P = 0.0000011). A substantial proportion of the depressed patients (40.5%) showed abnormally low CSF EA levels (<12.1 μM) . When patients with low EA and those with high EA levels were compared, the former had higher scores for overall depression severity (P = 0.0033) and ‘Somatic Anxiety’ symptoms (P = 0.00026). In unmedicated subjects, CSF EA levels showed a significant positive correlation with levels of homovanillic acid (P = 0.0030) and 5-hydroxyindoleacetic acid (P = 0.019). To our knowledge, this is the first study showing that patients with MDD have significantly lower CSF EA concentrations compared with control subjects. CSF EA could be a state-dependent biomarker for a subtype of MDD.Amino acids play key roles in the function of the central nervous system, and their alterations are implicated in psychiatric disorders. In the search for a biomarker for major depressive disorder (MDD), we used high-performance liquid chromatography to measure amino acids and related molecules in the cerebrospinal fluid (CSF) of 52 patients with MDD  and 54 matched controls. Significant differences were found in four amino acid concentrations between the depressed patients and controls. After Bonferroni correction, only ethanolamine (EA) levels remained significantly reduced in depressed patients (nominal  Major depressive disorder (MDD) is a common disease with a prevalence rate estimated at 4.4% worldwideSince cerebrospinal fluid (CSF) contacts the interstitial fluid in the central nervous system (CNS)P = 0.000059)We have focused on amino acids and related molecules in the CSF to identify a biomarker for MDD, because alterations in the serotonin, noradrenaline, dopamine, glutamate, and γ-amino-butyric acid (GABA) systems are implicated in MDD111213Although many studies compared CSF amino acid concentrations between MDD patients and healthy controls161718192021222324252627181921172021We measured CSF amino acids and related molecules in a relatively large sample to search for a biomarker for MDD. We also analyzed the correlations between CSF amino acid levels and depression severity, psychotropic medication, and monoamine metabolites.th edition (DSM-IV) criteriaSubjects were 52 patients with MDD and 54 healthy controls matched for age and sex. All participants were biologically-unrelated Japanese. Patients were recruited at the National Center of Neurology and Psychiatry (NCNP) Hospital , or through advertisements in free local magazines, and by our website. Healthy controls were from the same geographical area  via advertisements in magazines and website. Trained psychologists or psychiatrists conducted a structured Mini-International Neuropsychiatric Interview (M.I.N.I.)g. Supernatants were aliquoted and stored at −80°C until assays were performed. All samples were collected from August 2010 to August 2013. Initial 2 mL of CSF was used for measuring glucose, chloride, total protein levels and monoamine metabolites. Homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured by high-performance liquid chromatography (HPLC) at SRL Co., Inc. .Between 10:00 h and 16:00 h, CSF samples were obtained by lumbar puncture from the L4–5 or L3–4 interspace of participants, in the left decubitus position. CSF samples were immediately placed on ice, and centrifuged at 4000 × g and 4°C. Each supernatant was transferred to a micro-tube, filtered using a 0.22-μm pore-diameter syringe-filter , and subjected to HPLC . Acquired data were processed and quantified on the chromatography data station ChromNAV (JASCO). A detailed description of the HPLC protocol is available in the CSF sample was mixed with 4% 5-sulfosalicylic acid dihydrate , and centrifuged for 10 min at 12,000 × m/z values and normalized by migration times. Detailed CE-TOF-MS procedures are described elsewhereAmino acids and related molecules were also measured using CE-TOF-MS for a subset of the subjects . The CE-TOF-MS measurements were performed at Human Metabolome Technologies, Inc. , by coauthors who were blinded to the HPLC data obtained at the NCNP. Compounds were identified by their peaks using annotated tables with SD). Means were compared using t-tests or analysis of variance. Categorical variables were compared using the 2χ test with exact probability. Analysis of covariance (ANCOVA), controlling for age and sex, was performed to compare CSF levels of amino acids and related molecules in the patients and controls and between subgroups of the patients. Partial correlation analysis, controlling for age and sex, was performed to examine the correlations between equivalent doses of psychotropic drugs and concentrations of amino acids and related molecules, and between EA levels and other CSF substances including biogenic amine metabolites. The Mann-Whitney U test with exact probability was used to compare clinical symptoms (HAMD-17 scores) between MDD subgroups (Low-EA vs. High-EA). We obtained 95% CI for the difference between two medians for Mann-Whitney U using Hodges-Lehmann estimate. HAMD-17 items were assigned to the following subscales: ‘Core’ , ‘Sleep’ , ‘Activity’ , ‘Psychic Anxiety’ , and ‘Somatic Anxiety’ , according to Serretti et al.P-value was <0.05, and was corrected for multiple comparisons using the Bonferroni method. All analyses were performed using IBM SPSS Statistics 22.0 Japanese version .Data are reported as means ± standard deviation (P = 0.002 (0.05/25) was conservatively applied after the Bonferroni correction, only EA remained significant .Demographic and clinical characteristics of the subjects are shown in F = 0.045, df = 1, P = 0.83; 95% CI: −1.10 to 1.36), and no significant correlation between EA and age controlled for sex , between EA and time of CSF sampling controlled for sex and age , or between EA and number of days from sample collection controlled for sex and age , in a partial correlation analysis. F = 0.0030, df = 1, P = 0.96; 95%CI: −1.57 to 1.66) . Remitted MDD patients had significantly higher EA levels than depressed MDD patients  . These comparisons for CSF EA concentrations between subgroups are summarized in th percentile value of the controls (<12.1 μM), 17 depressed patients (40.5%) and 3 controls fell within this range .We then performed detailed analyses on the possible relationships between CSF EA levels and clinical variables. In controls, there was no significant difference in CSF EA levels between men and women controlled for age (to 1.66) , and theto 3.90) , and thest quartile of CSF EA values as ‘Low-EA’ (N = 13) and above the 3rd quartile as ‘High-EA’ (N = 13). The Low-EA group had higher HAMD-17 total scores , and ‘Core’ (P = 0.034) and ‘Somatic Anxiety’ (P = 0.00026) subscale scores  whose levels fell below the 1e scores . Other HP = 0.29), antidepressants (P = 0.34), or antipsychotics (P = 0.21). With respect to other molecules, several amino acid concentrations nominally showed significant correlations with medications (P = 0.00056)  = 0.001].Although there was no significant difference in CSF EA levels between medicated and unmedicated MDD patients, we examined the possible correlation between the equivalent dose of psychotropic drugs and CSF amino acid levels in the depressed MDD group . CSF EA ications . The cor0.00056) , remaineN = 67), based on reports that levels of CSF biogenic amine metabolites are affected by psychotropic drugsP = 0.0030), and 5-HIAA, a catabolite of serotonin (P = 0.019), showed significant correlations, while other substances  did not  in partial correlation analysis, with age and sex as covariates   .P = 0.0000011). Notably, as many as 40% of the depressed patients showed abnormally low levels, and EA levels were significantly lower in depressed patients than remitted patients. When relationships with clinical variables were examined in the patients, the Low-EA group showed higher HAMD-17 and subscale scores compared with the High-EA group. CSF EA did not correlate with the dose of psychotropic drugs, although isoleucine showed a correlation with antidepressants even after correcting for multiple testing. Lastly, CSF EA values were significantly correlated with CSF HVA and 5-HIAA levels in unmedicated subjects.Several of our findings are potentially of clinical significance. The levels of some CSF amino acids differed between MDD patients and controls. EA , in particular, remained significantly lower in patients than controls after correcting for multiple comparisons . Levine et al. reported that depressed patients (MDD and bipolar disorder) showed increased CSF glutamine levels than controlsN = 11) and controls . Therefore, the observed increase in glutamine in our total subjects may be attributable to medication. Regarding CSF GABA, several previous reports1819211720et al., who employed a metabolomics-based approach, reported that methionine was increased in remitted MDD patients compared with depressed patients and healthy controlsF = 9.1, df = 1, P = 0.0041; 95% CI: 0.31 to 1.57, ANCOVA) and controls . Methionine might be involved in the recovery processes of MDD and could be a biomarker for remission.An early study by Goodnick The significantly higher levels of CSF EA in remitted patients compared with depressed patients suggest that CSF EA levels might be state-dependent. In line, our Low-EA patients showed a higher HAMD-17 total score than the High-EA group. Vagus nerve stimulation (VNS), which is effective for MDD patients and alters the metabolites of neurotransmittersth percentile of the controls, approximately 40% of the depressed patients fell into this range, suggesting that a substantial proportion of subjects with MDD could be distinguished from normal subjects based on CSF EA levels, which would be useful for diagnosis. MDD patients with low CSF EA levels may constitute a subtype of MDD. Indeed, the Low-EA group was characterized by higher ‘Core’ and ‘Somatic Anxiety’ symptoms. In addition, we found a significant positive correlation between CSF EA and HVA and 5-HIAA levels, suggesting that MDD characterized by low CSF EA levels reflects impaired dopaminergic and serotonergic functions in the CNS, possibly due to synaptic dysregulation by an altered endocannabinoid system (see below).When we defined abnormally low EA levels based on the 5Since most of our patients were medicated, the observed decrease in CSF EA may be attributable to medication. However, this possibility is unlikely because CSF EA was decreased in unmedicated patients compared with controls; there was no significant difference in CSF EA levels between medicated and unmedicated patients; and there was no significant correlation between CSF EA levels and the dose of any class of psychotropic drugs. Our results therefore suggest that CSF EA could be a useful biomarker even in medicated patients. With respect to the effect of antidepressants, we found a significant correlation with CSF isoleucine levels