Synaptic basis of a sub-second representation of time in a neural circuit model.

Temporal sequences of neural activity are essential for driving well-timed behaviors, but the underlying cellular and circuit mechanisms remain elusive. We leveraged the well-defined architecture of the cerebellum, a brain region known to support temporally precise actions, to explore theoretically whether the experimentally observed diversity of short-term synaptic plasticity (STP) at the input layer could generate neural dynamics sufficient for sub-second temporal learning. A cerebellar circuit model equipped with dynamic synapses produced a diverse set of transient granule cell firing patterns that provided a temporal basis set for learning precisely timed pauses in Purkinje cell activity during simulated delay eyelid conditioning and Bayesian interval estimation. The learning performance across time intervals was influenced by the temporal bandwidth of the temporal basis, which was determined by the input layer synaptic properties. The ubiquity of STP throughout the brain positions it as a general, tunable cellular mechanism for sculpting neural dynamics and fine-tuning behavior.

Outdoor pollen is a trigger of child and adolescent asthma emergency department presentations: A systematic review and meta-analysis.

BACKGROUND: In the context of increased asthma exacerbations associated with climatic changes such as thunderstorm asthma, interest in establishing the link between pollen exposure and asthma hospital admissions has intensified. Here, we systematically reviewed and performed a meta-analysis of studies on pollen and emergency department (ED) attendance. METHODS: A search for studies with appropriate search strategy in MEDLINE, EMBASE, Web of Science and CINAHL was conducted. Each study was assessed for quality and risk of bias. The available evidence was summarized both qualitatively and meta-analysed using random-effects models when moderate heterogeneity was observed. RESULTS: Fourteen studies were included. The pollen taxa investigated differed between studies, allowing meta-analysis only of the effect of grass pollen. A statistically significant increase in the percentage change in the mean number of asthma ED presentations (MPC) (pooled results from 3 studies) was observed for an increase in 10 grass pollen grains per cubic metre of exposure 1.88% (95% CI = 0.94%, 2.82%). Time series studies showed positive correlations between pollen concentrations and ED presentations. Age-stratified studies found strongest associations in children aged 5-17 years old. CONCLUSION: Exposure to ambient grass pollen is an important trigger for childhood asthma exacerbations requiring ED attendance. As pollen exposure is increasingly a problem especially in relation to thunderstorm asthma, studies with uniform measures of pollen and similar analytical methods are necessary to fully understand its impact on human health.

In vitro Evaluation of the Relationship between Gray Scales in Digital Intraoral Radiographs and Hounsfield Units in CT Scans.

BACKGROUND: Jaw bone quality plays an essential role in treatment planning and prognosis of dental implants. Regarding several available methods for bone density measurements, they are not routinely used before implant surgery due to hard accessibility. OBJECTIVE: An in vitro investigation of correlation between average gray scale in direct digital radiographs and Hounsfield units in CT-Scan provides a feasible method for evaluating alveolar bone quality prior to implant surgery. METHODS: 26 sheep's mandibles in which a square shape ROI marked by gutta percha, were prepared. Three direct digital radiographs (CCD sensor) from every specimen were taken using 80, 100 and 200 milli-seconds. Then, the average gray levels for ROIs were calculated using a costume-made software. Next, the specimens were scanned using a 16-slice spiral CT and the Hounsfield Unit of each ROI was calculated. Pearson analysis measured the correlation between Hounsfield units and average gray levels. RESULTS: There was a positive correlation between Hounsfield unit and average gray level in the radiographs and the correlation was better in higher exposure times. CONCLUSION: It is possible to estimate Hounsfield unit and bone density in the jaw bones using average gray scale in a digital radiograph. This approach is easy, simple and available and also results in lower patient exposure comparing other bone densitometric analysis methods.

Epidemiology and trend of common cancers in Iran (2004-2008).

