Ultrasound-Guided Peripheral Nerve Stimulation for Shoulder Pain: Anatomic Review and Assessment of the Current Clinical Evidence.
The shoulder region is a common area for pain. The shoulder has the largest range of motion and the most complex mechanical anatomy. The shoulder girdle and related tendons allow for numerous painful disorders to occur. Also, given the overall use of the shoulder, arthritic deformities are all too common. Finally, pain from more complex states such as poststroke shoulder pain and status post total shoulder arthroplasty pain have always been a difficult diagnosis to treat with effectiveness. The innervation to the shoulder predominantly comes from the suprascapular and axillary nerves. Both nerves relatively follow an expected anatomic course and whereby they can be targeted with ultrasound or fluoroscopy. Recently, there has been an increase in evidence that suggests peripheral nerve stimulation can make a difference in these patients with shoulder pain. To provide a basic overview of peripheral nerve stimulator placement targeting the axillary and suprascapular nerves. Furthermore, to demonstrate the suggested implantation and current evidence of peripheral nerve stimulation for the treatment of shoulder pain. Anatomic clinical review. A comprehensive review was performed regarding the available literature through targeting articles reporting on the use of peripheral nerve stimulation to treat pain of the shoulder region. We compiled and discuss the current evidence available in treating shoulder pain utilizing peripheral stimulation. The strongest evidence currently is for peripheral nerve stimulation targeting either the axillary or suprascapular nerve, as well as placement targeting the motor points of the deltoid. The most common treated pathology is poststroke shoulder pain. Peripheral nerve stimulation has been trialed and is promising for several shoulder pain pathologies; however, there remains a need for large-scale, randomized, placebo-controlled clinical trials to further evaluate the efficacy of most treatments. Much of the current data relies on case reports without randomization or placebo controls. Overall there is fair to moderate evidence for peripheral nerve stimulation to treat shoulder pain in hemiplegic poststroke patients. There is limited evidence when treating other shoulder pain etiologies. Utilizing ultrasound or fluoroscopic guidance, the procedure has proven to be safe allowing proper placement of the electrodes near the target nerves. Considering the high prevalence of shoulder pain from degenerative conditions and overuse, future studies are undoubtedly warranted to evaluate whether peripheral nerve stimulation can modify our treatment algorithm for management of these conditions.


Breast cancer subtypes and outcomes of central nervous system metastases.
Central nervous system (CNS) metastases are detected in up to one third of patients with advanced breast cancer, but their incidence and outcomes by breast cancer subtypes are not precisely documented. Herein, we retrospectively analyzed clinicopathologic data of 259 breast cancer patients with CNS metastases to evaluate the association between breast cancer subtypes and CNS metastasis. The patient groups were classified according to their hormone receptor status and HER-2 expression. Median follow-up time among the patients was 42 months and median survival after CNS metastasis detection was 7.8 months. In HER-2 overexpressing group, median time period between the diagnosis of breast cancer and the detection of CNS metastasis (15.9 months) was significantly shorter compared to the other groups (p = 0.01). The triple negative group had the shortest median survival time after CNS metastasis (6.6 months), although statistically not significant (p = 0.3). In multivariate Cox regression analyses, having solitary CNS metastasis (HR 0.4, 95% CI; 0.2-0.7, p = 0.004), and receiving chemotherapy after CNS metastasis (HR 0.4, 95% CI; 0.287-0.772, p = 0.003) were independent prognostic factors for increasing survival after CNS metastasis. In conclusion, new and effective treatment strategies are required for breast carcinoma patients with brain metastasis considering the positive effect of the treatment on survival.


Dystrophic phenotype induced in vitro by antibody blockade of muscle alpha-dystroglycan-laminin interaction.
alpha-dystroglycan is a glycoprotein expressed on the surface of skeletal muscle fibres and other cell types. In muscle, alpha-dystroglycan provides a link between the myofibre cytoskeleton through its indirect binding to dystrophin, and the basal lamina through its binding to laminin-2, a protein of the extracellular matrix. The disruption of this linkage between the myofibre cytoskeleton and the extracellular matrix is a common feature of Duchenne and other muscular dystrophies, though the pathogenic mechanisms leading to muscle wasting remain unknown. By treating primary mouse muscle cultures with a monoclonal antibody which blocks alpha-dystroglycan binding to laminin, we show here the induction of a dystrophic phenotype in vitro. The phenotype is inducible in differentiated cultures only, is characterised by reduced myotube size, myofibril disorganisation, loss of contractile activity, reduced spontaneous clustering of acetylcholine receptors and is reversed by addition of excess exogenous laminin-2. Thus, alpha-dystroglycan may be part of a signalling pathway for the maturation and maintenance of skeletal myofibres. Detailed knowledge of this signalling pathway may provide insights into the molecular pathology of the various inherited muscular dystrophies, and identify valuable pharmacological targets and new therapeutic strategies.


Cerebral Microbleeds and Asundexian in Non-cardioembolic Ischemic Stroke: Secondary Analyses of the PACIFIC-STROKE Randomized Trial.
Cerebral microbleeds are MRI markers of hemorrhage-prone cerebral small-vessel disease that predict future risk of ischemic stroke and intracranial hemorrhage (ICrH). There exists concerns about the net benefit of antithrombotic therapy in patients with microbleeds. We aimed to investigate the effects of an oral factor-XIa inhibitor (asundexian), that is hypothesized to inhibit thrombosis without compromising hemostasis, on the development of new microbleeds over time and interactions between microbleeds and asundexian treatment on clinical outcomes. We additionally assessed associations between baseline microbleeds and the risks of clinical and neuroimaging outcomes in patients with non-cardioembomic ischemic stroke. This is a subgroup analysis of the PACIFIC-STROKE, international, multi-center Phase 2b double-blind, randomized clinical trial. PACIFIC-STROKE enrolled patients aged ≥45 years with mild-to-moderate non-cardioembolic ischemic stroke who presented within 48 hours of symptom onset for whom antiplatelet therapy was intended. Microbleeds were centrally adjudicated, and participants with an interpretable T2*-weighted sequence at their baseline MRI were included in this analysis. Patients were randomized to asundexian (10/20/50mg daily) vs. placebo plus standard antiplatelet treatment. Regression models were used to estimate the effects of i) all pooled asundexian doses and ii) asundexian 50 mg daily on new microbleed formation on 26-week MRIs. Cox proportional hazards or regression models were additionally used to estimate interactions between treatment assignment and microbleeds for ischemic stroke/TIA (primary outcome), as well as ICrH, all-cause mortality, hemorrhagic transformation (HT), and new microbleeds (secondary outcomes). Of 1746 participants (mean age, 67.0±10.0; 34% female) with baseline MRIs, 604 (35%) had microbleeds. During a median follow-up of 10.6 months, 7.0% (n=122) had ischemic stroke/TIA, 0.5% (n=8) ICrH, and 2.1% (n=37) died. New microbleeds developed in 10.3% (n=155) of participants with adequate up-MRIs and HT in 31.4% (n=345). In the total sample of patients with adequate baseline and 26-week follow-up MRIs (n=1507, ), new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR 0.96, 95%CI 0.66-1.41). There were no interactions between microbleeds and treatment assignment for any of the outcomes (p for interaction>0.05). The rates of new microbleeds, HT and ICrH were numerically less in patients with microbleeds assigned to asundexian relative to placebo. The presence of microbleeds was associated with a higher risk of HT (aOR, 1.6; 95%CI, 1.2-2.1) and new microbleeds (aOR, 4.4; 95%CI, 3.0-6.3). Factor XIa inhibition with asundexian appears safe in patients with non-cardioembolic ischemic stroke and hemorrhage-prone cerebral small-vessel disease marked by microbleeds on MRI. These preliminary findings will be confirmed in the ongoing OCEANIC-STROKE randomized trial. ClinicalTrials.gov Identifier: NCT04304508.


Gender differences in drinking behaviour in the Netherlands: convergence or stability?
Gender differences in drinking behavior are analysed with emphasis on their relationship with changes in roles and positions of men and women in society. The 'convergence hypothesis' is used as a starting point. From its implications, a number of specific hypotheses are derived and tested using data from six surveys of the general population of the Netherlands, held between 1958 and 1993. No convergence of gender differences is found for abstinence and heavy frequent drinking. Convergence of male-female differences in average weekly consumption appeared in the 1980s, but it is no longer significant at 5% level after controlling for age, education and family situation. Further elaboration of the gender by year interaction shows that convergence is related to a decrease in consumption among higher educated men. Contrary to expectation, an increase in consumption has occurred among women over 40 years of age. No relationship appears with female employment and religion. Having a family is related to lower consumption among women, while it has no significant effect on men's consumption. Although some evidence for convergence was found, results are not in agreement with expectations formulated from the perspective of the convergence hypothesis.


Tunica vaginalis reinforcement flap in reoperative Snodgrass procedure.
Interposing vascularized flaps between urethra and skin sutures is recommended in hypospadias surgery to decrease the rate of urethrocutaneous fistula. For this purpose nine patients with failed results after at least one hypospadias surgery and with insufficient foreskin were included in the study. Tubularized incised plate uretroplasty and tunica vaginalis reinforcement flap were performed to all patients with normal urethral plate. After a mean follow-up of 8.9 months (range 3-20) only one patient had developed a fistula. We believe that tunica vaginalis reinforcement flap decreases fistulas in reoperative hypospadias surgery in patients with insufficient foreskin or with a circumcised penis.


Correlation of pelvic magnetic resonance imaging diagnosis with pathology for indeterminate adnexal masses.
The aim of this study was to determine the accuracy of pelvic magnetic resonance imaging (MRI) diagnoses compared with the final pathology diagnoses for a series of women with indeterminate adnexal masses. We performed a retrospective cohort study of women who underwent pelvic MRI with a diagnosis of an adnexal mass between June 2009 and 2010 after indeterminate ultrasound at our tertiary care institution. Chart abstraction was performed for demographic information and radiologic interpretations (benign or malignant) and favored a specific histologic subtype on MRI reports. The radiologic diagnoses were compared with the diagnoses by surgical pathology. Data from 237 female patients who underwent pelvic MRI were included, and 41.35% underwent surgical intervention for the adnexal mass. Pelvic MRI (n = 88) was determined to have a sensitivity of 95.0% and specificity of 94.1%. The predicted specific histologic subtype by MRI (n = 84) was accurate in 56 (98.25%) of 57 women with an anticipated benign diagnosis and in 23 (85.19%) of 27 women with an anticipated malignancy. The agreement between a benign diagnosis from MRI and benign final surgical pathology was 0.85 (95% confidence interval, 0.716-0.976). In our tertiary care center, MRI is used to further characterize indeterminate adnexal masses and can accurately differentiate benign versus malignant adnexal masses. The diagnosis on MRI was highly correlative with the final histopathology. The majority of the cohort (59%) were able to be managed expectantly based on reassuring results of the MRI. Magnetic resonance imaging offered diagnostic value, more detailed patient counseling, appropriate subspecialty referral, and surgical planning, as well as reassurance to pursue conservative management of benign masses by MRI.