even after correcting for multiple comparisons. To our knowledge, no study has examined the effect of antidepressants on CSF amino acid levels; therefore, further studies are warranted.N-arachidonoylethanolamine), a ligand for cannabinoid receptors (CBs), and transient receptor potential vanilloid type 1 (TRPV1). The endocannabinoid system is implicated in depression, suicide, and stress-related affective disorders1 receptor density is high at presynaptic axon terminals, where it functions to inhibit neurotransmitter release41421 receptors, and is rapidly inactivated by active transport into neurons, followed by hydrolysisEA is closely related to endocannabinoid signaling in the CNS see . EA is bN-acylethanolamines or prostaglandin H2 ethanolamide48Decreased CSF EA may be due to inflammatory responses that have been implicated in MDDN = 13) and remitted individuals (N = 10) were small. However, we detected a significant difference in CSF EA levels between unmedicated patients and controls; and between depressed and remitted patients, which suggests large effect sizes. Secondly, the measurement of the CSF sample took place in a real-world setting; the majority of patients were medicated, and sampling was not performed after fasting or at a fixed time. However, we did not observe any correlation of EA with psychotropic medication or CSF sampling time. This makes CSF EA a feasible biomarker for everyday use in the clinical setting. Nevertheless, studies are necessary to elucidate the possible effects of fasting. Thirdly, there were missing values for several amino acids (see N = 13) received antipsychotic medication, which may have an effect on CSF EA levels. However, there was no significant correlation between daily chlorpromazine equivalent doses of antipsychotics and CSF EA levels; therefore, the possible effect might be minimal. Finally, we obtained data only for MDD patients and controls. Further studies on other neuropsychiatric disorders are necessary to determine whether low EA is specific to MDD.There are several limitations to this study. Firstly, the numbers of unmedicated patients with MDD  of depressed MDD patients. Such patients had characteristic symptomatology  and CSF monoamine metabolite profiles , and thus constitute a subtype of MDD.S.O. designed the study, managed the literature searches, profiled the CSF samples by HPLC, undertook the statistical analyses, and wrote the draft of the manuscript. K.H. and Y.Y. recruited the participants. K.H. and D.S. diagnosed the participants, and collected the CSF samples. K.H. selected the sample set. Y.Y. and R.M. made psychological assessments. R.M. created and maintained database system. M.O., H.H. and T.T. screened the participants and diagnosed the patients. Y.O. and H.S. performed the CE-TOF-MS measuring for data validation. N.M. and J.M. reviewed the draft and gave critical comments on the manuscript. T.H., S.Y. and T.N. contributed to the recruitment of clinical volunteers. H.K. supervised the entire project and gave critical comments on the manuscript. All authors contributed to and have approved the final manuscript.Supplementary Materials


Hepatic encephalopathy (HE) is a neurological complication of cirrhosis, impairing survival and quality of life. Its incidence is growing because of the improved prognosis of other complications of cirrhosis, and of the widespread use of TIPS. However, besides hyperammonemia which is often pointed out as a cause of HE, the pathophysiological mechanisms of HE remains poorly understood, which prevents the development of therapeutic strategies. To address this issue, metabolomics was used to identify dysfunction of metabolic pathways in cerebrospinal fluid (CSF) samples of cirrhotic patients suffering from HE.The aim of this study was to detect new therapeutic targets for HE associated with cirrhosis.Cerebrospinal Fluid (CSF) samples were collected on 14 cirrhotic patients admitted in ICU for HE, in whom infection of central nervous system has to be ruled out, and were compared to CSF of 27 control patients without any proven neurological disease. Metabolomic analysis was performed using 3 liquid chromatographies coupled to high resolution mass spectrometry methods (LC-HRMS). Informatic data processing tools were used.LC-HRMS methods led to the characterization of 150 metabolites in CSF samples of HE patients, which were mainly amino acids and organic acids. Interestingly, according to human metabolome database, 40% of those metabolites had never been retrieved were not reported as present in CSF before. HE patients could be easily discriminated from controls on the basis of metabolomicic information. Concentrations of 102 metabolites were found to be significantly altered in HE patients: metabolotypes displayed alterations in several major metabolite classes such as ammoniac, bile acids, but also amino-acids, acylcarnitines, and nucleosides. Accumulations of acetylated compounds, which could be due to a defect of the Krebs cycle, were reported for the first time in HE patients, and could constitute interesting therapeutic targets.By enabling the simultaneous monitoring of a large set of metabolites in cirrhotic patients with HE, CSF metabolomics highlighted several altered metabolite pathways linked to ammonia metabolism, neurotransmission and energy metabolism. The pharmacological relevance of our findings has to be explored on animal models, as they could constitute interesting new therapeutic targets.


Chronic myeloid leukemia is a myeloproliferative disorder that may be treated with hematopoietic stem cell transplantation (HSCT). While posttransplantation relapse of disease resulting from a failure to eradicate the patient's original leukemia could occur, patients may also rarely develop a secondary malignancy or myelodysplastic syndrome (MDS) of donor origin termed donor cell leukemia (DCL). Cases of donor-derived acute myeloid leukemia (AML) or MDS after HSCT or solid tumor transplantation have been published. However, very few cases of donor-derived multiple myeloma (MM) exist. We describe a patient who developed a donor-derived MM following allogeneic HSCT from a sibling donor.  Chronic myeloid or chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder that arises from the neoplastic transformation of undifferentiated hematopoietic stem cells . It is tTyrosine kinase inhibitors such as imatinib have revolutionized the treatment of CML. However, prior to the approval of this therapy, allogeneic stem cell transplantation was thought to be the only curative treatment for CML . PosttraWe describe a 54-year-old woman who initially presented in 1999 at the age of 40 with newly diagnosed CML identified on routine blood work during pregnancy. She eventually miscarried. She was initially treated with Hydrea and underwent sibling allogeneic HSCT with her brother as a donor in January 2000. She tolerated the transplant without complications and was in remission until January 2012 when routine blood work identified increased serum protein and anemia. Serum protein electrophoresis (SPEP) demonstrated an abnormal band in the gamma region and M protein spike of 1.9. Urine protein electrophoresis (UPEP) demonstrated a monoclonal kappa light chain. Bone marrow biopsy demonstrated a monoclonal plasmacytosis of 10–12% consistent with plasma cell dyscrasia. There was no evidence of CML. FISH studies and BCR-ABL testing were negative. A bone study was negative for blastic and lytic lesions. Cytogenetics showed a normal male karyotype of donor origin. These findings were consistent with a new diagnosis of IgG kappa smoldering multiple myeloma.Our patient was followed with watchful waiting until repeat bone marrow biopsy showed multiple myeloma with rapid progression to active disease. FISH study at diagnosis was positive for an IgH/FGFR3 rearrangement. She was treated with Revlimid, Velcade, and dexamethasone beginning in February 2013. She then continued to autologous HSCT with melphalan as a conditioning regimen in July 2013.Based on the patient's full chimerism, it was recommended that her sibling donor be evaluated. His labs were significant for an elevated serum protein, SPEP with an abnormal band in the gamma region, and an M protein spike of 2.3. Her sibling donor underwent bone marrow biopsy in April 2012 that showed monoclonal plasmacytosis (~20% on CD138 stain) consistent with myeloma. Similar to our patient, his FISH studies were also positive for IgH/FGFR3 rearrangement in 5.5% of cells. Flow cytometric analyses also showed a monoclonal plasma cell population with cytoplasmic kappa light chain restriction. Findings were consistent with IgG kappa smoldering multiple myeloma that also progressed to active disease. He was also treated with Velcade, dexamethasone, and Revlimid before undergoing autologous stem cell transplant in February 2014.Donor cell leukemia (DCL) is a rare complication of allogeneic stem cell transplantation. A 2011 review of the literature by Wiseman identified 51 cases of suspected or proven DCL and 13 cases of donor cell-derived MDS . MultiplWhile the incidence of recurrent leukemia decreases over time, donor-derived leukemia tends to occur late . A retroDiagnosis of DCL relies on the identification of cytogenetic and molecular differences between the recipient and donor. In early cases, diagnosis of DCL was made through demonstration of a sex mismatch  between a recipient and donor as evidenced by karyotype analysis or through florescent in situ hybridization (FISH) analyses. However, newer quantitative methods of diagnosis have proved to more effectively diagnose DCL through the study of polymorphic DNA sequences. These PCR based tools involve the study of variable nontandem repeats (VNTR), short tandem repeats (STR), and restriction fragment length polymorphism to identify donor/recipient chimerism .The treatment of DCL is dependent on the phenotype of the donor-derived malignancy. In our patient, her donor-derived multiple myeloma was treated with Velcade, Revlimid, and dexamethasone followed by autologous stem cell transplantation.The small number of reported cases, variable follow-up, and range of treatment strategies employed limit prognosis in patients.DCL is a complication of allogeneic stem cell transplantation with many cases going unidentified or underreported. Though rare, this disease provides an opportunity to study leukemogenesis in vivo. In our patient, FISH analysis identified a de novo MM of donor origin. Cytogenetic studies following bone marrow biopsy confirmed de novo myeloma of donor origin. While several case reports have been published documenting the development of AML and other tumors, few, if any, cases report a de novo MM arising in a patient treated for CML. The identification of DCL is important to recognize as it may affect treatment modalities and patient outcomes.