BACKGROUND: Cancer is one of the most important causes of mortality worldwide. It includes approximately 13% of death cases. This study aimed to investigate the incidence trend of common cancers in Iran during 2004-2008 to improve reporting distribution the disease. METHODS: This was a retrospective study. The study population was all cases of cancer diagnosed in Iran during 2004-2008. The crude incidence rate of cancers was calculated per 100 000 people by age groups and sex. Age-standardised incidence rates (ASRs) were calculated using direct standardisation and the world standard population. Data were analysed using SPSS (version 17) and Microsoft Office Excel 2007. RESULTS: In this study, a total of 301 055 cases of cancer were diagnosed. ASRs were 60.51 and 84.51 in women and men respectively. Most common cancers in men were skin (ASR = 18.85), stomach (15.02), bladder (ASR = 11.25), prostate (ASR = 8.93) and colorectal (ASR = 8.29). Most common cancers in women were breast (ASR = 18.24), skin (ASR = 12.01), colorectal (ASR = 7.75), stomach (ASR = 7.05) and haematocyte (ASR = 4.01). CONCLUSION: A significant increase was observed in the incidence of cancers in the country. Therefore, it is necessary to perform screening, early diagnosis and treatment in early stages of cancers.

Circulating exosomes and exosomal microRNAs as biomarkers in gastrointestinal cancer.

The most important biological function of exosomes is their possible use as biomarkers in clinical diagnosis. Compared with biomarkers identified in conventional specimens such as serum or urine, exosomal biomarkers provide the highest amount of sensitivity and specificity, which can be attributed to their excellent stability. Exosomes, which harbor different types of proteins, nucleic acids and lipids, are present in almost all bodily fluids. The molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), are promising as biomarkers in clinical diagnosis. This discovery that exosomes also contain messenger RNAs and miRNAs shows that they could be carriers of genetic information. Although the majority of RNAs found in exosomes are degraded RNA fragments with a length of <200 nucleotides, some full-length RNAs might be present that may affect protein production in the recipient cell. In addition, exosomal miRNAs have been found to be associated with certain diseases. Several studies have pointed out miRNA contents of circulating exosomes that are similar to those of originating cancer cells. In this review, the recent advances in circulating exosomal miRNAs as biomarkers in gastrointestinal cancers are discussed. These studies indicated that miRNAs can be detected in exosomes isolated from body fluids such as saliva, which suggests potential advantages of using exosomal miRNAs as noninvasive novel biomarkers.

Enhanced detection sensitivity of prostate-specific antigen via PSA-conjugated gold nanoparticles based on localized surface plasmon resonance: GNP-coated anti-PSA/LSPR as a novel approach for the identification of prostate anomalies.

Prostate-specific antigen (PSA) is used to screen for prostate disease, although it has several limitations in its application as an organ-specific or cancer-specific marker. Furthermore, a highly specific/sensitive and/or label-free identification of PSA still remains a challenge in the diagnosis of prostate anomalies. We aimed to develop a gold nanoparticle (GNP)-conjugated anti-PSA antibody-based localized surface plasmon resonance (LSPR) as a novel approach to detect prostatic disease. A total of 25 nm colloidal gold particles were prepared followed by conjugation with anti-PSA pAb (GNPs-PSA pAb). LSPR was used to monitor the absorption changes of the aggregation of the particles. The size, shape and stability of the GNP-anti-PSA were evaluated by dynamic light scattering transmission electron microscopy (TEM) and zetasizer. The GNPs-conjugated PSA-pAb was successfully synthesized and subsequently characterized using ultraviolet absorption spectroscopy and TEM to determine the size distribution, crystallinity and stability of the particles (for example, stability of GNP: 443 mV). To increase the stability of the particles, we pegylated GNPs using an N-(3-dimethylaminopropyl)-N*-ethylcarbodiimide hydrochloride (EDC)/N-hydroxylsuccinimide (NHS) linker (for example, stability of GNP after pegylation: 272 mV). We found a significant increase in the absorbance and intensity of the particles with extinction peak at 545/2 nm, which was shifted by ~1 nm after conjugation. To illustrate the potential of the GNPs-PSA pAb to bind specifically to PSA, LSPR was used. We found that the extinction peak shifted 3 nm for a solution of 100 nM unlabeled antigen. In summary, we have established a novel approach for improving the efficacy/sensitivity of PSA in the assessment of prostate disease, supporting further investigation on the diagnostic value of GNP-conjugated anti-PSA/LSPR for the detection of prostate cancer.