Effects of morphine on pain-elicited and pain-suppressed behavior in CB1 knockout and wildtype mice.
Pharmacological manipulations of the type 1 cannabinoid receptor (CB1) suggest a role for CB1 in morphine-induced antinociception, but studies utilizing CB1 knockout (KO) mice do not support this conclusion. Since studies using CB1 KO mice to study morphine's antinociceptive effects have only examined thermal nociception, this study examines these interactions in models that employ a chemical stimulus. To determine whether the findings obtained with thermal pain models extend to other models, the effects of morphine on acetic acid-induced writhing were examined in CB1 KO and wildtype (WT) mice. Behaviors that decrease in response to acid injection, feeding and wheel running, were also examined, and investigations were carried out in the thermal hotplate assay. The CB1 antagonist SR141716A was also examined in these assays. Morphine completely blocked acid-induced writhing (1.0-10.0 mg/kg) and increased response latencies in the hotplate (10.0-32.0 mg/kg) in both genotypes. Morphine (3.2 mg/kg) significantly attenuated the suppression of wheel running but did not completely prevent this effect in either genotype. Morphine did not alter pain-suppressed feeding. In each of these assays, morphine's effects were not altered in CB1 KO mice compared with WT mice; however, SR141716A attenuated morphine's effects in C57BL/6 mice. The effects of morphine do not differ in CB1 KO and WT mice in preclinical pain models using thermal and chemical stimuli. Since SR141716A did attenuate the effects of morphine, it is possible that CB1 KO mice undergo developmental changes that mask the role of CB1 receptors in morphine's antinociceptive effects.


Unmet needs and prospects for oritavancin in the management of vancomycin-resistant enterococcal infections.
The treatment of infections caused by vancomycin-resistant enterococci (VRE) has become an important clinical challenge and compromises the care of critically ill patients. A striking increase in the frequency of nosocomial isolation of multidrug-resistant Enterococcus faecium has dramatically reduced the therapeutic alternatives because the majority of E. faecium isolates are resistant to ampicillin and vancomycin. Only 2 agents have US Food and Drug Administration approval for the treatment of VRE (E. faecium) infections, namely, linezolid and quinupristin/dalfopristin (Q/D). However, the use of these compounds in severe VRE infections is hampered by the lack of in vivo bactericidal activity, reports of therapeutic failures with monotherapy, a requirement for central venous access for administration (Q/D), and adverse-effect profile. The lipopeptide antimicrobial daptomycin has in vitro bactericidal activity against VRE; however, clinical use of this compound for VRE has not been well studied, and the reports of resistance emerging during therapy at the approved doses are worrisome. Tigecycline has in vitro bacteriostatic activity against VRE, but its clinical use for serious enterococcal infections is unclear due to low serum levels and static effect. Thus, current reliable therapies for VRE appear to be limited, and clinical data that use the above compounds are certainly scant. Oritavancin is an investigational semisynthetic glycopeptide with potent in vitro activity against VRE (both VanA and VanB phenotypes). Although review of the available preclinical data indicates that this compound used as a single agent is likely to have important limitations for the treatment of a severe VRE infection (ie, endocarditis), combination of oritavancin with other agents such as aminoglycosides may offer promise and deserves further investigation, as does use of oritavancin for less serious infections as monotherapy for vancomycin-susceptible and multidrug-resistant enterococci.


[Results of kidney transplantation in children weighing less than 11 kilograms].
Weigh and age are risk factors of graft failure. The aim of the study is to review the characteristics and the outcome of cadaver renal transplant in children weighing less than 11 Kg. From 1985 to 1999 10 cadaver renal transplant were performed in 10 children (7 boys and 3 girls). Primary renal disease were renal dysplasia(3), posterior urethral valves(5) and congenital nephrotic syndrome(2). All except two suffered end stage disease from birth. The cadaver donor age ranged from 4 to 45 years (mean 12.3). Cold ischaemia time was 14 to 30 hours (median 22.8 h). Grafts were placed extraperitoneally in the iliac fossa in all patients and special care was taken in aggressive intravascular volume expansion. In the first 5 children initial immunosuppression consisted of CyA, Pd and Aza. After 1991, the other five received sequential induction therapy with polyclonal antibodies and triple therapy (CyA, Pd, Aza). Renal function was evaluated as GFR yearly by Swartz formula and the actuarial and graft survival rates were obtained by Kaplan-Meier analysis. Patient survival was 90% at 1 and 10 years. Graft survival was 80% at 1 and 5 years; it decreased to 64% at 7 years. Seven continue with their first graft and the mean follow-up time is 6.6 years. Their renal function measured by the mean of GFR yearly decreased lightly from 102 ml/min/1.73 m2 at 1 year to 87.6 ml/min/1.73 m2 at 5 years. A successful patient and graft survival can be achieved in young receiving kidneys and small reciepients can improve their physical and mental development after transplantation.


Epithelial Bmp (Bone morphogenetic protein) signaling for bulbourethral gland development: a mouse model for congenital cystic dilation.
The bulbourethral gland (BUG) is a male-specific organ, which secretes part of the semen fluid. As the BUG is located in the deep pelvic floor, its developmental process is still unclear. Bone morphogenetic protein (Bmp) signaling plays pivotal roles in various organs. However, the function of Bmp signaling for BUG development is still unclear. The present study aimed to elucidate the role of Bmp signaling in the development of the BUG. We observed the prominent nuclear accumulation of phosphorylated (p) SMAD1/5/8, the downstream molecules of Bmp signaling, during BUG epithelial development. These results suggest that Bmp signaling contributes to BUG development. Bmp receptor1a (Bmpr1a) is known as the major type 1 signal transducer in some organogeneses. To analyze the Bmp signaling function for BUG development, we examined epithelial cell-specific Bmpr1a gene conditional mutant mice utilizing the tamoxifen-inducible Cre recombinase system. We observed cystic dilation and epithelial hyperplasia of the BUG in the Bmpr1a conditional knockout mice. The mutant cystic BUG specimens also showed inflammatory lesions. These BUG abnormalities resembled some of the BUG malformations observed in human congenital syndromes. The current study suggests that Bmp signaling possesses an essential role in BUG development and homeostasis. This would be the first report showing that the mutation of the Bmpr1a gene in the BUG epithelia phenocopied some abnormalities of human congenital syndromes affecting the BUG duct.


Family-focused practice within a recovery framework: practitioners' qualitative perspectives.
Family-focused practice (FFP) is an effective approach to supporting individuals with mental illness. 'Recovery' is also central to contemporary mental health care. However, there is a dearth of evidence about how the two concepts are related and subsequently implemented in practice. The aim of this study was to explore practitioners' understandings and practices of FFP within a recovery framework. Purposive/snowball sampling was used to recruit and conduct qualitative interviews with 11 mental health practitioners in rural Australia. Concurrent sampling and data collection were informed by thematic analysis and continued until data saturation was reached. Participants found it difficult to articulate their understandings of FFP within a recovery framework. Nonetheless they were able to describe practices that embodied family-focused recovery. Barriers to such practices included medical models of care, where there are often a shortage of skilled staff and high demands for care. Stigma (self and from others) and confidentiality were also identified as barriers to involving family members in recovery focused care. Family-focused recovery care is a priority in many high-income countries. A family-focused recovery framework is needed to assist service planners, practitioners, family members and those with mental health needs and ensure such care is embedded within practice guidelines.


Analysis of site-specific glycosylation of renal and hepatic γ-glutamyl transpeptidase from normal human tissue.
The cell surface glycoprotein γ-glutamyl transpeptidase (GGT) was isolated from healthy human kidney and liver to characterize its glycosylation in normal human tissue in vivo. GGT is expressed by a single cell type in the kidney. The spectrum of N-glycans released from kidney GGT constituted a subset of the N-glycans identified from renal membrane glycoproteins. Recent advances in mass spectrometry enabled us to identify the microheterogeneity and relative abundance of glycans on specific glycopeptides and revealed a broader spectrum of glycans than was observed among glycans enzymatically released from isolated GGT. A total of 36 glycan compositions, with 40 unique structures, were identified by site-specific glycan analysis. Up to 15 different glycans were observed at a single site, with site-specific variation in glycan composition. N-Glycans released from liver membrane glycoproteins included many glycans also identified in the kidney. However, analysis of hepatic GGT glycopeptides revealed 11 glycan compositions, with 12 unique structures, none of which were observed on kidney GGT. No variation in glycosylation was observed among multiple kidney and liver donors. Two glycosylation sites on renal GGT were modified exclusively by neutral glycans. In silico modeling of GGT predicts that these two glycans are located in clefts on the surface of the protein facing the cell membrane, and their synthesis may be subject to steric constraints. This is the first analysis at the level of individual glycopeptides of a human glycoprotein produced by two different tissues in vivo and provides novel insights into tissue-specific and site-specific glycosylation in normal human tissues.


Hepatic adenomatosis in liver cirrhosis.
Hepatocellular adenoma (HCA) is a benign liver tumor most frequently occurring in women using oral contraception. HCA develops in normal or nearly normal livers and is extremely rare in cirrhosis. The authors present magnetic resonance imaging and histopathologic findings in a 57-year-old man with liver cirrhosis and hepatic adenomatosis. As the differentiation between HCA and hepatocellular carcinoma (HCC) can be difficult with imaging, we would like to highlight the importance of ancillary findings such as the presence of iron on MRI, which can be observed in HCA.


