Medical imaging data reconciliation, part 2: clinical order entry and imaging report data reconciliation.
Data reconciliation in medical imaging is designed to ensure the accuracy and integrity of data across multiple steps in the imaging cycle, ultimately leading to improved continuity of patient care. An integral component of this data reconciliation is tied to the steps of clinical order entry and radiology report creation. The clinical data presented at order entry by the referring clinician influence a number of important imaging decisions, including examination selection, protocol design, image acquisition and processing, and interpretation of the imaging data set. The subsequent data derived from the radiology report have a profound impact on diagnosis, treatment, and overall clinical management. As a result, the reconciliation of clinical order entry and radiology report data affect health care delivery and in many respects are dependent on each other for optimal outcomes. The creation of a standardized reconciliation database that proactively records, tracks, analyzes, and provides feedback to radiologists and clinicians offers the potential to improve the quality and efficiency of patient care, while providing objective accountability measures for individual and institutional health care providers.


Revealing impaired blood supply to the bile ducts on contrast-enhanced ultrasound: a novel diagnosis method to ischemic-type biliary lesions after orthotropic liver transplantation.
Ischemic-type biliary lesions (ITBLs) are a major source of morbidity and mortality after orthotropic liver transplantation (OLT). The study determines diagnostic accuracy of contrast-enhanced ultrasound (CEUS) in diagnosing ITBLs. Nine healthy volunteers, six OLT recipients without complications, 36 OLT patients with complications (12 without ITBLs and 24 with ITBLs) underwent CEUS. Two radiologists reviewed the sonograms of the hilar bile duct wall and established specific criteria used to detect ITBLs. Next, the sonograms of six OLT recipients without complications and 36 patients with complications (12 without ITBLs and 24 with ITBLs) were retrospectively reviewed by two other independent, blinded radiologists. The sensitivity, specificity and accuracy of CEUS were evaluated. The main feature differentiating ITBLs from three other groups was non- or hypo-enhancement of the hilar bile duct wall in arterial phase (all p < 0.05), which was selected as the primary criterion for subsequent study. The sensitivity, specificity and accuracy were 66.7%, 88.9% and 76.2% for reader 1 and 62.5%, 88.9% and 73.8% for reader 2, respectively. A good interobserver agreement (κ = 0.85) was achieved. In this study, CEUS shows promise of detection of ITBLs by revealing impaired blood supply to the bile ducts, but more studies will be needed to establish its usefulness.


Low back pain: current physiologic concepts.
It is clear that low back pain is not a simple process that can be explained on purely anatomic, biomechanical, or neurophysiologic theories. The intimate relationship of these processes have to be considered. Each of the potential biomechanical stresses influence the different spinal structures in different ways, depending on the forces applied and the structure being affected. The biomechanical response to the trauma caused by these forces may be immunologic, inflammatory, or neurochemical, depending on the structures being traumatized. Once a nociceptive process is underway, it is greatly influenced by the spinal cord and the brain. Only by following this process through its various steps can a clinician begin to formulate an understanding of the mechanisms involved in the genesis of low back pain.


Chemoenzymatic synthesis of biotinylated nucleotide sugars as substrates for glycosyltransferases.
The enzymatic oxidation of uridine 5'-diphospho-alpha-D-galactose (UDP-Gal) and uridine 5'-diphospho-N-acetyl-alpha-D-galactosamine (UDP-GalNAc) with galactose oxidase was combined with a chemical biotinylation step involving biotin-epsilon-amidocaproylhydrazide in a one-pot synthesis. The novel nucleotide sugar derivatives uridine 5'-diphospho-6-biotin-epsilon-amidocaproylhydrazino-alpha-D-galactose (UDP-6-biotinyl-Gal) and uridine 5'-diphospho-6-biotin-epsilon-amidocaproylhydrazino-N-acetyl-alpha-D-galactosamine (UDP-6-biotinyl-GalNAc) were synthesized on a 100-mg scale and characterized by mass spectrometry (fast atom bombardment and matrix-assisted laser desorption/ionization time of flight) and one/two dimensional NMR spectroscopy. It could be demonstrated for the first time, by use of UDP-6-biotinyl-Gal as a donor substrate, that the human recombinant galactosyltransferases beta3Gal-T5, beta4Gal-T1, and beta4Gal-T4 mediate biotinylation of the neoglycoconjugate bovine serum albumin-p-aminophenyl N-acetyl-beta-D-glucosaminide (BSA-(GlcNAc)17) and ovalbumin. The detection of the biotin tag transferred by beta3Gal-T5 onto BSA-(GlcNAc)17 with streptavidin-enzyme conjugates gave detection limits of 150 pmol of tagged GlcNAc in a Western blot analysis and 1 pmol of tagged GlcNAc in a microtiter plate assay. The degree of Gal-biotin tag transfer onto agalactosylated hybrid N-glycans present at the single glycosylation site of ovalbumin was dependent on the Gal-T used (either beta3Gal-T5, beta4Gal-T4, or beta4Gal-T1), which indicates that the acceptor specificity may direct the transfer of the Gal-biotin tag. The potential of this biotinylated UDP-Gal as a novel donor substrate for human galactosyltransferases lies in the targeting of distinct acceptor structures, for example, under-galactosylated glycoconjugates, which are related to diseases, or in the quality control of glycosylation of recombinant and native glycoproteins.