Effects of equiaxial strain on the differentiation of dental pulp stem cells without using biochemical reagents.

During orthodontic treatments, applied mechanical forces create strain and result in tooth movement through the alveolar bone. This response to mechanical strain is a fundamental biological reaction. The present study evaluated the effect of equiaxial strain within the range of orthodontic forces on the osteogenic differentiation of human dental pulp stem cells (hDPSCs). Following isolation and culture of hDPSCs, 3rd passage cells were transferred on a silicone membrane covered with collagen. Cell adhesion to the membrane was evaluated under scanning electron microscope (SEM). Cells were divided into three groups: the first group was placed in a conventional culture medium, transferred to an equiaxial stretching device (3% strain for 2 weeks). The positive control was placed in an osteogenic medium with no mechanical strain. The negative control group was placed in the conventional culture medium with no mechanical strain either. Study groups were evaluated for expression ofosteogenic markers (Alkaline phosphatase and Osteopontin) with immunofluorescence and real time PCR. SEM images revealed optimal adhesion of cells to the silicone membrane. Immunofluorescence study demonstrated that osteocalcin expression occurred after 2 weeks in the two groups under mechanical and chemical signals. After application of equiaxial strain, level of expression of osteogenic markers was significantly higher than in the negative and positive control groups. Based on the study results, static equiaxial strain which mimics the types of orthodontic forces can result in differentiation of hDPSCs to osteoblasts. The results obtained may be used in cell therapy and tissue engineering.

Psoriasin (S100A7) associates with integrin ß6 subunit and is required for αvß6-dependent carcinoma cell invasion.

Expression of the integrin αvß6 is upregulated in a variety of carcinomas where it appears to be involved in malignant progression, although the biology of this integrin is not fully explored. We have generated oral carcinoma cells that express αvß6 composed of wild-type αv and a mutant ß6 that lacks the unique C-terminal 11 amino acids (aa). We found that these residues, although not required for αvß6-dependent adhesion or migration, are essential for αvß6-dependent invasive activity. We have used a proteomic approach to identify novel binding partners for the ß6 subunit cytoplasmic tail and report that psoriasin (Psor) (S100A7) bound preferentially to the recombinant ß6 cytoplasmic domain, though not in the absence of the unique C-terminal 11aa. Endogenous cellular Psor co-precipitated with endogenous ß6 and colocalised with αvß6 at the cell membrane and intracellular vesicles. Knockdown of Psor, with small interfering RNA, had no effect on αvß6-dependent adhesion or migration but abrogated αvß6-mediated oral carcinoma cell invasion both in Transwell and, the more physiologically relevant, organotypic invasion assays, recapitulating the behaviour of the ß6-mutant cell line. Membrane-permeant Tat-peptides encoding the unique C-terminal residues of ß6, bound directly to recombinant Psor and inhibited cellular Psor binding to ß6; this blocked αvß6-dependent, but not αvß6-independent, invasion. These data identify a novel interaction between Psor and ß6 and demonstrate that it is required for αvß6-dependent invasion by carcinoma cells. Inhibition of this interaction may represent a novel therapeutic strategy to target carcinoma invasion.

Efficient replacing of fetal bovine serum with human platelet releasate during propagation and differentiation of human bone-marrow-derived mesenchymal stem cells to functional hepatocyte-like cells.

