Interaction of Nitrite Ions with Hydrated Portlandite Surfaces: Atomistic Computer Simulation Study.
The nitrite admixtures in cement and concrete are used as corrosion inhibitors for steel reinforcement and also as anti-freezing agents. The characterization of the protective properties should account for the decrease in the concentration of free NO2- ions in the pores of cement concretes due to their adsorption. Here we applied the classical molecular dynamics computer simulation approach to quantitatively study the molecular scale mechanisms of nitrite adsorption from NaNO2 aqueous solution on a portlandite surface. We used a new parameterization to model the hydrated NO2- ions in combination with the recently upgraded ClayFF force field (ClayFF-MOH) for the structure of portlandite. The new NO2- parameterization makes it possible to reproduce the properties of hydrated NO2- ions in good agreement with experimental data. In addition, the ClayFF-MOH model improves the description of the portlandite structure by explicitly taking into account the bending of Ca-O-H angles in the crystal and on its surface. The simulations showed that despite the formation of a well-structured water layer on the portlandite (001) crystal surface, NO2- ions can be strongly adsorbed. The nitrite adsorption is primarily due to the formation of hydrogen bonds between the structural hydroxyls on the portlandite surface and both the nitrogen and oxygen atoms of the NO2- ions. Due to that, the ions do not form surface adsorption complexes with a single well-defined structure but can assume various local coordinations. However, in all cases, the adsorbed ions did not show significant surface diffusional mobility. Moreover, we demonstrated that the nitrite ions can be adsorbed both near the previously-adsorbed hydrated Na+ ions as surface ion pairs, but also separately from the cations.


Adrenergic responsiveness of adipose tissue lipolysis in autonomic failure.
The sympathetic nervous system mobilizes lipids from adipose tissue through stimulation of beta-adrenergic receptors. The increase in lipid supply augments lipid oxidation. Patients with autonomic failure provide a unique opportunity to further elucidate the role of the adrenergic system in adipose tissue metabolism. In 4 patients with severe pure autonomic failure (PAF), in 3 multiple system atrophy patients (MSA), and in 16 healthy young controls, we inserted a microdialysis catheter in abdominal adipose tissue. The catheter was perfused with incremental concentrations of the nonselective beta-adrenoreceptor agonist isoproterenol. Dialysate glucose, lactate, and glycerol were measured to assess glucose supply, glycolysis, and lipolysis, respectively. Basal dialysate glycerol concentrations were 84 +/- 28 microM in PAF and 130 +/- 64 microM in MSA patients. The increase in dialysate glycerol with isoproterenol was identical in PAF and in MSA patients. We found an almost complete overlap in dialysate glycerol concentrations during isoproterenol stimulation between PAF and MSA patients and healthy young control subjects. Our findings suggest that adipose tissue metabolism is remarkably well preserved in patients with chronic sympathetic denervation, both at rest and during local adrenergic stimulation. We propose that beta-adrenoreceptor upregulation is compensated by a desensitization of post receptor mechanisms or by an upregulation of antilipolytic pathways.


Distinguishing cell shoving mechanisms.
Motivated by in vitro time-lapse images of ovarian cancer spheroids inducing mesothelial cell clearance, the traditional agent-based model of cell migration, based on simple volume exclusion, was extended to include the possibility that a cell seeking to move into an occupied location may push the resident cell, and any cells neighbouring it, out of the way to occupy that location. In traditional discrete models of motile cells with volume exclusion such a move would be aborted. We introduce a new shoving mechanism which allows cells to choose the direction to shove cells that expends the least amount of shoving effort (to account for the likely resistance of cells to being pushed). We call this motility rule 'smart shoving'. We examine whether agent-based simulations of different shoving mechanisms can be distinguished on the basis of single realisations and averages over many realisations. We emphasise the difficulty in distinguishing cell mechanisms from cellular automata simulations based on snap-shots of cell distributions, site-occupancy averages and the evolution of the number of cells of each species averaged over many realisations. This difficulty suggests the need for higher resolution cell tracking.


[Use of the great epiploon in the treatment of idiopathic retroperitoneal fibrosis].
Immediately after ureterolysis in the treatment of idiopathic retroperitoneal fibrosis, we covered the ureter with a large epiploon, forming a sheath with omentum covering the entire ureter from the renal pelvis to the juxtavesical area of the same. This technique revitalizes the ischemic ureter resulting from ureterolysis and protects against the reinclusion of the ureter mobilized inside the sclerolipomatous mass.


Do women with glandular abnormalities require colposcopy follow-up?
To determine whether cervical glandular abnormalities can be safely followed up by community cytology. A retrospective database review was conducted identifying women with a histological report of cervical glandular abnormalities over a three-year period. Fifty women were found to have a glandular abnormality diagnosed histologically. Twenty were initially referred for colposcopy with cytological glandular abnormalities. Thirty women with cytological squamous abnormalities were later found to have cervical glandular intraepithelial neoplasia (CGIN) at histological assessment. Two women had invasive adenocarcinoma and all others with endocervical dyskaryosis or CGIN were treated using large loop excision of the transformation zone (LLETZ). At follow-up 43 women had negative cytology, one woman defaulted further appointments, one had moved out of the area, seven were successfully treated by a repeat LLETZ following incomplete excision of CGIN at the endocervix, and five had negative cytology in the community. Three women continue to have cytological/histological abnormalities with one subsequently having a hysterectomy. Women with endocervical dyskaryosis or CGIN should be treated by LLETZ. Provided LLETZ is repeated in cases of incomplete endocervical CGIN excision cytological follow-up can take place in the community.


The Freiburg Visual Acuity test--automatic measurement of visual acuity.
The Freiburg Visual Acuity test is an automated procedure for self-administered measurement of visual acuity. Landolt-Cs are presented on a monitor in one of eight orientations. The subject presses one of eight buttons, which are spatially arranged on a response box according to the eight possible positions of the Landolt-Cs' gap. To estimate the acuity threshold, a best PEST (best Parameter Estimation by Sequential Testing) procedure is used in which a psychometric function having a constant slope on a logarithmic acuity scale is assumed. Measurement terminates after a fixed number of trials. With computer monitors, pixel-discreteness artifacts limit the presentation of small stimuli. By using anti-aliasing, i.e., smoothing of contours by multiple gray levels, the spatial resolution was improved by a factor of four. Thus, even the shape of small Landolt-Cs with oblique gaps is adequate and visual acuities from 5/80 (0.06) up to 5/1.4 (3.6) can be tested at a distance of 5 m.


[Endovideosurgical antireflux operations in combination with cholecystectomy].
In the city center of endovideosurgery during 1999-2005 there were 205 patients examined and treated for cholelithiasis combined with gastro-esophageal-reflux disease (GERD) and hiatal hernias. Simultaneous interventions, antireflux operation and cholecystectomy were performed in 150 patients. Cholecystectomy followed by conservative treatment of GERD was performed in 55 patients. The results of treatment were followed up during 1 and 6 months.


The Roles of Fibrosis Index Based on Four Factors and Aspartate Transaminase-to-Platelet Ratio Index Scoring Systems as an Alternative to Transient Elastography Liver Stiffness in Liver Fibrosis Staging in Human Immunodeficiency Virus and Hepatitis C Virus Co-Infected Patients.
Liver biopsy used to be the gold standard to assess liver fibrosis in patients infected with hepatitis C virus (HCV). Nonetheless, due to its invasive nature, techniques such as transient elastography liver stiffness (TE-LS), fibrosis index based on four factors (FIB-4) and aspartate transaminase-to-platelet ratio index (APRI) scores are currently being used. FIB-4 and APRI scores have the advantage of low cost and are readily available, compared with TE-LS. Herein, we evaluated the diagnostic performance of these scoring systems as compared to TE-LS in assessing liver fibrosis in patients with human immunodeficiency virus (HIV) and HCV co-infection. The medical records of patients with HIV and HCV co-infection who had TE-LS done at our facility between August 1, 2013 and January 1, 2020 were extracted and analyzed. Exclusion criteria include: 1) patients co-infected with hepatitis B virus; 2) invalid TE-LS assessment; 3) have ≥ 10th upper limit of normal (ULN) alanine aminotransferase (ALT) levels; and 4) excessive alcohol use. Patient demographics, medical history, biochemical and clinical data were retrieved. For each patient, we calculated the FIB-4 and APRI score. Descriptive analysis was performed and correlation of FIB-4 and APRI with TE-LS was assessed with GraphPad Prism statistical software. Five hundred forty-seven patients underwent TE-LS during the study period. After excluding those without complete laboratory parameters, the total study population was 344. Their age was 56 ± 10.4 years and 234 (68%) were male. The average aspartate aminotransferase (AST) and ALT were 27.95 and 30.73. The average platelet count was 224 and the average TE-LS was 7.29. Fourteen patients (4.1%) had TE-LS values between 9 and 11.9 kPa and were classified as F3, while 29 (8.5%) had TE-LS ≥ 12 kPa and were classified as F4. With the correlation analysis, both APRI (correlation coefficient, r = 0.1097, 95% confidence interval (CI) 0.0403 - 0.2130; P = 0.042) and FIB-4 (r = 0.0424, 95% CI -0.0634 - 0.1474; P = 0.4335) were not correlated with TE-LS stages of fibrosis. In our cohort, we failed to demonstrate that APRI and FIB-4 are reliable alternatives for screening liver fibrosis in patients with HIV and HCV co-infection. Nonetheless, APRI score still has a potential role as a screening tool instead of TE-LS measurement, which is costly and not readily available. It will be important to corroborate these findings in another large cohort, since this may have an important impact on patient management.