Current diagnosis and management of urachal remnants.
The purposes of this study are to review our experience with patients who were found to have urachal remnants. We discuss their diagnosis and management and we also evaluate post-operative complications in our cohort of patients with this entity. We performed a retrospective review of all patients diagnosed with a urachal remnant (UR) between January 2006 and December 2010. Patient variables included age, gender, presenting symptoms and signs, diagnostic modality, and type of urachal remnant. Operative management, post-operative complications, and non-operative follow-up were abstracted. We identified 103 pediatric patients with either a urachal cyst (n = 38), urachal diverticulum (n = 13), urachal sinus (n = 11), patent urachus (n = 21), or a non-specific atretic urachal remnant (n = 20). Seventy-eight patients had symptomatic URs. Thirty-four symptomatic patients underwent surgical excision of the UR and 44 symptomatic patients were observed. Eighteen URs were incidentally diagnosed in asymptomatic patients, none of whom underwent surgical excision. In 7 patients symptoms could not be determined from the records. No patients with non-specific atretic remnants were operated upon. Nineteen of the observed patients were reimaged subsequently. In fifteen (78.9%) of these patients, the URs had resolved spontaneously. None of the patients who were observed required subsequent excision of the UR. Post-operative complications occurred in 14.7% of patients in whom URs were excised. Review of our patients diagnosed with URs indicates there is a subset of patients in whom spontaneous resolution could be expected. Complications are not uncommon after surgical excision.


Human nasal polyp microenvironments maintained in a viable and functional state as xenografts in NOD-scid IL2rgamma(null) mice.
The objective was to develop a model with which to study the cellular and molecular events associated with nasal polyp progression. To accomplish this, we undertook to develop a system in which nondisrupted human nasal polyp tissue could be successfully implanted into severely immunocompromised mice, in which the histopathology of the original nasal polyp tissue, including inflammatory lymphocytes, epithelial and goblet cell hyperplasia, and subepithelial fibrosis, could be preserved for prolonged periods. Small, non-disrupted pieces of human nasal polyp tissues were subcutaneously implanted into NOD-scid IL2rgamma(null) mice. Xenografts at 8 to 12 weeks after implantation were examined histologically and immunohistochemically to identify human inflammatory leukocytes and to determine whether the characteristic histopathologic characteristics of the nasal polyps were maintained for a prolonged period. The xenografts, spleen, lung, liver, and kidneys were examined histologically and immunohistochemically and were evaluated for changes in volume. The sera of these mice were assayed for human cytokines and immunoglobulin. Xenografts of human nasal polyp tissues were established after their subcutaneous implantation into NOD-scid IL2rgamma(null) mice. The xenografts were maintained in a viable and functional state for up to 3 months, and retained a histopathologic appearance similar to that of the original tissue, with a noticeable increase in goblet cell hyperplasia and marked mucus accumulation in the submucosal glands compared to the original nasal polyp tissue. Inflammatory lymphocytes present in the polyp microenvironment were predominantly human CD8+ T cells with an effector memory phenotype. Human CD4+ T cells, CD138+ plasma cells, and CD68+ macrophages were also observed in the xenografts. Human immunoglobulin and interferon-gamma were detected in the sera of xenograft-bearing mice. The polyp-associated lymphocytes proliferated and were found to migrate from the xenografts to the spleens of the recipient mice, resulting in a significant splenomegaly. A progressive increase in the volume of the xenografts was observed with little or no evidence of mouse cell infiltration into the human leukocyte antigen-positive human tissue. An average twofold increase in polyp volume was found at 3 months after engraftment. The use of innate and adaptive immunodeficient NOD-scid mice homozygous for targeted mutations in the interleukin-2 receptor gamma-chain locus NOD-scid IL2rgamma(null) for establishing xenografts of nondisrupted pieces of human nasal polyp tissues represents a significant improvement over the previously reported xenograft model that used partially immunoincompetent CB17-scid mice as tissue recipients. The absence of the interleukin-2 receptor gamma-chain results in complete elimination of natural killer cell development, as well as severe impairments in T and B cell development. These mice, lacking both innate and adaptive immune responses, significantly improve upon the long-term engraftment of human nasal polyp tissues and provide a model with which to study how nasal polyp-associated lymphocytes and their secreted biologically active products contribute to the histopathology and progression of this chronic inflammatory disease.


[Neonatal Steinert's disease: apropos of 2 cases in 2 successive generations].
Description of a family who presents two cases of neonatal myotonic dystrophy (Steinert's disease) in two successive generations. The authors summarize the different genetic theories generally advanced; they sum up the antenatal means of diagnostic that is based on the knowledge of linkage of the loci for myotonic dystrophy and Lutheran blood group.


Optimization-based framework for inferring and testing hypothesized metabolic objective functions.
An optimization-based framework is introduced for testing whether experimental flux data are consistent with different hypothesized objective functions. Specifically, we examine whether the maximization of a weighted combination of fluxes can explain a set of observed experimental data. Coefficients of importance (CoIs) are identified that quantify the fraction of the additive contribution of a given flux to a fitness (objective) function with an optimization that can explain the experimental flux data. A high CoI value implies that the experimental flux data are consistent with the hypothesis that the corresponding flux is maximized by the network, whereas a low value implies the converse. This framework (i.e., ObjFind) is applied to both an aerobic and anaerobic set of Escherichia coli flux data derived from isotopomer analysis. Results reveal that the CoIs for both growth conditions are strikingly similar, even though the flux distributions for the two cases are quite different, which is consistent with the presence of a single metabolic objective driving the flux distributions in both cases. Interestingly, the CoI associated with a biomass production flux, complete with energy and reducing power requirements, assumes a value 9 and 15 times higher than the next largest coefficient for the aerobic and anaerobic cases, respectively.


[Vertebral artery dissection: peculiarities of clinical and magnetic resonance imaging manifestations].
The aim of this study was to analyze clinical and neuroimaging manifestations of vertebral artery (VA) dissection. Twenty seven patients (19 men, 8 women, mean age 34.1±6.1) with the VA dissection were enrolled. All the patients underwent MRA, neck MRI (T1 f-s, T2 f-s) and head MRI. Twenty six of 27 patients had follow-up MRA/MRT studies: during the acute period and after 2 months or later. Clinical manifestations of VA dissection included ischemic stroke (IS, 52%), transient ischemic attack (TIA, 4%) and isolated neck pain/headache (44%). Ninety two percent of patients in the group of patients with isolated pain and 53% in the group with brain ischemia were women. Bilateral dissection of VA was found in 10 of 27 patients (37%), concomitant internal carotid artery dissection -- in 2 patient (7,4%). In 93% of the patients, IS/TIA was associated with neck pain and/or headache. In 64% patients, the pain occurred after neck movements or mild head trauma. The pain preceded brain ischemia symptoms by a few days/2--3 weeks (80%) or appeared simultaneously with them (13%). Symptoms of brain ischemia developed abruptly (82%) usually in wakeful state (80%) during rotation/ bending of the head. Most patients (93%) had complete or good regress of neurological deficit. MRA/MRI revealed hemodynamically insignificant VA stenosis (92%), VA occlusion (5%), increasing of the external VA diameter (100%), dual lumen (8%) and small dissecting aneurysm (11%). In 4 of 6 stroke patients studied within the first week, the signs of arterial embolism were found. The follow up MRA/MRI showed the regress of all stenosis and recanalization of one of two occlusions. In patients with isolated pain, dissections occurred more often in the V1--V2 segments of VA (83%), while in patients with IS/TIA the dissections were mostly found in the V3--V4 segments (47%) (р<0.05). The patients with IS/TIA had more prominent VA stenosis and smaller external arterial diameters in comparison with patients with isolated pain. This suggests the subintimal localization of intramural hematoma (IMH) in the group of ischemic manifestation and subadventicial localization of IMH in patients with isolated head/neck pain. Clinical manifestations of VA dissection depend on the IMH localization. The main mechanism of brain ischemia appears to be an arterial embolism by clotted IMH fragments from the secondary intimal tear. It is suggested that in patients with isolated pain, the media may be weaker than in patients with brain ischemia that in turn promotes subadventicial IMH propagation.


Gadolinium enhanced magnetic resonance urography for upper urinary tract malignancy.
We retrospectively evaluated the accuracy of gadolinium enhanced magnetic resonance urography to detect upper urinary tract tumors. A total of 91 magnetic resonance urography studies for suspected upper tract malignancy were done in 70 males and 18 females with a mean age of 71.7 years. Breath hold coronal T2-weighted single shot fast spin-echo and breath-hold coronal 3-dimensional T1-weighted spoiled gradient-recalled echo images with fat suppression were obtained during the nephrographic and excretory phases after intravenous injection of gadolinium based contrast material. Two radiologists independently reviewed magnetic resonance images for a tumor by 4 regions (right/left and renal collecting system/ureter). Sensitivity, specificity and accuracy were calculated. A total of 35 urinary tract regions in 18 males and 7 females with a mean age of 70.4 years were confirmed to have an upper tract malignant tumor and 219 urinary tract regions were confirmed to be tumor-free. Sensitivity, specificity and accuracy to detect upper urinary tract malignancy were 74.3%, 96.8% and 93.7% for reviewer 1, and 62.9%, 96.3% and 91.7% for reviewer 2, respectively. When patients with a ureteral stent or nephrostomy tube were excluded from analysis, sensitivity, specificity and accuracy were 86.2%, 99.5% and 97.7% for reviewer 1, and 72.4%, 97.9% and 94.6% for reviewer 2, respectively. Gadolinium enhanced magnetic resonance urography is accurate to detect upper urinary tract malignant tumors.


Spatial expression of metallothionein, matrix metalloproteinase-1 and Ki-67 in human epidermal wounds treated with zinc and determined by quantitative immunohistochemistry: A randomised double-blind trial.
Reepithelialisation is fundamental to wound healing, but our current understanding largely relies on cellular and animal studies. The aim of the present randomised double-blind three-arm controlled trial was to correlate genuine epidermal wound healing with key proteins and topical zinc treatment in humans. Sixty wounds were produced using deroofed suction blisters in 30 healthy volunteers and randomised to topical zinc sulphate (n = 20), placebo (n = 20), or control (n = 20) treatment for 4 days. All wounds with perilesional skin were processed for automatic immunostaining of paraffin tissue sections with monoclonal antibodies against Ki-67, metallothionein (MT) and matrix metalloproteinase (MMP)-1. Protein expression was quantified by automated digital image analysis. Epidermal Ki-67 and MT labelling indices were increased in keratinocytes in the neoepidermis (∼1.1 mm) and at the wound edge (0.5 mm) compared to normal skin. Increased MMP-1 immunostaining was restricted to the neoepidermis. MT was robustly upregulated in the upper dermis of the wounds. Zinc treatment enhanced MMP-1 expression beneath the neoepidermis via paracrine mechanisms and MT under the neoepidermis and in the nonepithelialised wound bed via direct actions of zinc as indicated by the induction of MT2A mRNA but not MMP-1 mRNA in cultured normal human dermal fibroblasts by zinc sulphate. The present human study demonstrates that quantitative immunohistochemistry can identify proteins involved in reepithelialisation and actions of external compounds. Increased dermal MT expression may contribute to the anti-inflammatory activities of zinc and increased MMP-1 levels to promote keratinocyte migration.