Colchicine affects cell motility, pattern formation and stalk cell differentiation in Dictyostelium by altering calcium signaling.
Previous work, verified here, showed that colchicine affects Dictyostelium pattern formation, disrupts morphogenesis, inhibits spore differentiation and induces terminal stalk cell differentiation. Here we show that colchicine specifically induces ecmB expression and enhances accumulation of ecmB-expressing cells at the posterior end of multicellular structures. Colchicine did not induce a nuclear translocation of DimB, a DIF-1 responsive transcription factor in vitro. It also induced terminal stalk cell differentiation in a mutant strain that does not produce DIF-1 (dmtA-) and after the treatment of cells with DIF-1 synthesis inhibitor cerulenin (100 μM). This suggests that colchicine induces the differentiation of ecmB-expressing cells independent of DIF-1 production and likely through a signaling pathway that is distinct from the one that is utilized by DIF-1. Depending on concentration, colchicine enhanced random cell motility, but not chemotaxis, by 3-5 fold (10-50 mM colchicine, respectively) through a Ca(2+)-mediated signaling pathway involving phospholipase C, calmodulin and heterotrimeric G proteins. Colchicine's effects were not due to microtubule depolymerization as other microtubule-depolymerizing agents did not have these effects. Finally normal morphogenesis and stalk and spore cell differentiation of cells treated with 10 mM colchicine were rescued through chelation of Ca2+ by BAPTA-AM and EDTA and calmodulin antagonism by W-7 but not PLC inhibition by U-73122. Morphogenesis or spore cell differentiation of cells treated with 50 mM colchicine could not be rescued by the above treatments but terminal stalk cell differentiation was inhibited by BAPTA-AM, EDTA and W-7, but not U-73122. Thus colchicine disrupts morphogenesis and induces stalk cell differentiation through a Ca(2+)-mediated signaling pathway involving specific changes in gene expression and cell motility.


[Congenital rubella still exists in Tunisia!].
Congenital rubella syndrome resulting from maternal rubella infection can cause serious multisystemic malformations resulting in severe morbidity and mortality. After immunization, its incidence has been reduced in the developed world, though it remains a real problem in developing countries since it causes many handicaps. In Tunisia, despite including rubella immunization in the routine national program on immunization for girls once they reach the age of 12, the congenital rubella syndrome still exists. We describe the clinical pattern and the outcome of congenital rubella syndrome in 2 infants and emphasize the necessity of recommending universal screening and follow-up vaccination of susceptible females and including rubella immunization in the routine national immunization program, especially in developing countries.


Urine metabolomics of women from small villages exposed to high environmental cadmium levels.
The present study aimed to identify urine metabolites in women exposed to high cadmium (Cd) levels. Twenty-one women exposed to environmental Cd and 12 age-matched controls were categorized as high exposure (urine Cd ≥ 15 μg/g creatinine; n = 9) or low exposure (15 μg/g creatinine > urine Cd > 5 μg/g creatinine; n = 12). Low-molecular weight metabolites in urine were analyzed by gas chromatography and mass spectrometry after derivatization. An orthogonal partial least-squares discriminant analysis model was constructed, and metabolites from the dimensional model were selected according to the variable importance in projection (>1). Metabolites differing significantly in abundance between different exposure groups were identified by searching mass spectral databases, and related pathways were analyzed using the Kyoto Encyclopedia of Genes and Genomes. Approximately 110 significantly different metabolites were detected with variable importance in projection > 1, and 48 of them were found to differ markedly in abundance among the 3 groups. Twenty-seven matched with known metabolites, including 22 significantly increased and 5 markedly decreased in the high-exposure group (p < 0.01). Kyoto Encyclopedia of Genes and Genomes results indicated that carbohydrate, amino acid, bone, and intestinal flora metabolism and the tricarboxylic acid cycle were affected by Cd exposure. The present study identified metabolites that differed in abundance in response to Cd exposure. Further studies may connect these biomarkers to early damage caused by Cd.