[Pesticide detection in Costarican vegetables based on the inhibition of serum and erythrocytic human cholinesterases].
A simple and low cost method able to detect the presence of pesticides, organophosphates and carbamates based on the inhibition of serum and erythrocytic cholinesterases, was used in lettuce (Lactuca sativa), cilantro (Coriandum santivum) and celery (Apium graveolens) obtained from the Ferias del Agricultor from Valle Central of Costa Rica. The percentage inhibition of cholinesterases is related to the presence of plaguicide in the vegetable. Thirteen percent of the analyzed samples were positive for plaguicides using serum cholinesterase and 33% for erythrocytic cholinesterase. Washing and cooking the vegetables does not eliminate the presence of plaguicides but they lower slightly the concentration. Statistical evidence (p = 0.0001) indicates that erythrocytic cholinesterase has higher analytical sensitivity than serum cholinesterase. It is very important to establish the degree of contamination with pesticides in these agricultural products because they are exposed to direct contamination by fumigation, soil contamination and irrigation water, and are products that are often consumed without adequate cooking and washing.


British Gynaecological Cancer Society recommendations and guidance on patient-initiated follow-up (PIFU).
The National Cancer Survivorship Initiative through the National Health Service (NHS) improvement in the UK started the implementation of stratified pathways of patient-initiated follow-up (PIFU) across various tumor types. Now the initiative is continued through the Living With and Beyond Cancer program by NHS England. Evidence from non-randomized studies and systematic reviews does not demonstrate a survival advantage to the long-established practice of hospital-based follow-up regimens, traditionally over 5 years. Evidence shows that patient needs are inadequately met under the traditional follow-up programs and there is therefore an urgent need to adapt pathways to the needs of patients. The assumption that hospital-based follow-up is able to detect cancer recurrences early and hence improve patient prognosis has not been validated. A recent survey demonstrates that follow-up practice across the UK varies widely, with telephone follow-up clinics, nurse-led clinics and PIFU becoming increasingly common. There are currently no completed randomized controlled trials in PIFU in gynecological malignancies, although there is a drive towards implementing PIFU. PIFU aims to individualize patient care, based on risk of recurrence and holistic needs, and optimizing resources. The British Gynaecological Cancer Society wishes to provide the gynecological oncology community with guidance and a recommendations statement regarding the value, indications, and limitations of PIFU in endometrial, cervical, ovarian, and vulvar cancers in an effort to standardize practice and improve patient care.


Lipiodol UF retention in dental sialography.
Lipiodol is a lipid based contrast medium and is very useful in sialography. It gives very fine images and clearly shows the details of the gland. It is viscous and has a relatively high iodine content. However, lipiodol UF drops sometimes remain in the salivary gland and in the adjacent tissues for a long time and may cause irritation. We report a case where lipiodol UF leaked from Stensen's duct and was not resorbed after a period of 70 months.


A random six-phase switch regulates pneumococcal virulence via global epigenetic changes.
Streptococcus pneumoniae (the pneumococcus) is the world's foremost bacterial pathogen in both morbidity and mortality. Switching between phenotypic forms (or 'phases') that favour asymptomatic carriage or invasive disease was first reported in 1933. Here, we show that the underlying mechanism for such phase variation consists of genetic rearrangements in a Type I restriction-modification system (SpnD39III). The rearrangements generate six alternative specificities with distinct methylation patterns, as defined by single-molecule, real-time (SMRT) methylomics. The SpnD39III variants have distinct gene expression profiles. We demonstrate distinct virulence in experimental infection and in vivo selection for switching between SpnD39III variants. SpnD39III is ubiquitous in pneumococci, indicating an essential role in its biology. Future studies must recognize the potential for switching between these heretofore undetectable, differentiated pneumococcal subpopulations in vitro and in vivo. Similar systems exist in other bacterial genera, indicating the potential for broad exploitation of epigenetic gene regulation.


Predictors of extracapsular extension and positive margins in African American and white men.
Radical retropubic prostatectomy (RRP) pathology from African American (AA) and White men from 1988 to 1999 was examined to determine if the pre-treatment factors PSA, clinical stage, biopsy grade, age at surgery, and year of surgery (YOS) were predictive of extracapsular extension (ECE) and positive margins for each ethnic group. Clinical and pathologic data was collected on 179 AA and 548 white men undergoing RRP from 1988 to 1999 at a tertiary military medical facility. Logistic regression with multivariate analysis was used to determine which pre-operative data-points were predictive of pathologic ECE and positive margins for each ethnic group. PSA, biopsy grade, age, and YOS (more recent years had better surgical pathology) were predictive of ECE for AA and white men. PSA, biopsy grade, and YOS were predictive of positive margins for AA men, while PSA and YOS were predictive of positive margins for white men. PSA continues to be a strong predictor of ECE and positive margins for both AA and white men. However, we describe for the first time, YOS being predictive of ECE and positive margins for both AA and White men, using multivariate regression analysis. This is thought to be reflective of the improving public awareness of prostate cancer that has occurred during the PSA-era, resulting in patients participating in screening programs and being diagnosed earlier. Close follow-up of these patients is warranted to determine if the improved pathologic stage of those patients treated more recently translates into improved disease-specific mortality.


Dual energy x-ray laser measurement of calcaneal bone mineral density.
In dual energy x-ray absorptiometry (DXA) the photon attenuation is assumed to be similar in soft tissue overlying, adjacent to and inside the measured bone. In the calcaneal dual energy x-ray laser (DXL) technique, this assumption is not needed as attenuation by soft tissues at the local bone site is determined by combining DXA and heel thickness measurements. In the present study, 38 subjects were measured with DXL Calscan, Lunar PIXI and Lunar DPX-IQ DXA instruments and Hologic Sahara ultrasound instrument, and the performance and agreement of the instruments were analysed. Furthermore, numerical simulations on the effect of non-uniform fat-to-lean tissue ratio within soft tissue in heel were conducted. In vivo short-term precision (CV%, sCV%) of DXL Calscan (1.24%, 1.48%) was similar to that of Lunar PIXI (1.28%, 1.60%). Calcaneal areal bone mineral densities (BMD, g cm(-2)) measured using DXL Calscan and Lunar PIXI predicted equally well variations in BMD of femoral neck (r2 = 0.63 and 0.52, respectively) or lumbar spine (r2 = 0.61 and 0.64, respectively), determined with Lunar DPX-IQ. BMD values measured with DXL Calscan were, on average, 19% lower (p < 0.01) than those determined with Lunar PIXI. Interestingly, the difference in BMD values between instruments increased as a function of body mass index (BMI) (r2 = 0.17, p < 0.02) or heel thickness (r2 = 0.37, p < 0.01). Numerical simulations suggested that the spatial variation of soft tissue composition in heel can induce incontrollable inaccuracy in BMD when measured with the DXA technique. Theoretically, in contrast to DXA instruments, elimination of the effect of non-uniform soft tissue is possible with DXL Calscan.


Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys.
Monoamine releasers with varying selectivity for dopamine (DA)/norepinephrine and serotonin (5-HT) release are potential treatment medications for cocaine abuse. Although DA-selective monoamine releasers effectively reduce cocaine abuse, their clinical usefulness is limited by abuse liability. It is hypothesized that increasing 5-HT neurotransmission may reduce the abuse-related effects of DA releasers, but the optimal DA:5-HT release ratio remains to be determined. This study in rhesus monkeys compared the effects of two compounds with differing potency for 5-HT release. Methcathinone and 3-Cl-methcathinone (PAL-434) have equal potency for DA release, but PAL-434 has 10-fold higher potency for 5-HT release. In drug discrimination studies, monkeys were trained to discriminate cocaine (0.4 mg/kg i.m.) from saline in a two-key, food-reinforced procedure. In drug self-administration studies, a separate group of monkeys was trained to respond for cocaine [0.01 mg/kg/injection (inj)] and food (1 g pellets) under a second order schedule of reinforcement [FR2(VR16:S)]. When responding was stable, methcathinone (0.1–0.56 mg/kg.h i.v.) or PAL-434 (0.32–1.8 mg/kg.h i.v.) was administered chronically (one injection every 20 min for 23 h/d) for 7–10 d. In discrimination studies, both compounds dose-dependently increased cocaine-like responding but with different potencies (cocaine=methcathinone >PAL-434). Chronic treatment with methcathinone or PAL-434 dose-dependently and selectively reduced cocaine self-administration. PAL-434 was about 4-fold and methcathinone about 1.6-fold more potent at decreasing cocaine- over food-maintained responding. These data suggest that compounds with moderate selectivity for DA vs. 5-HT release (8–15-fold) may be effective for the treatment of cocaine dependence.


["Treatment of total atelectasis of the left lung in severe ARDS with side-separated ventilation and surfactant administration"].
Severe thoracic trauma is always an important risk factor for the development of acute pulmonary failure. The course is often complicated by barotrauma or volutrauma. We report on a 48-year-old patient who was transferred to us nine days after a bicycle accident because of a severe disturbance of gas exchange and atelectasis of the left lung refractory to therapy. The left lung could not be ventilated even after separate artificial ventilation on each side with positive end expiratory pressure. After administration of surfactant (50 mg Exosurf per kg body weight) and continued separate artificial ventilation on each side, there was a complete re-expansion of the left lung with an increase of the arterial pO2 value from 65 mm Hg to 416 mm Hg with a FIO2 of 1,0 and a decrease of the intrapulmonary venous admixture from 34% to 12% within a few hours. The extravascular pulmonary fluid was unaffected by the administration of surfactant (200 ml solution). The administration of surfactant preparations may be a new therapeutic approach in treatment of ARDS patients.


Unusual case of delayed congenital diaphragmatic hernia in Loeys-Dietz syndrome: a case report.
Congenital diaphragmatic hernias rarely present after 2 months of age and are typically diagnosed in the perinatal period. Moderate to severe diaphragmatic hernias present with respiratory symptoms, while late-onset hernias have a more varied presentation, depending on the age and content of the hernia. Very rarely, such hernias are found on incidental imaging, in which surgical repair is frequently recommended. A young girl with Loeys-Dietz syndrome and prior abdominal surgeries presents with 1-year history of increasingly severe, intermittent, abdominal and left shoulder pain. Prior imaging incidentally revealed a left diaphragmatic hernia with omentum protruding into the thoracic cavity. This was managed expectantly due to her other medical and surgical issues. Serial imaging revealed that the herniated omentum was increasing in size and symptoms began to develop. An uncomplicated primary thoracoscopic repair was performed. We report the first case of a congenital diaphragmatic hernia in a patient with Loeys-Dietz syndrome.


