How substrate solvation contributes to the enantioselectivity of subtilisin toward secondary alcohols.
The current rule to predict the enantiopreference of subtilisin toward secondary alcohols is based on the size of the substituents at the stereocenter and implies that the active site contains two differently sized pockets for these substituents. Several experiments are inconsistent with the current rule. First, the X-ray structures of subtilisin show there is only one pocket (the S1' pocket) approximately the size of a phenyl group to bind secondary alcohols. Second, the rule often predicts the incorrect enantiomer for reactions in water. To resolve these contradictions, we refine the current rule to show that subtilisin binds only one substituent of a secondary alcohol and leaves the other in solvent. To test this refined empirical rule, we show that the enantioselectivity of a series of secondary alcohols in water varied linearly with the difference in hydrophobicity (log P/P0) of the substituents. This hydrophobicity difference accounts for the solvation of one substituent in water.


Lysine degradation through the saccharopine pathway in mammals: involvement of both bifunctional and monofunctional lysine-degrading enzymes in mouse.
Lysine-oxoglutarate reductase and saccharopine dehydrogenase are enzymic activities that catalyse the first two steps of lysine degradation through the saccharopine pathway in upper eukaryotes. This paper describes the isolation and characterization of a cDNA clone encoding a bifunctional enzyme bearing domains corresponding to these two enzymic activities. We partly purified those activities from mouse liver and showed for the first time that both a bifunctional lysine-oxoglutarate reductase/saccharopine dehydrogenase and a monofunctional saccharopine dehydrogenase are likely to be present in this organ. Northern analyses indicate the existence of two mRNA species in liver and kidney. The longest molecule, 3.4 kb in size, corresponds to the isolated cDNA and encodes the bifunctional enzyme. The 2.4 kb short transcript probably codes for the monofunctional dehydrogenase. Sequence analyses show that the bifunctional enzyme is likely to be a mitochondrial protein. Furthermore, enzymic and expression analyses suggest that lysine-oxoglutarate reductase/saccharopine dehydrogenase levels increase in livers of mice under starvation. Lysine-injected mice also show an increase in lysine-oxoglutarate reductase and saccharopine dehydrogenase levels.


Bisphenol A aggravates renal ischemia-reperfusion injury by disrupting mitochondrial homeostasis and N-acetylcysteine mitigates the injurious outcomes.
Exposure to bisphenol A (BPA), a chemical generally used in consumer products, becomes a global public health concern, as humans are increasingly exposed through their daily consuming activities. Renal ischemia-reperfusion (RIR) is the major cause of acute kidney injury with high prevalence and increased long-term risks for multiple comorbidities and mortality. As the kidney is susceptible to these conditions, we explored whether the outcomes following the RIR episode could be influenced by BPA exposure, and investigated the therapeutic possibility by N-acetylcysteine (NAC) including the mechanisms involved. Three groups of male Wistar rats were fed with vehicle, BPA 5, and 50 mg/kg, respectively, for five consecutive weeks then underwent the sham operation. Three other groups with identical treatment underwent bilateral renal IR induction (45-min ischemia followed by 24-hr reperfusion). An additional RIR group was treated with BPA 50 plus NAC 100 mg/kg. BPA-exposed rats that encountered RIR episode showed dose-dependent worsening of RIR injury as evidenced by augmentations of renal dysfunction and histopathological abnormalities, oxidative stress, apoptosis, mitochondrial functional impairment, mitochondrial dynamic, and mitophagy disproportion compared with the vehicle-exposed RIR group. The NAC therapy considerably attenuated the exacerbated effects of BPA, which was associated with increased AMP-activated protein kinase (AMPK), PGC-1α, silent information regulator 3 or sirtuin 3 (SIRT3), and mitofusin 2 (MFN2) expressions but decreased Phosphorylated dynamin-related protein 1 (p-DRP1)/Dynamin-related protein 1 (DRP1), PTEN-induced putative kinase (PINK), and PARKIN expressions. These findings reveal the detrimental effect of repeated BPA exposure on the renal outcomes following the IR episode, and further demonstrate the protective efficacy of NAC by maintaining mitochondrial homeostasis, which is, partly, mediated through the AMPK-PGC-1α-SIRT3 axis.


[Person-organization fit and work ability].
Person-environment issue has long been in focus of researchers who explore the area of human labor. It is known that the level of fit is a predictor of many phenomena related to health and attitude to work. The aim of this study was to explore the association between the level of person- organization fit (P-O fit) and work ability, including indicators of somatic and mental health. Research was conducted on a representative sample of 600 Polish men and women at working age. The Person-Organization Fit Questionnaire was used to assess three dimensions of P-O fit (supplementary fit, complementary fit and identification with organization); mental health status was measured by GHQ-28; the number of diagnosed diseases was taken as an index of somatic health; work ability, ability to physical and mental efforts were measured by three items from the Work Ability Index. A significant relationship between P-O fit level and work ability was found. In men, work ability predictors were: age, supplementary fit and mental health status, which explained 25% of the variance in work ability. In women, work ability predictors were: the number of diagnosed somatic diseases, supplementary fit, age and complementary fit, which explained 27% of the variance in work ability. Some gender-related differences in the predictive value of variables under the study were also found. The results of this study indicate the importance of P-O fit in shaping the sense of work ability, a recognized predictor of workers' occupational activity and the frequency of taking sick leave in subsequent years. Therefore, this result may be a useful argument to motivate employers to employ workers adequately to their abilities and preferences.


Direct Superior Approach to the Hip for Total Hip Arthroplasty.
Traditional posterior approaches to the hip, posterolateral and mini-posterior, violate the iliotibial band and the short external rotators, specifically the quadratus femoris and obturator externus muscles1-4. The direct anterior approach does not violate the iliotibial band or the quadratus femoris, resulting in earlier ambulation and lower dislocation rates1,5-9. The direct superior (DS) is a posterior approach that spares the iliotibial band, obturator externus tendon, and quadratus femoris muscle. The goal of minimally invasive surgery (MIS) is to disrupt the least amount of tissue necessary to adequately expose the hip and correctly place implants. Although MIS total hip arthroplasty (THA) has not lived up to all of its promises10-13, MIS-THA may enable early ambulation and decrease length of stay14-16. The patient is positioned in the lateral decubitus position. An 8 to 10-cm incision is made at a 60° oblique angle starting from the posterior-proximal corner of the greater trochanter. Only the gluteus maximus fascia is incised; the Iliotibial band is completely spared. The gluteus maximus muscle is split bluntly, exposing the gluteus medius muscle, piriformis tendon, and triceps coxae (the obturator internus and superior and inferior gemellus muscles). The piriformis and conjoined tendon are released from the greater trochanter and tagged. The gluteus minimus is elevated, exposing the posterior hip capsule. An arthrotomy is performed prior to dislocating the hip with flexion, adduction, internal rotation, and axial compression. The femoral neck is resected, the acetabulum is reamed, and components or trials are impacted into position. Hip stability is assessed. Final implants are placed. The posterior capsule, piriformis, and obturator internus tendons are repaired anatomically. The fascia and skin are closed. Posterolateral approach.Mini-posterior approach.Direct lateral approach.Anterolateral approach.Percutaneously assisted total hip (PATH).Supercapsular PATH (SuperPath). The DS approach to the hip differs from the traditional posterior and mini-posterior approaches because it preserves the iliotibial band, quadratus femoris muscle, and obturator externus tendon1, potentially suppressing dislocation. The DS approach to the hip causes less soft-tissue destruction, especially to the gluteus minimus and tensor fasciae latae muscles, compared with the direct anterior approach to the hip, suggesting DS-THA may enhance postoperative mobility1,3,14-16. DS-THA is extensile by extending the incision distally, incising the iliotibial band, and releasing the quadratus femoris muscle. This converts a DS approach to a standard posterolateral approach, providing additional visualization.


Congenital malformations in twins.
Among 1195 twins born in the Collaborative Perinatal Project, for whom information was available, 219 (18.33%) were found to have malformations, 179 (14.98%) single and 40 (3.35%) multiple. The frequency of malformations among twins was significantly higher than that among singletons from the same population, but the difference was entirely contributed by MZ twins. This holds true for both major and minor malformations. The frequency among Negro twins was higher than among white, and among male twins higher than among female. Twins had more malformations of the central nervous, musculoskeletal, ear, respiratory, cardiovascular, and alimentary systems and fewer malformations of the genitourinary and integumentary systems than singletons. In a significant number of cases when one twin of a pair had a malformation, the cotwin also had a malformation though not necessarily the same as that of the first twin.


Helping reasoners succeed in the Wason selection task: when executive learning discourages heuristic response but does not necessarily encourage logic.
Reasoners make systematic logical errors by giving heuristic responses that reflect deviations from the logical norm. Influential studies have suggested first that our reasoning is often biased because we minimize cognitive effort to surpass a cognitive conflict between heuristic response from system 1 and analytic response from system 2 thinking. Additionally, cognitive control processes might be necessary to inhibit system 1 responses to activate a system 2 response. Previous studies have shown a significant effect of executive learning (EL) on adults who have transferred knowledge acquired on the Wason selection task (WST) to another isomorphic task, the rule falsification task (RFT). The original paradigm consisted of teaching participants to inhibit a classical matching heuristic that sufficed the first problem and led to significant EL transfer on the second problem. Interestingly, the reasoning tasks differed in inhibiting-heuristic metacognitive cost. Success on the WST requires half-suppression of the matching elements. In contrast, the RFT necessitates a global rejection of the matching elements for a correct answer. Therefore, metacognitive learning difficulty most likely differs depending on whether one uses the first or second task during the learning phase. We aimed to investigate this difficulty and various matching-bias inhibition effects in a new (reversed) paradigm. In this case, the transfer effect from the RFT to the WST could be more difficult because the reasoner learns to reject all matching elements in the first task. We observed that the EL leads to a significant reduction in matching selections on the WST without increasing logical performances. Interestingly, the acquired metacognitive knowledge was too "strictly" transferred and discouraged matching rather than encouraging logic. This finding underlines the complexity of learning transfer and adds new evidence to the pedagogy of reasoning.