Macular infarction and traumatic optic neuropathy following blunt ocular trauma.
Macular infarction is a visually disabling condition caused by a variety of reasons. It has rarely been described in association with blunt ocular trauma. We describe the case of a young healthy male who sustained injury with a bull's leg and presented with severe visual loss owing to macular infarction and traumatic optic neuropathy. This report of an angiographically documented macular infarct secondary to ocular contusion highlights an additional feature in the spectrum of ocular findings following blunt trauma that might lead to a severe and permanent affliction of vision.


Validity and reliability of short forms of parental-caregiver perception and family impact scale in a Telugu speaking population of India.
Parental-Caregiver Perception Questionnaire (P-CPQ) and Family Impact Scale (FIS) are commonly used measures to evaluate the parent's perception of the impact of children's oral health on quality of life and family respectively. Recently, shorter forms of P-CPQ and FIS have been developed. No study has sought to validate these short forms in other languages and cultures. This study aimed to evaluate the validity and reliability of FIS, 8 and 16-item P-CPQ in a Telugu speaking population of India. For this cross-sectional study, a multi-stage random sampling technique was used to recruit 11-13 year-old schoolchildren of Medak district, Telangana, India and their parents (n = 1342). Parents were approached with questionnaires through their children who underwent clinical examinations for dental caries, fluorosis and malocclusion. The translated versions underwent pilot testing (n = 40), test-retest reliability was also assessed (n = 161). The overall summary scale and subscales of the short forms of P-CPQ and FIS failed to discriminate between the categories of dental caries severity. Also, malocclusion status was not related to the domain or overall scores of both the short forms of P-CPQ. There were significant differences in subscale and overall scores of 16 and 8-item P-CPQ and FIS between the fluorosis categories. Both 16 and 8-item P-CPQ summary scales were significantly related to parent's global rating of oral health (16-item, r = 0.30, p < 0.01; 8-item, r = 0.28, p < 0.01) and overall wellbeing (16-item, r = 0.22, p < 0.01; 8-item, r = 0.22, p < 0.01), thereby exhibiting good construct validity. However, the correlation of emotional and social wellbeing scales of short forms of P-CPQ and FIS with global ratings was of low strength. Cronbach's alphas for FIS, 16-items and 8-items P-CPQ scales were 0.78, 0.83 and 0.71 respectively, while the Intra-Class Correlation coefficients were 0.752, 0.812 and 0.816 respectively. Cronbach's alphas for most of the subscales of short forms of P-CPQ were less than 0.7. The overall scales of 16 and 8-items P-CPQ scales demonstrated good construct validity while the construct validity of FIS was questionable. Discriminant validity of all the three instruments was good only in relation to fluorosis. Overall scales of all three short forms exhibited acceptable internal consistency and reliability on repeated administrations.


Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor.
Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.


VS38 Identifies Myeloma Cells With Dim CD38 Expression and Plasma Cells Following Daratumumab Therapy, Which Interferes With CD38 Detection for 4 to 6 Months.
We report our institutional experience using VS38 to evaluate plasma cells by flow cytometry. Flow cytometry data were reanalyzed to compare plasma cell percentages between the standard panel and VS38 panel. Natural killer (NK) and plasma cell CD38 median fluorescence intensity (MFI) values were calculated. Our cohort included 63 specimens from 38 patients. Twenty-six had received daratumumab (monoclonal anti-CD38 therapy) between less than 1 month and 17 months prior. For NK and plasma cells, CD38 MFI values were suppressed for 0 to 4 months and started to increase 4 to 6 months after last exposure. There was no significant difference in clonal plasma cell percentage calculated by the VS38 and standard panels; however, identification and quantification using the VS38 panel were easier. VS38 is a viable alternative to bright CD38 to identify plasma cells and particularly helpful in myeloma cases with dim CD38 and after daratumumab. Daratumumab interference with CD38 identification persists 4 to 6 months after the last exposure.


Neonatal distal femoral epiphyseal dislocation: an ultrasound diagnosis.
Traumatic epiphyseal dislocation related to birth injury is uncommon. The authors report a case of slipped distal femoral epiphysis during a breech presentation in a twin pregnancy birthing process, diagnosed by ultrasonography. This type of separation could be difficult to detect in the newborn on plain radiographs because of the non-ossification of the epiphysis. Therefore, the use of sonography is helpful to make an early and accurate diagnosis in order to avoid malunion and deformities of the affected limb. Through this case report we will see the diagnostic value of high-resolution ultrasonography in diagnosing newborn injuries of the limbs, and particularly in the diagnosis of radiographically occult epiphyseal separation.