Due to anatomical restrictions, the inflammatory response to intracerebral bacterial infections exposes swollen brain tissues to pressure and ischemia, resulting in life-threatening damage. Rapid diagnosis and immediate empirical antibiotic therapy is highly important. However, diagnosing meningitis in patients after neurosurgery is complicated, due to brain tissue damage and changes in cerebrospinal fluid (CSF) caused by surgery. Hepatocyte growth factor (HGF) is a local, acute-phase protein with healing properties. Previous studies on community-acquired septic meningitis reported high levels of intrathecally produced HGF. The present study focused on nosocomial meningitis in assessing the levels of HGF in the CSF.HGF concentrations (ELISA) and HGF binding to receptors; c-Met receptor and heparan sulfate proteoglycan were determined in CSF samples (surface plasmon resonance). CSF samples from patients with community-acquired or nosocomial meningitis (217 samples from 135 patients) were compared to those from controls without signs of cerebral nervous system involvement (N = 36) and patients with Alzheimer’s disease (N = 20).p < 0.001) and binding affinity to c-Met (p < 0.001) and HSPG (p = 0.043) receptors. The sensitivity and specificity to identify nosocomial septic meningitis were 69.7 and 93.4 %, respectively. The HGF concentration and binding affinity to HGF receptors were significantly higher in CSF from patients with community-acquired septic meningitis compared to patients with aseptic  meningitis as well as controls (p < 0.001). The sensitivity and specificity to identify community-acquired septic meningitis were 95.4 and 95.7 %, respectively.Compared to samples from patients that had undergone neurosurgery and had other infectious diseases, CSF samples from patients with nosocomial meningitis had significantly higher HGF concentrations  contains supplementary material, which is available to authorized users. An invasion of bacteria into the central nervous system (CNS) is followed by a rapidly evolving inflammatory process that affects the arachnoid space, the pia mater, and the cerebrospinal fluid (CSF). This condition leads to clinical symptoms of headache, fever, and meningism. The inflammatory response is caused by the release of various proinflammatory cytokines from meningeal cells into the subarachnoid space. As a result, neutrophils move into the subarachnoid space and cause pleocytosis in the CSF. The consequences include the breakdown of the blood–brain barrier, cerebral edema, reduced cerebral blood flow, focal areas of hypoperfusion, vascular thrombosis, ischemia, enhanced glucose metabolism via the anaerobic glycolytic pathway, and enhanced lactate accumulation in the brain and CSF . SurvivaOther causes of febrile meningitis include acute viral meningitis and non-pyogenic meningitis, where the clinical picture is typically sub-acute or chronic. The diagnostic procedures consist of a lumbar puncture to analyze the CSF for cells and bacteria, microbiological cultures of blood and CSF, serological tests involving PCR and antigen-detection, and radiographic techniques . In commNosocomial meningitis can occur when brain surgical procedures are complicated by infection . Due to Hepatocyte growth factor (HGF) is produced by mesenchymal cells during organ injury. It is produced as a single-chain precursor protein, and it is activated at the site of injury by proteolytic cleavage, resulting in a double-chained active form of HGF . Active The quality of endogenous HGF binding to receptors can be assessed with surface plasmon resonance (SPR), an optical technique appropriate for clinical studies that can determine the affinity of a protein for several ligands . SPR-basA high level of HGF in the CSF has been reported in patients with Alzheimer’s disease, a chronic disorder characterized by progressive neuronal degeneration and deposits of amyloid plaques and neurofibrillary tangles . CerebraWe have previously studied the concentration of HGF in CSF for patients with community-acquired meningitis . We haveg for 15 min) and then stored in in polypropylene tubes at −70 °C until use. CSF samples from patients diagnosed with Alzheimer’s disease were obtained from the Memory Clinic, Skåne University Hospital in Malmö, Sweden. The Regional Ethics Committees in Linköping and Lund, respectively, approved the study protocols. Five patients with pleocytosis of unknown origin and one patient with Creutzfeldt-Jakob disease (positive western blotting for protein 14-3-3 in CSF) were excluded. The remaining samples (n = 274) were assigned to one of six groups, depending on the type of meningitis (Group 1–4) or controls   and aseptic meningitis were collected at the University Hospital in Linköping, Sweden, over the 8-year period of 2006–2013. The CSF specimens from patients with community-acquired infection or controls were collected after lumbar punctures and handled promptly. In one patient the sample was collected from ventricular drain. The samples from patients that had undergone neurosurgical intervention were collected from ventricular drains. The samples were collected and centrifuged (3000×Group 1: septic meningitis (n = 22 samples) Patients with community-acquired acute bacterial meningitis (N = 20) had a median age of 62 years . In 2 cases, samples were collected on two occasions . The cases presented with fever, CSF polynuclear pleocytosis, and elevated CSF lactate and protein levels. The causes were identified as Streptococcus pneumonia (N = 6), Haemophilus influenzae (N = 2), Listeria monocytogenes (N = 1), Streptococcus intermedius (N = 3), α-hemolytic streptococci (N = 1), rickettsial meningitis (N = 1), Coagulase-negative staphylococcus (N = 1), Cryptococcus neoformans (N = 1), Aspergillus (N = 1), Staphylococcus aureus (N = 1), and unknown (N = 2), due to negative results in microbiological assessments.Group 2: Aseptic meningitis (n = 46 samples) Patients with viral or subacute meningitis or encephalitis were considered one group in statistical calculations. The laboratory findings included CSF pleocytosis, normal CSF lactate levels, and negative blood and CSF cultures.15 patients had viral meningitis . Laboratory assessments revealed Herpes zoster , enterovirus , and negative results in the laboratory assessments (N = 6). In 1 case, samples were collected on two occasions (n = 16 samples).Borrelia burgdorferi , syphilis , and highly suspected tuberculosis .30 samples were collected from patients with subacute meningitis or encephalitis (N = 30). Laboratory assessments revealed CSF samples (n = 149) were collected from patients (N = 69) that were admitted to the Department of Neurosurgery, University Hospital in Linköping, Sweden. The patients had undergone a neurosurgical procedure, and the management was complicated with infection. Thus, several CSF specimens were collected from some patients on different occasions. Ventilator associated pneumonia and meningitis were the differential diagnoses of infection in the majority of cases. Antibiotic therapy was initiated or changed to broad spectrum antibiotics by the physician in charge, directly after cultures of blood, CSF, catheters, and drains were taken.Because no golden standard is available to define the diagnosis in post neurosurgery patients that develop fever, among the CSF samples, two major groups were identified based on medical history, the clinical judgment of physician in charge, the follow-up and the diagnose code in medical records.Group 3: Nosocomial meningitis (n = 33 samples) CSF specimens (n = 61) were collected from patients  that had undergone brain tumor surgery (N = 8), intracerebral hemorrhage (N = 15), shunt dysfunction (N = 3), skull fracture (N = 2), or two different periods of disease (N = 1). In these patients, microbiological assessments yielded bacterial growth or CSF pleocytosis, and they were treated for bacterial meningitis. Prior to antibiotic therapy, 33 CSF samples were collected . The CSF cultures showed growth of Coagulase-negative staphylococcus (N = 7), Propionibacterium acnes (N = 5), Enterococcus faecalis (N = 2), α-hemolytic streptococci (N = 1), and Candida glabrata (N = 1). In blood cultures, we found Pseudomonas aeroginosa (N = 1) and Lactococcus lactis (N = 1). 