(eta2-tetracyanoethene)bis(triphenylphosphine-kappaP)palladium-dichloromethane (1/0.7).
The title compound, [Pd(C(6)N(4))(C(18)H(15)P)(2)].0.7CH(2)Cl(2), shows a planar coordination geometry around the metal atom that is an almost perfect isosceles triangle if the tetracyanoethene (tcne) ligand is deemed to occupy a single coordination site. The framework of the tcne ligand shows small distortions due to intramolecular steric contacts between the C[triple-bond]N groups and phenyl rings of the triphenylphosphine ligands.


Neoadjuvant chemoradiotherapy for clinical stage II-III esophageal squamous cell carcinoma.
The clinical significance of neoadjuvant chemoradiotherapy (NACRT) for potentially resectable esophageal squamous cell carcinoma (ESCC) is unclear. Patients with clinical stage II-III ESCC were classified into an NACRT group (n=76) and surgery alone group (n=92). The prognosis and the incidence of postoperative complications were retrospectively investigated. The pathological response to NACRT and patient prognosis were also analyzed. The 5-year survival rate was 47.7% in the surgery alone group and 56.5% in the NACRT group (p=0.4831). The 5-year survival rates of patients in whom NACRT was markedly effective was clearly better than that of the other patients (ineffective/slightly effective: 36.9%, moderately effective: 53.8%, markedly effective: 100%). The incidence of postoperative complications was 31.5% in the surgery alone group and 40.8% in the NACRT group (p=0.2121). A pathological complete response to NACRT is critical for improving the survival of patients with clinical stageII-III ESCC.


New semi-biodegradable materials from semi-interpenetrated networks of poly(ϵ-caprolactone) and poly(ethyl acrylate).
Semi-degradable materials may have many applications. Here poly(ethyl acrylate) and poly(ϵ-caprolactone) were combined as semi-interpenetrated networks, and thoroughly characterized in terms of final composition, interactions between components, wettability, and mechanical properties. PCL modulates the mechanical properties of the PEA elastomeric network. Cultures of fibroblasts and adipose-tissue derived stem cells showed excellent biological performance of the materials. The results are relevant for applications seeking materials leaving a permanent supporting skeleton after the partial degradation, as in patches for cardiac regeneration or in abdominal wall meshes.


[Health technology assessment: experience in the Ministry of Health of Brazil].
This article aims to describe the main activities carried out by the Ministry of Health of Brazil (MHB) for the development of Health Technology Assessments (HTA). It is a description based on the MHB efforts and strategies to strengthen this area in the last years. Five are the lines of action put in place for that purpose: (i) adoption of a National Policy for the Management of Health Technology, (ii) supporting the decision making process in the Unified Health System, (iii ) promotion of the performance of studies on HTA, (iv) training of strategic human resources, and (v) institutional coordination at national and international levels. However, challenges remain to achieve a more effective structure for HTA in Brazil, like the creation of a government institution with greater administrative flexibility, among others.


T helper 1 and T helper 2 cytokines in atopic children with steroid-sensitive nephrotic syndrome.
A higher incidence of allergic disorders has been documented in children with steroid-sensitive nephrotic syndrome (SSNS); however, the role of cytokines associated with T helper 1 and T helper 2 cells is not fully elucidated. This study aimed to evaluate the role of T helper 1 and T helper 2 cytokines in both remission and activity phases among atopic versus nonatopic children with SSNS. Fifty-two children with SSNS (21 with atopic disorders and 31 nonatopics) and 60 healthy children were enrolled in the study. The healthy controls were comparable with the patients in terms of age and sex distribution. Serum levels of immunoglobulin E (IgE), interleukin (IL)-2, tumor necrosis factor (TNF)-α, IL-4, and IL-13 were measured in activity and remission phases of the disease and in controls. Serum levels of IgE, TNF-α, IL-4, and IL-13 were significantly increased in the children with SSNS during the active compared to remission phase and the controls. T helper 2 markers (IgE, IL-4, and IL-13) were also higher in the atopic patients with SSNS than those without atopy. No significant difference was observed in IL-2 levels between the SSNS children in activity and remission phases and the controls, or between atopic and nonatopic children with SSNS in activity and remission phases. Our findings suggested that type 2 immune response prevailed during the active stage in children with SSNS, atopic or not, with persistent elevation of IgE during remission. T helper 2 imbalance was markedly exaggerated in atopic children.


Deletion of a fur-like gene affects iron homeostasis and magnetosome formation in Magnetospirillum gryphiswaldense.
Magnetotactic bacteria synthesize specific organelles, the magnetosomes, which are membrane-enveloped crystals of the magnetic mineral magnetite (Fe(3)O(4)). The biomineralization of magnetite involves the uptake and intracellular accumulation of large amounts of iron. However, it is not clear how iron uptake and biomineralization are regulated and balanced with the biochemical iron requirement and intracellular homeostasis. In this study, we identified and analyzed a homologue of the ferric uptake regulator Fur in Magnetospirillum gryphiswaldense, which was able to complement a fur mutant of Escherichia coli. A fur deletion mutant of M. gryphiswaldense biomineralized fewer and slightly smaller magnetite crystals than did the wild type. Although the total cellular iron accumulation of the mutant was decreased due to reduced magnetite biomineralization, it exhibited an increased level of free intracellular iron, which was bound mostly to a ferritin-like metabolite that was found significantly increased in Mössbauer spectra of the mutant. Compared to that of the wild type, growth of the fur mutant was impaired in the presence of paraquat and under aerobic conditions. Using a Fur titration assay and proteomic analysis, we identified constituents of the Fur regulon. Whereas the expression of most known magnetosome genes was unaffected in the fur mutant, we identified 14 proteins whose expression was altered between the mutant and the wild type, including five proteins whose genes constitute putative iron uptake systems. Our data demonstrate that Fur is a regulator involved in global iron homeostasis, which also affects magnetite biomineralization, probably by balancing the competing demands for biochemical iron supply and magnetite biomineralization.


[The treatment of obliterating arterial diseases of the extremities by a revascularizing osteotrepanation method].
A new method to treat obliterative atherosclerosis and thromboangiitis is proposed. The method consists in local osteal trepanation of the ischemic extremity. The access to the bones was preferably performed in bioactive points. The operation called osteotrepanation was performed in 307 patients. 219 of them had obliterative atherosclerosis, 75--thromboangiitis obliterans, 13--Raynaud's disease. In 63% of patients there was 3d and 4th stage of extremity ischemia. In 90.5% of patients improvement was observed. After 1 year the improvement of blood circulation in the extremity was observed in 92.8% of patients, after 5 years--in 92,8% also. Revascularizing osteal trepanation is a method of choice in thromboangiitis obliterans and in impossibility to perform reconstructive surgery in case of grafts thrombosis.


Changes in authoritarianism before and during the COVID-19 pandemic: Comparisons of latent means across East and West Germany, gender, age, and education.
Modern theories of authoritarianism have stressed the importance of threat to the expression of authoritarian attitudes and intolerance. Arguably, authoritarian tendencies may have increased during COVID-19 pandemic, a major threat to life and security. One issue arising when comparing mean scores is that of measurement invariance. Meaningful comparisons are only possible, if latent constructs are similar between groups and/or across time. This prerequisite is rarely ever tested in research on authoritarianism. In this study, we aim to analyze the short scale for authoritarianism KSA-3 by investigating its measurement invariance on two levels (three first-order and one second-order factors) and latent mean changes using two German representative samples (N = 4,905). Specifically, we look at differences before and during the pandemic (2017 vs. 2020). While measurement invariance holds across both levels in all conditions, we find a decrease in latent means in 2020, contrary to expectations and established theories. Moreover, latent means differ with regard to gender, education, and east-west Germany. We conclude that analyses of latent means and measurement invariance instead of mean comparisons with composites should become the standard. Future studies should focus on threat as a moderator between authoritarianism and intolerance, and on possible interactions with context variables.


Risk stratification for the early diagnosis of borderline personality disorder using psychiatric co-morbidities.
To develop a risk stratification model for the early diagnosis of borderline personality disorder (BPD) using Taiwan National Health Insurance Research Database. We conducted a retrospective case-control study of 6132 patients (292 BPD patients and 5840 control subjects) who were selected from the National Health Insurance Research Database. Psychiatric co-morbidities including depressive disorder, bipolar disorder, anxiety disorder, substance-use disorder, personality disorders other than BPD, sleep disorder, eating disorder, autistic spectrum disorder, mental retardation and attention-deficit hyperactivity disorder, which were diagnosed within 3 years before enrolment, were collected. A logistic regression was used to calculate the odds ratio of psychiatric co-morbidities between subjects with and without BPD. The classification and regression tree method was used to generate a risk stratification model. The odds ratios for depressive disorder, bipolar disorder, anxiety disorder, substance-use disorder, personality disorders other than BPD, sleep disorder, eating disorder, mental retardation and attention-deficit hyperactivity disorder were greater for BPD patients than for the control subjects. Furthermore, the risk of BPD can be reliably estimated using age and psychiatric co-morbidities including bipolar disorder, substance-use disorder and depressive disorder. Most psychiatric disorders were more common in BPD patients than in the control subjects. Using psychiatric co-morbidities, we identified four variables as significant risk predictors of BPD and permitted identification of subjects with low, intermediate or high risk for BPD. The accuracy of the risk stratification model is high and can be easily applied in clinical practice.


Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study.
The histopathological features of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome remain poorly characterized. To better characterize the histopathological features of DRESS syndrome, and define the phenotype of the effector cells in the skin and compare it with maculopapular rash (MPR). We conducted a retrospective study on 50 skin biopsies from patients with DRESS syndrome (n = 36). Histopathological and immunophenotypical features were studied and compared with a series of MPRs (n = 20). Foci of interface dermatitis, involving cutaneous adnexae, were frequently seen in cases of DRESS. Eosinophils were seen in only 20% of cases and neutrophils in 42%. Eczematous (40%), interface dermatitis (74%), acute generalized exanthematic pustulosis-like (20%) and erythema multiforme-like (24%) patterns were observed. The association of two or three of these patterns in a single biopsy was significantly more frequent in cases of DRESS than in a series of nondrug-induced dermatoses (P < 0.01), and appeared to be more marked in DRESS syndrome with severe cutaneous lesions (P = 0.01) than in less severe cases of DRESS and MPR. A higher proportion of CD8(+) and granzyme B(+) lymphocytes was observed in cases of DRESS with severe cutaneous eruptions (erythroderma and/or bullae). Atypical lymphocytes were found in 28% of biopsies, and expressed CD8 in most cases; a cutaneous T-cell clone was rarely found (6%). The histopathology of DRESS syndrome highlights various associated inflammatory patterns in a single biopsy. Cutaneous effector lymphocytes comprise a high proportion of polyclonal CD8(+) granzyme B(+) T lymphocytes.


A critical analysis of barriers to the clinical implementation of pharmacogenomics.
Over recent decades, basic research has yielded a large volume of data on many potentially clinically relevant genetic determinants of drug efficacy and toxicity. Until recently, most examples involved genes encoding drug-metabolizing enzymes, particularly the cytochromes P450. More recently, rapid advances in genomic technologies have enabled broader, genome-wide searches for determinants of drug response. In parallel with these pharmacogenetic studies, a new drug discovery platform, termed pharmacogenomics, has emerged which utilises genetic information to guide the selection of new drugs most likely to survive increasingly demanding safety and efficacy assessments. Together, these advances are widely promoted as the basis of a new era of drug-based therapeutics tailored to the individual. The extent to which individualized or personalized medicine will emerge as a sustainable new therapeutic paradigm is, however, the topic of much debate. It is clear that an increasingly complex series of barriers must be overcome if we are to successfully harness genomic advances in the clinical setting. Potential barriers may include cost-effectiveness of the test, ethical concerns over the use of DNA, and required educational and equipment infrastructure. Although long overdue, many of these potential barriers are now being subjected to closer examination and as a result, a framework for successful clinical uptake of pharmacogenomics is emerging.


Pyramidal Cell-Interneuron Circuit Architecture and Dynamics in Hippocampal Networks.
Excitatory control of inhibitory neurons is poorly understood due to the difficulty of studying synaptic connectivity in vivo. We inferred such connectivity through analysis of spike timing and validated this inference using juxtacellular and optogenetic control of presynaptic spikes in behaving mice. We observed that neighboring CA1 neurons had stronger connections and that superficial pyramidal cells projected more to deep interneurons. Connection probability and strength were skewed, with a minority of highly connected hubs. Divergent presynaptic connections led to synchrony between interneurons. Synchrony of convergent presynaptic inputs boosted postsynaptic drive. Presynaptic firing frequency was read out by postsynaptic neurons through short-term depression and facilitation, with individual pyramidal cells and interneurons displaying a diversity of spike transmission filters. Additionally, spike transmission was strongly modulated by prior spike timing of the postsynaptic cell. These results bridge anatomical structure with physiological function.


Rapid and transient reorganization of the cytoskeleton in GH3B6 cells during short-term exposure to thyroliberin.
The cytoskeletal organization of the rat pituitary tumor cell line GH3B6 was analysed using immunofluorescence, in basal conditions and after stimulation by thyroliberin (TRH). Under basal conditions, a dense and entangled cytoplasmic microtubule network, a perinuclear cage of cytokeratin fibers, and a diffuse distribution of F-actin were revealed. Short-term stimulation of these cells by TRH induces a first early phase of PRL release (0-2 min), concomitant with a rarefaction of cytoplasmic PRL-containing granules, followed by a second plateau phase (5-30 min), concomitant with modifications of the Golgi zone. We show that TRH induced early and transient modifications in the cytoskeletal distribution during these short periods of stimulation. First, after 2 min of stimulation, small fluorescent tubulin blebs appeared under the plasma membrane. Then, after 5 min they disappeared, and a thin actin network, accentuated by thicker fibers, organized transiently in the cytoplasm. After 30 min, the microtubules and cytokeratin networks had extended throughout the cytoplasm and the actin distribution was diffuse again. So, in this study, we have shown the existence of a parallelism between the redistribution of intracellular PRL compartments and the reorganization of cytoskeletal elements, during exposure to TRH. We could not clearly correlate these modifications with transduction mechanisms involved in TRH action.


Natural outdoor environments and mental health: Stress as a possible mechanism.
Better mental health has been associated with exposure to natural outdoor environments (NOE). However, comprehensive studies including several indicators of exposure and outcomes, potential effect modifiers and mediators are scarce. We used novel, objective measures to explore the relationships between exposure to NOE (i.e. residential availability and contact) and different indicators of mental health, and possible modifiers and mediators. A nested cross-sectional study was conducted in: Barcelona, Spain; Stoke-on-Trent, United Kingdom; Doetinchem, Netherlands; Kaunas, Lithuania. Participants' exposure to NOE (including both surrounding greenness and green and/or blue spaces) was measured in terms of (a) amount in their residential environment (using Geographical Information Systems) and (b) their contact with NOE (using smartphone data collected over seven days). Self-reported information was collected for mental health (psychological wellbeing, sleep quality, vitality, and somatisation), and potential effect modifiers (gender, age, education level, and city) and mediators (perceived stress and social contacts), with additional objective NOE physical activity (potential mediator) derived from smartphone accelerometers. Analysis of data from 406 participants showed no statistically significant associations linking mental health and residential NOE exposure. However, NOE contact, especially surrounding greenness, was statistically significantly tied to better mental health. There were indications that these relationships were stronger for males, younger people, low-medium educated, and Doetinchem residents. Perceived stress was a mediator of most associations, and physical activity and social contacts were not. Our findings indicate that contact with NOE benefits mental health. Our results also suggest that having contact with NOE that can facilitate stress reduction could be particularly beneficial.


Enhancement of dissolution rate and oral bioavailability of poorly soluble drug florfenicol by using solid dispersion and effervescent disintegration technology.
ObjectiveFlorfenicol(FF) is an excellent veterinary antibiotic, limited by poor solubility and poor bioavailability. Here in, we aimed to explore the applicability of fast disintegrating tablets compressed from Florfenicol-loaded solid dispersions (FF-SD-FDTs) to improve the dissolution rate and oral bioavailability of Florfenicol. Utilizing selecting appropriate preparation methods and carriers, the solid dispersions of Florfenicol (FF-SDs) were prepared by solvent evaporation and the fast disintegrating tablets (FF-SD-FDTs) were prepared by the direct compression (DC) method. The tablet properties including hardness, friability, disintegration time, weight variation, etc. all met the specifications of Chinese Veterinary Pharmacopoeia(CVP). FF-SD-FDTs significantly improved drug dissolution and dispersion of FF in vitro compared to florfenicol conventional tablets (FF-CTs). A pharmacokinetics study in German shepherd dogs proved the AUC0-∞ and Cmax values of FF-SD-FDTs are 1.38 and 1.38 times more than FF-CTs, respectively. Overall, it can be concluded that FF-SD-FDTs with excellent disintegration and dissolution properties were successfully produced, which greatly improved the oral bioavailability of the poorly soluble drug FF, and the study provided a new idea for a broader role of FF in pet clinics.


Rice fields along the East Asian-Australasian flyway are important habitats for an inland wader's migration.
To maintain and recover populations of migratory waders, we must identify the important stopover sites and habitat use along migration routes. However, we have little such information for waders that depend on inland freshwater areas compared with those that depend on coastal areas. Recent technological developments in tracking devices now allow us to define habitat use at a fine scale. In this study, we used GPS loggers to track both spring and autumn migration along the East Asian-Australasian flyway of the little ringed plover (Charadrius dubius) as birds moved to and from their breeding grounds, gravel riverbeds in Japan. The birds we tracked overwintered in the Philippines and made stopovers mainly in Taiwan and the Philippines. The most important habitat during the non-breeding season was rice paddy fields. Our findings imply that changes in agriculture management policy in the countries along the migration route could critically affect the migration of waders that depend on rice paddy fields. To maintain populations of migrant inland waders that move within the East Asian-Australasian flyway, it is necessary not only to sustain the breeding habitat but also wetlands including the rice paddy fields as foraging habitat for the non-breeding season.


Cardiac arrest after interscalene brachial plexus block with ropivacaine and lidocaine.
Serious adverse reactions to ropivacaine and lidocaine are rare. In this report, we describe a case of sudden cardiac arrest after an interscalene brachial plexus block with a mixture of 150 mg of ropivacaine and 360 mg of lidocaine in a previously healthy, 34-year-old, 97-kg man. Severe hypotension occurred after successful resuscitation, necessitating an infusion of epinephrine. The patient developed pulmonary oedema, and was mechanically ventilated for 22 h. He eventually made a good recovery. We conclude that although ropivacaine and lidocaine are often considered relatively safe local anesthetics, serious cardiovascular complications can occur after the use of these drugs.


The evaluation of small-vessel flow; a study of dynamic non-invasive techniques.
A series of thirty-three patients with a variety of vascular problems in the hands were studied by one or more of four dynamic non-invasive techniques. Such non-invasive techniques can be used for diagnostic studies as well as operative and postoperative monitoring. The techniques, which are safe, reliable, and easily interpreted at the bedside, offer methods by which monitoring of flow can be done repeatedly and provide reliable and painless means to identify cases of thrombosis in which early operation may be vital to save a hand or finger.