OBJECTIVES: The aim of this study was to find out substitution effect of fetal bovine serum (FBS) with human platelet releasate (HPR) as a major growth factor source during expansion and differentiation of human bone marrow-derived mesenchymal stem cells (hBMSC) into hepatocytes. METHODS: Propagation and differentiation potential of hBMSCs into hepatocyte-like cells in a medium fortified with HPR instead of FBS were investigated with morphological, cytochemical and molecular experiments. RESULTS: Multiplex analysis showed that HPR was more efficient than FBS in supporting hBMSC outgrowth. The proliferation rate of MSC in presence of HPR (derived from 10(9) platelets/ml) was about threefold greater than that of FBS (P < 0.001). Despite the differences in MTT value, hBMSCs-driven HPR or FBS did not differ in terms of gross morphology, immunophenotype and osteogenic differentiation potential. Hepatic differentiation of hBMSCs was successfully performed in the media enriched with HPR. Immunoreactivity of cells with monoclonal antibodies against for albumin and alpha-fetoprotein (AFP) was even more positive in hepatocytes differentiated in presence of HPR as compared to that of FBS. The gene expression of albumin, AFP and cytokeratin-18 at mRNA levels in differentiated cells attest to supporting role of HPR in hepatic differentiation media. These findings were further confirmed with greater urea production (approximately twofold) in the culture media of cells differentiated under HPR compared to that in FBS (P < 0.001). CONCLUSION: Human platelet releasate is an efficient and safe substitute for FBS in culture media used for expansion and differentiation of hBMSCs to hepatocyte.

HBV core sequence: definition of genotype-specific variability and correlation with geographical origin.

There are eight genotypes and nine subtypes of HBV. Small differences in geographical origin are associated with sequence changes in the surface gene. Here, we compared core gene sequences from different genotypes and geographical regions. Specific combinations of 24 amino acid substitutions at nine residues allowed allocation of a sequence to a subtype. Six of these nine residues were located in different T cell epitopes depending on HBV geographical area and/or genotype. Thirty-seven nucleotide changes were associated uniquely with specific genotypes and subtypes. Unique amino acid and nucleotide variants were found in a majority of sequences from specific countries as well as within subtype ayw2 and adr. Specific nucleotide motifs were defined for Korean, Indian, Chinese, Italian and Pacific region isolates. Finally, we observed amino acid motifs that were common to either South-east Asian or Western populations, irrespective of subtype. We believe that HBV strains spread within constrained ethnic groups, result in selection pressures that define sequence variability within each subtype. It suggests that particular T cell epitopes are specific for geographical regions, and thus ethnic groups; this may affect the design of immunomodulatory therapies.

A study of the sympathetic skin response and sensory nerve action potential after median and ulnar nerve repair.

The purpose of this study was to compare SSR with sensory nerve action potential (SNAP) responses in regeneration of injured peripheral nerves after nerve repair. We studied 10 male patients with a mean age of 26.7 years. All the patients had complete laceration of median or ulnar nerves. The patients were followed up at least for six months. SSR and SNAP assessment were performed every one to two months. Normal hands were used as controls. SSR was positive after 15.8 +/- 9.4 weeks (mean +/- 2 SD) and SNAP after 27.8 +/- 12.9 weeks (mean +/- 2 SD). The difference was statistically significant (P value < 0.001). This can be due to more rapid growth of sympathetic unmyelinated fibers relative to sensory myelinated fibers. This study also shows that recovery of the sudomotor activity following nerve repair is satisfactory in general and SSR can be used as a useful and sensitive method in the evaluation of sudomotor nerve regeneration.

A prospective study of vaginal pH as a predictor of preterm delivery.

OBJECTIVE: To test the usefulness of vaginal pH determinations in the prediction of the risk of preterm delivery at or before 36 weeks of gestation. METHODS: This was a prospective study of asymptomatic pregnant women. Vaginal pH was determined using pH paper in a sterile speculum examination during prenatal visits. Patients were followed to delivery and hospital records were reviewed to extract obstetric information. A total of 308 women agreed to participate and met the criteria for enrolment. Preterm delivery was defined as delivery at or prior to 36 weeks of gestation. Abnormal pH was defined as a pH of > 5.0. RESULTS: Abnormal vaginal pH was associated with increased risk of preterm delivery, (OR 3.3, 95% CI 1.15, 9.2; p = 0.02). In the first trimester, an abnormal vaginal pH was not associated with preterm delivery (p = 0.3). After the first trimester, a vaginal pH of 5.0 or greater was associated with increased risk of preterm delivery (OR 9.6, 95% CI 2.0, 45.5; p = 0.001) as well as delivering an infant of less than 2500 g (OR 3.1, 95% CI 1.2, 7.8; p = 0.015). History of a previous preterm delivery was associated with increased risk of preterm delivery (OR 6.2, 95% CI 1.6, 23.7; p = 0.02). A logistic regression model used to control for a history of preterm delivery and race showed abnormal vaginal pH to remain as an independent predictor of preterm delivery (p = 0.01). CONCLUSIONS: High vaginal pH (> or = 5.0) identified women at risk for preterm delivery.

