity. Treatment options are currently limited to prolongation of the pregnancy using cervical cerclage, pessaries or progesterone or administration of drugs including steroids to promote lung maturity and neuroprotective agents such as magnesium sulphate, the timing of which are highly critical. Although delivery is expedited in cases of overt infection, decisions regarding timing and mode of delivery in subclinical infection are not clear-cut. This review aims to explore the use of magnetic resonance imaging (MRI) in the antenatal assessment of pregnancies at high risk of preterm birth and its potential to guide management decisions in the future.

Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase.

BACKGROUND AND PURPOSE: Rho-kinase (ROCK) has been implicated in the pathophysiology of altered vasoregulation leading to hypertension. Here we describe the pharmacological characterization of a potent, highly selective and orally active ROCK inhibitor, the derivative of a class of azaindoles, azaindole 1 (6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}pyrimidine-2,4-diamine). EXPERIMENTAL APPROACH: Pharmacological characterization of azaindole 1 was performed with human recombinant ROCK in vitro. Vasodilator activity was determined using isolated vessels in vitro and different animal models in vivo. KEY RESULTS: This compound inhibited the ROCK-1 and ROCK-2 isoenzymes with IC50 s of 0.6 and 1.1 nM in an ATP-competitive manner. Although ATP-competitive, azaindole 1 was inactive against 89 kinases (IC50>10 microM) and showed only weak activity against an additional 21 different kinases (IC50=1-10 microM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub-micromolar range, albeit with IC50 values of 252 and 303 nM, respectively. In vivo, azaindole 1 lowered blood pressure dose-dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1 induced a dose-dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1 induced vasodilatation with a moderately elevated heart rate. CONCLUSIONS AND IMPLICATIONS: Azaindole 1 is representative of a new class of selective and potent ROCK inhibitors and is a valuable tool for the elucidation of the role of ROCK in the cardiovascular system.

PDE5 inhibitors beyond erectile dysfunction.

The phosphodiesterase type-5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are widely used first-line therapy for erectile dysfunction (ED). Since the advent of sildenafil in 1998, more than 40 million men worldwide have been successfully treated with these compounds. The safety and high tolerability of PDE5 inhibitors make them an attractive tool to investigate further physiological functions of PDE5, for example the modulation of intracellular cyclic GMP (cGMP) pools. As cGMP is a key component of intracellular signaling this may provide novel therapeutic opportunities beyond ED even for indications in which chronic administration is necessary. The approval of sildenafil for the treatment of pulmonary hypertension in 2005 was a notable success in this area of research. A number of other potential new indications are currently in various phases of preclinical research and development. In recent years, extensive but very heterogeneous information has been published in this field. The aim of this review is to summarize existing preclinical and clinical knowledge and critically discuss the evidence to support potential future indications for PDE5 inhibitors.

Flexible versus rigid endoscopy for treatment of foreign body impaction in the esophagus.

BACKGROUND: The use of either flexible endoscopy (FE) or rigid endoscopy (RE) for removal of ingested foreign bodies (FBs) impacted in the esophagus is still discussed controversially. METHODS: We report a consecutive series of 139 patients with FB impaction in the esophagus. During a 6-year period, 69 men and 70 women (median age, 64 [0.7-97] years) requiring removal of an impacted FB underwent either RE (n = 63) in the Otolaryngology Department of our hospital or FE (n = 76) in the Surgical Endoscopy Unit. RESULTS: Foreign body removal was equally effective with FE (success rate 93.4%) and RE (95.2%, p = n.s.). The cases in which foreign body removal failed (5 FE cases [6.6%] and 3 RE cases [4.8%]) were all subsequently successfully managed with "conversion" and use of the other technique. No severe complications occurred when FB removal was attempted with FE (0 of 76 cases; 0.0%), whereas RE was associated with esophageal rupture requiring immediate surgical intervention in 2 of 63 cases (3.2%; p < 0.002). Patient comfort differed significantly between the two procedures (p < 0.0001); RE was always performed under general anesthesia (100.0%), whereas only a minority of patients undergoing FE required general anesthesia (13.0%; p < 0.0001) or mild analgosedation (20.0%). The better patient comfort with FE was also reflected in a significantly lower rate of dysphagia (15%) compared to RE (48%; p < 0.0001). Rigid endoscopy was more frequently used in removal of FBs of the upper esophagus (p < 0.0001), whereas FE was the predominate approach to FBs in the lower esophagus (p < 0.0001). CONCLUSIONS: A tailored approach to treatment of FB impaction is recommended. Because of the lower rate of severe complications, better patient comfort with a lower rate of dysphagia, and lack of requirement for general anesthesia, FE should be the "first line" approach to FBs, although RE has its place as the "second line" therapy.