12 patients had negative cultures.CSF samples were collected both before and after successful therapy (N = 7);CSF samples were collected from patients that failed therapy or from patients before therapy was initiated (N = 6).In 13 patients, CSF samples were collected before and after therapy at 2–5 occasions . Assessments of the 13 patient reports indicated two sub-groups:Group 4: Other nosocomial infections (n = 76 samples) CSF specimens (n = 76) were collected from patients (N = 37)  that underwent neurosurgery for tumors (N = 6), cerebral hemorrhage (N = 23), shunt dysfunction (N = 5), fractures (N = 2), or surgical complications (N = 1). The course of treatment was complicated with bronchitis or pneumonia , other infections  or unverified or treated infections (CSF samples obtained after 1 week treatment) .Among the nosocomial infections, 12/149 CSF specimens were unclear cases  and were excluded from statistical calculations.Group 5: Alzheimer’s disease (n = 20) CSF samples were collected from patients (N = 20) with a median age of 78.5 years  that were diagnosed with Alzheimer’s disease at the Memory Clinic, Skåne University Hospital in Malmö. The patients had all undergone a routine lumbar puncture, cognitive testing, and computed tomography or magnetic resonance imaging of the brain as part of the dementia investigation. The revised DSM-III and NINDS-ADRDA criteria were used for diagnosis of Alzheimer’s dementia [dementia , 27.Group 6: Normal CSF (n = 37) This group consists of two subgroups, but it is considered one group in statistical calculations. One subgroup included patients (N = 19) with a median age of 50 years  (n = 20). These patients underwent lumbar puncture to rule out meningitis, and they had normal CSF. The other subgroup comprised patients (N = 17) with a median age of 58 years . These patients had very subtle cognitive symptoms, and they were judged to be cognitively healthy after a dementia evaluation at the Memory Clinic, Skåne University Hospital in Malmö.The biological activity of HGF was analyzed with SPR. We measured the binding affinity to HSPG  and to a c-Met recombinant chimera (R&D Systems), as previously described . Brieflyg for 10 min, and diluted 1:1 in phosphate buffered saline solution . CSF regeneration was induced by adding an equal volume of 1 M NaCl and 10 mM glycine, pH 2, followed by one injection of borate, pH 8.5. The positive control consisted of HGF produced by leukocytes from a healthy volunteer; the negative control was PBS. Both were included at the beginning and end of each run to confirm the reliability of the surfaces.CSF samples were thawed, centrifuged at 3000×A specific enzyme-linked immunosorbent assay (ELISA) kit  was used to determine HGF concentrations in CSF, according to the manufacturer`s instructions. All measurements were performed with an ELISA reader  at 450 nm, which was calibrated with the recombinant human HGF reference samples and the standards provided in the kit.CSF was analyzed to determine parameter values at the Departments of Clinical Chemistry, University Hospitals, in Linköping and Malmö, Sweden. All cultures, PCR assays, antigen detection assays, and serological assessments were performed at the Department of Microbiology, University Hospital, Linköping, Sweden.CSF-cells Performed by manual phase contrast microscopy (Zeiss) using Jessen Chamber for counting the number of erythrocytes and leukocytes (polymorphonuclear neutrophils and monocytes).CSF lactate Performed using benchtop blood gas analyzer ABL 800 .Antigen detection Antigen  was detected by latex agglutination method Pastorex Meningitis™ .CSF culture Performed in aerobe and anaerobe flasks as well as in Hematin plates.Lyme neuroborreliosis Intrathecal antibodies against Borrelia burgdorferi were detected by capture Elisa technique.Virus detection PCR Herpes virus type 1 and 2  and HZV DNA were detected by PCR. Human enterovirus (HEV) was analyzed by automated instrument (Cepheid GeneXpert).Because the HGF concentrations and binding affinity data were not normally distributed, we compared values before and after therapy with the Kruskal–Wallis test followed by the Mann–Whitney U test or the Wilcoxon matched pairs test. All analyses were performed with Graph Pad Prism version 5 . Values are expressed as the median. P-values <0.05 were considered statistically significant. The sensitivity, specificity, positive predictive values, and negative predictive values were calculated manually. The intra- and inter-assay coefficient of variation (CV) for determination of HGF concentration was calculated manually and was found to be 12.9 and 11 %, respectively.p = 0.0133), as well as HGF binding affinity to the c-Met and HSPG receptors  compared to nosocomial meningitis. CSF samples from patients with septic meningitis  was significantly higher in HGF concentrations (p = 0.0014), HGF binding to HSPG (p < 0.0001), and HGF binding to c-Met (p < 0.0001) compared to samples from patients with aseptic  meningitis. CSF samples from patients with septic meningitis was higher from samples from the control group  and from patients with Alzheimer’s disease in HGF concentration , HGF binding to HSPG , and HGF binding to c-Met (both p < 0.0001).The community-acquired septic meningitis showed significantly higher HGF concentration (p < 0.0001) and HGF binding affinity to c-Met (p < 0.0001) and HSPG (p = 0.043) receptors.Compared to samples from patients that had undergone neurosurgery and had other infectious diseases, CSF samples from patients with nosocomial meningitis had significantly higher HGF concentrations (p < 0.0001), samples from controls (p < 0.0001), and samples from patients that had undergone neurosurgery and had infections other than meningitis (p < 0.0001)  Table .Table 1TWe measured the binding of CSF-derived HGF to c-Met receptors in the SPR system. We used a cut off value of 10 response units (RU) to diagnose pyogenic meningitis in nosocomial   and white blood cells was tested in cases having nosocomial meningitis (G3) and other nosocomial infections (G4) by using Spearman’s rho. In these cases, the white blood cells count correlated to HGF amounts ELISA , c-Met binding , and to HSPG binding . These results suggest that some diagnostic information is shared between white blood cell count and HGF variables, and, to elucidate the independent value of HGF, we further subdivided the 109 nosocomial cases into two groups according to WBC (<10 … and >10….). All 30 cases with a low WBC count had a low c-Met binding (<10 RU) and in this group 2 had septic meningitis (2/30 = 7 %). Fifty-one nosocomial cases had a high WBC count but a low c-Met binding and 8 of these had meningitis (8/51 = 16 %). Among the 28 cases with both a high WBC count and a high c-Met binding, 23 were diagnosed with septic meningitis (23/28 = 82 %). The difference in the proportion of cases with meningitis between the two last groups was statistically significant (p < 0.001) indicating that there is independent diagnostic information in c-Met binding .9, n = 132) was tested by using Spearman’s rho. In these cases, the correlations to HGF concentration Elisa, c-Met binding and HSPG binding were R = 0.12, 0.20 and 0.40 respectively  and red blood cells (>500 × 10p = 0.06). In contrast, HGF binding to c-Met increased in CSF samples from patients that did not respond to therapy; again, the change was not statistically significant . However, the post-treatment levels of binding differed significantly between responder and non-responder sub-groups , CSF samples had been collected before and after antibiotic therapy. We found that CSF-derived HGF binding to c-Met receptors decreased after treatment in CSF samples from patients that responded to antibiotic treatment. However, the change did not achieve significance  from nosocomial infections after surgery (ventricular drains). As far as we know there are no reports about differences in concentration of circulating proteins in CSF collected by lumbar puncture or from ventricular drains. The major message of this study is the higher level of HGF in CSF in patients who suffered from nosocomial septic meningitis compared to other nosocomial infections and the method of collection of CSF did not differ between these patient groups.The patients that had undergone neurosurgery had high red blood cell count in CSF that might indicate a passive transfer of HGF from blood into CSF . There wThe samples were collected during several years and kept frozen until they were analyzed. We have previously studied the stability of HGF in blood and feces and observed that HGF was stable in these body fluids during longer storage and several freeze–thaw cycles , 39.Consistent with our previous studies, from the present study, we concluded that a determination of HGF in CSF might be used as an indicator, complementary to clinical status and routine laboratory findings, for diagnosing bacterial invasion into the CSF at an early stage of disease. The benefit of this kind of diagnosis is that it can limit the brain damage and guide the selection of an appropriate antibiotic therapy, particularly in nosocomial infections, where standard diagnostic methods are of limited value.