Artificial Emotional Intelligence in Socially Assistive Robots for Older Adults: A Pilot Study.
This paper presents our recent research on integrating artificial emotional intelligence in a social robot (Ryan) and studies the robot's effectiveness in engaging older adults. Ryan is a socially assistive robot designed to provide companionship for older adults with depression and dementia through conversation. We used two versions of Ryan for our study, empathic and non-empathic. The empathic Ryan utilizes a multimodal emotion recognition algorithm and a multimodal emotion expression system. Using different input modalities for emotion, i.e. facial expression and speech sentiment, the empathic Ryan detects users emotional state and utilizes an affective dialogue manager to generate a response. On the other hand, the non-empathic Ryan lacks facial expression and uses scripted dialogues that do not factor in the users emotional state. We studied these two versions of Ryan with 10 older adults living in a senior care facility. The statistically significant improvement in the users' reported face-scale mood measurement indicates an overall positive effect from the interaction with both the empathic and non-empathic versions of Ryan. However, the number of spoken words measurement and the exit survey analysis suggest that the users perceive the empathic Ryan as more engaging and likable.


Readability and content of postoperative tonsillectomy instructions given to patients in Scotland, a completed audit cycle.
The aim of this study was to assess the impact of the recommendations and interventions of the 2003 audit of 'readability and content of postoperative tonsillectomy instructions, given to patients in Scotland'. A two-cycle audit of readability and content of postoperative tonsillectomy instructions was undertaken. All National Health Service (NHS) hospital wards and associated Otolaryngology Departments in Scotland where tonsillectomies were being performed were contacted. Interventions following the first cycle included the mailing copies of original audit results and conclusions to all ear, nose and throat wards in Scotland, presentation at a National Meeting and publication of results in a peer reviewed journal. While changes had occurred in 61% of the information sheets, and with six of the 31 (19%) postoperative information sheets now being written at or below the recommended reading level, the average reading grade/age required to understand these information sheets still remains above those recommended by patient education experts. In conclusion, the majority of postoperative tonsillectomy information sheets in Scotland remain written at a level above those recommended by patient education experts. The interventions undertaken in this audit were of limited success. The ENT-UK Tonsillectomy Information sheets (2006) are written at reasonable reading levels, have good content levels and we continue to recommend these information sheets.


Vacuum-ultraviolet circular dichroism spectroscopy of DNA: a valuable tool to elucidate topology and electronic coupling in DNA.
Circular dichroism (CD) is a powerful technique to obtain information on electronic transitions and has been used extensively for studies on DNA. Most experiments are done in the UV region but new information is often revealed from extending the wavelength region down into the vacuum ultraviolet (VUV) region. Such experiments are most easily carried out with synchrotron radiation (SR) light sources that provide large photon fluxes. Here we provide a summary of the SRCD data taken on different DNA strands with emphasis on results from our own laboratory within the last five years.(1-3) Signal intensities in the VUV are often significantly larger than those in the UV, and the electronic coupling between bases may increase with excitation energy. CD spectroscopy is particularly useful for investigating the extent of electronic coupling within a strand, i.e., the degree of delocalisation of the excited-state electronic wavefunction. The spatial extent of the wavefunction may be limited to just one base or it extends over two or more bases in a stack or between bases on different strands.(4,5) The actual character of the electronically excited state is linked to base composition and sequence as well as DNA folding motif (A-, B-, Z-DNA, triplexes, quadruplexes, etc.). The latter depends on experimental conditions such as solution acidity, temperature, ionic strength, and solvent.


[Structural research on silicate dental materials].
Comparative studies of the structural features of Gamma porcelain, Sikor glass ceramic, and Cast Glass Ceramic (CGC) by x-ray structural analysis and IR spectroscopy have revealed that improvement of the physical characteristics of stomatological silicate material in transition to glass ceramic is explained by similarity of their composition with lithium disilicate. CGC structure due to convergence of the composition of the major areas of chemical heterogeneities is the most compact as compared to Sikor structure and more so us. Gamma. As evidenced by IR spectroscopy, super microhardness of CGC, observed in practice, appears to be related to their higher solidity in contrast to that of Gamma porcelain, structurally similar to amorphous silica, and that of Sikor characterized by a poorly crystallized tridymite structure. Higher physical characteristics of CGC distinguish it among the known silicate materials used in dentistry and recommend it for wide practice.


Systematic review of the impact of surgical harm on quality of life after general and gastrointestinal surgery.
To assess the impact of surgical harm on quality of life (QoL) in general and gastrointestinal surgery. Surgical adverse events (SAEs) are associated with poor outcome. Although SAEs are likely to affect QoL, this has not been demonstrated in surgery. Studies in general and gastrointestinal surgery measuring postoperative QoL in patients who suffered SAEs were identified. The overall impact of SAEs on QoL scores was determined by combining results from different studies. Component scores, adjustment for confounders, and time trends were evaluated. Data from 57,058 patients in 31 studies were analyzed. Most studies assessed the combined effect of different SAEs. High-quality studies adjusted for preoperative QoL. When different QoL instruments were scaled down to a common 0 to 1 score, the mean difference in QoL between SAE and no-SAE patients was 0.140 in esophagectomy, 0.110 in the Crohn resection, 0.089 in colorectal resection, 0.085 in gastric bypass, 0.072 in cholecystectomy, and 0.060 in inguinal hernia repair. Studies evaluating ileal pouch formation and antireflux surgery showed conflicting results. SAEs did not significantly affect QoL in emergency laparotomy and pancreatectomy. The frequency of SAEs was 5% to 48%. Physical QoL was affected more than emotional QoL. Significantly negative effects of SAEs on QoL were demonstrated in a range of procedures. Postoperative QoL seems to be a surrogate for the severity of impact of SAEs on patients. QoL may be an important utility to evaluate the economic and societal impact of SAEs thereby defining the threshold for safe practice.


N -Acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion.
A decrease of plasma homocysteine (Hcy) may represent a therapeutic promise for reducing the impact of atherosclerosis. N -Acetyl-cysteine (NAC) is a thiol-containing compound interfering with endogenous thiols, cysteine (Cys) and Hcy, by forming with them mixed disulphides with a possibly more efficient renal clearance. The aim of this work was to assess the effect of NAC intravenous infusion on plasma levels of different forms of Hcy and particularly to verify the effect on Hcy renal excretion. We collected basal blood samples at 0.5, 1, 2, 5, 8 and 24 h after the beginning of NAC infusion (50 mg kg(-1)body wt.) and also 24-h urine samples of the day of NAC infusion and of the day before and of the day after the infusion in ten healthy subjects (mean age 73+/-15). Urinary and plasma thiols (Hcy, Cys and NAC) were assayed by HPLC. Both total plasma Hcy (approx. 69%vs basal values) and Cys (approx. 40%vs basal values) fell progressively, reaching a minimum 5 h after infusion start; total free (i.e. not bound to proteins) Hcy (2.2+/-1.8 down from 4.4+/-4.2 nmol ml(-1)) and Cys (70.4+/-39.8 down from 113. 3+/-61.2 nmol ml(-1)) decreased as well. Reduced (thiolic-free form) Hcy and Cys decreased during infusion, though not as pronounced as for the other forms. Percentagewise, out of the total plasma levels, Hcy and Cys total free form and reduced form tended to increase over infusion as well as their difference (i.e. the plasma mixed disulphide moiety), thus supporting the idea that excess NAC displaces thiols from their plasma binding sites forming mixed disulphides. Urinary total Cys and Hcy excretion significantly increased at the end of the day of NAC infusion (tenfold for Cys and fivefold for Hcy) and reduced appreciably on the following day. Also urinary excretion of the free form of Cys and Hcy increased at the end of the day of NAC infusion, although in a lower amount with respect of total amounts, meaning a reduction of percentage Cys and Hcy excreted as the free form; for none of the patients had proteinuria, the 'free' form of urine thiols has to be identified in the 'reduced' form, the difference between the total and free form reflecting the 'mixed disulphide' moiety. NAC intravenous administration induces an efficient and rapid reduction of plasma thiols, particularly of Hcy; our data support the hypothesis that NAC displaces thiols from their binding protein sites and forms, in excess of plasma NAC, mixed disulphides (NAC-Hcy) with an high renal clearance. This effect may represent the start of an alternative approach in the treatment of hyperhomocysteinaemic conditions.


Dual Effects of Cellular Immunotherapy in Inhibition of Virus Replication and Prolongation of Survival in HCV-Positive Hepatocellular Carcinoma Patients.
Immune cells play an important role in the development and progression of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). We conducted a retrospective study to evaluate the influence of adoptive cellular immunotherapy (CIT) on viral load and progression-free survival (PFS) for HCC patients infected with HCV. Patients (n = 104) were divided into a control group (conventional therapy, n = 73) and study group (combination of CIT and conventional therapy, n = 31). Autologous mononuclear cells were induced into natural killer, γδT, and cytokine-induced killer cells and infused intravenously to study group patients. More patients had shown viral load decrease or were stable in study group (100% versus 75%) (p = 0.014). The median PFS of the study group and control group was 16 and 10 months, respectively (p = 0.0041), and only CIT was an independent prognostic factor for PFS (hazard ratio, 0.422; p = 0.005). Three patients developed transient moderate fever after infusion, and there were no significant differences in alanine aminotransferase and aspartate aminotransferase levels before and after treatment in both groups. Our results show that CIT contributes to improvement of prognosis and inhibition of viral replication in HCV-related HCC patients, without impairment of liver function.


Design and evaluation of self-nanoemulsifying pellets of repaglinide.
The aim of study was to develop self-nanoemulsifying pellets (SNEP) for oral delivery of poorly water soluble drug, repaglinide (RPG). Solubility of RPG in oily phases and surfactants was determined to identify components of self-nanoemulsifying drug delivery system (SNEDDS). The surfactants and cosurfactants were screened for their ability to emulsify oily phase. Ternary phase diagrams were constructed to identify nanoemulsification area for the selected systems. SNEDDS formulations with globule size less than 100 nm were evaluated for in vivo anti-hyperglycemic activity in neonatal streptozotocin rat model. A significant reduction in glucose levels was produced by optimized SNEDDS formulation in comparison to the control group. The optimized SNEDDS formulations were pelletized via extrusion/spheronization technique using microcrystalline cellulose and lactose. SNEP were characterized by X-ray powder diffraction and scanning electron microscopy. X-ray diffraction study indicated loss of crystallinity of RPG in SNEP. The SNEP exhibited good flow properties, mechanical strength and formed nanoemulsion with globule size less than 200 nm. SNEP showed in vitro release of more than 80% RPG in 10 min which was significantly higher than RPG containing reference pellets. In conclusion, our studies illustrated that RPG, a poorly water soluble drug can be successfully formulated into SNEP which can serve as a promising system for the delivery of poorly water soluble drugs.