Population-Based Epidemiology Study of Paraneoplastic Neurologic Syndromes.
Population-based epidemiologic data for paraneoplastic neurologic syndromes (PNSs) in the United States are lacking. Our objective was to evaluate the incidence, prevalence, and associated morbidity of PNS. We performed a population-based epidemiology study in Olmsted County, Minnesota, with patients identified between January 1, 1987, and December 31, 2018, using the medical records linkage system of the Rochester Epidemiology Project (REP) who met the definite/probable 2021 PNS criteria and 2004 PNS criteria. Patients with dermatomyositis and myasthenia gravis with underlying tumors were included. Age- and sex-specific population counts were obtained from REP resources for January 1, 2014 (prevalence denominator) and annually for 1987-2018 (incidence denominator). Morbidity was estimated using disability-adjusted life years (DALYs; years lived with disability [YLD] plus years of life lost [YLL]). There were 28 patients with PNS identified (50% female) residing in Olmsted County, Minnesota, with median age at diagnosis of 54.5 (IQR 46.5-69.0) years. All patients had a cancer diagnosis, and 18 (64%) patients were neural autoantibody positive including antineuronal nuclear autoantibody type 1 (ANNA-1/anti-Hu; n = 1), ANNA-2/anti-Ri (n = 1), muscle-type acetylcholine receptor (AChR; n = 6), Purkinje cell cytoplasmic antibody type 1 (PCA-1/anti-Yo; n = 1), kelch-like protein 11 (KLH11; n = 3), collapsin response mediator protein 5 (CRMP-5/anti-CV2; n = 2), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (n = 1), neurofilament light chain (n = 1), leucine zipper 4 (LUZP4; n = 1), and unclassified neural antibodies (n = 1). PNS incidence was 0.6/100,000 person-years and increased over time from 0.4/100,000 person-years (1987-2002) to 0.8/100,000 person-years (2003-2018) (p = 0.06). Prevalence was 5.4/100,000 people. The median follow-up period after PNS diagnosis was 3.1 years (IQR, 1.1-9.9 years). Total disability-adjusted life years (DALYs) for 28 patients with PNS were 472.7 years, based on total years of life lost (YLL) for patients dying between 1987 and 2018 (n = 15) of 445.3 years plus years lived with disability (YLD) 27.4 years. PNSs are rare neurologic disorders but are associated with severe morbidity and mortality. The estimated number of prevalent PNS cases in the United States is 17,099, and predicted DALY for all US PNS cases is 292,393 years. Their apparent increasing rate of detection is attributable to increasing physician awareness and availability of serologic testing.


Functional regions of the peroxin Pex19 necessary for peroxisome biogenesis.
The peroxins Pex19 and Pex3 play an indispensable role in peroxisomal membrane protein (PMP) biogenesis, peroxisome division, and inheritance. Pex19 plays multiple roles in these processes, but how these functions relate to the structural organization of the Pex19 domains is unresolved. To this end, using deletion mutants, we mapped the Pex19 regions required for peroxisome biogenesis in the yeast Pichia pastoris Surprisingly, import-competent peroxisomes still formed when Pex19 domains previously believed to be required for biogenesis were deleted, although the peroxisome size was larger than that in wild-type cells. Moreover, these mutants exhibited a delay of 14-24 h in peroxisome biogenesis. The shortest functional N-terminal (NTCs) and C-terminal constructs (CTCs) were Pex19 (aa 1-150) and Pex19 (aa 89-300), respectively. Deletions of the N-terminal Pex3-binding site disrupted the direct interactions of Pex19 with Pex3, but preserved interactions with a membrane peroxisomal targeting signal (mPTS)-containing PMP, Pex10. In contrast, deletion of the C-terminal mPTS-binding domain of Pex19 disrupted its interaction with Pex10 while leaving the Pex19-Pex3 interactions intact. However, Pex11 and Pex25 retained their interactions with both N- and C-terminal deletion mutants. NTC-CTC co-expression improved growth and reversed the larger-than-normal peroxisome size observed with the single deletions. Pex25 was critical for peroxisome formation with the CTC variants, and its overexpression enhanced their interactions with Pex3 and aided the growth of both NTC and CTC Pex19 variants. In conclusion, physical segregation of the Pex3- and PMP-binding domains of Pex19 has provided novel insights into the modular architecture of Pex19. We define the minimum region of Pex19 required for peroxisome biogenesis and a unique role for Pex25 in this process.


[99mTc-OCTREOTIDE in patients with neuroendocrine tumors from the GI tract].
It has been demonstrated that scintigraphy with somatostatin analogues is useful for the diagnosis, staging and follow up of patients with neuroendocrine tumors from the gastrointestinal tract (NET-GIT). Some studies suggest that the use of 99mTc-Hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) yields similar diagnostic results than the use of 111In-DTPA-octreotide. To determine the clinical value of scintigraphy using 99mTc-HYNIC-TOC for the detection of primary and secondary lesions in patients with NET-GIT. From September 2004 to May 2009, 32 patients (17 women, age range 18 to 82 years old) with histologically proven or clinically suspected NET-GIT underwent scintigraphy using 99mTc-HYNIC-TOC Patients underwent a whole body scan, with additional static images of abdomen and pelvis, followed by SPECT at 4-hrs post injection of 925 MBq of the tracer. Patients underwent clinical, imaging and histopathology follow-up during 3 to 18 months. Histopathology demonstrated carcinoid tumor in 20 patients, insulinoma in 2, gastrinoma in 2 and non-specific NET-GIT in 6. Total sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 87%, 100%, 100%, 89% and 94%, respectively. To detect the primary lesion, the values were 94%, 100% 100%, 94% and 97%, respectively and to detect secondary lesions, 79%, 100%, 100%, 86% and 91%, respectively. 99mTc-HYNIC-TOC is a specific somatostatin analog, with high affinity to receptor subtype SST-2, widely available and affordable by Latin American countries. It has a good performance to be used for diagnosis, staging and follow-up of patients with NET-GIT.


The classical arabinogalactan protein gene family of arabidopsis.
Arabinogalactan proteins (AGPs) are extracellular proteoglycans implicated in plant growth and development. We searched for classical AGPs in Arabidopsis by identifying expressed sequence tags based on the conserved domain structure of the predicted protein backbone. To confirm that these genes encoded bona fide AGPs, we purified native AGPs and then deglycosylated and deblocked them for N-terminal protein sequencing. In total, we identified 15 genes encoding the protein backbones of classical AGPs, including genes for AG peptides-AGPs with very short backbones (10 to 13 amino acid residues). Seven of the AGPs were verified as AGPs by protein sequencing. A gene encoding a putative cell adhesion molecule with AGP-like domains was also identified. This work provides a firm foundation for beginning functional analysis by using a genetic approach.


A Retrospective Chart Review to Determine Hypophosphatemia Incidence and Phosphorus Supplementation Requirements in Patients With Severe Thermal Cutaneous Injuries Receiving High-Volume Hemofiltration.
Patients with severe thermal injuries have increased metabolic demands necessitating frequent phosphate supplementation. Patients with acute renal failure may have less requirements, due to reduced elimination. However, patients being supported with renal replacement therapy have varying degree of requirements. Little published evidence depicts the incidence of hypophosphatemia and repletion requirements in patients with severe thermal injuries treated with high-volume hemofiltration (HVHF) and a high-flux membrane. The objective of this retrospective chart review was to determine the incidence of hypophosphatemia and characterize repletion requirements and response in this population. Enrolled patients had at least 20% TBSA thermal injuries and required continuous hemofiltration with prefilter replacement fluid doses ≥35 mL/kg IBW/hr. A randomly selected cohort without acute kidney injury (AKI) and matched based on age and extent of TBSA was used to compare phosphorus requirements over an initial 14-day period. Demographics, diet, and variables affecting phosphorus concentrations were collected. Sixteen patients were included in the retrospective HVHF group and 16 patients in a case-control cohort to better depict the impact of HVHF. The average age was 60.2 ± 15.1 years and median TBSA was 30% (23.4, 56.3) in the HVHF group, compared to 53.3 ± 16.4 years (P = .22) and TBSA 29% (26.4, 33.9; P = .73). All patients in the HVHF group were started on HVHF with a 1.6 m2 polyethersulfone membrane for AKI. As expected, the HVHF group exhibited statistically higher than normal baseline potassium and phosphorous laboratory values. The HVHF group experienced more days with hypophosphatemia (49.6 ± 12.4% vs 29.3 ± 16.3%, P = .012), despite 0.75 mmol/kg/day phosphorous supplementation (compared to 0.66 mmol/kg/day for the control group, P = .45). Patients with longer durations of HVHF therapy experienced increasing risk of hypophosphatemia, reaching 100% by the end of the study period. This study demonstrates severe thermally injured patients receiving HVHF for AKI are at increased risk for hypophosphatemia, and require high phosphate supplementation.


Microcomputed tomographic analysis of bone microarchitecture after sinus augmentation with hyaluronic matrix: a case-control study.
The aim of this study was to analyze trabecular microarchitecture of augmented sinuses with hyaluronic matrix and xenograft by microcomputed tomography, and to investigate whether hyaluronic matrix has an effect on the newly formed bone quality. Thirteen patients undergoing maxillary sinus augmentation were included in this split-mouth study. Right and left sinus sites were randomly assigned to test and control group. In test group, the sinus was grafted with hyaluronic matrix and xenograft; in control group, only with xenograft. Four months after augmentation, bone samples were harvested during implant placement and analyzed for the following trabecular microarchitecture parameters using microcomputed tomography: bone volume (BV), total volume (TV), bone volume fraction (BV/TV), bone surface (BS), specific bone surface (BS/BV), bone surface density (BS/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), trabecular pattern factor (Tb.Pf), and fractal dimension (FD). There was statistically significant difference only for BS/TV parameter between two groups. BS/TV was higher in hyaluronic matrix group compared with control group. Addition of hyaluronic matrix to xenograft may enhance bone quality in terms of bone surface density. However, more research investigating the microstructural variation of augmented sinuses is needed with a greater sample.