Polygonum hydropiper were investigated in hydroponic media containing various concentrations of Po (1–8 mmol L-1) supplied as phytate. The mining ecotype (ME) showed significantly higher biomass in both shoots and roots compared to the non-mining ecotype (NME) at 4, 6, and 8 m mol L-1. Shoot P content of both ecotypes increased up to 4 mmol L-1 while root P content increased continually up to 8 mmol L-1 for the ME and up to 6 mmol L-1 for the NME. Root P content of the ME exceeded 1% dry weight under 6 and 8 mmol L-1. The ME had significantly higher P accumulation in both shoots and roots compared to the NME supplied with 6 and 8 mmol L-1. The ME showed higher total root length, specific root length, root surface area, root volume, and displayed significantly greater root length, root surface area, and root volume of lateral roots compared to the NME grown in all Po treatments. Average diameter of lateral roots was 0.17–19 mm for the ME and 0.18–0.21 mm for the NME. Greater acid phosphatase and phytase activities were observed in the ME grown under different levels of Po relative to the NME. This indicated fine root morphology, enhanced acid phosphatase and phytase activities might be adaptations to high Po media. Results from this study establish that the ME of P. hydropiper is capable of assimilating P from Po media and is a potential material for phytoremediation of polluted area with high Po.It is important to seek out plant species, high in phosphorus (P) uptake, for phytoremediation of P-enriched environments with a large amount of organic P (Po). P assimilation characteristics and the related mechanisms of  Soils contain an enormous amount of phosphorus (P), commonly the bulk (greater than 50%) of which is fixed into organic P (Po) depending on land use, location, and soil type . OrthophCucurbita pepo var. melopepo) and slicing cucumber (Cucumis sativus) were screened as potential P accumulators with shoot P > 1% dry weight (DW). Marshall and Gulf ryegrass (Lolium multiflorum L.) could accumulate great shoot P (excess of 1% DW) from P-enriched nutrient solution, agar media or soils (Duo festulolium) originated from the hybridization between a ryegrass (L. perenne L. or L. multiflorum L.) and Meadow Fescue (Festuca pratensis H.) was also identified as a P accumulator for phytoremediation  to provide important P sources. Acid phosphatase (Apase) can catalyze the hydrolysis of Po compounds to release Pi for plant uptake . PhytasePolygonum hydropiper, including a mining ecotype (ME) and a non-mining ecotype (NME), is able to grow both on land and in water as a kind of annual herbage. P. hydropiper is generally used as a seasoning or a kind of herbal medicine with alexeteric and styptic effects  with average annual temperature of 16.1°C and average annual precipitation of 1732.0 mm. The ME was collected from a P-mine site in Shifang, Sichuan  which has similar climatic and topographic environments. Healthy and uniform seedlings were chosen, the roots sterilized, and pre-cultured on vermiculite for 1 week based on the method of Seedlings of L-1 hydrated calcium nitrate, 506 mg L-1 potassium nitrate, 80 mg L-1 ammonium nitrate, 493 mg L-1 magnesium sulfate, 18.35 mg L-1 EDTA-Fe, 4.15 μg L-1 potassium iodide, 31 μg L-1 boric acid, 111.5 μg L-1 manganese sulfate, 43 μg L-1 zinc sulfate, 1.25 μg L-1 sodium molybdate, 0.125 μg L-1 cupric sulfate, and 0.125 μg L-1 cobalt dichloride) was used as basal nutrient medium for plant growth. To investigate the effect of different concentrations of Po, media were supplemented with 1, 2, 4, 6, and 8 mmol P L-1 added as phytate isolated from rice . The pH of these media was adjusted to 5.8 by 0.1 mol L-1 HCl or 0.1 mol L-1 NaOH during the culture period. The periphery of hydroponics container was covered with black paint to prevent light diffusion into the root. Pot experiments were carried out using barrels with volume of 5 L full of nutrient solution. Apertured, hard cystosepiment  was chosen as barrel cover. The cystosepiment and sponge were used to fix the seedlings to keep the roots in the barrels and maintain the shoots in the above of cystosepiments. Two uniform and healthy seedlings of P. hydropiper were planted in each barrel based on the principle of “one aperture, one seedling.” The aforementioned ‘two seedlings per barrel’ was just one replicate per treatment and four replicates were performed for each treatment. The nutrient media were replaced every 5 days. Pots were placed according to a completely randomized design in a greenhouse with sunlight.Healthy, similar sized seedlings (∼10 cm) were selected for the pot experiments. Modified Hoagland nutrient solution without monopotassium phosphate . Root length, root surface area, and root volume of each plant were measured immediately. Parts of main and lateral roots in these images were randomly selected to measure their diameter. Base on the real diameter of main and lateral roots, threshold of 0.4 mm was able to well differentiate the two kinds of roots. Thus, two levels of >0.4 and ≤0.4 mm were used to divide roots into main roots and lateral roots. Root length, root surface area, root volume, and average diameter for main and lateral roots were also determined. Specific root length was estimated based on the method of To determine plant P content, the dried samples were ground with a stainless steel grinder  and sieved through a 0.15 mm nylon sieve. 0.3 g ground samples were dissolved with 8 mL concentrated sulphuric acid in a 50 mL triangular flask using a hotplate at low temperature for 8 min. During this process, 0.5 mL of 30% hydrogen peroxide was added into the digested samples when they were cooled to room temperature. The procedure was repeated twice or three times till the samples were clear. Ultimately, the samples were heated at low temperature for 5–10 min to remove residual hydrogen peroxide. Tissue P content was determined colorimetrically at 700 nm by using an ultraviolet-visible spectrophotometer .Commonly, the bioaccumulation coefficient (BCF) is used to estimate the enrichment capacity. The translocation factor (TF) is described to evaluate the translocation efficiency. Therefore, the BCF and TF were calculated based on the methods of 2H2O, 1 mM EDTA). The mixture was centrifuged at 4°C for 10 min at 14,000 rpm. After centrifugation, the supernatants were collected to use for analysis of Apase and phytase activities.Fresh root materials were frozen in liquid nitrogen and stored at -80°C after being washed thoroughly with running tap water and distilled water, respectively. Fresh tissues (∼0.3 g) were homogenized in ice bath with quartz sand in 5 mL of 15 mM 2-morpholinoethanesulfonic acid, monohydrate (MES) buffer with pH of 5.5  as substrate for APase activity and phytase activity. Determination of Apase and phytase activities was done according to the methods of earlier reports (-1 fresh weight (FW) min-1. Phytase activity was calculated as mU g-1 root FW, where 1 U releases 1 μmol of soluble Pi min-1 quantified by the molybdenum-blue method.These enzyme activities were performed using p-nitrophenyl phosphate disodium salt hexahydrate (pNPP) and  reports . In the p < 0.05. Graphical work was accomplished by Origin (Version 8.0).Data from 4 replicates were sorted out by Excel (Microsoft) software packages. Statistical analyses were performed using variance analysis by the DPS software package (Version 11.0). The least-significant difference was used to estimate differences among plants or treatments at significant level of P. hydropiper grown under hydroponic media containing various concentrations of Po up to 8 mmol L-1 are displayed in Figure 1. A significant decrease in shoot biomass was observed in media with 8 mmol L-1 for the ME and 4 mmol L-1 for the NME . Growth in the ME was greater than in the NME at all concentrations of Po. In addition, shoot biomass of the ME was significantly higher relative to that of the NME when both were grown in media with 4, 6, and 8 mmol L-1. No significant difference in root biomass was noticed in the ME, whereas the NME exhibited a persistent decrease in various concentrations of Po . Root biomass of the ME was significantly greater than that of the NME at any level of P except for 2 mmol L-1.Shoot and root biomass of the two ecotypes of L-1 . The maximum shoot P content was 5.94 g kg-1 DW for the ME and 5.44 g kg-1 DW for the NME. In the case of root P content, a persistence of sharp increase was observed in the ME with respect to the increasing Po levels in the growth media while a significant reduction occurred in the NME beyond 6 mmol L-1 . Root P content in the ME was 5.74–20.24 g kg-1 DW, whereas root P content in the NME varied from 4.62 to 9.39 g kg-1 DW depending on Po concentration in the media. Root P content of the ME was 1.74, 2.02, and 3.23 times greater compared with that of the NME when grown in media supplied with 4, 6, and 8 mmol L-1, respectively.Shoot P content in both ecotypes increased with increasing applications of Po until it reached 4 mmol Table 1, BCF in the ME of P. hydropiper was 1.24–3.23 times higher compared to that of the NME when grown in the same concentration media. TF of the ME was lower than that of the NME and TF for both ecotypes was lower than 1.0, suggesting that P mainly accumulated in the roots.As shown in P. hydropiper were highly variable, depending on plant ecotypes and concentrations of Po in the growth media . Shoot P accumulation of the ME reached its peak value (11.32 mg plant-1) when grown in media supplemented with 4 mmol L-1. However, a continued decrease was observed in P accumulation of the NME. Furthermore, the pattern in root P accumulation of P. hydropiper was similar to that in root biomass. Root P accumulation of the ME significantly increased with the increasing Po concentrations and it was 2.06 and 4.78 times higher than that of the NME at 6 and 8 mmol L-1, respectively.P accumulation is the product of biomass and P content. P accumulation in both shoots and roots of Figure 4. Root length, specific root length, root surface area, and root volume were determined in the study. Root length evidently decreased with Po concentration up to 6 mmol L-1 for the ME and 2 mmol L-1 for the NME, and the ME demonstrated larger root length in a range of 9.24–15.84 m compared to the NME. Specific root length of the ME reached its maximum (6201.48 m g-1 DW) at 4 mmol L-1, whereas in the NME specific root length continuously decreased in response to the increased Po addition in the media. The two ecotypes differed greatly in root surface area and root volume. Root surface area of the ME increased until the Po concentration reached 4 mmol L-1 in the nutrient media. Root surface area of the NME had a great sensitivity to Po application, with root surface area becoming less than that cultivated in the media with a relatively low Po concentration (1 mmol L-1). Root volume had the same tendency as root surface area in both ecotypes of P. hydropiper. The ME registered great root volume in rang of 1.75–3.74 cm3 while the NME showed a lower root volume ranging from 0.71 to 2.84 cm3.Morphological developments in the root systems of the two ecotypes subjected to various Po levels in the nutrient media are depicted in Table 2). Main and lateral root length, surface area and volume of the NME decreases proportionally to the increase of Po. However, main root length of the ME increased with Po until a level of 4 mmol L-1, and the same phenomenon was observed in main and lateral root surface area and volume. The lateral root length of the ME is not affected at all until 4 mmol L-1. At levels greater than 4 mmol L-1, main and lateral root length, surface area and volume of the ME sharply