The influence of residual coronary stenosis on size of infarction after reperfusion in a canine preparation.
The effect of a residual coronary artery stenosis on size of myocardial infarction was studied in an open-chest canine preparation of coronary occlusion and reperfusion. Eighteen male mongrel dogs (16 to 26 kg) underwent left thoracotomy under general anesthesia; the circumflex artery was instrumented with a hydraulic cuff occluder, a screw clamp, and an electromagnetic flow probe. Animals were randomized to one of three groups: group I (n = 6) had a 6 hr circumflex occlusion, group II (n = 6) had a 2 hr occlusion followed by 4 hr of partial reperfusion through a residual stenosis adjusted to approximately 30% of baseline flow, and group III (n = 6) had full reperfusion for 4 hr after a 2 hr occlusion. Zones of risk, infarction, and no reflow were defined by staining with Evans blue, triphenyl tetrazolium chloride, and fluorescein, respectively. At 6 hr the hearts were excised and areas of risk, infarction, no reflow, and hemorrhage were determined by planimetry of serial transverse heart slices (5 mm thick). Infarction as a percent of the risk area was 96 +/- 1% in group I, 90 +/- 2% in group II, and 79 +/- 4% in group III (p less than .001), and the differences between each of the groups were significant. Gross hemorrhage was seen in none of the six dogs in group I, two of the six in group II, and five of the six in group III, but did not affect infarct size. We conclude that residual stenoses may exert a deleterious effect on the outcome of coronary reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)


[Metabolic/nutrition programming of the enzyme system in the offspring small intestine].
Protein deficiency in female rats diet during pregnancy and lactation resulted in changes of the intestine enzymes activity in posterity in early and late periods of ontogenesis. In the former period, deceleration of sucrase induction, acceleration of lactase suppression and maltase induction, and an earlier occurrence of the adult-type distribution of the intestine alkaline phosphatase, were found. At 2 to 4-month age a reduction of the latter enzyme activity was revealed in the doudenum, jejunum and ileum. The changes in the intestine enzymes activities led to a disorder in intermediary metabolism and to occurrence of "risk diseases".


Metabolic spectroscopy of inflammation in a bleomycin-induced lung injury model using hyperpolarized 1-(13) C pyruvate.
Metabolic activity in the lung is known to change in response to external insults, inflammation, and cancer. We report measurements of metabolism in the isolated, perfused rat lung of healthy controls and in diseased lungs undergoing acute inflammation using hyperpolarized 1-(13) C-labeled pyruvate. The overall apparent activity of lactate dehydrogenase is shown to increase significantly (on average by a factor of 3.3) at the 7 day acute stage and to revert substantially to baseline at 21 days, while other markers indicating monocarboxylate uptake and transamination rate are unchanged. Elevated lung lactate signal levels correlate well with phosphodiester levels as determined with (31) P spectroscopy and with the presence of neutrophils as determined by histology, consistent with a relationship between intracellular lactate pool labeling and the density and type of inflammatory cells present. We discuss several alternate hypotheses, and conclude that the most probable source of the observed signal increase is direct uptake and metabolism of pyruvate by inflammatory cells and primarily neutrophils. This signal is seen in high contrast to the low baseline activity of the lung.


Outpatient operative hysteroscopy with bipolar electrode: a prospective multicentre randomized study between local anaesthesia and conscious sedation.
The study was designed to compare local anaesthesia and conscious sedation for outpatient bipolar operative hysteroscopy in terms of pain control and patients' satisfaction. A prospective multicentre randomized study was carried out in university hospitals and in a private endoscopy unit. A total of 166 women with surgically treatable lesions associated with infertility or abnormal uterine bleeding was considered eligible for the study. Patients were randomized, using a computer-generated randomization list, into two groups. Group A (82 patients) underwent operative hysteroscopy with local anaesthesia. Group B (84 patients) received conscious sedation. Operative hysteroscopy was performed with a bipolar electrosurgical device to cut, vaporize and coagulate. Main outcome measures were pain control during the procedure, the post-operative pain score at 15 and 60 min, and at 24 h after the procedure, and patients' satisfaction rate. All procedures were completed within 35 min, the amount of saline used varied from 400-1200 ml. There were no significant differences between local anaesthesia and conscious sedation in terms of pain control during the procedure and in postoperative pain at different intervals. Satisfaction rate was similar in the two groups. Both local anaesthesia and conscious sedation can be used for operative hysteroscopy using a bipolar electrosurgical system without significant differences in terms of pain control and patients' satisfaction.


Intraoperative Radiation Therapy as a Safe Alternative to Whole Breast Radiation for Treatment of Minimally Invasive Breast Cancers: A Retrospective Cohort Study.
Intraoperative radiation therapy (IORT) in select populations is a viable alternative to whole breast radiation therapy (WBRT) in the treatment of biopsy-proven localized invasive and non-invasive breast cancer. We aim to assess recurrence and complication rates following IORT in lumpectomy patients at a community hospital in Baltimore City. An IRB-approved retrospective cohort study was conducted on consecutive cases of lumpectomy with IORT from 2013 through 2020 by a single surgeon. Patient demographics, tumor and operative characteristics, and complications were retrieved from electronic medical records. Primary outcomes were postoperative complications and local recurrence rates. The final cohort included 117 patients with mean follow-up time of 2.60 + 1.78 years. Mean age was 69.84 + 8.77 years. Thirty-three (28.21%) of patients developed a seroma. Odds of seroma formation were mildly significant for skin spacing [OR: 1.18, 95% CI: (1.02-1.37)] and balloon fill volume [1.04 (1.00-1.08)], but not for age, BMI, diabetes, former or current smoking status, history of WBRT, tumor size, or balloon size. Three (2.6%) patients had local recurrence. Odds of local recurrence were mildly significant for increased tumor size [1.14 (1.04-1.24)] and not significant for any other covariates. IORT exposure did not confer higher rates of complications and the local recurrence rate mirrored that of the general population undergoing lumpectomy and WBRT. This study demonstrates the need for equitable treatment options based on individual needs: IORT is a safe alternative to WBRT in certain subpopulations, especially those with physical, social, or personal limitations preventing participation in a 3- to 7-week time commitment of WBRT.


ssDNA-binding protein 2 is frequently hypermethylated and suppresses cell growth in human prostate cancer.
Prostate cancer is a major cause of cancer death among men and the development of new biomarkers is important to augment current detection approaches. We identified hypermethylation of the ssDNA-binding protein 2 (SSBP2) promoter as a potential DNA marker for human prostate cancer based on previous bioinformatics results and pharmacologic unmasking microarray. We then did quantitative methylation-specific PCR in primary prostate cancer tissues to confirm hypermethylation of the SSBP2 promoter, and analyzed its correlation with clinicopathologic data. We further examined SSBP2 expression in primary prostate cancer and studied its role in cell growth. Quantitative methylation-specific PCR results showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%) primary prostate cancers versus 0 of 23 (0%) in benign prostatic hyperplasia using a cutoff value of 120. Furthermore, we found that expression of SSBP2 was down-regulated in primary prostate cancers and cancer cell lines. Hypermethylation of the SSBP2 promoter and its expression were closely associated with higher stages of prostate cancer. Reactivation of SSBP2 expression by the demethylating agent 5-aza-2'-deoxycytidine in prostate cancer cell lines confirmed epigenetic inactivation as one major mechanism of SSBP2 regulation. Moreover, forced expression of SSBP2 inhibited prostate cancer cell proliferation in the colony formation assay and caused cell cycle arrest. SSBP2 inhibits prostate cancer cell proliferation and seems to represent a novel prostate cancer-specific DNA marker, especially in high stages of human prostate cancer.


Multiple-analyte fluoroimmunoassay using an integrated optical waveguide sensor.
A silicon oxynitride integrated optical waveguide was used to evanescently excite fluorescence from a multianalyte sensor surface in a rapid, sandwich immunoassay format. Multiple analyte immunoassay (MAIA) results for two sets of three different analytes, one employing polyclonal and the other monoclonal capture antibodies, were compared with results for identical analytes performed in a single-analyte immunoassay (SAIA) format. The MAIA protocol was applied in both phosphate-buffered saline and simulated serum solutions. Point-to-point correlation values between the MAIA and SAIA results varied widely for the polyclonal antibodies (R2 = 0.42-0.98) and were acceptable for the monoclonal antibodies (R2 = 0.93-0.99). Differences in calculated receptor affinities were also evident with polyclonal antibodies, but not so with monoclonal antibodies. Polyclonal antibody capture layers tended to demonstrate departure from ideal receptor-ligand binding while monoclonal antibodies generally displayed monovalent binding. A third set of three antibodies, specific for three cardiac proteins routinely used to categorize myocardial infarction, were also evaluated with the two assay protocols. MAIA responses, over clinically significant ranges for creatin kinase MB, cardiac troponin I, and myoglobin agreed well with responses generated with SAIA protocols (R2 = 0.97-0.99).


Preservation of P300 event-related potential topographic asymmetries in schizophrenia with use of either linked-ear or nose reference sites.
Previous studies of the auditory P300 event-related potential (ERP) from our laboratory have reported a left- greater than right-sided attenuation in medicated chronic schizophrenics compared with normal controls. A possible confound in these studies has been the use of the linked-ear reference (LER), which has been criticized on the grounds that it might either induce or suppress topographic asymmetries. To test the effects of LER on P300 asymmetries in schizophrenia, we recorded ERPs with both LER and a nose reference (NR) in a group of 20 chronic medicated schizophrenics and in group of 20 age-matched normal controls. We here report: (1) confirmation of our previous P300 findings of left temporal scalp region deficit using both LER and NR with a 28-electrode montage; this feature was prominent in the wave form associated with the target stimulus, without the use of the wave form subtractions of our previous studies; (2) no statistically significant topographic differences between the LER and NR for either the schizophrenic or normal subjects; and (3) better performance of the LER in differentiating schizophrenics versus normal controls, due to lower wave form variability. We conclude that the LER is preferable for studies using subject groups and methodology similar to the present study.