NMR studies of active N-terminal peptides of stromal cell-derived factor-1. Structural basis for receptor binding.
Stromal cell-derived factor 1 (SDF-1), a member of the CXC chemokine family, is the only chemokine to bind to the receptor CXCR4. This receptor is also a co-receptor for syncytia-inducing forms of HIV in CD4(+) cells. In addition, SDF-1 is responsible for attracting mature lymphocytes to the bone marrow and can therefore contribute to host versus graft rejection in bone marrow transplantation. Clearly, by manipulating SDF-1 activity, we could find a possible anti-viral AIDS treatment and aid in bone marrow transplantation. SDF-1 binds to CXCR4 primarily via the N terminus, which appears flexible in the recently determined three-dimensional structure of SDF-1. Strikingly, short N-terminal SDF-1 peptides have been shown to have significant SDF-1 activity. By using NMR, we have determined the major conformation of the N terminus of SDF-1 in a 17-mer (residues 1-17 of SDF-1) and a 9-mer dimer (residues 1-9 of SDF-1 linked by a disulfide bond at residue 9). Residues 5-8 and 11-14 form similar structures that can be characterized as a beta-turn of the beta-alphaR type. These structural motifs are likely to be interconverting with other states, but the major conformation may be important for recognition in receptor binding. These results suggest for the first time that there may be a link between structuring of short N-terminal chemokine peptides and their ability to activate their receptor. These studies will act as a starting point for synthesizing non-peptide analogs that act as CXCR4 antagonists.


Effect of temporary tracheal occlusion on the endothelin system in experimental cases of diaphragmatic hernia.
Previously, the authors have shown that tracheal occlusion (TO) partially reverses the onset of congenital diaphragmatic hernia (CDH)-induced pulmonary hypertension (PH) and abnormal pulmonary vascular development whereas release of the occlusion (TR) abolishes these clinical benefits. As a consequence of their mitogenic and vasoactive properties, the authors hypothesize that the expression of endothelin (ET)-1 and ET receptor (ETA) genes is increased in lungs of CDH lambs, and that this increase is abolished partially in CDH + TO but not in CDH + TO + TR. A surgical left-sided CDH was created in fetal lambs at 80 days of gestation (gd), followed by TO at 108 gd, and by TR at 129 gd. Four groups were compared: CDH, CDH + TO, CDH + TO + TR, and nonoperated controls (C). Assessment of mRNA expression by Northern blot showed significantly lower ET-1 and ETA levels in the CDH group than in the CDH + TO +/- TR groups (P < .05). Endothelin protein expression levels were lower in CDH +/- TO +/- TR groups when compared with controls for airways and vessels (P < .05) with the exception of endothelial cells. In contrast, ETA protein expression levels were higher in CDH +/- TO +/- TR groups compared with controls for airways and blood vessels smooth muscles (P < .05). These results suggest that involvement of the endothelin system in the pulmonary hypertension associated with CDH is limited. However, the endothelin system appears to be modulated during development.


Effect of a patient-centered hypertension delivery strategy on all-cause mortality: Secondary analysis of SEARCH, a community-randomized trial in rural Kenya and Uganda.
Hypertension treatment reduces morbidity and mortality yet has not been broadly implemented in many low-resource settings, including sub-Saharan Africa (SSA). We hypothesized that a patient-centered integrated chronic disease model that included hypertension treatment and leveraged the HIV care system would reduce mortality among adults with uncontrolled hypertension in rural Kenya and Uganda. This is a secondary analysis of the SEARCH trial (NCT:01864603), in which 32 communities underwent baseline population-based multidisease testing, including hypertension screening, and were randomized to standard country-guided treatment or to a patient-centered integrated chronic care model including treatment for hypertension, diabetes, and HIV. Patient-centered care included on-site introduction to clinic staff at screening, nursing triage to expedite visits, reduced visit frequency, flexible clinic hours, and a welcoming clinic environment. The analytic population included nonpregnant adults (≥18 years) with baseline uncontrolled hypertension (blood pressure ≥140/90 mm Hg). The primary outcome was 3-year all-cause mortality with comprehensive population-level assessment. Secondary outcomes included hypertension control assessed at a population level at year 3 (defined per country guidelines as at least 1 blood pressure measure <140/90 mm Hg on 3 repeated measures). Between-arm comparisons used cluster-level targeted maximum likelihood estimation. Among 86,078 adults screened at study baseline (June 2013 to July 2014), 10,928 (13%) had uncontrolled hypertension. Median age was 53 years (25th to 75th percentile 40 to 66); 6,058 (55%) were female; 677 (6%) were HIV infected; and 477 (4%) had diabetes mellitus. Overall, 174 participants (3.2%) in the intervention group and 225 participants (4.1%) in the control group died during 3 years of follow-up (adjusted relative risk (aRR) 0.79, 95% confidence interval (CI) 0.64 to 0.97, p = 0.028). Among those with baseline grade 3 hypertension (≥180/110 mm Hg), 22 (4.9%) in the intervention group and 42 (7.9%) in the control group died during 3 years of follow-up (aRR 0.62, 95% CI 0.39 to 0.97, p = 0.038). Estimated population-level hypertension control at year 3 was 53% in intervention and 44% in control communities (aRR 1.22, 95% CI 1.12 to 1.33, p < 0.001). Study limitations include inability to identify specific causes of death and control conditions that exceeded current standard hypertension care. In this cluster randomized comparison where both arms received population-level hypertension screening, implementation of a patient-centered hypertension care model was associated with a 21% reduction in all-cause mortality and a 22% improvement in hypertension control compared to standard care among adults with baseline uncontrolled hypertension. Patient-centered chronic care programs for HIV can be leveraged to reduce the overall burden of cardiovascular mortality in SSA. ClinicalTrials.gov NCT01864603.


Induction of experimental autoimmune myasthenia gravis with acetylcholine receptors using a nonionic block copolymer as adjuvant.
To induce autoimmune diseases in animals, the auto-antigen has to be emulsified in adjuvants (e.g., complete Freund's adjuvant) containing microbial products such as Mycobacterium tuberculosis. But these powerful immunoadjuvants are not without undesirable immune response to the microbial proteins and induction of adjuvant arthritis, which could interfere with the antigen specific autoimmune response to be tested. This study was performed to evaluate the requirement of microbial products in the induction of experimental autoimmune diseases, and to identify an adjuvant without unwanted immune responses. C57BL/6 mice were inoculated with Torpedo acetylcholine receptors (T-AChR) emulsified in Titermax (TM), an adjuvant containing nonionic block copolymer and no microbial products, and evaluated for experimental autoimmune myasthenia gravis (EAMG) susceptibility. Mice immunized with T-AChR in TM demonstrated characteristic myasthenic muscle weakness with electrophysiological defect, elevated serum anti-AChR antibodies, and muscle AChR loss. None of the mice that received TM alone had muscle weakness, serum anti-AChR antibodies or muscle AChR loss. The data imply that microbial products are not critical in the induction of autoimmune diseases like myasthenia gravis in mice. Further, nonionic block copolymer could be an ideal adjuvant in the induction of autoimmune diseases in animals.


Structure and processing of yeast precursor tRNAs containing intervening sequences.
We have isolated a precursor of yeast tRNATyr and shown that it contains an intervening sequence identical to that found in the gene for tRNATyr. The conformation of pre-tRNATyr is similar to that of mature tRNATyr except for the anticodon loop. The loop is sensitive to endonucleolytic cleavage by S1 nuclease near to the ends of the intervening sequence. This pre-tRNA is functionally inactive as it cannot be aminoacylated and the anticodon is not accessible for hydrogen bonding. A crude nuclear extract from yeast contains an excision-ligase activity which will process pre-tRNATyr into mature tRNATyr.


Translational Potential of MicroRNAs for Preoperative Staging and Prediction of Chemoradiotherapy Response in Rectal Cancer.
Abstract: Colorectal cancer is the third most common cancer and the second cause of cancer-related deaths. Rectal cancer presents roughly one-third of all colorectal cancer cases and differs from it on both anatomical and molecular levels. While standard treatment of colon cancer patients is radical surgery, rectal cancer is usually treated with pre-operative chemoradiotherapy followed by total mesorectal excision, which requires precise estimation of TNM staging. Unfortunately, stage evaluation is based solely on imaging modalities, and they often do not correlate with postoperative pathological findings. Moreover, approximately half of rectal cancer patients do not respond to such pre-operative therapy, so they are exposed to its toxic effects without any clinical benefit. Thus, biomarkers that could precisely predict pre-operative TNM staging, and especially response to therapy, would significantly advance rectal cancer treatment-but till now, no such biomarker has been identified. In cancer research, microRNAs are emerging biomarkers due to their connection with carcinogenesis and exceptional stability. Circulating miRNAs are promising non-invasive biomarkers that could allow monitoring of a patient throughout the whole therapeutic process. This mini-review aims to summarize the current knowledge on miRNAs and circulating miRNAs involved in the prediction of response to treatment and pre-operative staging in rectal cancer patients.


Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment.
Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral nucleus of the amygdala (BLA) and prelimbic (PL) medial prefrontal cortex have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task wherein competing shock- and sucrose-predictive cues were simultaneously presented. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, BLA neurons optogenetically identified as projecting to PL more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally photostimulation of the BLA→PL projection increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. Therefore, the BLA→PL circuit is critical in governing the selection of behavioral responses in the face of competing signals.