Food insecurity is associated with social capital, perceived personal disparity, and partnership status among older and senior adults in a largely rural area of central Texas.
This study examined the association of compositional measures of collective social functioning, composed of community and familial social capital and perceived personal disparity, with food security among older (aged 50-59 y) and senior (aged ≥ 60 y) adult residents of the largely rural Brazos Valley in Central Texas using data from the 2006 Brazos Valley Community Health Assessment (analytic N = 1059, 74% response rate). Among older adults and seniors, 18.6% reported food insecurity (5.5% often and 13.1% sometimes), defined as running out of food and not having money to buy more. Low community social capital was reported by 22.4% of participants, and 30.8% indicated they were single, widowed, or divorced, an indicator of limited familial social capital. A robust multinomial regression model found the odds of reporting greater food insecurity increased for individuals who were women, African American, residents of a household with a low or poverty-level income, individuals who perceived themselves to be worse off than others within their community, and those who had low social capital. The odds of being food insecure decreased for older respondents, partnered respondents and persons with more education (pseudo r(2) = 0.27, p < 0.0000). Compositional level measures of collective social functioning are important associates of food insecurity among older adults and seniors, regardless of severity.


Highly precise and developmentally programmed genome assembly in Paramecium requires ligase IV-dependent end joining.
During the sexual cycle of the ciliate Paramecium, assembly of the somatic genome includes the precise excision of tens of thousands of short, non-coding germline sequences (Internal Eliminated Sequences or IESs), each one flanked by two TA dinucleotides. It has been reported previously that these genome rearrangements are initiated by the introduction of developmentally programmed DNA double-strand breaks (DSBs), which depend on the domesticated transposase PiggyMac. These DSBs all exhibit a characteristic geometry, with 4-base 5' overhangs centered on the conserved TA, and may readily align and undergo ligation with minimal processing. However, the molecular steps and actors involved in the final and precise assembly of somatic genes have remained unknown. We demonstrate here that Ligase IV and Xrcc4p, core components of the non-homologous end-joining pathway (NHEJ), are required both for the repair of IES excision sites and for the circularization of excised IESs. The transcription of LIG4 and XRCC4 is induced early during the sexual cycle and a Lig4p-GFP fusion protein accumulates in the developing somatic nucleus by the time IES excision takes place. RNAi-mediated silencing of either gene results in the persistence of free broken DNA ends, apparently protected against extensive resection. At the nucleotide level, controlled removal of the 5'-terminal nucleotide occurs normally in LIG4-silenced cells, while nucleotide addition to the 3' ends of the breaks is blocked, together with the final joining step, indicative of a coupling between NHEJ polymerase and ligase activities. Taken together, our data indicate that IES excision is a "cut-and-close" mechanism, which involves the introduction of initiating double-strand cleavages at both ends of each IES, followed by DSB repair via highly precise end joining. This work broadens our current view on how the cellular NHEJ pathway has cooperated with domesticated transposases for the emergence of new mechanisms involved in genome dynamics.


Predictors of quality of life at 1 month after implantation of a left ventricular assist device.
To describe quality-of-life outcomes; determine relationships between quality of life and demographic, physical, psychosocial, and clinical variables; and identify predictors of quality of life at 1 month after implantation of a left ventricular assist device. Patients who received either an implantable pneumatic (n = 38) or a vented electric (n = 54) left ventricular assist device as a bridge to heart transplantation between August 1, 1994, and August 31, 1999, completed 6 instruments used to measure quality of life andfactors related to quality of life. Data were analyzed by using descriptive statistics, Pearson correlations, Mann-Whitney U tests, and forward, stepwise multiple regression. Overall satisfaction with quality of life was quite high as determined from the total score on the Quality of Life Index (mean = 0.69). Patients were very satisfied with the implantation and thought that they would do well after future heart transplant surgery. Patients had a moderate level of stress. Significant predictors of overall quality of life were psychological symptoms, stress, and race; these accounted for 46% of variance in quality of life. Patients were satisfied with their quality of life at 1 month after implantation of a left ventricular assist device. However, they were least satisfied with their health and functioning and yet were optimistic about how well they thought they would do after heart transplantation. Psychological factors were the strongest predictors of satisfaction with overall quality of life.


Membrane protein organization of peripheral blood lymphocytes from healthy young and aged adults.
Membrane-mediated events are important in the function of lymphocytes and age-dependent changes in the integrity of lymphocytic membranes could account, in part, for the loss of immune responsiveness observed in the aged. To test the hypothesis that membranes of lymphocytes undergo age-dependent change in their biophysical parameters, a method utilizing electron spin resonance spectroscopy was developed as a means to assess the dynamic character of lymphocytic membrane protein organization. This methodology allowed identification of weakly (W) and strongly (S) immobilized membrane proteins. By taking the ratio of these two protein classes (W/S ratio), lymphocytes from elderly were found to have a slightly increased W/S ratio when compared to young adults, but this difference was not statistically significant. This study contrasts with previous reports which indicated that the lipid microenvironment of lymphocytes undergoes age-dependent change. Thus, despite previously reported age-related changes in the biophysical parameters of lipids in resting lymphocytes, this alteration does not appear to affect the dynamic character of membrane-bound proteins.


A roadmap for optimizing chronic kidney disease patient care and patient-oriented research in the Eastern European nephrology community.
Chronic kidney disease (CKD) is a major health problem because of its high prevalence, associated complications and high treatment costs. Several aspects of CKD differ significantly in the Eastern European nephrology community compared with Western Europe because of different geographic, socio-economic, infrastructure, cultural and educational features. The two most frequent aetiologies of CKD, DM and hypertension, and many other predisposing factors, are more frequent in the Eastern region, resulting in more prevalent CKD Stages 3-5. Interventions may minimize the potential drawbacks of the high prevalence of CKD in Eastern Europe, which include several options at various stages of the disease, such as raising public, medical personnel and healthcare authorities awareness; early detection by screening high-risk populations; preventing progression and CKD-related complications by training health professionals and patients; promoting transplantation or home dialysis as the preferred modality; disseminating and implementing guidelines and guided therapy and encouraging/supporting country-specific observational research as well as international collaborative projects. Specific ways to significantly impact CKD-related problems in every region of Europe through education, science and networking are collaboration with non-nephrology European societies who have a common interest in CKD and its associated complications, representation through an advisory role within nephrology via national nephrology societies, contributing to the training of local nephrologists and stimulating patient-oriented research. The latter is mandatory to identify country-specific kidney disease-related priorities. Active involvement of patients in this research via collaboration with the European Kidney Patient Federation or national patient federations is imperative to ensure that projects reflect specific patient needs.


Diversity and antimicrobial activities of actinobacteria isolated from tropical mangrove sediments in Malaysia.
The aim of this study was to isolate and identify Actinobacteria from Malaysia mangrove forest and screen them for production of antimicrobial secondary metabolites. Eighty-seven isolates were isolated from soil samples collected at 4 different sites. This is the first report to describe the isolation of Streptomyces, Mycobacterium, Leifsonia, Microbacterium, Sinomonas, Nocardia, Terrabacter, Streptacidiphilus, Micromonospora, Gordonia, and Nocardioides from mangrove in east coast of Malaysia. Of 87 isolates, at least 5 isolates are considered as putative novel taxa. Nine Streptomyces sp. isolates were producing potent antimicrobial secondary metabolites, indicating that Streptomyces isolates are providing high quality metabolites for drug discovery purposes. The discovery of a novel species, Streptomyces pluripotens sp. nov. MUSC 135(T) that produced potent secondary metabolites inhibiting the growth of MRSA, had provided promising metabolites for drug discovery research. The biosynthetic potential of 87 isolates was investigated by the detection of polyketide synthetase (PKS) and nonribosomal polyketide synthetase (NRPS) genes, the hallmarks of secondary metabolites production. Results showed that many isolates were positive for PKS-I (19.5%), PKS-II (42.5%), and NRPS (5.7%) genes, indicating that mangrove Actinobacteria have significant biosynthetic potential. Our results highlighted that mangrove environment represented a rich reservoir for isolation of Actinobacteria, which are potential sources for discovery of antimicrobial secondary metabolites.


First identification of microcystins in Irish lakes aided by a new derivatisation procedure for electrospray mass spectrometric analysis.
Recent animal and bird deaths at several lakes in Ireland were indicative of possible cyanobacterial poisoning. Using protein phosphatase inhibition assays, microcystins (MCs) were identified in extracts of cyanobacteria from several lakes at concentrations ranging from 1.6 to 168 micrograms/g. This is the first report of MCs in Irish freshwaters. The protein phosphatase inhibition assay was used to screen fractions during HPLC purification of the MCs in cyanobacteria (Anabaena and Oscillatoria) and water samples from Corbally and Caragh Lakes. MC-LR, MC-HtyR, MC-FR, and MC-YR and 3 unidentified MCs of m/z values 1028.5, 981, 1042.7 were isolated from the Corbally sample; while the Caragh Lake sample contained largely MC-LR and MC-YR. A new microanalytical technique was developed for the confirmation of MCs which involved the derivatisation of the methyldehydroalanine group of MCs with 2-aminoethanethiol. Electrospray mass spectrometry of these products showed characteristic double-charged ions, and this novel technique was useful for differentiating MCs from co-eluting impurities in HPLC fractions of cyanobacterial extracts.


Study Smarter: Applying the Science of Learning to Radiology.
Lifelong learning is critical to a successful career in radiology, but many learners use inefficient or ineffective studying strategies developed from personal experience. Decades of cognitive psychology research have identified several techniques that consistently improve knowledge consolidation and retrieval. To improve their knowledge and ultimately patient care, radiologists should strive to understand and adopt these learning techniques. The first part of this article reviews several evidence-based learning principles, including active retrieval and the testing effect, spaced repetition, interleaving, deliberate practice, and growth mind-set. The second part provides practical suggestions on how to incorporate these principles into radiology learning, both during training and beyond.


Is the use of oral creatine supplementation safe?
This review focuses on the potential side effects caused by oral creatine supplementation on gastrointestinal, cardiovascular, musculoskeletal, renal and liver functions. No strong evidence linking creatine supplementation to deterioration of these functions has been found. In fact, most reports on side effects, such as muscle cramping, gastrointestinal symptoms, changes in renal and hepatic laboratory values, remain anecdotal because the case studies do not represent well-controlled trials, so no causal relationship between creatine supplementation and these side-effects has yet been established. The only documented side effect is an increase in body mass. Furthermore, a possibly unexpected outcome related to creatine monohydrate ingestion is the amount of contaminants present that may be generated during the industrial production. Recently, controlled studies made to integrate the existing knowledge based on anecdotal reports on the side effects of creatine have indicated that, in healthy subjects, oral supplementation with creatine, even with long-term dosage, may be considered an effective and safe ergogenic aid. However, athletes should be educated as to proper dosing or to take creatine under medical supervision.