decreases. Average diameter of main and lateral roots was less affected by Po concentrations compared to ecotypes. The ME demonstrated significantly greater lateral root length, surface area compared to the NME in each Po treatment. Furthermore, the ME displayed higher main root length, surface area compared to the NME when grown in 2 and 4 mmol L-1. Higher main and lateral root volume was observed in the ME than the NME at relatively high Po concentrations, viz. 4, 6, and 8 mmol L-1. In addition, lower average diameter of lateral roots in the ME was noticed relative to the NME.Root length, surface area, volume, average diameter in main and lateral roots mainly affected by Po concentrations and ecotypes . APase activities in the roots ranged from 9.87 to 15.37 pNP ug (g FW)-1 min-1 for the ME and from 6.61 to 9.83 pNP ug (g FW)-1 min-1 for the NME, respectively. Root APase of the ME displayed on average 30% higher relative to that of the NME. Phytase activity followed a different trend from APase in both ecotypes. Phytase activity of the ME increased in the growth media, irrespective of Po level, whereas that of the other ecotype had no significant increase . Phytase activity in the ME was also higher (∼1.20–2.75-fold) than that in the NME grown in media containing various Po concentrations.The greatest increase in root APase activity were obtained from the ME grown under 4 mmol P. hydropiper, as a P-accumulator, was grown in the presence of high levels of Po added as phytate for 5 weeks . Fewer branches and smaller leaves were observed in the NME compared to the ME. The high Po reduced shoot growth in the ME but to a lesser extent compared to the NME. The data showed that the ME exihibited better adaptability, tolerance and less toxicity compared to the NME grown in phytate-rich media. Biomass in both shoots and roots of the ME was significantly greater than that of the NME under relatively high levels of Po . These results corresponded well with earlier researches which reported that the ME demonstrated greater biomass compared to the NME when grown in high P conditions (Arabidopsis (Glycine max (Phaseolus vulgaris (Triticum aestivum L.) grown in sterile phytate agar substrate, demonstrated no significant increase in shoot DW compared to without P-fed controls  indicated not taking up the P into shoots may be an adaptation involved in reducing the P toxicity from phytate-rich media. The aerial part is taken to remove contaminant and root is much harder to collect from soils. However, the whole plant is relatively easy to harvest from eutrophication water. P. hydropiper can be grown in high P soil, as well as in water, providing various ways for high P remediation. The shoot P content of ME was exactly the same as NME (<1% DW) and significantly lower than Gulf and Marshall ryegrass grown in media containing various concentrations of phytate (Pennisetum purpureum Schum.) were verified to be available for P phytoremediation, however, its P content in the harvested shoot was just 2.9 g kg-1 (Pistia stratiotes and Myriophyllum aquaticum (-1) was steady in response to the increasing Po concentrations, whereas that of the NME (3.63–10.84 mg plant-1) significantly decreased under the same conditions. The data presented above were significantly higher compared to P accumulation of other plants grown under phytate agar media . Gulf and Marshall ryegrass (L. multiflorum) had greater Apase activity in root extracts when grown in phytate-sufficient agar substrate . This observation agreed with previous studies which reported that P-sufficient enhanced root phytase  were responsible for great DW performance and P accumulation when transgenic alfalfa (M. sativa) were grown on sand culture containing phytate  and therefore exhibited greater biomass, tissue P content, BCF compared to the NME. A difference in high Po tolerance between the ME and NME caused the variation in root physiological adaptations. The ME showed greater total root length, specific root length, root surface area, and root volume compared with the NME, irrespective of phytate-P level in the growth media. Higher allocation of lateral roots in the ME compared to the NME as a result of the ME demonstrated significantly higher root length, surface area, and volume and finer average diameter in lateral roots when grown in high Po media. Higher APase and phytase activities were also observed in the ME. Thus, high P uptake efficiency from phytate in the ME was due to fine root morphology and high levels of root Apase and phytase activities. Therefore, the ME of P. hydropiper is relatively efficient in assimilating P from phytate-rich media and has potential for phytoremediation of contaminated area with high Po.In the two ecotypes of Daihua Ye and Tingxuan Li carried out the majority of this research work . Zicheng Zheng and Xizhou Zhang participated in collection of seedlings, plant cultivation, and experiment management. Haiying Yu and Guangdeng Chen participated in the statistical analysis process and modified this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The proposed architecture allows reducing the sampling rate to 25% of Nyquist Rate (NR). In addition, the proposed architecture reduces the power consumption to 40%, Percentage Residual Difference (PRD) to 24%, Root Mean Squared Error (RMSE) to 2%, and the computation time from 22 s to 9.01 s, which provide good background for establishing wearable wireless healthcare systems. The proposed architecture achieves robust performance in low Signal-to-Noise Ratio (SNR) for the reconstruction process.Surface Electromyography (sEMG) is a non-invasive measurement process that does not involve tools and instruments to break the skin or physically enter the body to investigate and evaluate the muscular activities produced by skeletal muscles. The main drawbacks of existing sEMG systems are: (1) they are not able to provide real-time monitoring; (2) they suffer from long processing time and low speed; (3) they are not effective for wireless healthcare systems because they consume huge power. In this work, we present an analog-based Compressed Sensing (CS) architecture, which consists of three novel algorithms for design and implementation of wearable wireless sEMG bio-sensor. At the transmitter side, two new algorithms are presented in order to apply the analog-CS theory before Analog to Digital Converter (ADC). At the receiver side, a robust reconstruction algorithm based on a combination of ℓ Furthermore, there is a need for increasing patient mobility because in many cases biomedical sensors for medical monitoring are not wireless yet . This cri.e., amplitude (ranging from 1 μV to 50 mV), frequency, and phase. The sEMG signals exhibit good level of sparsity in the time and frequency domains . If D has the most compact representation in Ψ, then D can be compressed in the proper basis M1 norm by solving the following convex optimization problem  N × 1 is compressed to output analog bio-signal [C] M × 1 such that M ≪ N and then, the ADC needs to digitize a smaller amount of data  is the original sEMG bio-signal, D̂ [i] is the reconstructed sEMG bio-signal, and N is the total number of samples. The CF is calculated by:bD is the number of bits for the original sEMG bio-signal and bC is the amount of bits necessary for processing the compressed sEMG bio-signal. It can be seen from fined as :(9)PRD=6.The existing long-term sEMG monitoring systems with multiple channels suffer from serious problems such as very large amount of data from sampling, limited processing capacity, limited storage, low transmission rate and power, bulky size, poor mobility, and high power consumption. Therefore, they are not suitable for wearable wireless applications that must have small size, excellent mobility, low power consumption, and high transmission rate. As most of the power in a wearable wireless sEMG sensor is dissipated for transmitting bio-data to the receiver, which may reside in a smartphone or any portable device, an optimal solution for minimizing the power consumption is to decrease the amount of bio-data and reduce the duty cycle. Therefore, real-time analog data compression plays an important role for wireless portable devices. Wearable wireless sEMG sensors based on the analog-CS theory aim to establish low power and low sampling rate algorithms for the long-term recording of the electrical activity produced by muscles, which are very useful for treatment and diagnostic purposes as well as for detection of various pathologies.D]N ×1 is compressed to output analog bio-signal [D]M× 1 with M ≪ N. This work has presented a novel approach based on the analog-CS theory, which consists of three algorithms for the acquisition and reconstruction of analog data for a wearable wireless sEMG sensor. At the transmitter side, two new algorithms have presented in order to apply the analog-CS theory before ADC. At the receiver side, a reconstruction algorithm based on a combination of either ℓ1-ℓ1-optimization or ℓ1-optimization and BSBL framework has presented to reconstruct the original signals from the compressed signals with high probability and enough accuracy.In the analog-CS scenario at the transmitter side, the input analog sEMG bio-signal [1-optimization and BSBL framework at the receiver side of the sEMG bio-sensor, lower values for SNR and PC as well as higher values for classification and reconstruction accuracy are obtained. Based on the results in 1-optimization in terms of different values of CR. 1-ℓ1-optimization and BSBL framework for three types of sEMG signals.The proposed algorithms enable recovery of the full sEMG bio-signal while simultaneously compressing the amount of collected analog data at the transmitter side and relaxing the noise at the receiver side. The proposed architecture has offered lower energy consumption compared with the digital-CS scheme and enabled analog data compression. It can be seen from 7.Today's healthcare systems are based on wired/fixed sensors because in many cases biomedical sensors for medical monitoring are not yet wireless. This creates the need for the implementation of new wireless bio-sensors for long-term recording and monitoring of bio-signals. The benefit of using wireless healthcare systems based on wearable wireless bio-sensors can be divided into two areas.One area is the use of new wireless technological solutions for individually based multi-parameter monitoring at home. It means patients with chronic diseases, as well as the constantly growing population of seniors, will benefit from treatment and medical monitoring at home or workplace. Moreover, unrestricted freedom of movement implies the use of wireless and even implanted biomedical sensors that greatly enhance home monitoring and follow-up of medical conditions. The second area of benefit rests in increasing the efficiency of treatments at hospital and medical centers. The ambulatory systems based on new technologies can become lighter, smaller, and capable of recording multiple signals up to 48 h. The recorded signals are saved in flash-type memories, which can be transferred to the hospital and medical centers for further actions. On the other hand, the increase of heath costs urgently prompts the development of ambulatory systems to reduce the number of patients going to hospital and medical centers.1-optimization and BSBL framework has been presented to reconstruct the original bio-signals from the compressed bio-signals with high accuracy. In addition, this work has presented an analog-based CS theory procedure that consists of two interesting properties: (1) reduction in power consumption, which significantly lowers the average bio-sensor power; (2) a reconstruction