Nephron-sparing surgery for bilateral Wilms' tumours: a single-centre experience with 23 cases.
The challenge of management with bilateral Wilms' tumours is the eradication of the neoplasm, while at the same time preserving renal function. Surgical management with a variety of nephron-sparing techniques, combined with chemotherapy and occasionally supplemented by transplantation has evolved over the last 30 years to achieve remarkable success. We document the experience of a single centre in a developing country. Twenty-three bilateral Wilms' tumours were seen in our service between 1981 and 2007. Treatment was, in most cases, according to National Wilms' Tumour Study Group protocols, with initial bilateral biopsy, neoadjuvant chemotherapy, and tumourectomy. Technique of nephrectomy included full mobilization of the tumour-involved kidney, topical cooling with slush ice, vascular exclusion, tumour resection and reconstruction of the remnant kidney. Twelve patients are alive and free of disease one to 15 years after treatment, all with well-preserved renal function (lowest glomerular filtration rate was 65 ml/min per (1.73 m 2 ). None of the survivors have hypertension. Eleven have died (two of unrelated disease) including six of the seven with spread outside the kidney. All three with unfavourable histology are alive. Four of the five metachronous presentations are alive, as are eight of 12 patients with synchronous bilateral tumours who presented since 2000. Appropriate chemotherapy and nephron-sparing surgery can achieve good results with preservation of adequate renal function in nearly all cases. Unfavourable histology did not have a reduced survival in our series. Metastatic spread outside the kidney had a poor prognosis.


Media Coverage of Ethical Issues in Predictive Genetic Testing: A Qualitative Analysis.
Background: Predictive genetic testing (PGT) raises many ethical issues and is of increasing interest to the general population. Mass media, especially newspapers, are the public's main source of information on this topic. Methods: We conducted a content analysis of British newspaper reporting, assessing which ethical issues were mentioned. The analysis was qualitative with semi-quantitative aspects. All articles about PGT published in The Guardian and the Daily Telegraph from 2011 to 2016 were included. Results: Most ethical issues discussed in the scientific and ethical literature are implicitly or explicitly covered in newspapers, but there was no discussion of incidental findings and the possibility of false reassurance of a negative test result was mentioned only once. There are also important gaps regarding the multidimensional nature and complexity of many issues. The Guardian mentioned ethical issues more frequently than the Daily Telegraph. Most ethical issues were portrayed as first-person narratives. Conclusions: Ethical issues concern potential test users and society more than scientific background knowledge about such tests; therefore, more efforts should be taken to address these complex issues in a manner that is comprehensible for the lay public.


Provoked Vestibulodynia: A Comparative Examination of Mental Health, Sleep, Sexual Functioning, and Relationship Adjustment.
Provoked vestibulodynia (PVD) is an idiopathic vulvar pain condition characterized by burning pain at the vaginal opening in response to contact or pressure. Previous research has established some of the psychosocial difficulties experienced by these patients, but direct comparisons with other pain conditions are needed. The purpose of this study was to compare women with PVD to those with postherpetic neuralgia and pain-free control participants. Participants were invited to complete an anonymous online survey consisting of sociodemographic questions and a range of validated measures. Women with PVD and postherpetic neuralgia (PHN) did not differ in terms of pain catastrophizing or pain anxiety, but women with PHN reported greater pain disability than those with PVD. Participants in both pain groups reported significantly more symptoms of stress, depression, anxiety, and sleep disturbances than pain-free controls; women with PHN reported more symptoms of depression than those with PVD, with no other differences between pain groups. Groups did not differ on relationship adjustment, but participants with PVD reported poorer sexual functioning than the other groups. These results indicate that women with PVD and PHN experience similar mental health difficulties, but women with PHN experience more severe impact on their day-to-day functioning and mood. These results support the classification of PVD as a chronic pain condition, as both the pain groups differed from pain-free control participants on a range of measures. Finally, the presence of mental health difficulties and poorer sexual functioning highlights the importance of conducting biopsychosocial pain assessments.


The Utility of Obtaining Postmobilization Imaging in Nonsurgical Pelvic Ring Injuries.
Pelvic fractures are diverse injuries with varying degrees of severity. Treatment recommendations are determined by the associated instability. For likely stable patterns, postmobilization imaging is used to assess for occult instability. This study assesses the utility of postmobilization images and determines how often they alter the recommendations for treatment. Records at a single level 1 trauma center from January 2007 through December 2014 were reviewed, and patients with Current Procedural Terminology codes and International Classification of Diseases, Ninth Revision codes for pelvic and acetabular fractures were identified. For those chosen for nonsurgical treatment at presentation, a detailed chart review was performed to identify patients who had postmobilization radiographs and to determine whether this imaging led to a change in treatment recommendations. Inclusion criteria were met by 762 patients whose average age was 50 years. Of 331 patients planned for nonsurgical treatment at presentation, 168 (51%) had postmobilization images. The postmobilization radiographs did not alter treatment recommendations in any of these patients; however, three of these patients underwent surgical stabilization based on the patients' report of pain with attempted mobilization. Routine postmobilization imaging has limited value for patients with pelvic injuries and a low likelihood for instability, such as those with incomplete sacral fractures. Eliminating this step would reduce cost and decrease radiation exposure. The need for change in treatment plan or further imaging should be based on the patient's clinical progress with weight bearing. Level 4.


Full path compensation laser feedback interferometry for remote sensing with recovered nanometer resolutions.
The accuracy of the existing laser feedback interferometry for measuring the remote target is limited to several microns due to environmental disturbances. A novel approach is presented in this paper based on the double-beam frequency-shift feedback of the laser, which can completely eliminate the dead path errors and measure the displacement or vibration with accuracy at nanometer scale even at a far measurement distance. The two beams emitted from one Nd:YVO4 crystal are incident on the measurement target and its adjacent reference surface, respectively. The reference surface could be taken from the nearby stationary object, without the need to put a reference mirror. The feedback paths and shift frequencies of the two beams are the same, so the air disturbances and the thermal effects in the way could be fully compensated. Under common room conditions, the displacement of a steel block at a distance of 10 m is measured, which proved that the system's stability is ±12 nm in 100 s and ±50 nm in 1000 s, the short-term resolution is better than 3 nm, and the linearity within the 300 mm range is 5 × 10-6 and within the 100 μm range is 1 × 10-4.


Integrated opioid use disorder and HIV treatment: rationale, clinical guidelines for addiction treatment, and review of interactions of antiretroviral agents and opioid agonist therapies.
Injection drug use (IDU) is an important vector of HIV infection in the United States. Many patients with HIV infection have comorbid substance use disorders. Integrated treatment for HIV and substance use disorders has been shown to improve HIV and other health outcomes, but significant barriers to integrated treatment exist. For individuals who are dependent on injection opioid drugs, agonist therapies of methadone or buprenorphine maintenance are available as part of a treatment program. Patients who are infected with HIV and require antiretroviral therapy (ART) are at risk for drug-drug interaction between ART and methadone or buprenorphine. We present a programmatic approach to the evaluation and treatment of opioid use disorders for HIV care providers, as well as a summary of the available knowledge of interactions of methadone and buprenorphine with ART, along with the level of evidence for each actual or potential interaction. Based on the available information of practice and the level of clinical significance of drug-drug interactions, we conclude that buprenorphine-based maintenance treatment for opioid dependent patients is the preferred maintenance therapy for integrated treatment systems.


Longitudinal changes of adiponectin, carbohydrate and lipid metabolism in pregnant women at high risk for gestational diabetes.
To evaluate, in pregnant women at high risk for gestational diabetes (GDM), the longitudinal changes of adiponectin, carbohydrate and lipid metabolism, and to assess their independent value as risk factors for the development of GDM. Fifty women at beginning of pregnancy were studied. Adiponectin, insulin sensitivity (homeostasis model assessment, HOMA) and lipid panel were measured at 1st, 2nd and 3rd trimesters of pregnancy. Twelve patients developed GDM. In both groups, GDM and normal glucose tolerance (NGT), adiponectin decreased from 1st to 2nd and 3rd trimesters by about 5 and 20% (GDM, p < 0.05), and of about 17 and 25% in NGT (p < 0.05), respectively. Values observed in NGT were similar to those of GDM (F = 9.401; p = 0.238). The Cox regression model identified as the strongest independent risk factor for GDM HOMA over 1.24 (RR = 14.12) at 1st trimester, fasting glycaemia over 87 mg/dl (RR = 42.68) triglycerides over 158 mg/dl (RR = 5.87) and body mass index (BMI) over 27 kg/m(2) (RR = 4.38) at 2nd trimester. Adiponectin in high-risk women is characterised by a constant reduction throughout gestation, irrespective of the development of GDM. HOMA, fasting glycaemia, triglycerides and BMI, but not adiponectin are independent predictors of GDM.


The case for small-scale domestic cannabis cultivation.
The shift to (inter)regional production, trade and domestic cultivation has become an irreversible international trend. Until now, the focus of most empirical work has been on large-scale, commercially oriented and professionally organized segments of the cannabis industry, often based on police data and on the perspective of law enforcement agencies. This paper offers a review of recent Dutch-language research that focuses on cannabis cultivation. Empirical studies were identified through literature searches using relevant search terms and Web of Science, Elin, Social Science Research Network and Elsevier ScienceDirect. The paper presents the main findings of Dutch and Belgian empirical work on the factors that stimulated the import substitution process on the cannabis market, aspects related to quality and potency issues, typologies of cannabis growers, and (unintended) effects of pursued policies. In the light of this (selective) review the author offers some commentary and analysis concerning the claims made by different stakeholders, and concludes with some reflections on future research and on policy implications. The author outlines the importance of small-scale, independent or ideologically oriented cannabis cultivation as an under-researched market segment. The author also makes a case for greater toleration of small-scale cannabis cultivation, to secure the least worst of cannabis markets.


Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility.
Estrogen production and metabolism play critical roles in the development and pathogenesis of endometrial carcinoma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in the estrogen metabolism pathway that result in the hydroxylation and conjugation of estradiol, respectively. We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls). We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk. Conditional logistic regression was used to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with subjects who were homozygous for the wild-type allele. Carriers of the CYP1B1 Ser allele had a statistically significant decreased risk of endometrial cancer (OR = 0.62; 95% CI, 0.42-0.91); there was no significant association between the CYP1B1 Val allele and endometrial cancer risk (OR = 1.10; 95% CI, 0.75-1.59). Compared with the COMT Val/Val wildtype genotype, the adjusted OR of endometrial cancer for women with the COMT Val/Met or COMT Met/Met genotype was 0.96 (95% CI, 0.65-1.43). We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes. Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens. However, further studies are warranted to elucidate the role of CYP1B1 in endometrial cancer.


Conformational changes in fragments D and double-D from human fibrin(ogen) upon binding the peptide ligand Gly-His-Arg-Pro-amide.
The structure of fragment double-D from human fibrin has been solved in the presence and absence of the peptide ligands that simulate the two knobs exposed by the removal of fibrinopeptides A and B, respectively. All told, six crystal structures have been determined, three of which are reported here for the first time: namely, fragments D and double-D with the peptide GHRPam alone and double-D in the absence of any peptide ligand. Comparison of the structures has revealed a series of conformational changes that are brought about by the various knob-hole interactions. Of greatest interest is a moveable "flap" of two negatively charged amino acids (Glubeta397 and Aspbeta398) whose side chains are pinned back to the coiled coil with a calcium atom bridge until GHRPam occupies the beta-chain pocket. Additionally, in the absence of the peptide ligand GPRPam, GHRPam binds to the gamma-chain pocket, a new calcium-binding site being formed concomitantly.


[The evaluation of stored feces in elderly patients by ultrasonography: Three case studies].
Providing defecation care can be challenging because bowel movements cannot be directly observed in home-care settings, and the objective evaluation of constipation symptoms is difficult, particularly for elderly patients with cognitive impairment. We evaluated the use of rectal ultrasonography (US) to assess the properties and volume of feces in three cases with different fecal properties. Case 1: In a 94-year-old man with normal feces (Bristol stool score: BS type 4), rectal US revealed a crescent-shaped high-echo area without acoustic shadow that was present until the next defecation. Case 2: In a 92-year-old woman with hard stool (BS type 1), rectal US showed a crescent-shaped strong-echo area with acoustic shadow that was present until the next defecation. The length of the high-echo area gradually increased during the observation period and decreased after defecation in Cases 1 and 2. Case 3: In a 67-year-old man with watery stool (BS type 7), rectal US revealed a low-peripheral-frequency-echo area without acoustic shadow. Rectal ultrasonography was able to demonstrate the presence or absence of hard stool, which was observed as a crescent-shaped a strong, high-echo area with acoustic shadow; the presence or absence of hard stool may be evaluated based on these findings. Furthermore, the fecal volume may be able to be evaluated based on the long diameter of the crescent-shaped high-echo area. Determining the best course of defecation care based on the fecal properties/volume evaluated using rectal US will likely be possible in the future.


In vivo confocal microstructural analysis of corneas presenting Kayser-Fleischer rings in patients with Wilson's disease.
To evaluate microstructural differences between corneas with and without Kayser-Fleischer rings in age-matched subjects with Wilson's disease with neurological symptoms, using confocal laser scanning microscopy. The study included 12 subjects with Wilson's disease with neurological symptoms. Twelve corneas presented clinically with classic Kayser-Fleischer rings, visible on slit lamp examination; the other 12 served as controls. The subjects underwent a comprehensive clinical examination. Microstructural analysis using confocal laser scanning microscopy evaluated increased corneal thickness, decreased number of cells, increased debris or specific deposits, and unusual microstructures. Clinically, the subjects with Kayser-Fleischer rings had similar corneal findings and normal intraocular pressure; two had typical sunflower cataracts and decreased visual acuity. The control eyes all presented normal visual acuity, intraocular pressure, and corneal appearance. The microstructural analysis demonstrated similar findings in all the affected corneas. Compared with the control corneas, there were fewer keratocytes in the anterior stroma (17.380 vs. 22.380/mm3). Round, "hollow" dark areas were observed between the keratocytes; these were universal and similar in appearance in all affected corneas and all cornea layers. In the peripheral posterior stroma, there were dust-like, bright, granular deposits that tended to increase in number and density toward Descemet's membrane, masking the peripheral endothelium. The control corneas presented a normal microstructure apart from dust-like granular deposits in the periphery. In vivo confocal microscopy is a useful tool for evaluating the corneal microstructure when a Kayser-Fleischer ring is clinically present. The ring consists of granular, bright particles that increase in density toward Descemet's membrane, and is associated with a decreased number of keratocytes and peculiar dark, round areas in all stromal layers, probably a sign of corneal damage. When the ring is not visible in subjects with Wilson's disease, changes to the corneal microstructure are insignificant.


[Evidences of Existence of Serotoninergic Nerves, Enhancing Duodenal Motility].
The review is devoted to the mechanism of duodenal motility activation caused by sympathetic nerves. The authors havefound that stimulation of the sympathetic trunk in the thoracic cavity in dogs in most cases provide not inhibitory but excitatory motor responses of the duodenum. Excitatory effects were eliminated during 5HT-receptors blockade by promedol and lysergol. Analysis ofpublications showed that sympathetic trunk contains serotoninergic fibers, providing excitatory motor responses of the duodenum to electrical nerve stimulation. According to histochemical and physiological studies, amount of serotonergic fibers in the sympathetic trunk is several times more than the adrenergic. This means that the body has sertoninergic nerves. Serotoninergic nerve as well as the sympathetic is a collective notion. There are: sympathetic trunks, their ramifications and branches that innervate the internal organs. Since promedol blocks serotonergic nerves, this is plausible cause of constipation in patients after surgical treatment along with the application of this drug.


Associations of prenatal exposure to phthalates with measures of cognition in 7.5-month-old infants.
Phthalates are endocrine disrupting chemicals that have been associated with adverse neurobehavior, but little is known about their influence on infant cognition. A visual recognition memory task was used to assess cognition in 244 7-8-month-old infants (121 females; 123 males) from a prospective cohort study. Phthalate metabolites were quantified in maternal urines pooled from across pregnancy. The task included familiarization trials (infant shown 2 identical faces) and test trials (infant shown the now familiar face paired with a novel one). Half of the infants saw one set of faces as familiar (set 1) and half saw the other set as familiar (set 2). During familiarization trials, average run duration (time looking at stimuli before looking away, measure of processing speed), and time to familiarization (time to reach 20 s looking at the stimuli, measure of attention) were assessed. During test trials, novelty preference (proportion of time looking at the novel face, measure of recognition memory) was assessed. Multivariable generalized linear models were used to assess associations of monoethyl phthalate (MEP), sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of di(isononyl) phthalate metabolites (ΣDINP), and sum of anti-androgenic phthalate metabolites (ΣAA) with each outcome. Mothers were mostly white and college educated, and urine phthalate concentrations were similar to those in reproductive age women in the U.S. All phthalate exposure biomarkers, except MEP, were associated with increases in average run duration. However, depending on the phthalate, associations were only in males or infants who saw the set 2 stimuli as familiar. Unexpectedly, ΣAA was associated with a shorter time to reach familiarization. Phthalate biomarkers also were associated with modest decrements in novelty preference, but these associations were nonsignificant. Prenatal exposure to phthalates may be related to slower information processing and poorer recognition memory in infants.


Dynamic ligand exchange of the lanthanide complex leading to structural and functional transformation: one-pot sequential catalytic asymmetric epoxidation-regioselective epoxide-opening process.
The characteristic property of the lanthanide complex, which easily undergoes a dynamic ligand exchange and alters its structure and function in situ, is described. After the completion of the catalytic asymmetric epoxidation of various alpha,beta-unsaturated amides 2 in the presence of the Sm-(S)-BINOL-Ph3As=O (1:1:1) complex 1 (2-10 mol %), the addition of Me3SiN3 directly to the reaction mixture led to smooth epoxide-opening at room temperature, affording the corresponding anti-beta-azido-alpha-hydroxyamide 4 in excellent overall yield (up to 99%) with complete regioselectivity and excellent enantiomeric excess (up to >99%). The key to the success of the sequential process was the in situ generation of the highly reactive samarium azide complex through dynamic ligand exchange. In situ IR spectroscopy and other experiments provided strong evidence that the samarium azide complex was generated. In addition, the relatively high Lewis basicity of the amide moiety had a key role in the high reactivity of both the epoxidation and the epoxide-opening reactions. Examinations of other nucleophiles such as sulfur or carbon nucleophiles as well as transformations of epoxide-opened products are also described.


Infants Show Physiological Responses Specific to Parental Hugs.
Caregivers hug their infants to express affection and joy. However, it remains unknown how infants react to being hugged. Here we examined heart rate responses in first-year infants during a hug, hold, and tight hug from parents. Infants older than four months showed an increased R-R interval (RRI) during a hug, indicating reduced heart rates and pronounced parasympathetic activity. Few head movements predicted a higher RRI increase in infants during a parental hug compared with that during a hold and tight hug. Infants did not show an increased RRI during a hug from a female stranger. Infants younger than four months did not show RRI increase during parental hug but exhibited a decreased RRI correlated with contact pressure. Parents showed an increased RRI during hugging their infants. These results suggest the parent-infant hug underlies the parent-infant bonding and psychophysiological development of infants.


Drug therapy for chronic asthma in children.
Asthma is a common chronic illness in children and a successful symptom control improves quality of life. Guidelines for the use of drugs in its management are widely available, but for children are often based on consensus opinion and extrapolation of data from studies in adolescents and adults. The aim of this review is to describe the clinical pharmacology of the drugs commonly used to manage chronic asthma in children and identify areas where further study might be useful to determine their best use.


Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.
Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. ClinicalTrials.gov (NCT03334747).