General Properties of Colon Polyps in Central Anatolia.
Polyp is called formations protruding into the lumen in the gastrointestinal tract. In this study, we aimed to determine frequency, anatomic distribution within the large bowel and pathologic types of colon polyps based on the colonoscopy results. The colonoscopy reports between 2010 and 2011 were analyzed retrospectively. Complaint of the patients on admission, the presence of polyps, anatomic distribution of polyps, polyp type and polyp size were evaluated. A total of 4000 colonoscopy reports were examined. The largest proportion of polyps occurred in the left colon (74.4%), followed by the ascending colon (11.5%). Eighty-five were adenomatous polyps, 71 were hyperplastic polyps, 12 were inflammatory polyps, 12 were serrated adenoma, 3 were adenocarcinoma, and 8 were tubulovillous adenomas. In light of like this study, the development of screening and follow-up programs in Turkey will be useful to reduce the incidence and mortality of colorectal cancer.How to cite this article: Kefeli A, Basyigit S, Yeniova AO, Nazligul Y, Kucukazman M, Aktas B. General Properties of Colon Polyps in Central Anatolia. Euroasian J Hepato-Gastroenterol 2014;4(1):7-10.


Paramedic accuracy using SALT triage after a brief initial training.
To determine paramedics' understanding of and accuracy using SALT (sort-assess-lifesaving interventions-treatment/transport) triage, a proposed national guideline for primary triage during mass-casualty incidents, immediately and four months after training. A 20-minute lecture on SALT triage was provided to all paramedics (n = 320) from a single county during mandatory continuing education. Triage concepts were reemphasized during a 10-minute small-group lecture throughout the study period as part of standard refresher training. After the initial training, all paramedics were asked to complete a posttest consisting of three general knowledge questions about SALT triage and 10 patient scenarios in which they had to assign a triage category. The same test was administered four months after the original educational session. Demographic and job experience information was also obtained. Responses were scored and matched for each paramedic and compared using paired t-test. A total of 290 (91%) paramedics completed the initial posttest. They correctly answered an average (± standard deviation) of 10.7 ± 2.3 of the 13 questions (82%). For the 10 patient scenarios, they correctly triaged an average of 8.1 ± 2.0 patients. A total of 159 paramedics completed both tests. Sixty-seven percent had more than 10 years of emergency medical services (EMS) experience; 72% had prior mass-casualty drill experience; 51% had prior actual mass-casualty experience; and 23% had heard of SALT triage prior to the training. There were no statistically significant differences in initial test scores for any of these demographic groups. For those subjects who completed both tests, the mean overall score for the initial test was 10.9 ± 1.9 (84%) and for the later test was 11.0 ± 1.9 (85%) (p < 0.770; 95% confidence interval [CI] -0.3 to 0.3). For the 10 patient scenarios, the paramedics correctly triaged an average of 8.3 ± 1.7 patients on the initial test and 8.3 ± 1.4 patients on the later test (p < 0.565; 95% CI -0.4 to 0.2). Following a short didactic course, paramedics were able to accurately perform SALT triage during a written scenario. Four months after the training, they had retained their understanding of and accuracy using SALT triage. It appears that a brief educational tool was effective for training EMS providers in SALT triage.


In migrating cells, the Golgi complex and the position of the centrosome depend on geometrical constraints of the substratum.
Although cells migrate in a constrained 3D environment in vivo, in-vitro studies have mainly focused on the analysis of cells moving on 2D substrates. Under such conditions, the Golgi complex is always located towards the leading edge of the cell, suggesting that it is involved in the directional movement. However, several lines of evidence indicate that this location can vary depending on the cell type, the environment or the developmental processes. We have used micro contact printing (microCP) to study the migration of cells that have a geometrically constrained shape within a polarized phenotype. Cells migrating on micropatterned lines of fibronectin are polarized and migrate in the same direction. Under such conditions, the Golgi complex and the centrosome are located behind the nucleus. In addition, the Golgi complex is often displaced several micrometres away from the nucleus. Finally, we used the zebrafish lateral line primordium as an in-vivo model of cells migrating in a constrained environment and observe a similar localization of both the Golgi and the centrosome in the leading cells. We propose that the positioning of the Golgi complex and the centrosome depends on the geometrical constraints applied to the cell rather than on a precise migratory function in the leading region.


Diverse DNA Sequence Motifs Activate Meiotic Recombination Hotspots Through a Common Chromatin Remodeling Pathway.
In meiosis, multiple different DNA sequence motifs help to position homologous recombination at hotspots in the genome. How do the seemingly disparate cis-acting regulatory modules each promote locally the activity of the basal recombination machinery? We defined molecular mechanisms of action for five different hotspot-activating DNA motifs (M26, CCAAT, Oligo-C, 4095, 4156) located independently at the same site within the ade6 locus of the fission yeast Schizosaccharomyces pombe Each motif promoted meiotic recombination (i.e., is active) within this context, and this activity required the respective binding proteins (transcription factors Atf1, Pcr1, Php2, Php3, Php5, Rst2). High-resolution analyses of chromatin structure by nucleosome scanning assays revealed that each motif triggers the displacement of nucleosomes surrounding the hotspot motif in meiosis. This chromatin remodeling required the respective sequence-specific binding proteins, was constitutive for two motifs, and was enhanced meiotically for three others. Hotspot activity of each motif strongly required the ATP-dependent chromatin remodeling enzyme Snf22 (Snf2/Swi2), with lesser dependence on Gcn5, Mst2, and Hrp3. These findings support a model in which most meiotic recombination hotspots are positioned by the binding of transcription factors to their respective DNA sites. The functional redundancy of multiple, sequence-specific protein-DNA complexes converges upon shared chromatin remodeling pathways that help provide the basal recombination machinery (Spo11/Rec12 complex) access to its DNA substrates within chromatin.


Moving MobileMums forward: protocol for a larger randomized controlled trial of an improved physical activity program for women with young children.
Women with young children (under 5 years) are a key population group for physical activity intervention. Previous evidence highlights the need for individually tailored programs with flexible delivery mechanisms for this group. Our previous pilot study suggested that an intervention primarily delivered via mobile phone text messaging (MobileMums) increased self-reported physical activity in women with young children. An improved version of the MobileMums program is being compared with a minimal contact control group in a large randomised controlled trial (RCT). This RCT will evaluate the efficacy, feasibility and acceptability, cost-effectiveness, mediators and moderators of the MobileMums program. Primary (moderate-vigorous physical activity) and secondary (intervention implementation data, health service use costs, intervention costs, health benefits, theoretical constructs) outcomes are assessed at baseline, 3-months (end of intervention) and 9-months (following 6-month no contact: maintenance period).The intervention commences with a face-to-face session with a behavioural counsellor to initiate rapport and gather information for tailoring the 12-week text message program. During the program participants also have access to a: MobileMums Participant Handbook, MobileMums refrigerator magnet, MobileMums Facebook© group, and a MobileMums website with a searchable, on-line exercise directory. A nominated support person also receives text messages for 12-weeks encouraging them to offer their MobileMum social support for physical activity. Results of this trial will determine the efficacy and cost-effectiveness of the MobileMums program, and the feasibility of delivering it in a community setting. It will inform the broader literature of physical activity interventions for women with young children and determine whether further investment in the translation of the program is warranted. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12611000481976).


Genome-wide reduction in H3K9 acetylation during human embryonic stem cell differentiation.
Epigenetic marks are important factors regulating the pluripotency and differentiation of human embryonic stem cells (hESCs). In this study, we analyzed H3K9 acetylation, an epigenetic mark associated with transcriptionally active chromatin, during endoderm-like differentiation of hESCs. ChIP-on-chip analysis revealed that differentiation results in a genome-wide decrease in promoter H3K9 acetylation. Among the 24,659 promoters analyzed, only 117 are likely to be involved in pluripotency, while 25 acetylated promoters are likely to be responsible for endoderm-like differentiation. In pluripotent hESCs, the chromosomes with the highest absolute levels of H3K9 acetylation are chromosomes 1, 6, 2, 17, 11, and 12 (listed in order of decreasing acetylation). Chromosomes 17, 19, 11, 20, 22, and 12 are the most prone to differentiation-related changes (both increased acetylation and deacetylation). When chromosome size (in Mb) was accounted for, the highest H3K9 acetylation levels were found on chromosome 19, 17, 6, 12, 11, and 1, and the greatest differentiation-associated decreases in H3K9 acetylation occurred on chromosomes 19, 17, 11, 12, 16, and 1. The gene density and size of individual chromosomes were strongly correlated with the levels of H3K9 acetylation. Our analyses point to chromosomes 11, 12, 17, and 19 as being critical for hESC pluripotency and endoderm-like differentiation. J. Cell. Physiol. 219: 677-687, 2009. (c) 2009 Wiley-Liss, Inc.


Autophagy is increased in cryptorchid testis resulting in abnormal spermatozoa.
Autophagy is involved in spermatogenesis by regulating germ cell maturation. This catabolic process increases with hyperthermic conditions to prevent the accumulation of damaged organelles. Cryptorchidism is associated with impairment of germ cell maturation revealed by the presence of immature forms of sperm cells in ejaculates. The aim of the present study was to evaluate the status of autophagy in sperm cells from cryptorchid patients. Semen samples of cryptorchid patients and normozoospermic controls were analyzed by immunocytochemistry and electron microscopy. Autophagy proteins, autophagy-related protein 9 (ATG9) and microtubule-associated protein, 1A/1B-light chain 3 (LC3) were localized by immunocytochemistry on the acrosome and on the equatorial segment of sperm cells. LC3 was also detected in the midpiece of cryptorchid sperm tail. Autophagy substrate p62 protein was present in the acrosome and in the postequatorial segment of sperm in control samples, but not in the cryptorchid ones. Transmission electron microscopy revealed double-membrane-limited autophagosomes in postequatorial part of spermatozoa head and midpiece in cryptorchid samples. Partly degraded mitochondria were frequently discerned in autophagic vacuoles. In conclusion, autophagy is increased in sperm cells from patients with cryptorchid history comparatively to control. Our work provides insights into the role of autophagy in the maturation and survival of human male gametes in pathological conditions. Thus, regulating autophagy could represent a potential way to improve sperm quality in cryptorchid men.