Characterization of the structure and properties of authentic and counterfeit polypropylene surgical meshes.

A counterfeit version of the Ethicon Prolene polypropylene mesh was distributed to hospitals and clinics and unintentionally implanted into patients undergoing tension-free hernia repair. On December 19, 2003, the Food and Drug Administration (FDA) issued a public health web notification indicating that the counterfeit mesh was not sterile or safe to use. To develop safety recommendations for patients with the counterfeit mesh implant, we compared the counterfeit's structural, physical, chemical and mechanical properties with polypropylene meshes previously cleared by FDA. The mesh fibers for all the products tested were found to have similar chemical and physical properties. The mechanical properties were directly related to the knitted structure (loop size, repeat distance, fabric tightness) and the porosity. Extracts from the counterfeit mesh passed cytotoxicity screening tests. The FDA further recommended that if the mesh had been inadvertently implanted, then those patients should be monitored as would be the practice for any patient with an implanted surgical mesh.

Effects of hypoxia and fatty acids on the distribution of metabolites in rat heart.

The effects of exogenous fatty acids and hypoxia on cardiac energy metabolism were studied by measuring mitochondrial and cytosolic adenine nucleotides as well as CoA and carnitine esters using a tissue fractionation technique in non-aqueous solvents. During normoxia, the administration of 0.5 mM palmitate caused a considerable increase in acyl-CoA and acylcarnitine, particularly in mitochondria. High-energy phosphates, however, were only slightly altered. A 90 min low-flow hypoxia caused a dramatic increase in mitochondrial acyl esters. The mitochondrial ATP content decreased significantly, while the cytosolic concentration was only slightly diminished, suggesting an inhibition of mitochondrial adenine nucleotide translocation by long-chain acyl-CoA. Addition of palmitate during hypoxia amplified hypoxic damage and reduced adenine nucleotides in both compartments considerably, while fatty acid metabolites were only slightly affected. In presence of an inhibitor of fatty acid oxidation (BM 42.304), the fatty-acid-induced acceleration of cardiac injury was prevented. Since BM 42.304 decreased mitochondrial acylcarnitine and increased the cytosolic concentration significantly, BM 42.304 was presumed to inhibit mitochondrial acylcarnitine translocase. However, a causal relationship between lipid metabolites and ischemic damage seemed unlikely.

Fatty acid-membrane interactions in isolated cardiac mitochondria and erythrocytes.

The effects of long-chain fatty acids on mitochondrial functions and red cell stability were studied. In albumin-containing incubation media, fatty acid distribution between the albumin-bound and the unbound fraction was estimated by calculation. When fatty acids are compared to one another on the basis of identical unbound concentrations, their effectiveness differs by orders of magnitude. Fatty acids stimulate mitochondrial basic oxygen consumption, thus lowering the respiratory control index, without changing the ATP/O ratio at lower concentrations. Lower concentrations increase Ca2+ uptake velocity, but decrease maximal Ca2+ storage capacity. The order of effectiveness of different fatty acids is the same for both oxidative phosphorylation and Ca2+ uptake. The influence of fatty acids on red cell stability in hypotonic media is similar to these effects both in concentration range and in order of effectiveness. The influence of fatty acids on red cell stability and their critical micellar concentrations were investigated because these are general characteristics of 'detergent-like' compounds. Critical micellar concentrations of the fatty acids in physiological salt buffers are, in general, at least 10-fold higher than the concentrations exhibiting membrane effects in vitro. Based on these findings it is suggested that, of the various concentrations reported in literature for myocardial non-esterified fatty acids, only the lowest values are physiologically possible.

Effect of ischaemia and reperfusion on the intracellular concentration of taurine and glutamine in the hearts of patients undergoing coronary artery surgery.

Taurine and glutamine are the most abundant intracellular free amino acids in mammalian hearts where changes in their intracellular concentrations are likely to influence a number of cellular activities. In this study we investigated the effects of ischaemia and reperfusion on the intracellular concentrations of taurine and glutamine in the hearts of patients undergoing coronary artery bypass surgery using cold crystalloid or cold blood cardioplegic solutions. Ischaemic arrest (30 min), using cold crystalloid cardioplegic solution (n = 19), decreased the intracellular concentrations (micromol/g wet weight) of taurine (from 9.8 +/- 0.8 to 7.7 +/- 0.7, P < 0.05) and glutamine (8.7 +/- 0.5 to 7.2 +/- 0.6). After 20 min of normothermic reperfusion the fall in taurine and glutamine was maintained (7.5 +/- 0.5 and 7.4 +/- 0.7 for taurine and glutamine respectively). Myocardial ischaemic arrest with cold blood cardioplegic solution (n = 16) did not cause a significant fall in tissue taurine or glutamine. However, on reperfusion there was a marked fall in the intracellular concentrations of taurine (9.4 +/- 0.5 to 6.5 +/- 0.7) and glutamine (8.0 +/- 0.7 to 5.8 +/- 0.4). The fall in amino acids was associated with a fall in ATP and a rise in tissue lactate. This work demonstrates that irrespective of the cardioplegic solution used to arrest the heart, there is a marked fall in tissue taurine and glutamine which may influence the extent of recovery following surgery. The fall in taurine is largely due to efflux whereas changes in glutamine are due to both transport and metabolism. Ischaemia, hypothermia and changes in the transmembrane concentration gradients are the likely factors responsible for the changes in tissue amino acids.

Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.

PURPOSE: To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. PATIENTS AND METHODS: Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [i.v.]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. RESULTS: Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephrotoxic antibiotics. Steady-state blood concentrations of CsA > or = 1,500 ng/mL were achieved in all patients receiving CI doses > or = 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. CONCLUSION: High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

Dobutamine stress echocardiography: a sensitive indicator of diminished myocardial function in asymptomatic doxorubicin-treated long-term survivors of childhood cancer.

Doxorubicin is an effective anticancer chemotherapeutic agent known to cause acute and chronic cardiomyopathy. To develop a more sensitive echocardiographic screening test for cardiac damage due to doxorubicin, a cohort study was performed using dobutamine infusion to differentiate asymptomatic long-term survivors of childhood cancer treated with doxorubicin from healthy control subjects. Echocardiographic data from the experimental group of 21 patients (mean age 16 +/- 5 years) treated from 1.6 to 14.3 years (median 5.3) before this study with 27 to 532 mg/m2 of doxorubicin (mean 196) were compared with echocardiographic data from 12 normal age-matched control subjects. Graded dobutamine infusions of 0.5, 2.5, 5 and 10 micrograms/kg per min were administered. Echocardiographic Doppler studies were performed before infusion and after 15 min of infusion at each rate. Dobutamine infusion at 10 micrograms/kg per min was discontinued after six studies secondary to a 50% incidence rate of adverse symptoms. The most important findings were that compared with values in control subjects, end-systolic left ventricular posterior wall dimension and percent of left ventricular posterior wall thickening in doxorubicin-treated patients were decreased at baseline study and these findings were more clearly delineated with dobutamine stimulation. End-systolic left ventricular posterior wall dimension at baseline for the doxorubicin-treated group was 11 +/- 1.9 mm versus 13.1 +/- 1.5 mm for control subjects (p less than 0.01). End-systolic left ventricular posterior wall dimension at the 5-micrograms/kg per min dobutamine infusion for the doxorubicin-treated group was 14.1 +/- 2.4 mm versus 19.3 +/- 2.6 mm for control subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Heart-lung transplantation: better use of resources.

PURPOSE: Our goal was to review the experience at Papworth Hospital, Cambridgeshire, England, with combined heart-lung transplantation. PATIENTS AND METHODS: Since April 1984, 31 patients have undergone heart-lung transplantation. Donors and recipients are carefully matched with regards to serology, morphology, and cytomegalovirus compatibility. A pulmonary preservation fluid has been developed that allows distant organ procurement with a single pulmonary artery flush technique. RESULTS: Acute cardiac rejection has not occurred in these patients. Twenty-three patients are alive between two months and over three years following transplantation. The actuarial survival rate at one year is 78 percent, and 70 percent at two years. Three patients died as a result of cytomegalovirus pneumonitis; in two patients, obliterative bronchiolitis developed, and both died, one after an opportunistic infection developed. Three patients died from other causes. The use of transbronchial biopsy of the lung has provided accurate, early, and safe diagnosis of pulmonary rejection. CONCLUSION: Developments in organ preservation and patient management, as well as careful selection of recipients and donors, have led to the effective use of resources and thereby to these good results. In particular, the incidence of obliterative bronchiolitis has been low, which is attributed to the early treatment of pulmonary rejection following diagnosis by transbronchial biopsy.

Effects of the immunosuppressant cyclosporine on the circulation of heart transplant recipients.

The effect of cyclosporine on the systemic circulation and on heart rate is unknown for heart transplant recipients. Thirty-four heart transplant recipients were studied by right-sided cardiac catheterization after endomyocardial biopsy. A direct linear relation was found between systemic and pulmonary vascular resistance and cyclosporine trough blood levels, which were negatively related to heart rate. The effect of cyclosporine on pulmonary vascular resistance, however, was not statistically significant by multivariate analysis when patient age was considered. In contrast, renal function appeared unrelated to systemic vascular resistance or heart rate. It appears that cyclosporine trough blood levels may have a direct effect on systemic vascular resistance as well as an unexplained negative chronotropic effect on heart rate.