In situ transfer of antibiotic resistance genes from transgenic (transplastomic) tobacco plants to bacteria.
Interkingdom gene transfer is limited by a combination of physical, biological, and genetic barriers. The results of greenhouse experiments involving transplastomic plants (genetically engineered chloroplast genomes) cocolonized by pathogenic and opportunistic soil bacteria demonstrated that these barriers could be eliminated. The Acinetobacter sp. strain BD413, which is outfitted with homologous sequences to chloroplastic genes, coinfected a transplastomic tobacco plant with Ralstonia solanacearum and was transformed by the plant's transgene (aadA) containing resistance to spectinomycin and streptomycin. However, no transformants were observed when the homologous sequences were omitted from the Acinetobacter sp. strain. Detectable gene transfer from these transgenic plants to bacteria were dependent on gene copy number, bacterial competence, and the presence of homologous sequences. Our data suggest that by selecting plant transgene sequences that are nonhomologous to bacterial sequences, plant biotechnologists could restore the genetic barrier to transgene transfer to bacteria.


Human odontoblasts express functional thermo-sensitive TRP channels: implications for dentin sensitivity.
Odontoblasts form the outermost cellular layer of the dental pulp where they have been proposed to act as sensory receptor cells. Despite this suggestion, evidence supporting their direct role in mediating thermo-sensation and nociception is lacking. Transient receptor potential (TRP) ion channels directly mediate nociceptive functions, but their functional expression in human odontoblasts has yet to be elucidated. In the present study, we have examined the molecular and functional expression of thermo-sensitive TRP channels in cultured odontoblast-like cells and in native human odontoblasts obtained from healthy wisdom teeth. PCR and western blotting confirmed gene and protein expression of TRPV1, TRPA1 and TRPM8 channels. Immunohistochemistry revealed that these channels were localised to odontoblast-like cells as determined by double staining with dentin sialoprotein (DSP) antibody. In functional assays, agonists of TRPV1, TRPA1 and TRPM8 channels elicited [Ca2+]i transients that could be blocked by relevant antagonists. Application of hot and cold stimuli to the cells also evoked rises in [Ca2+]i which could be blocked by TRP-channel antagonists. Using a gene silencing approached we further confirmed a role for TRPA1 in mediating noxious cold responses in odontoblasts. We conclude that human odontoblasts express functional TRP channels that may play a crucial role in mediating thermal sensation in teeth. Cultured and native human odontoblasts express functional TRP channels that may play a crucial role in mediating thermal sensation in teeth.


Specific distribution behavior of a ternary mixture of solvents fed into bent and wound microchannels in microchips.
The tube radial distribution of ternary solvents (water-hydrophilic/hydrophobic organic mixture) fed into bent and wound microchannels in a microchip was examined by fluorescence observations of dyes dissolved in the solvents under laminar flow conditions. Four kinds of microchips incorporating bent microchannels were used, together with a microchip with a straight channel. The microchannels had different bending times (2, 4, or 12 times), bending radii (0.8, 2.3, or 3 mm), and total channel lengths (80, 120, 200, or 500 mm). A water-acetonitrile (hydrophilic)-ethyl acetate (hydrophobic) mixture containing relatively hydrophilic Eosin Y (green) and hydrophobic perylene (blue) was delivered into the bent microchannels in the microchips. The fluorescence of the green and blue dyes enabled us to observe the specific radial distribution behavior of the ternary solvents in the bent micro channels at 0°C, including liquid-liquid interfaces. Further, the radial distribution pattern of the solvents was clearly observed in the wound microchannel (bending radius, ca. 0.1 mm; real total channel length, 500 mm; and apparent straight channel length, 40 mm) at 20°C (room temperature) as well as 0°C. It was found that the radial distribution behaviors of the solvents were successfully generated in even specific microchannels including various types of curves under the present conditions.


What parents in Australia know and do about head lice.
Although parents in developed market economies regard head lice infections (pediculosis) as a significant problem, health departments generally rate pediculosis as a low priority health issue, encouraging parents to manage and control it. But how well equipped and willing are parents to manage the infections? There do not appear to be any studies in the literature addressing these issues. This article presents the results of a survey conducted in Australia that aimed to answer these questions. A cross-sectional survey of parents of primary school aged children in Victoria (Vic) and north Queensland (NQ) was conducted using a self-administered questionnaire. The study investigated the knowledge, attitudes and practices of parents regarding head lice infections. Only 7.1% of 1338 who completed the questionnaire answered all 10 knowledge questions correctly and more than one-third failed to answer half correctly. There was a weak negative correlation between parents' knowledge and the prevalence of active pediculosis in the school. Almost all parents wanted the responsibility for treating pediculosis and more than three-quarters saw it as a health concern. A higher proportion of parents in NQ used preventative strategies (67% vs 41%). Most parents spent less than AU$50 per year on treatments. Alarmingly, however, the proportion of children missing school as a result of pediculosis was 24.4% and 30.3% in Vic and NQ, respectively. In Vic there was a positive correlation (r = 0.39) between missing school in the previous 12 months and prevalence of pediculosis in the school. This appears to be the most comprehensive study of parental knowledge, beliefs, and practices regarding head lice infections. Although parents wanted responsibility for the management of pediculosis, deficiencies in their knowledge indicate they may be inadequately equipped to do so. Given the high proportion of children in both states who have missed school as a result of head lice, it is recommended that health departments in Australia should work to ensure that consistent and accurate messages about pediculosis are disseminated, and that relevant legislation is amended to prevent children being excluded from school.


Vigilance. Evolution and definition for caregivers of family members with Alzheimer's disease.
The language of caregiving relies heavily on terms that are frequently negative such as caregiver stress and burden, but these are not universally accepted phenomenon. The purpose of this article is to report on the development of caregiver vigilance and to suggest it offers both neutral terminology and a means to include caregivers' perceptions of their supervisory role. The concept of vigilance emerged from a qualitative study of caregivers of family members with Alzheimer's disease. Vigilance is defined as the caregivers' continual oversight of their care recipients' activities. The five key components of vigilance were watchful supervision, protective intervening, anticipating, always on duty, and being there. Vigilant caregivers saw themselves as "on duty" even when they were not "doing things." The findings of this study support caregivers' perceptions of 24-hour-a-day responsibility. Nurses need to realize that caregiver vigilance is not necessarily diminished when professional caregivers intervene or institutionalization occurs. Debriefing caregivers about their unique family caregiving knowledge and incorporating it into caregiving is a key strategy for nurses to use to build caregiver trust and reduce their vigilance time.


Enzyme content and acid stability of enteric-coated pancreatic enzyme products in vitro.
Pancreatic enzymes are prescribed routinely for pancreatic insufficiency. In the current health care environment, drug substitution is commonly performed although there is no proof of therapeutic or bioequivalence for these products. The purpose of this in vitro, prospective study was to evaluate the enzyme contents and dissolution of various capsules of pancreatic enzyme using current United States Pharmacopoeia (USP) methodology. Nine different pancreatic enzyme products were purchased on the market and supplied to Irvine Analytical Laboratories (IAL) (Irvine, CA). All test products were maintained in the laboratory environment, at room temperature, throughout the testing period by IAL. USP procedures for assay and dissolution testing of pancrelipase delayed-release capsules, as described in the latest USP supplement were observed during product testing, including determination of amylase, lipase, and protease activity. In addition, a point assay with measurement of lipase after dissolution in simulated gastric fluid pH of 1.0 for 1 hour and then dissolution in pH 6 phosphate buffer for 30 minutes performed in accordance with USP guidelines. Assay results of amylase, protease, and lipase from the 9 tested products are within USP specified limits. The percentage of label claim for these enzymes was higher than depicted in their label except for one drug batch. However, the percentage of lipase activity after dissolution varied with 2 of 3 batches of 1 drug not dissolving, and 1 batch of another drug, revealing only 8% lipase activity in the USP dissolution test. While assay of pancreatic enzymes reveal they were equal to their USP claims regarding their enzyme content, not all pancreatic enzyme replacements are equal in their release of lipase activity according to USP requirements. The findings maybe clinically seen with therapeutic failures of enzyme products. The FDA has recently decreed that all pancreatic enzyme products will require an approved NDA as differences in pharmaceutical quality have been identified in this product. Thus, it is considered that substitution of these products maybe questionable. Things are seldom what they seem- not all pancreatic enzyme replacements are equal. Further studies are warranted to investigate dissolution characteristics.


Characterization of the running-in period in total hip resurfacing arthroplasty: an in vivo and in vitro metal ion analysis.
Metal-on-metal total hip resurfacing arthroplasty is increasingly being performed in young and active patients. Preclinical in vitro testing of implants is usually performed with use of hip simulators, and the serum metal ion concentration is determined for the purpose of monitoring the patients. The goal of this study was to characterize the early running-in period in vivo and in vitro by characterizing metal ion levels. A well-functioning total hip resurfacing prosthesis was implanted in fifteen consecutive patients, and the serum metal ion concentrations in these patients were then determined preoperatively and at intervals during the first postoperative year (at one, six, twelve, twenty-four, and fifty-two weeks). The number of walking cycles was measured with use of a computerized accelerometer in order to compare walking cycles to hip simulator cycles. In vitro, five similar components were investigated for 3 million cycles with use of a hip simulator. Serum samples were obtained at different time points, and wear was measured by quantifying wear particles and ions in the samples. All patient and simulation serum samples were analyzed with use of inductively coupled plasma-mass spectrometry. One simulator implant was investigated with use of scanning electron microscopy. The serum chromium and cobalt levels of the patients continuously increased during the first six months and showed an insignificant decrease thereafter. The molybdenum concentration was unchanged compared with preoperative values. In contrast, the simulator measurements showed a different wear pattern with a high-wear running-in period and a low-wear steady-state phase. The running-in period was delayed by 300,000 cycles and lasted up to 1 million cycles. Scanning electron microscopic analysis showed a carbon-rich protein film predominantly in the early phases of simulation. Scratches were detected originating from pits filled with aluminum oxide and silicon oxide and from pulled-out carbides that were causing third-body wear. The simulator study allowed an exact characterization of the running-in period and showed a delayed onset of running-in wear. In contrast, the clinical data showed a slow increase in measured ion concentrations. These different wear patterns are probably due to the effects of distribution, accumulation, and excretion of particles and ions in vivo.