Intraneural perineurioma involving the median nerve.

Intraneural perineurioma is a rare clinical entity, which tends to affect major nerve trunks in the upper extremities. On light microscopy, numerous pseudo-onion-bulb structures having a central clear area are surrounded by concentric layers of eosinophilic elongate cells having spindled nuclei. Immunohistochemistry of concentric cells stains positive for epithelial membrane antigen but negative for S100 protein. Because of the small number of cases, no consensus has been made on proper treatment of this entity. Although none of the patients who have had excision of tumor with nerve grafting have had sensory nerve recovery, we believe each patient should be individualized until more data are available regarding this tumor.

Antepartum and postpartum Papanicolaou smears. Are they both necessary?

OBJECTIVE: To determine if a Papanicolaou smear performed during pregnancy needs to be repeated at the postpartum visit. STUDY DESIGN: A retrospective chart review was performed on women who received prenatal care from our obstetric clinic and returned for a postpartum visit. All pregnant women who had both a Papanicolaou smear in pregnancy and another at the postpartum visit, about six weeks after delivery, were included. Six hundred one patients were studied who had complete records between 1995 and 1996. RESULTS: The average length of time between the two smears was 209 days. With the exception of a lower frequency of the presence of endocervical cells in the antepartum Papanicolaou smears, there were no differences between the distribution of Papanicolaou smear results. In patients without risk factors and a normal antepartum Papanicolaou smear, the prevalence of squamous intraepithelial lesion on the postpartum smear was very low (4 in 1,000). CONCLUSION: In patients without risk factors for cervical intraepithelial neoplasia and a normal Papanicolaou smear in pregnancy, a Papanicolaou smear should be repeated at the recommended yearly interval.

Ventricular arrhythmias, electrophysiologic studies, and devices.

Because of the high incidence of heart disease in the elderly, ventricular tachyarrhythmias are not infrequent. Determining the nature and extent of the underlying heart disease and identifying precipitating causes is required prior to instituting long-term therapy. Recent studies suggest that for hemodynamically unstable ventricular tachyarrhythmias, mortality is lower with the implantable cardioverter-defibrillator compared with pharmacologic therapy. This benefit is likely to be more modest in the elderly because of competing cardiac and noncardiac causes of death. For similar reasons, the favorable results reported with the prophylactic use of the implantable cardioverter-defibrillator are likely to be attenuated in the elderly.

Reversing the initial phase polarity in biphasic shocks: is the polarity benefit reproducible?

The effect of initial phase polarity (IPP) reversal using biphasic shocks on DFT at the time of implantation of implantable cardioverter defibrillator and the reproducibility of this effect during predischarge testing was evaluated in a randomized fashion. Twenty-two patients with ventricular tachycardia or ventricular fibrillation (VF) who received either the Medtronic 7219D (7 patients), 7219C (12 patients), 7223 (1 patient), or CPI Ventak MINI (2 patients) were studied. The DFT was determined in a randomized fashion at implantation and during predischarge testing using a binary search protocol. Initial shock was delivered at 12 J. If successful, subsequent shock was delivered at 6 J, following which the shock was incremented or decremented by 3 J depending upon the success. The DFT for right ventricular (RV)- and RV + IPP was 10.9 +/- 4.1 J and 11.1 +/- 4.0 J, respectively, at implant (P = ns) and 9.7 +/- 4.3 J and 8.4 +/- 6 J, respectively, (P = ns) at predischarge testing. Of the six patients who had better DFT with RV + at implantation, only one patient maintained the benefit during predischarge testing. The differences observed in IPP in individual patients may not be demonstrable during repeated testing. These findings may have implications on how these devices should be programmed.