Validation of rules to predict emergent surgical intervention in pediatric trauma patients.
Trauma centers use guidelines to determine when a trauma surgeon is needed in the emergency department (ED) on patient arrival. A decision rule from Loma Linda University identified patients with penetrating injury and tachycardia as requiring emergent surgical intervention. Our goal was to validate this rule and to compare it with the American College of Surgeons' Major Resuscitation Criteria (MRC). We used data from 1993 through 2010 from 2 level 1 trauma centers in Denver, CO. Patient demographics, injury severity, times of ED arrival and surgical intervention, and all variables of the Loma Linda Rule and the MRC were obtained. The outcome, emergent intervention (defined as requiring operative intervention by a trauma surgeon within 1 hour of arrival to the ED or performance of cricothyroidotomy or thoracotomy in the ED), was confirmed using standardized abstraction. Sensitivities, specificities, and 95% confidence intervals were calculated. There were 8,078 patients included, and 47 (0.6%) required emergent intervention. Of the 47 patients, the median age was 11 years (interquartile range [IQR] 7 to 14 years), 70% were male, 30% had penetrating mechanisms, and the median Injury Severity Score (ISS) was 25 (IQR 9 to 41). At the 2 institutions, the Loma Linda Rule had a sensitivity and specificity of 69% (95% CI 45% to 94%) and 76% (95% CI 69% to 83%), respectively, and the MRC had a sensitivity and specificity of 80% (95% CI 70% to 92%) and 81% (95% CI 77% to 85%), respectively. Emergent surgical intervention is rare in the pediatric trauma population. Although precision of predictive accuracies of the Loma Linda Rule and MRC were limited by small numbers of outcomes, neither set of criteria appears to be sufficiently accurate to recommend their routine use.


Helping Her Heal-Group: a pilot study to evaluate a group delivered educational intervention for male spouses of women with breast cancer.
Distress in husbands of women with early-stage breast cancer may be equivalent to or even higher than their wives. Husbands often struggle to help and support their wives cope with the illness and its treatment. In response, we developed a five-session group educational counselling intervention (Helping Her Heal-Group (HHH-G)) for husbands of women with early-stage breast cancer. The primary aim of the current pilot study was to determine the acceptability and feasibility of HHH-G and to obtain a preliminary estimate of its impact on participating men's skills, self-confidence and self care. Secondary aims were to assess the impact of the intervention on both the participating spouses' and wives' ratings of marital quality and depressed mood. The study employed a one-arm, pre-post-intervention design whereby participating men (n=54) and their wives (n=54) independently completed measures at baseline (T0), immediately following the last session (T1) and 3 months after the last session (T2). Overall, there was very high study retention (87%). On the basis of the questionnaire data, we found significant improvements in spouses' self-efficacy (p<0.001) and self-reported skills including wife support (p=0.003) and self-care (p<0.001). In addition, there was a significant improvement in wives' mood scores (p=0.003). Post-intervention interviews support acceptability and impact of the HHH-G intervention, and provide support for the group format of the program. The feasibility and acceptability of HHH-G was supported, and treatment outcomes suggest the potential benefits of the intervention. Phase III evaluation of HHH-G program is warranted.


[Experiences with liposuction of established surgeons].
Liposuction under tumescent local anesthesia is an suitable surgical treatment for ambulatory surgical practice.


Small average differences in attenuation corrected images between men and women in myocardial perfusion scintigraphy: a novel normal stress database.
The American Society of Nuclear Cardiology and the Society of Nuclear Medicine state that incorporation of attenuation-corrected (AC) images in myocardial perfusion scintigraphy (MPS) will improve image quality, interpretive certainty, and diagnostic accuracy. However, commonly used software packages for MPS usually include normal stress databases for non-attenuation corrected (NC) images but not for attenuation-corrected (AC) images. The aim of the study was to develop and compare different normal stress databases for MPS in relation to NC vs. AC images, male vs. female gender, and presence vs. absence of obesity. The principal hypothesis was that differences in mean count values between men and women would be smaller with AC than NC images, thereby allowing for construction and use of gender-independent AC stress database. Normal stress perfusion databases were developed with data from 126 male and 205 female patients with normal MPS. The following comparisons were performed for all patients and separately for normal weight vs. obese patients: men vs. women for AC; men vs. women for NC; AC vs. NC for men; and AC vs. NC for women. When comparing AC for men vs. women, only minor differences in mean count values were observed, and there were no differences for normal weight vs. obese patients. For all other analyses major differences were found, particularly for the inferior wall. The results support the hypothesis that it is possible to use not only gender independent but also weight independent AC stress databases.