4′,6-dihydroxy-4-methoxyisoaurone inhibits the HIF-1α pathway through inhibition of Akt/mTOR/p70S6K/4E-BP1 phosphorylation.
4′,6-Dihydroxy-4-methoxyisoaurone (ISOA) is an isoaurone compound isolated from Trichosanthes kirilowii seeds, which was identified as an inhibitor of tumor growth. However, the mechanism by which ISOA inhibits hypoxia-inducible factor-1 (HIF-1)-mediated tumor growth is not fully understood. We here demonstrated the effect of ISOA on HIF-1 activation. ISOA showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1a protein dose-dependently, whereas it did not affect the expressions of HIF-1b and topoisomerase-I (Topo-I). Further analysis revealed that the suppression of HIF-1a accumulation by ISOA was closely correlated with strong dephosphorylation of Akt, mammalian target of rapamycin (mTOR), and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1a expression at the translational level. Furthermore, ISOA prevented hypoxia-induced expression of HIF-1 target genes and suppresses the invasiveness of tumor cells. Taken together, our results suggested that ISOA is an effective inhibitor of HIF-1 through targeting Akt/mTOR/p70S6K/4E-BP1 pathway, thereby, providing new perspectives into the mechanism of its anticancer activity.


Infrapatellar Fat Pad Gene Expression and Protein Production in Patients with and without Osteoarthritis.
Osteoarthritis (OA) is one of the most common joint disorders. Evidence suggests that the infrapatellar fat pad (IFP) is directly involved in OA pathology. However, a comparison between OA versus non-OA IFP is still missing. Thus, the aim of this study was to compare IFP molecular, adipocytes and extracellular matrix characteristics of patients affected by OA, and patients undergoing anterior cruciate ligament (ACL) reconstruction. We hypothesized that not only inflammation but also changes in adipocytes and extracellular matrix (ECM) composition might be involved in OA pathogenesis. Fifty-three patients were enrolled. IFP biopsies were obtained, evaluating: (a) lymphocytic infiltration and vascularization; (b) adipocytes area and number; (c) adipo-cytokines and extracellular matrix gene expression levels; (d) IL-6 and VEGF protein production; (e) collagen fibers distribution. OA IFP was more inflamed and vascularized compared to ACL IFP. OA IFP adipocytes were larger and numerically lower (1.3-fold) than ACL IFP adipocytes. An increase of gene expression of typical white adipose tissue genes was observed in OA compared to ACL IFP. Collagen-types distribution was different in the OA IFP group compared to controls, possibly explaining the change of the biomechanical characteristics found in OA IFP. Statistical linear models revealed that the adipocyte area correlated with BMI in the OA group. In conclusion, inflammation and fibrotic changes of OA IFP could represent novel therapeutic targets to counteract OA.


Evaluation of Intestinal Damage Biomarkers in Calves with Atresia Coli.
Intestinal obstruction such as atresia coli causes pathophysiological changes in gastrointestinal tissue due to the rise of intra-abdominal pressure. The aim of this study is to determine the intestinal damage with intestinal biomarkers in calves with atresia coli. The study was conducted on 40 Holstein calves diagnosed with atresia coli with mild to moderate abdominal distention and 10 healthy Holstein calves which served as the control. Blood samples were collected from all calves, and then serum concentrations of intestinal biomarkers were estimated, namely intestinal fatty acid binding protein (IFABP), liver fatty acid binding protein (LFABP), trefoil factor 3 (TFF3), and intestinal alkaline phosphatase (IAP), using commercially available specific bovine ELISA kits. An automatic blood gas analyser was employed for determining the lactate concentration. The concentrations of serum LFABP (P < 0.01), IFABP, TFF3, IAP, and blood lactate (P < 0.001) were significantly higher in calves with atresia coli than in healthy calves. The calves affected with atresia coli exhibited severe intestinal damage, and IFABP, LFABP, and TFF3 have significant diagnostic importance and play a useful role in determining the intestinal damage due to intestinal obstruction. High levels of IAP and lactate may serve as a signal for the development of intestinal injury.


The effect of vegetarian diet on selected essential nutrients in children.
Vegetarian diets are considered to promote health and reduce the risk of some chronic diseases. It is also known that restriction or exclusion of animal foods may result in low intake of essential nutrients. The aim of the presented study was to assess the intake and serum status of vitamin B12, folate, vitamins A, E and D, as well as concentrations of homocysteine, total antioxidant status and iron balance in Polish vegetarian children. The study included 50 children, aged 5-11 who had been referred to the Institute of Mother and Child for dietary consultation. From those, 32 were vegetarians (aged 6.5±4.2 years) and 18 omnivores (aged 7.9±2.7 years). Dietary constituents were analyzed using the nutritional programme Dietetyk2®. Folate and vitamin B12 were determined with a chemiluminescence immunoassay, total homocysteine with a fluorescence polarization immunoassay and TAS (total antioxidant status) by colorimetric method. Vitamin A and E in serum were determined by the high-pressure liquid chromatography method (HPLC) and vitamin D by immunoenzymatic assay (ELISA). Concentrations of iron, ferritin, transferrin and total iron-binding capacity (TIBC) in serum were determined by commercially available kits. In vegetarian children daily intake of vitamin B12 (1.6 ěg) was in the recommended range, that of folate (195 ěg) and vitamin A (1245 ěg) higher, but vitamin E slightly lower (6.6 ěg) and three-fold lower vitamin D (1.1 ěg) than references allowance. Serum concentrations of vitamin B12 (548 pg/ml), folate (12.8 ng/ml), vitamin A (1.2 ěmol/L), vitamin E (15.6 ěmol/l) were within physiological range, but that of vitamin D (13.7 ěg/L) was only half of the lowest limit of the reference value. In vegetarian children in comparison to omnivorous similar levels of homocysteine (6.13 ěmol/L vs 5.45 ěmol/L) and vitamin A (1,17 ěmol/L vs 1.32 ěmol/L) were observed. Lower (p<0.05) values of vitamin E (15.6 ěmol/L vs 18.4 ěmol/L) and TAS (1.21 mmol/L vs 1.30 mmol/L; p<0.0001) were found. Concentrations of iron markers were in physiological range. Obtained results indicated that intakes of vitamin B12 and folic acid from vegetarian diets are sufficient to maintain serum concentrations of both homocysteine and iron in the range observed in omnivorous children. High consumption of vitamin A and low vitamin E only slightly affected their serum values. Significantly lower concentration of serum vitamin E in vegetarian children in comparison to nonvegetarians may be reflected with statistically significant lowering of total antioxidant status. Insufficient intake of vitamin D and its low serum concentration should be under close monitoring in vegetarian children. In order to prevent vitamin D deficiency appropriate age-dependent supplementation should be considered.


Genomic history of the Sardinian population.
The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.


Toxic metal mixtures in private well water and increased risk for preterm birth in North Carolina.
Prenatal exposure to metals in private well water may increase the risk of preterm birth (PTB) (delivery < 37 weeks' gestation). In this study, we estimated associations between arsenic, manganese, lead, cadmium, chromium, copper, and zinc concentrations in private well water and PTB incidence in North Carolina (NC). Birth certificates from 2003-2015 (n = 1,329,071) were obtained and pregnancies were assigned exposure using the mean concentration and the percentage of tests above the maximum contaminant level (MCL) for the census tract of each individuals' residence at the time of delivery using the NCWELL database (117,960 well water tests from 1998-2019). We evaluated associations between single metals and PTB using adjusted logistic regression models. Metals mixtures were assessed using quantile-based g-computation. Compared with those in other census tracts, individuals residing in tracts where > 25% of tests exceeded the MCL for lead (aOR 1.10, 95%CI 1.02,1.18) or cadmium (aOR 1.11, 95% CI 1.00,1.23) had an increased odds of PTB. Conversely, those residing in areas with > 25% MCL for zinc (aOR 0.77 (95% CI: 0.56,1.02) and copper (aOR 0.53 (95% CI: 0.13,1.34)) had a reduced odds of PTB. A quartile increase in the concentrations of a mixture of lead, cadmium, and chromium was associated with a small increased odds for PTB (aOR 1.02, 95% CI 1.01, 1.03). This metal mixture effect was most pronounced among American Indian individuals (aOR per quartile increase in all metals: 1.19 (95% CI 1.06,1.34)). In a large study population of over one million births, lead and cadmium were found to increase the risk of PTB individually and in a mixture, with additional mixtures-related impacts estimated from co-exposure with chromium. This study highlights critical racial and ethnic health disparities in relation to private well water thereby emphasizing the urgent need for improved private well water quality to protect vulnerable populations.


Prominence of direct entorhinal-CA1 pathway activation in sensorimotor and cognitive tasks revealed by 2-DG functional mapping in nonhuman primate.
The trisynaptic pathway from entorhinal cortex to the hippocampus has long been regarded as the major route of information transfer underlying memory consolidation. Most physiological studies of this pathway involve recording from hippocampal slices. We have used both single- and double-label 2-deoxyglucose autoradiographic methods to image the pattern of activation in the hippocampal formation of 14 rhesus monkeys performing cognitive tasks, varying in content (spatial or nonspatial), process (working memory or associative memory), and mode of response (oculomotor or manual). These studies revealed a highly differentiated pattern of metabolic activation throughout the rostrocaudal extent of the hippocampal formation that was common to all behavioral conditions examined. This pattern consisted of intense activation of the stratum lacunosum-moleculare of CA1 and the subiculum, contrasting with barely detectable activity in CA3 and modest activation in the dentate gyrus, which did not include its molecular layer. These findings indicate a remarkable invariance in hippocampal activation under conditions of varied content, varied process, and varied mode of response and an heretofore-unappreciated preferential engagement of the direct rather than the trisynaptic pathway during performance of a wide range of behavioral tasks.


A three-dimensional placoderm (stem-group gnathostome) pharyngeal skeleton and its implications for primitive gnathostome pharyngeal architecture.
The pharyngeal skeleton is a key vertebrate anatomical system in debates on the origin of jaws and gnathostome (jawed vertebrate) feeding. Furthermore, it offers considerable potential as a source of phylogenetic data. Well-preserved examples of pharyngeal skeletons from stem-group gnathostomes remain poorly known. Here, we describe an articulated, nearly complete pharyngeal skeleton in an Early Devonian placoderm fish, Paraplesiobatis heinrichsi Broili, from Hunsrück Slate of Germany. Using synchrotron light tomography, we resolve and reconstruct the three-dimensional gill arch architecture of Paraplesiobatis and compare it with other gnathostomes. The preserved pharyngeal skeleton comprises elements of the hyoid arch (probable ceratohyal) and a series of branchial arches. Limited resolution in the tomography scan causes some uncertainty in interpreting the exact number of arches preserved. However, at least four branchial arches are present. The final and penultimate arches are connected as in osteichthyans. A single median basihyal is present as in chondrichthyans. No dorsal (epibranchial or pharyngobranchial) elements are observed. The structure of the pharyngeal skeleton of Paraplesiobatis agrees well with Pseudopetalichthys from the same deposit, allowing an alternative interpretation of the latter taxon. The phylogenetic significance of Paraplesiobatis is considered. A median basihyal is likely an ancestral gnathostome character, probably with some connection to both the hyoid and the first branchial arch pair. Unpaired basibranchial bones may be independently derived in chondrichthyans and osteichthyans.