Visualization of peroxynitrite/GSH cross-talk in the oxidant-antioxidant balance by a dual-fluorophore and dual-site based mito-specific fluorescent probe.
Peroxynitrite (ONOO-) and glutathione (GSH) play mutually regulating roles in the oxidant-antioxidant balance of organisms, which has a profound relationship with people's health and disease. In this study, we designed a two-photon fluorescent probe CD-NA that could simultaneously detect ONOO- and GSH via dual-fluorophore and dual-site properties. CD-NA shows different fluorescence responses to ONOO- (annihilated red fluorescence) and GSH (enhanced green emission) with high specificity and sensitivity. Notably, the response of CD-NA to ONOO- was unaffected by GSH, and the reverse is also true. It allows the ONOO-/GSH cross-talk to be successfully imaged. Given these excellent properties, CD-NA has been favorably employed in detecting ONOO- and GSH in living cells with the ability to target mitochondria. Therefore, CD-NA offers an efficient method for understanding the oxidant-antioxidant balance and interrelated physiological functions of ONOO- and GSH in living systems, and provides a new strategy to sort out the complex relationships and roles of various analytes in complex physiological processes.


Collagen I Induces Preeclampsia-Like Symptoms by Suppressing Proliferation and Invasion of Trophoblasts.
Preeclampsia is a common obstetric disorder affecting 2-8% of pregnancy worldwide. Fibrosis is an important histological change occurring in preeclamptic placenta, and might depend on the excess deposition of collagen I. However, the role of fibrotic placenta and collagen I in the pathogenesis of preeclampsia remains unclear. Therefore, we analyzed the collagen deposition and the expression of Collagen I in human placenta by Masson staining, Sirius red staining and western blotting. Further, the role of collagen I in preeclampsia pathogenesis was studied in C57BL/6 mice. HTR-8/SVneo cells were used to investigate the mechanisms underlying the effects of collagen I in trophoblasts by transcriptome sequencing and pharmacological agonists. Human preeclamptic placenta exhibited a significantly higher degree of fibrosis in stem villi and terminal villi than normal placenta, and was characterized by collagen I deposition. In vivo, a single injection of collagen I on gestational day 0.5 led to an increase in systolic pressure of pregnant mice from gestational days 4.5-17.5, to a decrease in weight and number of embryos, and to enhanced placental collagen I expression and degree of fibrosis compared with control mice. In vitro, collagen I attenuated the proliferation and invasion of HTR-8SV/neo cells. This effect could be reversed by treatment with agonists of ERK and β-catenin. Moreover, transcriptome sequencing demonstrated that signaling pathways related to cell proliferation and invasion were significantly downregulated in HTR-8SV/neo cells. Thus, we propose that collagen I induced preeclampsia-like symptoms by suppressing the proliferation and invasion of trophoblasts through inhibition of the ERK phosphorylation and WNT/β-catenin signaling pathways. Our findings could pave the way to the discovery of small-molecule inhibitors for preeclampsia treatment and future studies with larger sample size are required.


Increased level of platelet P-selectin in nonarteritic anterior ischemic optic neuropathy.
P-selectin receptor is expressed in platelets and endothelial cells in a cell-activation-dependent manner. Platelet P-selectin (CD62) levels may become elevated in a number of vasoocclusive diseases, including arteriosclerosis, atherothrombosis, and diabetes mellitus (DM). Nonarteritic anterior ischemic optic neuropathy (NAION) is associated with a sudden loss of vision due to the vascular insufficiency of ciliary arteries supplying the optic nerve. In this study, our aim was to investigate the presence of increased platelet reactivity in the development of NAION. Twenty-one NAION patients, 39 healthy control subjects, and 44 patients suffering from diabetes mellitus (DM) were examined in our case-control, pilot study. Platelet activation was investigated by flow cytometric analysis of the mean fluorescence intensity (MFI) of CD62 on platelets. These results were compared among the different study groups. NAION patients showed considerably although not significantly (p = 0.2017) higher P-selectin MFI values (71.98 ± 40.30) versus healthy subjects (55.48 ± 20.95), insulin-dependent DM patients (50.02 ± 13.08), and non-insulin-dependent DM subjects (54.72 ± 24.74). However, logistic regression analysis resulted in a statistically significant adjusted effect on the odds of NAION when CD62 MFI values were logarithmically transformed (OR: 3.86, 95 % CI: 1.10 to 13.53, p = 0.0346). Elevated platelet CD62 positivity may be related to NAION, suggesting a possible role of enlarged platelet activity in the generation of this type of ischemic optic neuropathy.


Distribution of developmental markers in rat mammary tumors induced by N-nitrosomethylurea.
We have examined the distribution of immunological markers in 55 intraductal carcinomas induced in rats by N-nitrosomethylurea using several different regimens of carcinogen treatment. The goal was to determine the possible relationship of the marker distribution to those existing at various stages of development of the mammary gland. We have also examined two passage lines in syngeneic rats derived from two of the tumors. The distribution of markers was not affected by the regimen of administration. The primary tumors were found to maintain the general topography of mammary ducts but with infoldings of the basal layer without accompanying stroma. We attribute this to an abnormal expression of the tendency of basal cells to migrate towards the lumen to generate luminal cells. The distribution of markers in the tumors was evaluated by identifying 13 special features of distribution that are common in tumors, using all-or-none criteria. The distribution of these features bears out the high heterogeneity of tumors in which the various features vary in a seemingly independent way. There is also heterogeneity within tumors, adjacent nodes often having different marker distributions. The distribution of the markers is related to that found in the early stages of mammary development. Because of this characteristic and of the fact that the tumors contain both basal and luminal cells, they must originate from multipotent cells, probably the stem cells present in end buds and ducts as already proposed by other work. As they develop, the tumors can both differentiate towards the adult type and dedifferentiate towards a fetal type. Of the two transplanted lines one retained the same general features of primary tumors in several passages, whereas the other evolved into a fusiform cell type with a marker distribution not seen at any stage of mammary development. Foci of similar cells were already present in the primary tumor, suggesting that the tendency to progress was already determined at an early stage. The fusiform cells are similar and probably equivalent to the fusiform cells that arise in vitro in cultures of rat mammary cancers.


Random regression analyses to model the longitudinal measurements of yolk proportions in the laying chicken.
Cubic spline function was used in a genetic evaluation to model the change of yolk proportion over the lay life. A total of 19,862 yolk proportion records of 2,324 hens was used. The evaluated submodels consisted of 3 to 6 knot models. The same knots were fitted for genetic and permanent environmental splines. The residual effects were specified to be independently and normally distributed, but with heterogeneous variance for each test week. (Co)variance components were estimated by the average information restricted maximum likelihood (AIREML) method. The best fitting random regression model (RRM) was a submodel with 4 knots at 32, 36, 52, and 72 wk of age for genetic and permanent environmental effects. The estimate of genetic variance was larger than that of permanent environmental variance at the same time point. The heritability of yolk proportion ranged from 0.32 to 0.55, and the repeatability ranged between 0.45 and 0.73. The genetic correlations between test wk were from moderate to unity. To the best of our knowledge, this was the first report on the use of a RRM to evaluate yolk proportion. The results of this study showed that random regression models with the spline function could be used for improvement of yolk proportion.


Marked mydriasis and neuritis nervi optici associated with galactorrhea following citalopram treatment: a case report and discussion.
We report the case of a 25-year-old women suffering from major depression who was treated with citalopram for several weeks with doses between 20 mg and 60 mg. She gradually developed marked mydriasis within 2 months after treatment and subsequently neuritis nervi optici. Moreover, abrupt galactorrhea occurred after 2 months of treatment. All neuro-ophthalmological, neurophysiological, clinical laboratory, and neuroradiological diagnostic efforts did not reveal an underlying organic pathophysiology. The ocular symptoms disappeared rapidly after the discontinuation of citalopram and pulse therapy with methyl-prednisolone. However, galactorrhea persisted for a few weeks necessitating treatment with bromocriptine.


The underestimation of a glass injury to the hand.
This study sought to ascertain the differences between what is found on an orthopedic preoperative examination of a glass injury to the hand and the actual intraoperative deficiencies noted in the operating room. The cases of 34 patients who presented to our institution for a shattered glass laceration to the hand, forearm, or wrist between 1998 and 2001 were reviewed. The preoperative examination significantly underestimated the amount of damage to tendons, arteries and nerves. The most frequent injury pattern was the flexor digitorum superficialis (34/103 = 33%), the radial artery (7/18 = 39%), and the superficial branch of the radial nerve (7/32 = 22%). A glass injury to the hand can be a deceivingly debilitating and significant injury. The preoperative examination, even when specifically evaluating for deficiencies, significantly underestimates the extent of damage. If glass is implicated as a causative agent, careful orthopedic evaluation and surgical management should be considered even in light of a normal preoperative examination.


The interaction between ribonuclease A and surfactants.
1. U.v. difference spectra show that the anionic surfactant sodium n-dodecyl sulphate unfolds ribonuclease A at pH7.3 and 10.3, but that the cationic surfactant n-dodecyltrimethylammonium bromide does not affect the conformation of the enzyme. 2. Equilibrium-dialysis experiments show that sodium n-dodecyl sulphate binds to ribonuclease A, but no binding of n-dodecyltrimethylammonium bromide could be detected at pH7.3. 3. The enzymic activity of ribonuclease A is unaffected by n-dodecyltrimethylammonium bromide up to a concentration of 0.03m at 25 degrees C. 4. Ultracentrifuge studies support the conclusion that n-dodecyltrimethylammonium bromide does not interact significantly with ribonuclease A. 5. The enthalpy change as measured by microcalorimetry on binding of sodium n-dodecyl sulphate to ribonuclease A is consistent with an exothermic enthalpy of binding occurring simultaneously with an endothermic enthalpy of chain unfolding.