Implantable atrial defibrillator for atrial fibrillation.

Atrial fibrillation is a common problem. Pharmacological and nonpharmacological approaches have limited therapeutic efficacy in many patients. Low energy transvenous atrial defibrillation using catheters positioned inside the right atrium and cornonary sinus has been shown to be efficacious in converting atrial fibrillation to sinus rhythm. We report the successful use of this technology in an implantable form in a patient with symptomatic atrial fibrillation. The patient could be kept in sinus rhythm using an implanted atrial defibrillator.

Optimization of shocking lead configuration for transvenous atrial defibrillation.

INTRODUCTION: High atrial defibrillation energy requirements (ADER) in patients with chronic atrial fibrillation (AF) may limit the acceptance of transvenous atrial defibrillation. We evaluated an optimized defibrillation electrode configuration that could help to reduce the ADER in patients with AF. METHODS AND RESULTS: We tested ten different configurations in nine dogs with AF (3.33+/-2.92 days) induced by rapid atrial pacing. The configurations were: right atrial (RA) appendage as anode and coronary sinus (CS) as cathode; RA and innominate vein (I) as anode to CS (cathode); RA-CS (anode) to I (cathode); I-CS (anode) to RA (cathode); RA and left lateral subcutaneous patch (P) as anode to CS (cathode); RA-CS (anode) to P (cathode); P-CS (anode) to RA (cathode); superior vena cava (SVC) and CS (anode) to RA (cathode); RA-CS (anode) to SVC (cathode); and RA-SVC (anode) to CS (cathode). ADER was defined as the voltage needed to defibrillate the atria in 10% to 90% of 20 consecutive shocks. Three lead systems had ADER lower than the RA (anode) to CS (cathode) configuration, which required a mean of 143+/-58 volts. These three were: RA-SVC (anode) to CS (cathode) 103+/-29 V; I-CS (anode) to RA (cathode) 129+/-39 V; and P-CS (anode) to RA (cathode) 130+/-38 V. The remaining configurations had ADER higher than the RA (anode) to CS (cathode) configuration. CONCLUSION: Adding an additional shocking electrode may reduce ADER when compared with the RA (anode) to CS (cathode) configuration. This concept could be incorporated into future implantable atrial defibrillators or used for refractory patients undergoing temporary transvenous cardioversion.

Urine protein dipstick measurements. A screen for a standard, 24-hour urine collection.

OBJECTIVE: To determine if the sum of urine protein dipstick values recorded during every void can be used to screen for patients who need a standard, 24-hour urine collection for determination of protein excretion. STUDY DESIGN: Thirty inpatient and 17 outpatient pregnant women undergoing 24-hour urine collection for protein concentration were enrolled. The volume, dipstick protein values and time of void were recorded. The 24-hour quantitative analysis of protein excretion performed by the laboratory was compared to the 24-hour sum of the products of each voided volume and dipstick value (dipstick factor). RESULTS: The dipstick factor significantly correlated with the total 24-hour protein excretion (correlation coefficient 0.84, P < 1 x 10(-7)). A dipstick factor of > or = 300 mg, indicated proteinuria with a sensitivity of 96%, specificity of 90%, positive predictive value of 92% and negative predictive value of 95%. Separately, we found differences in the amount of protein excretion when the 24-hour period was divided into six 4-hour periods, using analysis of variance. Paired t test analysis of the mean protein excretion from 16:00 to 04:00 showed significantly higher results than did the protein excretion from 04:01 to 16:00 (1,197 +/- 356 mg vs. 674 +/- 158 mg, P < .0001). CONCLUSION: The sum of dipstick factors in a 24-hour period is a reliable screening test for identifying patients who need the standard laboratory test for proteinuria.