Hybrid design evaluating new biomarkers when there is an existing screening test.
Development of cancer screening biomarkers usually follows the Early Detection Research Network 5-Phase guideline in Pepe et al. A key feature of this guide is that the phased development follows a sequential order, moving to the next phase only when the current phase study is complete and has met its target performance. Motivated by a newly funded Newly onset Diabetes cohort study, we propose a design evaluating new biomarkers to discriminate between cases and controls in the presence of an existing screening test. The proposed design achieves two goals: (1) avoiding bias in estimating sensitivity or specificity in predicting cancer at a given time period prior to clinical diagnosis, using data from both screening detected cancers in Phase IV study and clinically diagnosed cancers in Phase III study; and (2) building a panel with biomarkers for Phase III and IV studies based on all data. A simulation study shows that the proposed design outperforms both a conventional method using data in Phase III arm only and a naive method using data in Phase III and IV arms ignoring the difference between the time of screening the detected cancer and the time of clinical diagnosis. The proposed design yields a smaller standard error of the estimation and increases the statistical power to confirm biomarker performance. This proposed method has the potential to shorten the cancer screening biomarker development process, use resources more effectively, and bring benefits to patients quickly.


Exclusive breastfeeding changes in Brazil attributable to pacifier use.
Identifying key interventions to increase exclusive breastfeeding duration has been a challenge. Pacifier use has been associated with exclusive breastfeeding discontinuation in Brazil. However, the proportion of the improvement in exclusive breastfeeding duration attributable to pacifier use remains unknown. Quantify the proportion of increases in exclusive breastfeeding prevalence that can be attributed to reduced pacifier use over time. Secondary data analyses of two nationally representative cross-sectional surveys conducted in States' capitals in 1999 and in 2008 (N = 42,395 Brazilian infants under 6 months of age). We estimated the fraction of exclusive breastfeeding prevalence improvements that could be attributed to pacifier use based on multilevel regression analysis. From 1999 to 2008, there was an increase of 15.2 percentage points in exclusive breastfeeding prevalence and a decrease of approximately 17 percentage points in the prevalence of pacifier use among infants under 6 months. Reduction in pacifier use explained an increase in 5.5 percentage points' exclusive breastfeeding rates. If pacifier use were to decrease from 41.6% (prevalence in 2008) to 14% (as found in New Zealand), there would be an expected additional increase in exclusive breastfeeding of approximately 12 percentage points. About one-third of the improvements in EBF prevalence observed in Brazil over a decade can be attributed to the corresponding decline in pacifier use.


Intensive Care Nurses' Perceptions of Routine Dyspnea Assessment.
Dyspnea (breathing discomfort) is commonly experienced by critically ill patients and at this time is not routinely assessed and documented. Intensive care unit nurses at the study institution recently instituted routine assessment and documentation of dyspnea in all patients able to report using a numeric scale ranging from 0 to 10. To assess nurses' perceptions of the utility of routine dyspnea measurement, patients' comprehension of assessment questions, and the impact on nursing practice and to gather nurses' suggestions for improvement. Data were obtained from interviews with intensive care unit nurses in small focus groups and an anonymous online survey randomly distributed to nurses representing all intensive care units. Intensive care unit nurses affirmed the importance of routine dyspnea assessment and documentation. Before implementing the measurement tool, nurses often assessed for breathing discomfort in patients by using observed signs. Most nurses agreed that routine assessment can be used to predict patients' outcomes and improve patient-centered care. Nurses found the assessment tool easy to use and reported that it did not interfere with workflow. Nurses felt that patients were able to provide meaningful ratings of dyspnea, similar to ratings of pain, and often used patients' ratings in conjunction with observed physical signs to optimize patient care. Our study shows that nurses understand the importance of routine dyspnea assessment and that the addition of a simple patient report scale can improve care delivery and does not add to the burden of work-flow.


Prevalence of cigarette smoking and associated factors in a large sample of HIV-positive patients receiving antiretroviral therapy in Vietnam.
Cigarette smoking presents a salient risk for HIV-positive populations. This study is among the first to examine smoking prevalence, nicotine dependence, and associated factors in a large sample of HIV-positive patients receiving antiretroviral therapy (ART) in Vietnam. A cross-sectional study of 1133 HIV-positive people was conducted from January to September 2013 at 8 ART clinics in Hanoi (the capital) and Nam Dinh (a rural area). Smoking history and nicotine dependence (Fagerstrom Test of Nicotine Dependence-FTND) were assessed by participant self-report. Logistic regression and Tobit linear regression were performed to identify factors significantly associated with smoking outcomes. Prevalence of current, former, and never smokers in the sample was 36.1%, 9.5%, and 54.4%, respectively. The current smoking proportion was higher in males (59.7%) than females (2.6%). The mean FTND score was 3.6 (SD = 2.1). Males were more likely to currently smoke than females (OR = 23.4, 95% CI = 11.6-47.3). Individuals with problem drinking (OR = 1.8, 95% CI = 1.1-2.9) and ever drug use (OR = 3.7, 95%CI = 2.5-5.7) were more likely to be current smokers. Older age and currently feeling pain were associated with lower nicotine dependence. Conversely, receiving care in Nam Dinh, greater alcohol consumption, ever drug use, and a longer smoking duration were associated with greater nicotine dependence. Given the high prevalence of smoking among HIV-positive patients, smoking screening and cessation support should be offered at ART clinics in Vietnam. Risk factors (i.e., substance use) linked with smoking behavior should be considered in prevention programs.


Saxagliptin reduces the injury of Alzheimer's disease cell model by down-regulating the expression of miR-483-5p.
This study aimed to investigate the effect of saxagliptin on the injury of Alzheimer's disease (AD) cell model and its possible mechanism. SK-N-SH cells were cultured in vitro and divided into CON group, AD group, AD+L-SAX group, AD+M-SAX group, AD+H-SAX group, AD+anti-miR-NC group, AD+anti-miR-483-5p group, AD+SAX+miR-NC group and AD+SAX+miR-483-5p group. Then the levels of MDA, SOD and GSH-Px in each group were detected by ELISA method; cell apoptosis was detected by flow cytometry; the protein expression levels of Bax and Bcl-2 were detected by Western Blot; the expression level of miR-483-5p was detected by RT-qPCR. Compared with the control group, MDA content, apoptosis rate, and the expression of Bax protein and miR-483-5p increased in the AD group (P<0.05), while the activity of SOD and GSH-Px and the expression of Bcl-2 protein decreased (P<0.05). Compared with the AD group, MDA content, apoptosis rate, and the expression of Bax protein and miR-483-5p decreased in the AD+L-SAX group, AD+M-SAX group and AD+H-SAX group (P<0.05), while the activity of SOD and GSH-Px and the expression of Bcl-2 protein increased (P<0.05). Compared with AD+anti-miR-NC group, MDA content, apoptosis rate, and the expression of Bax protein and miR-483-5p decreased in the AD+anti-miR-483-5p group (P<0.05), while the activity of SOD and GSH-Px and the expression of Bcl-2 protein increased (P<0.05). Compared with AD+SAX+miR-NC group, MDA content, apoptosis rate, and the expression of Bax protein and miR-483-5p increased in the AD+SAX+miR-483-5p group (P<0.05), while the activity of SOD and GSH-Px and the expression of Bcl-2 protein decreased (P<0.05). Saxagliptin may reduce the injury of Alzheimer's disease cell model by down-regulating the expression of miR-483-5p.


Ethanol suppression of locus coeruleus neurons: relevancy to the fetal alcohol syndrome.
The effect of intraperitoneal injection and microiontophoretic application of ethanol on spontaneous single neuron activity of adult rat locus coeruleus was studied. Systemic administration of ethanol (1-2 g/kg) markedly slowed a majority of locus coeruleus neurons. Direct application of ethanol also substantially suppressed locus coeruleus cell firing in the absence of any detectable membrane effects. Percent inhibition of firing rate ranged from 6% to 100% with ejection currents up to 40NA for 40 sec. These data demonstrate ethanol can directly suppress locus coeruleus unit activity. Since locus coeruleus neurons are present at a relatively early fetal age, maternal consumption of ethanol during gestation could profoundly influence the development and function of fetal central noradrenergic processes.


Analgesic targets: today and tomorrow.
Pain is recognized as a multifactorial sensory experience that is wholly unpleasant. It can vary in intensity from mild to severe and its duration can be anything from transient to persistent. Today we know so much more about the peripheral nociceptor as the primary detection apparatus for painful stimuli. We also understand in far greater detail the neurochemical mechanisms that occur at the level of the spinal cord and the complex interplay that exists between excitatory and inhibitory neural pathways. As a consequence of the assembly of this new body of evidence there are clear pointers that direct our attention to receptors, signaling pathways, enzymes and ion channels that all have the potential to be targets for novel, effective analgesics. The purpose of this review is to highlight some of the knowledge that has been assembled on this subject in recent years.


Structure modulation of manganese coordination polymers consisting of 1,4-naphthalene dicarboxylate and 1,10-phenanthroline.
Three new manganese coordination polymers, {[Mn2(1,4-NDC)2(phen)2](H2O)}n (1), [Mn2(1,4-NDC)2(phen)(H2O)]n (2) and {[Mn4(1,4-NDC)4(phen)4](DMF)2}n (3) (1,4-H2NDC = 1,4-naphthalene dicarboxylic acid; phen = 1,10-phenanthroline; DMF = N,N-dimethylformamide), have been synthesized solvo/hydrothermally. 1,4-NDC(2-) ligands adopt different coordination modes under different solvents and concentrations which promotes different crystal structure formation. X-ray crystal structural data reveal that compounds 1, 2 and 3 crystallize in monoclinic space groups C2/c, P21/c and C2/c, respectively. Compound 1 has Mn2 dimers connected by 1,4-NDC(2-) linkers, packing into a 2D structure in a grid pattern. Compound 2 has a three-dimensional (3D) structure which is constructed by Mn2 dimers and 1,4-NDC(2-) linkers. Each MnO4N2 node of compound 3 is linked to another by 1,4-NDC(2-) ligands to form a two-dimensional (2D) structure. Variable-temperature magnetic susceptibilities of compounds 1-3 exhibit overall weak antiferromagnetic coupling between the adjacent Mn(II) ions.