The eta7/csn3-3 auxin response mutant of Arabidopsis defines a novel function for the CSN3 subunit of the COP9 signalosome.
The COP9 signalosome (CSN) is an eight subunit protein complex conserved in all higher eukaryotes. In Arabidopsis thaliana, the CSN regulates auxin response by removing the ubiquitin-like protein NEDD8/RUB1 from the CUL1 subunit of the SCF(TIR1/AFB) ubiquitin-ligase (deneddylation). Previously described null mutations in any CSN subunit result in the pleiotropic cop/det/fus phenotype and cause seedling lethality, hampering the study of CSN functions in plant development. In a genetic screen to identify enhancers of the auxin response defects conferred by the tir1-1 mutation, we identified a viable csn mutant of subunit 3 (CSN3), designated eta7/csn3-3. In addition to enhancing tir1-1 mutant phenotypes, the csn3-3 mutation alone confers several phenotypes indicative of impaired auxin signaling including auxin resistant root growth and diminished auxin responsive gene expression. Unexpectedly however, csn3-3 plants are not defective in either the CSN-mediated deneddylation of CUL1 or in SCF(TIR1)-mediated degradation of Aux/IAA proteins. These findings suggest that csn3-3 is an atypical csn mutant that defines a novel CSN or CSN3-specific function. Consistent with this possibility, we observe dramatic differences in double mutant interactions between csn3-3 and other auxin signaling mutants compared to another weak csn mutant, csn1-10. Lastly, unlike other csn mutants, assembly of the CSN holocomplex is unaffected in csn3-3 plants. However, we detected a small CSN3-containing protein complex that is altered in csn3-3 plants. We hypothesize that in addition to its role in the CSN as a cullin deneddylase, CSN3 functions in a distinct protein complex that is required for proper auxin signaling.


A Comparison of Traditional and Novel Definitions (RIFLE, AKIN, and KDIGO) of Acute Kidney Injury for the Prediction of Outcomes in Acute Decompensated Heart Failure.
To determine if newer criteria for diagnosing and staging acute kidney injury (AKI) during heart failure (HF) admission are more predictive of clinical outcomes at 30 days and 1 year than the traditional worsening renal function (WRF) definition. We analyzed prospectively collected clinical data on 637 HF admissions with 30-day and 1-year follow-up. The incidence, stages, and outcomes of AKI were determined using the following four definitions: KDIGO, RIFLE, AKIN, and WRF (serum creatinine rise ≥0.3 mg/dl). Receiver operating curves were used to compare the predictive ability of each AKI definition for the occurrence of adverse outcomes (death, rehospitalization, dialysis). AKI by any definition occurred in 38.3% (244/637) of cases and was associated with an increased incidence of 30-day (32.3 vs. 6.9%, χ(2) = 70.1; p < 0.001) and 1-year adverse outcomes (67.5 vs. 31.0%, χ(2) = 81.4; p < 0.001). Most importantly, there was a stepwise increase in primary outcome with increasing stages of AKI severity using RIFLE, KDIGO, or AKIN (p < 0.001). In direct comparison, there were only small differences in predictive abilities between RIFLE and KDIGO and WRF concerning clinical outcomes at 30 days (AUC 0.76 and 0.74 vs. 0.72, χ(2) = 5.6; p = 0.02) as well as for KDIGO and WRF at 1 year (AUC 0.67 vs. 0.65, χ(2) = 4.8; p = 0.03). During admission for HF, the benefits of using newer AKI classification systems (RIFLE, AKIN, KDIGO) lie with the ability to identify those patients with more severe degrees of AKI who will go on to experience adverse events at 30 days and 1 year. The differences in terms of predictive abilities were only marginal.


The efficacy of noninvasive mechanical ventilation on nocturnal hypoxaemia in Duchenne's muscular dystrophy.
The aim of this 2 yr follow-up study was to evaluate the efficacy of nocturnal noninvasive mechanical ventilation in a group of 10 Duchenne's muscular dystrophy (DMD) patients who desaturated during the night but had normal daytime blood gases: mean (range) age 18.3 (15-22) yrs; mean (SD) vital capacity (VC) 752.5 (460-1,308) mL; mean time in bed (TIB) with arterial oxygen saturation (Sa,O2) < 90% 22.8% of total TIB (range: 16.6-32.0); mean arterial oxygen tension (Pa,O2) 10.3 (9.3-11.7) kPa (78 (70.0-87.8) mmHg); mean arterial carbon dioxide tension (Pa,CO2) 5.9 (4.8-6.5) kPa (44.3 (36.3-48.5) mmHg). All the patients were noninvasively ventilated during the night with a bilevel positive pressure ventilation (BiPAP) devise in spontaneous mode in order to correct the episodes of nocturnal desaturation. Nocturnal Sa,O2 values normalized during nocturnal noninvasive mechanical ventilation, and daytime sleep-disordered breathing disappeared, for the entire study period. No statistically significant differences were observed between baseline and follow-up daytime blood gas values, although a slight increase in Pa,O2 was found. During the follow-up, VC declined at a rate of 79.1 +/- 25 mL.yr-1, less than that generally reported in the past in untreated patients in the same age range. In conclusion, our data suggest that patients with advanced Duchenne's muscular dystrophy with pronounced nocturnal desaturation, not fulfilling criteria for imperative ventilation, could be successfully treated with "elective" nocturnal ventilation with immediate benefits consequent to the correction of the nocturnal blood gas anomalies and with long-term benefits related to the preservation of residual respiratory function, delay of development of chronic hypercapnia and thus the requirement for imperative mechanical ventilation.


Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing.
Chronic inflammatory diseases, such as periodontal disease, associate with adverse wound healing in response to myocardial infarction (MI). The goal of this study was to elucidate the molecular basis for impaired cardiac wound healing in the setting of periodontal-induced chronic inflammation. Causal network analysis of 168 inflammatory and extracellular matrix genes revealed that chronic inflammation induced by a subseptic dose of Porphyromonas gingivalis lipopolysaccharide (LPS) exacerbated infarct expression of the proinflammatory cytokine Ccl12. Ccl12 prevented initiation of the reparative response by prolonging inflammation and inhibiting fibroblast conversion to myofibroblasts, resulting in diminished scar formation. Macrophage secretion of Ccl12 directly impaired fibronectin and collagen deposition and indirectly stimulated collagen degradation through upregulation of matrix metalloproteinase-2. In post-MI patients, circulating LPS levels strongly associated with the Ccl12 homologue monocyte chemotactic protein 1 (MCP-1). Patients with LPS levels ≥ 1 endotoxin units (EU)/ml (subseptic endotoxemia) at the time of hospitalization had increased end diastolic and systolic dimensions compared with post-MI patients with < 1 EU/ml, indicating that low yet pathological concentrations of circulating LPS adversely impact post-MI left ventricle (LV) remodeling by increasing MCP-1. Our study provides the first evidence to our knowledge that chronic inflammation inhibits reparative fibroblast activation and generates an unfavorable cardiac-healing environment through Ccl12-dependent mechanisms.


A Japanese computer-assisted facial identification system successfully identifies non-Japanese faces.
The method developed by Yoshino et al. in [Forensic Sci. Int. 109 (2000) 225 and Jpn. J. Sci. Tech. Iden. 5 (2000) 9] and already being applied in Japan utilizes a three-dimensional (3D) physiognomic rangefinder combined with a computer-assisted superimposition system. Facial outlines can be compared between two-dimensional (2D) surveillance images and data extracted from 3D images obtained from the rangefinder. Also, the loci of potentially concordant features can be compared and differences measured. The method is largely objective and gives statistics for false positive/false negative findings. This recently developed method by Yoshino et al. is currently being introduced to the Japanese courts. To enable courts outside Japan to assess the admissibility of this new method, studies of non-Japanese faces have been undertaken and shown to produce similar low error rates. The present authors, therefore, consider the Yoshino method to be applicable in a non-Japanese context. As part of this study a comparison of morphological features between two ethnic groups has been undertaken using 3D measurements for the first time and will serve as the foundation for an anthropological database in the future.


CD8+ T cell responses following replication-defective adenovirus serotype 5 immunization are dependent on CD11c+ dendritic cells but show redundancy in their requirement of TLR and nucleotide-binding oligomerization domain-like receptor signaling.
Replication-defective adenovirus serotype 5 (rAd5) is the most potent recombinant vector for eliciting CD8 T cell responses in humans. In this study, the innate mechanisms that influence T cell responses following rAd5 immunization were assessed in mice. Using rAd5 expressing enhanced GFP (eGFP-rAd5), we show that rAd5 transfects CD11c(+) dendritic cells (DCs) in draining lymph nodes in vivo following s.c. or i.m. immunization. Among distinct DC subsets, eGFP expression was highest in CD11c(+)CD8(-)B220(-) with a lower frequency detected in CD11c(+)CD8(+)B220(-) and CD11c(+)B220(+) plasmacytoid DCs. CD11c(+) DCs but not CD11c(-) cells from mice immunized with rAd5 encoding the SIINFEKL peptide induced proliferation of naive OT-I CD8 T cells. Furthermore, CD11c(+)CD8(+)B220(-) was the most potent DC subset for eliciting naive OT-I CD8 T cell proliferation. Of note, mice with pre-existing immunity to rAd5 had a substantial decrease in eGFP expression in DCs, which was associated with approximately 2-fold decrease in Th1 and complete inhibition of CD8 responses. Thus, pre-existing rAd5 immunity has a greater influence on CD8 compared with CD4 T cell responses. In terms of how innate cytokines and signaling pathways influenced T cell immunity following rAd5 immunization, we show that the magnitude and quality of CD8 T cell responses are partially dependent on MyD88 but independent of IL-12, type I IFN, apoptosis-associated speck-like protein, nucleotide-binding oligomerization domain-like receptor protein 3, and IL-1. Taken together, these data demonstrate a critical role for CD11c(+) DCs for CD8 responses but striking redundancy for innate cytokines and signaling by TLR and nucleotide-binding oligomerization domain-like receptor pathways.


The expanding roles of long non-coding RNAs in the regulation of cancer stem cells.
Long non-coding RNAs (lncRNAs) are a novel class of gene regulators playing multifaceted roles in physiological processes as well as pathological conditions such as cancer. Cancer stem cells (CSCs) are a small subset of tumor cells that constitute the origin and development of various malignant tumors. CSCs have been identified in a wide spectrum of human tumors and could act as a critical link underlying the processes of tumor metastasis and recurrence. Mounting evidence indicates that lncRNAs are aberrantly expressed in diverse CSCs and regulate CSC properties at different molecular levels. Here, we very briefly summarize the recent findings on the potential roles of lncRNAs in regulating various functions of CSCs, and elaborate on how can lncRNAs impact CSC properties via interacting with other macromolecules at the epigenetic, transcriptional, and post-transcriptional levels. This mini-review also highlights the understanding of the modular regulatory principles of lncRNA interactions in CSCs.