process robust to noise, because the noise is not sparse on the sparsity basis. Therefore, the resolution of the data acquisition step, and hence the ADC, can be relaxed without undermining the quality of the reconstruction. The proposed architecture has reduced the sampling rate down to 25% of NR, power consumption to 40%, PRD to 24%, RMSE to 2%,and total computation time from 22 s to 9.01 s, which provide good background for establishing wearable wireless healthcare systems. In addition, the proposed architecture simultaneously has recovered the original bio-signals with good level of accuracy and SNR greater than 95.8 dB. Wireless sEMG systems based on the proposed architecture and the three novel proposed algorithms will be able to improve healthcare services for patients not only in hospital or at medical center but also at their homes and workplaces, to improve the overall quality of life and to minimize healthcare costs.Therefore, it is necessary to design portable, low power, low sampling rate, high performance wireless health care systems that can deliver healthcare services anywhere at any time. This paper has presented an analog-based CS theory procedure that consists of three novel algorithms to design and implement the wearable wireless sEMG bio-sensor architecture for sEMG bio-signals, which are sparse in both the time and the frequency domains. At the transmitter side, two new algorithms have been presented in order to apply the analog-CS theory before ADC to maximize the processing speed by minimizing both the load of processing time and the duty cycle. At the receiver side, a faithful reconstruction algorithm based on the combination of multi-ℓ8.1-optimization and BSBL framework for other types of multi-sparse bio-signals to decrease the computational complexity at the receiver side.We intend to develop the tools for wireless sEMG bio-sensor and provide them to the web-based portals. The developed tools can be designed to access the valuable data stored on medical servers. Furthermore, we will develop a hybrid reconstruction algorithm based on multi-ℓ


Behavior change communication for improving handwashing with soap can be labor and resource intensive, yet quality results are difficult to achieve. Nudges are environmental cues engaging unconscious decision-making processes to prompt behavior change. In this proof-of-concept study, we developed an inexpensive set of nudges to encourage handwashing with soap after toilet use in two primary schools in rural Bangladesh. We completed direct observation of behaviors at baseline, after providing traditional handwashing infrastructure, and at multiple time periods following targeted handwashing nudges . No additional handwashing education or motivational messages were completed. Handwashing with soap among school children was low at baseline (4%), increasing to 68% the day after nudges were completed and 74% at both 2 weeks and 6 weeks post intervention. Results indicate that nudge-based interventions have the potential to improve handwashing with soap among school-aged children in Bangladesh and specific areas of further inquiry are discussed. Handwashing with soap at key junctures can reduce the risk of enteric and respiratory infections ,2; howevIn high-income countries, “nudging” has gained attention as a means to trigger desired behavioral outcomes. Instead of changing the conscious decision-making process, nudges alter the environmental context in which a decision or behavior is completed . Nudges In this pilot study, we tested the potential for nudge-based interventions to improve handwashing behaviors after toilet use among primary school-aged children in rural Bangladesh. We focused our proof-of-concept study on primary schools in Bangladesh. The school environment presents an opportunity for the efficient spread of enteric and respiratory pathogens, and prevention in schools must be prioritized. Behavior change interventions in schools have resulted in handwashing improvements similar to those seen in domestic settings. Two trials in Kenya—one in rural western Kenya , one in In August 2014, we identified two rural primary schools in Bangladesh for our proof-of-concept study. Schools had 220 and 514 students each. Both had on-site water connections (handpumps) and latrines . Prior tDuring the study, soap was provided to all participating schools and school custodians were instructed to make soap available and refill water storage containers at the start of each school day. No other hygiene promotion activities were included as part of the intervention.For direct observations, trained staff positioned at discreet locations on school grounds completed structured observations of handwashing practices after leaving the school latrine, specifically if the children washed both hands and whether soap was used. Observations were completed at baseline (prior to construction), 1 day after each infrastructure and nudge installation  and 2 and 6 weeks after the intervention was completed. Each observation period consisted of one full school day, typically ranging from 8 am to 3 pm. Observers were allowed to take short breaks during observations during periods when students were in class. Observers were given extra soap to place either at the handpump (at baseline) or at the handwashing station if supplies were not available that day, although this was only necessary during baseline observations.loco parentis) for participation prior to interventions and data collection. The study was conducted in accordance with standard ethical guidelines for research, and the protocol was approved by the Institutational Review Board at the University of Oklahoma (Protocol 4499).School principles gave informed consent . Direct comparison of intervention costs should be considered with caution, however. Education-based interventions are typically intended to promote improved handwashing beyond the immediate school environment, thus can have a broader impact on behaviors. If and how nudges inform the creation of new habits that extend beyond the school environment requires further exploration.There is general recognition that handwashing infrastructure and materials are an important component of the enabling environment for behavior change ,24. InfrObserved rates of handwashing in our study after nudges were installed are comparable to those seen following intensive educational and/or motivational messaging in both community ,4,6 and The high rates of observed handwashing at 2-weeks and 6-weeks (74%) after the intervention suggest that environmental nudges can have lasting effects on behaviors. External nudges may require pre-existing knowledge or behavioral intention to successfully trigger desired behavioral outcomes. It is beyond the scope of the study to determine if this latent knowledge of handwashing is due to targeted behavior change interventions or modeling behaviors in the home and other settings. Nudges may present a viable alternative to traditional messaging and behavior change communication programs when handwashing knowledge already exists. The potential synergies of combining the two approaches in school settings (education + nudges) requires further investigation.Our pilot project was limited to just two schools based on budgetary constraints. Trials with a larger number of participating schools and over prolonged durations are needed in order to fully document the potential and limitations of environmental nudges. Schools with robust water infrastructure were selected in order to concentrate on the immediate environment surrounding handwashing—our intervention did not address underlying issues of water availability and inconsistent provision of materials that limit handwashing in many resource-constrained settings . While oOur proof-of-concept study has demonstrated that strategic environmental nudges can have a positive and potentially lasting influence on handwashing behaviors among school-aged children. Future studies in a larger number of schools will compare the behavioral impact of nudges against and in combination with motivational and/or educational messaging, explore the long-term sustainability of behavioral impacts, and investigate the potential for nudges to influence handwashing behaviors in domestic and other institutional settings.


Ictidomys tridecemlineatus) has the remarkable ability to descend to low, near 0°C temperatures without falling into cardiac arrest. We hypothesized that the transcription factors GATA4 and Nkx2-5 may play a role in cardioprotection by facilitating the expression of key downstream targets such as troponin I, troponin C, and ANP . This study measured relative changes in transcript levels, protein levels, protein post-translational modifications, and transcription factor binding over six stages: euthermic control (EC), entrance into torpor (EN), early torpor (ET), late torpor (LT), early arousal (EA), and interbout arousal (IA). We found differential regulation of GATA4 whereby transcript/protein expression, post-translational modification (phosphorylation of serine 261), and DNA binding were enhanced during the transitory phases  of hibernation. Activation of GATA4 was paired with increases in cardiac troponin I, troponin C and ANP protein levels during entrance, while increases in p-GATA4 DNA binding during early arousal was paired with decreases in troponin I and no changes in troponin C and ANP protein levels. Unlike its binding partner, the relative mRNA/protein expression and DNA binding of Nkx2-5 did not change during hibernation. This suggests that either Nkx2-5 does not play a substantial role or other regulatory mechanisms not presently studied  are important during hibernation. The data suggest a significant role for GATA4-mediated gene transcription in the differential regulation of genes which aid cardiac-specific challenges associated with torpor-arousal.Hibernation is an adaptive strategy used by various mammals to survive the winter under situations of low ambient temperatures and limited or no food availability. The heart of hibernating thirteen-lined ground squirrels ( The transcription, translation, and post-translational modification of GATA4 are regulated throughout the torpor-arousal cycle and this regulation is essential to achieving increases in the relative expression of downstream genes. In turn, changes in the relative expression levels of Troponin I, Troponin C, and ANP may represent adaptive mechanisms which will facilitate the expected physiological changes such as shifts in heart contraction rate and coping mechanisms to deal with changes in blood pressure.Our findings demonstrate that GATA4 and its downstream targets are regulated in the heart of the hibernating thirteen-lined ground squirrel over the torpor-arousal cycle with significant changes occurring particularly in entrance and early arousal stages. Nkx2–5, the binding partner of GATA4, is not differentially regulated over the torpor-arousal cycle, but is nevertheless present and capable of interacting with GATA4 to facilitate increased expression of