Recent advances in prion chemotherapeutics.
The transmissible spongiform encephalopathies are rapidly progressive and invariably fatal neurodegenerative diseases for which there are no proven efficacious treatments. Many approaches have been undertaken to find ways to prevent, halt, or reverse these prion diseases, with limited success to date. However, as both our understanding of pathogenesis and our ability to detect early disease increases, so do our potential therapeutic targets and our chances of finding effective drugs. There is increasing pressure to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) has been shown to be transmissible by blood, and to find non-toxic preventative therapies, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD). Within the realm of chemotherapeutic approaches, much research has focussed on blocking the conversion of the normal form of prion protein (PrP(c)) to its abnormal counterpart (PrP(res)). Structurally, these chemotherapeutic agents are often polyanionic or polycyclic and may directly bind PrP(c) or PrP(res), or act by redistributing, sequestering, or down-regulating PrP(c), thus preventing its conversion. There are also some polycationic compounds which proport to enhance the clearance of PrP(res). Other targets include accessory molecules such as the laminin receptor precursor which influences conversion, or cell signalling molecules which may be required for pathogenesis. Of recent interest are the possible neuroprotective effects of some drugs. Importantly, there is evidence that combining compounds may provide synergistic responses. This review provides an update on current testing methods, therapeutic targets, and promising candidates for chemical-based therapy.


Congenital syphilis after maternal treatment with erythromycin.
A case is reported in which erythromycin was used successfully to treat maternal syphilis but failed to adequately treat the fetus. This report and similar studies suggest that oral erythromycin is not a reasonable alternative drug for the treatment of lues in the penicillin-allergic gravid female.


Testing hypotheses concerning the phenotypic plasticity of escape performance in fish of the family Cottidae.
A knowledge of the natural history of two species of marine Cottidae was used to construct a set of complex a priori hypotheses to test the idea that seasonal temperature acclimation conferred a fitness advantage and to examine whether acclimation responses were constant through development. The species studied were the short-horn sculpin (Myoxocephalus scorpius L.) and the long-spined sea scorpion (Taurulus bubalis Euphr.). Fast-start escape performance was measured as a proxy of fitness, and maximum body-length-specific speed (Umax) and acceleration (Amax), and angular velocity (max) and cumulative turning angle (CTA) were quantified. Fish were acclimated to 5, 15 and 20 degreesC and filmed using high-speed cinematography at 0.8, 5.0, 15.0 and 20.0 degreesC. The following hypotheses were tested: (1) improvements in escape performance following acclimation to high temperature in adult short-horn sculpin that live offshore would involve a trade-off in performance at low temperature, (2) the escape response of the sea scorpion, which experiences large daily temperature variation, would exhibit low thermal sensitivity and be unchanged by acclimation between 5 and 15 degreesC, and (3) in short-horn sculpin, the ability to acclimate maximum speed thermally is acquired during ontogeny in parallel with the offshore migration of the late juvenile stage. At 20.0 degreesC, in adult short-horn sculpin, Umax and Amax were 110 % and 55 % higher, respectively, in 15 degreesC- than in 5 degreesC-acclimated fish. No evidence was obtained for improved fast-start performance at 0.8 degreesC or 5.0 degreesC following cold acclimation. In the long-spined sea scorpion, acclimation to 5 and 15 degreesC did not improve Umax or Amax compared with fish acutely exposed to these temperatures, although acclimation to 5 degreesC increased max (P=0.005). When tested over the most extreme thermal range found in the field, all variables were improved at a test temperature of 0.8 degreesC in 5 degreesC- compared with 15 degreesC-acclimated sea scorpion. Acclimation therefore appeared to be beneficial in some instances in both species. How this affects relative fitness is uncertain. The scaling of Umax with acclimation to 5 and 15 degreesC was examined in both species over the test range 5.0-15.0 degreesC. Temperature acclimation did not affect scaling relationships of Umax in long-spined sea scorpion ranging in total body length (L) from 45 to 160 mm. At a test temperature of 15.0 degreesC, the scaling of Umax for short-horn sculpin ranging in total body length from 43 to 270 mm changed from aL-0.98 in 5 degreesC-acclimated fish to aL-0.50 (where a is the proportionality coefficient in the regression equation) in 15 degreesC-acclimated fish (P<0.01). In short-horn sculpin, therefore, the ability to modify escape performance with temperature acclimation was found to vary during ontogeny, potentially paralleling a migration from a more variable to a more stable thermal environment.


Self-treatment with oral transmucosal fentanyl citrate to prevent emergency room visits for pain crises: patient self-reports of efficacy and utility.
Ninety (90) patients with chronic pain who were treated with a long-acting opioid were instructed on use of oral transmucosal fentanyl citrate (OTFC) for self-treatment of emergency pain flares. Eighty-six (95.6%) believed OTFC was effective and safe for self-treatment of emergency pain flares, and 71 (78.8%) believed they had prevented one or more emergency room visits for treatment of pain flares. A subgroup of 45 patients who had collectively used OTFC for 375 months, based on their past experience, estimated they had prevented 1.26 emergency room visits per month per patient. OTFC should be further studied for cost-savings and effectiveness in self-treatment of emergency pain flares.


Chemopreventive Action by Ethanol-extracted Brazilian Green Propolis on Post-initiation Phase of Inflammation-associated Rat Colon Tumorigenesis.
Propolis has since long been utilized in numerous folk medicines with a variety of medicinal properties. In this study, the effects of ethanol-extracted (EEP) and water-extracted (WEP) Brazilian green propolis on the post-initiation phase of inflammation-associated rat colon tumorigenesis were directly compared. Male F344 rats at 6 weeks of age were subcutaneously injected with 1,2-dimethylhydrazine (DMH) at 40 mg/kg body weight twice during the first week, followed by 1% dextran sodium sulfate (DSS) in drinking water for one week. After a 1-week no-treatment period, animals were administered either basal Oriental MF powdered diet, or 1% EEP or 1% WEP in the basal diet until week 32. Post-initiation treatment with EEP significantly reduced the multiplicity of colorectal carcinomas compared to the control (0.40±0.13/rat vs. 2.29±0.84/rat, respectively, p<0.05), and EEP also reduced the tumor volume. Immunohistochemically, expression of inflammation-associated proteins inducible nitric oxide synthase, tumor necrotic factor alpha, nuclear factor kappa B and glutathione peroxidase-2 were significantly diminished in colorectal tumors from EEP-treated rats. Suppression of inflammation and oxidative stress, which had been triggered by DMH and promoted by DSS, was a primary mechanism by which EEP suppressed carcinogenesis.


Mechanical tuning and amplification within the apex of the guinea pig cochlea.
A popular conception of mammalian cochlear physiology is that tuned mechanical vibration of the basilar membrane defines the frequency response of the innervating auditory nerve fibres However, the data supporting these concepts come from vibratory measurements at cochlear locations tuned to high frequencies (>7 kHz). Here, we measured the travelling wave in regions of the guinea pig cochlea that respond to low frequencies (<2 kHz) and found that mechanical tuning was broad and did not match auditory nerve tuning characteristics. Non-linear amplification of the travelling wave functioned over a broad frequency range and did not substantially sharpen frequency tuning. Thus, the neural encoding of low-frequency sounds, which includes most of the information conveyed by human speech, is not principally determined by basilar membrane mechanics. The popular notion of mammalian cochlear function is that auditory nerves are tuned to respond best to different sound frequencies because basilar membrane vibration is mechanically tuned to different frequencies along its length. However, this concept has only been demonstrated in regions of the cochlea tuned to frequencies >7 kHz, not in regions sensitive to lower frequencies where human speech is encoded. Here, we overcame historical technical limitations and non-invasively measured sound-induced vibrations at four locations distributed over the apical two turns of the guinea pig cochlea. In turn 3, the responses demonstrated low-pass filter characteristics. In turn 2, the responses were low-pass-like, in that they occasionally did have a slight peak near the corner frequency. The corner frequencies of the responses were tonotopically tuned and ranged from 384 to 668 Hz. Non-linear gain, or amplification of the vibrations in response to low-intensity stimuli, was found both below and above the corner frequencies. Post mortem, cochlear gain disappeared. The non-linear gain was typically 10-30 dB and was broad-band rather than sharply tuned. However, the gain did reach nearly 50 dB in turn 2 for higher stimulus frequencies, nearly the amount of gain found in basal cochlear regions. Thus, our data prove that mechanical responses do not match neural responses and that cochlear amplification does not appreciably sharpen frequency tuning for cochlear regions that respond to frequencies <2 kHz. These data indicate that the non-linear processing of sound performed by the guinea pig cochlea varies substantially between the cochlear apex and base.


Seedling emergence response of rare arable plants to soil tillage varies by species.
Very little information is available on emergence of rare arable plants (RAP) in relation to soil disturbance and seed burial conditions in Europe. This information is essential to design conservation and soil management strategies to prevent the decline of these species in agroecosystems. The objective of this research was to investigate the effect of soil cultivation with burial time on the emergence and seed persistence of RAP. Seeds of 30 RAP species were collected from Spanish arable fields and subjected to two tillage treatments: (a) no soil disturbance, and (b) autumnal soil disturbance down to 10 cm depth every year. The treatments simulated no-till and tilled (disking), respectively. In plots under no-till, RAP seeds were sown at 1-cm depth. In the tilled plots, seeds were sown homogeneously mixed in the top 1-10 cm of soil. The trial was established every two consecutive seasons, and each trial was maintained for two years. Annual cumulative plant emergence was calculated each year; whereas the first trial was monitored for a third year to estimate seed longevity using a persistence index. The response in emergence of the 30 RAP to annual tillage varied among species. With burial time (number of years), higher emergence was observed for seeds sown in tilled soil. This was true across all species, and with strong season effects. The persistence index was correlated with seed weight, species with bigger seeds had low persistence indices while no pattern was observed for small seeded species. Most RAP species, particularly those with high persistence, showed induction of secondary dormancy processes, highlighting the importance of tillage to promote RAP emergence, and hence, seed bank replenishment. Therefore, as time passes the absence of soil tillage may represent a driver of RAP seed bank decline for those species with secondary dormancy processes. In conclusion, it is important to design soil management strategies, such as regular tillage to promote emergence, on a species basis to preserve RAP in Europe.