Brain parcellation selection: An overlooked decision point with meaningful effects on individual differences in resting-state functional connectivity.
Over the past decade extensive research has examined the segregation of the human brain into large-scale functional networks. The resulting network maps, i.e. parcellations, are now commonly used for the a priori identification of functional networks. However, the use of these parcellations, particularly in developmental and clinical samples, hinges on four fundamental assumptions: (1) the various parcellations are equally able to recover the networks of interest; (2) adult-derived parcellations well represent the networks in children's brains; (3) network properties, such as within-network connectivity, are reliably measured across parcellations; and (4) parcellation selection does not impact the results with regard to individual differences in given network properties. In the present study we examined these assumptions using eight common parcellation schemes in two independent developmental samples. We found that the parcellations are equally able to capture networks of interest in both children and adults. However, networks bearing the same name across parcellations (e.g., default network) do not produce reliable within-network measures of functional connectivity. Critically, parcellation selection significantly impacted the magnitude of associations of functional connectivity with age, poverty, and cognitive ability, producing meaningful differences in interpretation of individual differences in functional connectivity based on parcellation choice. Our findings suggest that work employing parcellations may benefit from the use of multiple schemes to confirm the robustness and generalizability of results. Furthermore, researchers looking to gain insight into functional networks may benefit from employing more nuanced network identification approaches such as using densely-sampled data to produce individual-derived network parcellations. A transition towards precision neuroscience will provide new avenues in the characterization of functional brain organization across development and within clinical populations.


Listening to the Mind: Tracing the Auditory History of Mental Illness in Archives and Exhibitions.
With increasing interest in the representation of histories of mental health in museums, sound has played a key role as a tool to access a range of voices. This essay discusses how sound can be used to give voice to those previously silenced. The focus is on the use of sound recording in the history of mental health care, and the archival sources left behind for potential reuse. Exhibition strategies explored include the use of sound to interrogate established narratives, to interrupt associations visitors make when viewing the material culture of mental health, and to foster empathic listening among audiences.


[Benefits of hierarchical generalization and storage of the representations of "object-place" associations in the hippocampal subfields (a hypothesis)].
We analyzed the results of experimental research of features of processing sensory information in the hippocampus and neocortex available in literature and results of modelling the perception of information in the neocortex. It is noted that "place" fields of neurons become wider, and overlapping of receptive fields increases during upward moving in trisynaptic hippocampal pathway. These effects specify the generalization of the information processed. The results of our analysis allow us to put forward a hypothesis that a hierarchical complication of"object - place" associations occurs during upward propagation of signals through all hippocampal subfields. Complexity of neural representations of "object - place" associations that are formed and permanently stored in the hippocampal areas increases in process of propagation of signals from the entorhinal cortex to the hierarchically higher dentate gyrus, area CA3 and area CA1. Therefore, with the aim to extract information about "object - place" associations with certain details it is necessary to access that hippocampal area in which associations were processed and stored with the required degree of elaboration. By analogy with the neocortex, it is proposed that such processing of information in the hippocampus makes it possible to avoid the combinatorial explosion and provides storing (memory) the associations accumulated during the life. The proposed mechanism can serve as an addition to the known multiple trace theory, which states that the hippocampus is an integrating part of memory trace and is always involved in recall of long-delayed episodes.


Major COL4A5 gene rearrangements in patients with juvenile type Alport syndrome.
Mutations in the COL4A5 gene, which encodes the a5 chain of type IV collagen, are found in a large fraction of patients with X-linked Alport syndrome. The recently discovered COL4A6, tightly linked and highly homologous to COL4A5, represents a second candidate gene for Alport syndrome. We analyzed 177 Italian Alport syndrome families by Southern blotting using cDNA probes from both COL4A5 and COL4A6. Nine unrelated families, accounting for 5% of the cases, were found to have a rearrangement in COL4A5. No rearrangements were found in COL4A6, with the exception of a deletion encompassing the 5' ends of both COL4A5 and COL4A6 genes in a patient with Alport syndrome and leiomyomatosis. COL4A5 rearrangements were all intragenic and included 1 duplication and 7 deletions. Polymerase chain reaction (PCR) analysis was carried out to characterize deletion and duplication boundaries and to predict the resulting protein abnormality. The two smallest deletions involved a single exon (exons 17 and 40, respectively), while the largest ones spanned exons 1 to 36. The clinical phenotype of patients in whom a rearrangement in COL4A5 was detected was severe, with progression to end-stage renal failure in juvenile age and hypoacusis occurring in most cases. These data have some important implications in the diagnosis of patients with Alport syndrome.


WARD: a pneumatic system for body weight relief in gait rehabilitation.
The paper presents Walking Assistance and Rehabilitation Device (WARD), a system for walking rehabilitation devised to relieve the patient of his/her body weight of a constant and prescribed amount by externally supporting the subject at the upper trunk and pelvis level by means of a harness. The system is based on a pneumatic actuator that has proved to be effective at maintaining a constant relief force. The constancy of this force that should be maintained even under high body weight support (BWS) conditions (70-80% of body weight) seems to be important for a correct motor pattern. A law has been identified that may be useful to adjust walking speed as a function of the prescribed BWS. WARD is simple to construct, practical to use, and has been characterized on healthy subjects.


Immunophenotypic analysis of abnormal plasma cell clones in bone marrow of primary systemic light chain amyloidosis patients.
Primary systemic light chain amyloidosis (AL) is a rare plasma cell disease, our purpose was to analyze the immunophenotypic characteristics of the plasma cells in bone marrow in AL patients, and explore whether the detection of abnormal plasma cell clones in bone marrow by flow cytometry (FCM) could be used as an important indicator of AL diagnosis. Fresh bone marrow samples were collected from 51 AL, 21 multiple myeloma (MM), and 5 Waldenström's macroglobulinemia (WM) patients. The immunophenotype of bone marrow cells were analyzed and compared by FCM using a panel of antibodies including CD45, CD38, CD138, CD117, CD56, and CD19. In AL, light chain restriction could be identified in 31 cases (60.9%), in which the λ light chain restriction was found in 24 cases (77.4%). In MM, κ light chain restriction was found in 13 cases (61.9%), and λ light chain restriction in eight cases. CD45 on abnormal plasma cells was negative to weakly positive in both AL and MM, but was positive to strongly positive in WM. In the bone marrow plasma cells of the 51 AL, 78.4% were CD56+, 68.6% were CD117+, and 88.2% were CD19-. While in the 21 MM cases, 66.7% were CD56+, 38.1% were CD117+, and 90.4% were CD19-. The plasmacytoid lymphocytes in the five WM patients were CD19+ and CD56-, CD117-. Detection of abnormal plasma cell clones in bone marrow by FCM is valuable for the diagnosis of AL.


Dietary Nucleotides Promote Neonatal Rat Microbiota-Gut-Brain Axis Development by Affecting Gut Microbiota Composition and Metabolic Function.
A variety of active factors in milk and foods have been proven to serve as microbial nutrients that regulate the formation of early gut microbiota (GM), thereby ensuring the healthy development of infants. This study demonstrated that dietary nucleotides (NTs), one of the main nitrogen-containing substances in human milk, promoted the neurodevelopment of neonatal rats and the expression of Sox2, Dcx, Tuj1, and NeuN in the prefrontal cortex and hippocampus, but had no significant regulatory effects in the striatum. 16s rRNA sequencing and metabolomics of the colon contents of neonatal rats at different developmental stages showed that the early intake of NTs promoted an increase in the abundance of beneficial microorganisms related to neurodevelopment, digestion, and gut absorption, such as g_Romboutsia and g_Akkermansia. Changes in the ability of the GM to regulate folate synthesis, riboflavin metabolism, and other processes were also observed. Further analysis revealed significant correlations between the level of characteristic metabolites, namely, trans-3-indoleacrylic acid, urocanic acid, inosine, and adenosine, in the gut with neurodevelopment and characteristic GM components. These findings suggest that NTs in milk may affect neurodevelopment and maturation in early life by regulating the GM composition-gut-brain axis.


A Narrative Review: The Effect and Importance of Carotenoids on Aging and Aging-Related Diseases.
Aging is generally defined as a time-dependent functional decline that affects most living organisms. The positive increase in life expectancy has brought along aging-related diseases. Oxidative stress caused by the imbalance between pro-oxidants and antioxidants can be given as one of the causes of aging. At the same time, the increase in oxidative stress and reactive oxygen species (ROS) is main reason for the increase in aging-related diseases such as cardiovascular, neurodegenerative, liver, skin, and eye diseases and diabetes. Carotenoids, a natural compound, can be used to change the course of aging and aging-related diseases, thanks to their highly effective oxygen-quenching and ROS-scavenging properties. Therefore, in this narrative review, conducted using the PubMed, ScienceDirect, and Google Scholar databases and complying with the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines, the effects of carotenoids on aging and aging-related diseases were analyzed. Carotenoids are fat-soluble, highly unsaturated pigments that occur naturally in plants, fungi, algae, and photosynthetic bacteria. A large number of works have been conducted on carotenoids in relation to aging and aging-related diseases. Animal and human studies have found that carotenoids can significantly reduce obesity and fatty liver, lower blood sugar, and improve liver fibrosis in cirrhosis, as well as reduce the risk of cardiovascular disease and erythema formation, while also lowering glycated hemoglobin and fasting plasma glucose levels. Carotenoid supplementation may be effective in preventing and delaying aging and aging-related diseases, preventing and treating eye fatigue and dry eye disease, and improving macular function. These pigments can be used to stop, delay, or treat aging-related diseases due to their powerful antioxidant, restorative, anti-proliferative, anti-inflammatory, and anti-aging properties. As an increasingly aging population emerges globally, this review could provide an important prospective contribution to public health.