Time-spatial labeling inversion pulse (Time-SLIP) magnetic resonance imaging allows non-invasive visualization of cerebrospinal fluid (CSF) movement. Our study evaluated the sensitivity of the Time-SLIP tag placement on the measurement of CSF reflux from the third ventricle into the lateral ventricles via the foramen of Monro.2 = 0.74). The further the distance of the top (superior edge) of the tag from the plane of the free margin of the septum pellucidum, the less reflux into the lateral ventricles was observed (P = 0.006).Multiple Time-SLIP MRI scans were obtained in three healthy volunteers (23–55 years of age) evaluating the observed CSF pulsation and reflux from the third ventricle into the lateral ventricles while varying the placement of the tag. Linear regression was performed to evaluate the effects of tag position on the amount of visualized reflux and pulsation. Variation in the position of the tag relative to the plane of the free margin of the septum pellucidum produced a significant inverse variation in the observed reflux into the lateral ventricles  contains supplementary material, which is available to authorized users. Cerebrospinal fluid (CSF) plays a pivotal role in normal physiology of the human central nervous system (CNS). CSF is thought to perform many functions such as supplying mechanical support for the brain, contributing to maintenance of intracranial pressure, stability against traumatic forces, and in clearance of metabolic by-products , 2. WithMR sequences such as phase-contrast imaging (PC-MRI) have had a substantial impact on our ability to monitor changes in CSF flow , 8. YamaThe purpose of our study is to evaluate the effects of tag placement on the measurement of CSF reflux from the third ventricle into the lateral ventricles via the foramen of Monro. This normal physiologic phenomenon has been reported to be abnormal in various clinical conditions such as normal pressure hydrocephalus and noncommunicating hydrocephalus , 10. TheOur HIPAA-compliant study met criteria for exemption from full review of the University Institutional Review Board. Informed consent was waived for retrospective review of pre-existing data. Three healthy volunteers ranging from 23 to 55 years of age were imaged.Imaging was performed on a Vantage Titan 3T MRI  with a 32-channel head coil. The Time-SLIP sequence was obtained in an oblique coronal plane oriented parallel to the long-axis of the foramen of Monro  and a TE of 80 ms. The matrix size was 224 × 224 with a field of view of 23 × 23 cm and slice thickness of 5-mm. Electrocardiographic time delay from an R wave to the initiation of the nonselective inversion recovery pulse was 0 ms. The subsequent 2-D single-shot FSE images were obtained within one acquisition with variable TIs increasing in increments of 200 ms for a total of 15 times starting at 2,000 ms. The acquisition time for each individual run averaged about 3.5 min depending on pulse rate.Multiple scans were obtained in each subject with the tag varying in position. The top (superior) of the tag was placed in locations ranging from 8.5 mm below the free margin of the septum pellucidum (FMSP) to 13 mm above the FMSP. Images were reviewed at a dedicated radiology imaging workstation. The distance from the top (superior aspect) of the tag and the plane of the FMSP was determined. The plane of the FMSP was defined as a perpendicular line tangential to the inferior-most aspect of the septum pellucidum . Data was analyzed with a linear regression model to determine correlations between measurements of CSF displacement relative to the placement of the CSF tag. Only those measurements with the tag placed below the plane of the FMSP were used in regression analysis of the reflux height above the plane of the FMSP.2 = 0.74). That is, the further the distance of the top (superior edge) of the tag from the plane of the FMSP, the less visualized reflux into the lateral ventricles (P = 0.006). Analysis of each individual subject also confirmed a progressive decrease in visualized reflux with increasing distance from the FMSP within each subject .The position of the tag also had a measurable effect on the visualized total height of CSF pulsation Figure c. As theDespite increasing height of pulsation as the tag is moved caudally, there continued to be a decrease in the amount of observed reflux into the lateral ventricles Figure . We idenThe results of our study show a substantial variation in the amount of observed reflux from the third ventricle into the lateral ventricles based upon the position of the CSF tag in Time-SLIP imaging. For demonstration of reflux into the lateral ventricles, we found that the optimum tag location is with the top (superior) border of the tag at the level of the FMSP.We postulate the explanation of these findings is that the majority of CSF exchanged between the third and lateral ventricles during normal pulsation is from fluid located in the cephalad portion of the third ventricle. Fluid tagged in the more caudal portion of the third ventricle contributes less to the overall exchanged pool of fluid. An alternative hypothesis would be that fluid closer to the foramen experiences a higher reflux velocity resulting in an apparent increase in reflux height.Modern investigation into the normal flow of CSF has suggested a much more complex circulation than was historically thought –15. In vDisturbance of the normal pulsatile nature of CSF flow has been shown to correlate with many diseases of the CNS. Recent studies have confirmed decreased reflux from the third ventricle into the lateral ventricles in conditions such as aqueductal stenosis , noncommThe advent of MRI sequences sensitive to flow effects has greatly advanced our understanding of normal and abnormal CSF flow patterns. One of the most commonly used MRI pulse sequences is phase-contrast imaging (PC-MRI) , 8. PhasWe have shown that the amount of visualized CSF reflux into the lateral ventricles in Time-SLIP imaging is dependent on the positioning of the CSF tag. To the authors’ knowledge, there are no existing publications describing the distance dependence of Time-SLIP tag placement on the amount of visualized CSF reflux. Our results suggest caution be exercised when interpreting a lack of reflux as pathologic when the tag position is not optimal. We have also illustrated that inappropriate tag positioning may continue to show CSF reflux, but the amount of reflux will be underestimated. The information presented herein is essential for future studies assessing the physiologic and pathologic variability of this phenomenon.The amount of observed CSF reflux into the lateral ventricles in Time-SLIP imaging is dependent on the positioning of the CSF tag with decreasing amount of reflux the further caudal the CSF tag is relative to the free margin of the septum pellucidum.


The aim of this study is to investigate the efficacy and safety of sedoanalgesia performed outside the operating room by pediatricians trained in advanced airway management and life support.Midazolam and ketamine were administered consecutively by intravenous route under cardiorespiratory monitoring for painful procedures of pediatric hematology.A total of 115 patients had 237 sedoanalgesia sessions. Sedation time was 24.02±23.37 s and sedation success was 92.5% (Ramsay scores of ≥5). Patient satisfaction was high. The recovery time was 28.81±14.4 min. Although statistically significant (p<0.01) increases in systolic and diastolic blood pressure, heart rate, and respiratory rate were observed without clinical importance, they improved without any intervention. No severe adverse events were observed.Sedoanalgesia with intravenous midazolam and ketamine for pediatric hematology and oncology patients’ painful minor invasive procedures performed in an optimally equipped setting outside the operating room by pediatricians trained and certificated in advanced airway management and life support is effective and safe. Lumbar puncture, bone marrow aspiration/biopsy, and intrathecal therapy are painful procedures. In patients with leukemia, traumatic lumbar puncture due to poor patient stabilization is a diagnostic dilemma and may cause seeding of the blasts into the cerebrospinal fluid from circulation ,2. The bIn this study, the aim was to evaluate the efficacy and safety of procedural sedoanalgesia performed by pediatricians and hematologists trained in advanced airway management and life support.This prospective study was planned by pediatric hematologists. The ethics committee of the center approved the study and written informed consent was obtained. Physicians were trained in advanced life support and had a proficient command of the characteristics and pharmacology of the sedatives/analgesics. One of the physicians performed the invasive procedure, and the other administered the drugs, assisted in patient monitoring, and recorded the vital signs and sedation and recovery times. During the lumbar punctures and intrathecal therapy a nurse assisted in proper positioning of the patient.Sedation time (the period to induce sedation after the administration of both drugs) and recovery time  were recorded.Sedation was initiated with midazolam  and continued with ketamine . Level of sedation was assessed according to the modified Ramsay scale . When thStatistical analysis was performed using SPSS 2.0 . For evaluation of demographic characteristics descriptive statistics were used, and for intergroup comparison of the parameters that had normal distribution the paired samples t-test was used.Between May 2012 and May 2013, a total of 237 invasive procedures  were performed in 115 children  with sedoanalgesia.Median sedation time was 24.02±23.37 s (range: 1-300 s). Median recovery time was 28.81±14.45 min (range: 5-90 min). In 87% (n=207) of the sessions no additional dose was administered. Due to prolongation of the procedures or unsatisfactory sedation 1 additional dose of midazolam, 1 additional dose of ketamine, and 2 additional doses of ketamine were administered in 2 (0.8%), 29 (12.2%), and 1 (0.8%) of the sedoanalgesia sessions, respectively. Out of 32 additional doses, 17 (53%) were administered due to multiple painful procedures in the same session.Oxygen saturation was over 90% in all the patients during sedation and at recovery. There was no apnea, respiratory depression, or need for assisted ventilation/intubation. None of the patients required flumazenil administration. No severe adverse events were observed. Vital signs are shown in In developing countries during painful procedures many centers perform no sedoanalgesia due to limited numbers of anesthesiologists, busy operation rooms, and inadequate training in sedoanalgesia, advanced airway management, and life support . In manyWhen midazolam and ketamine are used alone, respiratory depression with midazolam and dysphoric reactions  with ketamine may occur. When midazolam is used with ketamine, faster analgesia, amnesia, and fewer side effects occur ,10,11. OIn recent reports, similar to our findings, a significant increase in cardiovascular parameters was seen due to ketamine’s sympathomimetic action via inhibition of catecholamine reuptake, but these parameters returned to baseline values at recovery and no treatment was required ,15,16,17In other published studies the sedation time was similar to that of the present study ,14,16. POverall adverse event rate in our study was comparable to those of some other studies ,19,20. KVenipuncture is another painful procedure for outpatient children, but oral, nasal, and rectal administrations of midazolam can provide slower sedation and this may cause a delay in the procedure. The intramuscular route is also painful and may require additional injections. With the intravenous route, sedoanalgesia can be achieved faster and, if necessary, additional doses and drugs for cardiopulmonary resuscitation can be administered easily.With adherence to the published guidelines, sedoanalgesia with intravenous midazolam and ketamine performed by two physicians, trained in airway management and life support, in an optimally equipped setting outside the operating room is safe and efficient. Sedoanalgesia reduces the physical and psychological trauma of the invasive procedures for the patients, parents, and physicians and increases the success of the procedures.