Functional reorganization of a prefrontal cortical network mediating consolidation of trace eyeblink conditioning.
The medial prefrontal cortex (mPFC) has been studied for its role in various cognitive functions, but the roles of its subregions remain unclear. We performed tetrode recordings simultaneously from prelimbic (PL) and rostral (rACC) and caudal (cACC) anterior cingulate subregions of the rabbit mPFC to understand their interactions during learning and tests of remote memory retention for whisker-signaled trace eyeblink conditioning. cACC neurons exhibited an innate response to the conditioning stimulus (CS) that rapidly decreased across sessions, suggesting an attentional role for facilitating CS-US associations. rACC neurons from conditioned rabbits exhibited robust responses to the CS that decreased within each session, possibly evaluating its emotional salience. PL neurons exhibited robust persistent activity during the trace interval during tests of remote memory retention, suggesting its involvement in retrieval and execution of a consolidated response. Mechanistically, conditioning was associated with a greater percentage of persistently responsive neurons than neurons from pseudoconditioned control rabbits, and responses differed significantly between trials with and without conditioned responses. Collectively, these responses reflect a functional reorganization of neural activity within the prefrontal network from an attentional mode to one that orchestrates the retrieval and execution of the learned response.


Effect of a nonpeptide vasopressin V1 antagonist (OPC-21268) on experimental accelerated focal glomerulosclerosis.
The effects of the nonpeptide orally effective vasopressin V1 receptor antagonist OPC-21268 were studied in progressive focal glomerulosclerosis (FGS) which developed in spontaneously hypercholesterolemic (SHC) rats with manifestations of hypercholesterolemia and proteinuria. Unilateral nephrectomy was performed at 7 weeks of age to accelerate spontaneous FGS. After nephrectomy, OPC-administered rats were fed chow containing 1% OPC-21268 for 9 weeks. Treatment with vasopressin V1 antagonist significantly reduced the rate of increase in the levels of triglyceride, systolic blood pressure, serum creatinine and BUN, and prevented a significant deterioration in creatinine clearance. Rats were sacrificed at 16 weeks of age. Histologically, the index of glomerular sclerosis in the OPC group showed a significant decrease compared to that in the control group (2.2 +/- 0.1 vs. 2.6 +/- 0.1, p < 0.01). Relative interstitial volume and glomerular volume in the OPC group showed a tendency to decrease compared to those in the control group. These results indicate that vasopressin plays an important role through V1 receptors in the development of glomerulosclerosis, and vasopressin V1 antagonist may prevent the progression of renal injury in glomerulosclerosis.


Advanced mucinous adenocarcinoma in pregnancy.
The incidence of masses in pregnancy is estimated to occur in 1/81 to 1/2,500 pregnancies. The development of colorectal carcinoma during pregnancy is a more rare event, with less than 30 cases above the peritoneal reflection reported in the last 70 years. The differential diagnosis of mucinous adenocarcinoma of ovarian vs. gastrointestinal origin is often difficult. We report a pregnant patient affected by advanced colorectal cancer, who presented with an asymptomatic unilateral adnexal mass on ultrasound. A 28-year old woman was referred to our hospital after a routine ultrasound examination at 26 weeks gestation showing a right adnexal mass. At elective exploratory laparotomy, the patient was found to have metastatic mucinous adenocarcinoma. Diagnostic and treatment choices of such a cancer in a pregnant patient were explored. The final diagnosis of colorectal cancer was made only at the time of a subsequent emergency laparotomy. The goal of an obstetrician/gynecologist and other care givers of pregnant patients, is to achieve a healthy mother and child. Unfortunately, physicians may unwillingly sacrifice the health of the mother by denying or delaying her procedures or treatments simply because she is pregnant. It is especially important in the case of adnexal masses and their related pathology, due to the difficulty in detection and management of such cases during pregnancy, that doctors actively assume the responsibility of assuring that pregnant patients receive the proper care they need.


Clinics in diagnostic imaging (205). Baxter's neuropathy.
A 48-year-old woman presented with chronic right heel pain and paraesthesia over the foot. Magnetic resonance imaging of the right foot demonstrated isolated atrophy of the abductor digiti minimi. A diagnosis of Baxter's neuropathy was made and the patient was managed successfully via surgical release. We describe the clinical and radiological features of Baxter's neuropathy and, with brief examples, outline other causes of chronic heel pain.


Classifying cerebral palsy: are we nearly there?
Cerebral palsy (CP) is the most common cause of physical disability in childhood in developed countries and encompasses a wide range of clinical phenotypes. Classification of CP according to movement disorder or topographical distribution is widely used. However, these classifications are not reliable nor do they accurately predict musculoskeletal pathology. More recently, the Gross Motor Function Classification System (GMFCS) has been introduced and its validity, reliability, and clinical utility have been confirmed. In 2005 it was suggested that children should be described and classified according to the GMFCS in all outcome studies involving children with CP, in the Journal of Pediatric Orthopaedics (JPO). This study aimed to describe utilization of the GMFCS in 3 journals: Journal of Bone and Joint Surgery (JBJS Am), JPO, and Developmental Medicine and Child Neurology (DMCN), over a 7-year period (2005 to 2011), and any relationship to the journal's impact factor. A secondary aim was to establish if differences in methodological quality existed between those studies utilizing GMFCS and those that did not. A targeted literature search of the 3 selected journals using the term "cerebral palsy" was conducted using the Medline database. Utilization of the GMFCS was assessed using report of these data in the methods or results section of the retrieved papers. The Methodological Index for Non-Randomized Studies (MINORS) was employed to evaluate the quality of papers published in JPO. One hundred and fifty-four studies met the inclusion criteria and in 85 (68%) the GMFCS was used. Of these, 112 were published in JPO, of which 51 (46%) utilized the GMFCS, compared with 72% for JBJS Am, and 88% for DMCN. In the JPO, utilization of the GMFCS improved from 13% to 80%, over the 7-year study period. Utilization of the GMFCS has increased rapidly over the past 7 years in the JPO but there is room for further improvement. Not applicable.


Anthropogenic disturbance of element cycles at the Earth's surface.
The extent to which humans are modifying Earth's surface chemistry can be quantified by comparing total anthropogenic element fluxes with their natural counterparts (Klee and Graedel, 2004). We quantify anthropogenic mass transfer of 77 elements from mining, fossil fuel burning, biomass burning, construction activities, and human apportionment of terrestrial net primary productivity, and compare it to natural mass transfer from terrestrial and marine net primary productivity, riverine dissolved and suspended matter fluxes to the ocean, soil erosion, eolian dust, sea-salt spray, cosmic dust, volcanic emissions, and for helium, hydrodynamic escape from the Earth's atmosphere. We introduce an approach to correct for losses during industrial processing of elements belonging to geochemically coherent groups, and explicitly incorporate uncertainties of element mass fluxes through Monte Carlo simulations. We find that at the Earth's surface anthropogenic fluxes of iridium, osmium, helium, gold, ruthenium, antimony, platinum, palladium, rhenium, rhodium and chromium currently exceed natural fluxes. For these elements mining is the major factor of anthropogenic influence, whereas petroleum burning strongly influences the surficial cycle of rhenium. Our assessment indicates that if anthropogenic contributions to soil erosion and eolian dust are considered, anthropogenic fluxes of up to 62 elements surpass their corresponding natural fluxes.


Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome.
Nav1.5 is the primary voltage-gated Na+ (Nav) channel in the heart. Mutations of Nav1.5 are associated with various cardiac disorders exemplified by the type 3 long QT syndrome (LQT3) and Brugada syndrome (BrS). E1784K is a common mutation that has been found in both LQT3 and BrS patients. Here we present the cryo-EM structure of the human Nav1.5-E1784K variant at an overall resolution of 3.3 Å. The structure is nearly identical to that of the wild-type human Nav1.5 bound to quinidine. Structural mapping of 91- and 178-point mutations that are respectively associated with LQT3 and BrS reveals a unique distribution pattern for LQT3 mutations. Whereas the BrS mutations spread evenly on the structure, LQT3 mutations are clustered mainly to the segments in repeats III and IV that are involved in gating, voltage-sensing, and particularly inactivation. A mutational hotspot involving the fast inactivation segments is identified and can be mechanistically interpreted by our "door wedge" model for fast inactivation. The structural analysis presented here, with a focus on the impact of mutations on inactivation and late sodium current, establishes a structure-function relationship for the mechanistic understanding of Nav1.5 channelopathies.


Development of a novel imaging system for cell therapy in the brain.
Stem cells have been evaluated as a potential therapeutic approach for several neurological disorders of the central and peripheral nervous system as well as for traumatic brain and spinal cord injury. Currently, the lack of a reliable and safe method to accurately and non-invasively locate the site of implantation and track the migration of stem cells in vivo hampers the development of stem cell therapy and its clinical application. In this report, we present data that demonstrate the feasibility of using the human sodium iodide symporter (hNIS) as a reporter gene for tracking neural stem cells (NSCs) after transplantation in the brain by using single-photon emission tomography/computed tomography (SPECT/CT) imaging. NSCs were isolated from the hippocampus of adult rats (Hipp-NSCs) and transduced with a lentiviral vector containing the hNIS gene. Hipp-NSCs expressing the hNIS (NIS-Hipp-NSCs) were characterized in vitro and in vivo after transplantation in the rat brain and imaged by using technetium-99m ((99m)Tc) and a small rodent SPECT/CT apparatus. Comparisons were made between Hipp-NSCs and NIS-Hipp-NSCs, and statistical analysis was performed by using two-tailed Student's t test. Our results show that the expression of the hNIS allows the repeated visualization of NSCs in vivo in the brain by using SPECT/CT imaging and does not affect the ability of Hipp-NSCs to generate neuronal and glial cells in vitro and in vivo. These data support the use of the hNIS as a reporter gene for non-invasive imaging of NSCs in the brain. The repeated, non-invasive tracking of implanted cells will accelerate the development of effective stem cell therapies for traumatic brain injury and other types of central nervous system injury.