The changing face of disorders of fatty acid oxidation.
To review the current understanding of the rapidly changing field of disorders of fatty acid metabolism and to discuss the future directions for research. A literature review of the basic biochemistry of the beta-oxidation pathway and clinical cases of defects of fatty acid metabolism are presented, and the diagnosis and treatment of such defects are discussed. In many cases, a correct diagnosis will be made only if these disorders are specifically considered and appropriate tests are obtained, because results of screening tests for other organic acidemias are often normal in these entities. The first disorder of fatty acid metabolism was described only 20 years ago. Since then, at least 15 different inborn errors of metabolism that affect beta-oxidation have been identified, most in the past 10 years. Within the past 5 years, investigators have realized that a deficiency of one of these enzymes, medium-chain acyl coenzyme A dehydrogenase, may be one of the most common inborn errors of metabolism. This disorder may have a frequency equal to that of phenylketonuria in some populations in the United States and northern Europe. Approximately 1 to 3% of all unexplained deaths during infancy and childhood are probably related to disorders of beta-oxidation. Diagnosis of these disorders can be difficult because of the intermittent nature of the excretion of characteristic compounds. The mainstay of therapy for defects of beta-oxidation is avoidance of fasting. All patients with a suspected defect of fatty acid metabolism should be assessed and monitored by a specialist trained in the care of such patients. Continued improvements in the ability to diagnose and treat these disorders will be directly linked to new advances in the basic research on these enzymes. Movements to screen newborns for medium-chain acyl coenzyme A dehydrogenase are under way in some medical centers. Proposed tests include metabolite analysis or direct mutation analysis (or both) from blood spots from newborn screening cards already obtained for every newborn in the United States.


Single Fraction and Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, and Reduced Viability of Merlin-Deficient Schwann Cells.
Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.


Simplified AIT for allergy to several tree pollens-Arguments from the immune outcome analyses following treatment with SQ tree SLIT-tablet.
The SQ tree SLIT-tablet (containing birch extract) proved clinically significant effects during the pollen season for birch as well as alder/hazel. Immune outcomes of this treatment for allergens from multiple birch homologous trees need further investigation. We hypothesize that birch pollen extract AIT modulates a highly cross-reactive immune response and that this may be the basis for the observed clinical cross-protection. Blood samples were collected from 397 birch allergic patients during SQ tree SLIT-tablet or placebo treatment (1:1) for up to 40 weeks. Serum IgE and IgG4 specific to birch, and birch homologous tree pollens from alder, hazel, hornbeam, beech and chestnut were measured by ImmunoCAP. IgE-Blocking Factor (IgE-BF) for alder, birch and hazel during treatment was measured by Advia Centaur and blocking effects for birch and all these birch homologous tree pollens were further investigated by basophil activation (BAT). Antibody readouts were investigated in patient subsets. T-cell responses (proliferation) to allergen extracts and peptide pools (group 1 allergens) were investigated in T-cell lines from 29 untreated birch pollen-allergic individuals. Significant Pearson correlations between serum IgE towards birch, alder, hazel, hornbeam and beech were observed (r-values > .86). T-cell reactivity was observed throughout the birch homologous group. Almost identical kinetics for changes in IgE towards birch, alder and hazel were observed during treatment and similar species-specific changes were seen for serum-IgG4 . IgG4 reactivity towards birch and alder, hazel, hornbeam and beech correlated significantly at end-of-treatment (r-values > .72). Treatment resulted in similar IgE-BF kinetics for alder, birch, and hazel and blocking of BAT for multiple trees in most actively treated patients investigated. Systematic analyses of T-cell and antibody cross-reactivities before and during birch pollen extract AIT provide the immunological basis for the observed clinical effect of SQ tree SLIT-tablet treatment of tree pollen allergy induced by multiple trees in the birch homologous group.


Remission induction therapy containing rituximab markedly improved the outcome of untreated mature B cell lymphoma.
Many controlled clinical trials have proven that rituximab improves the clinical outcome of patients with mature B cell lymphoma. This study was conducted to assess the contribution of rituximab in the actual clinical practice. Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The endpoint was to evaluate the rituximab benefit based on 2-year progression-free survival (PFS) and 2-year overall survival (OS). A total 1126 patients received chemotherapies. Of these, 762 were diagnosed as diffuse large B cell lymphoma (DLBCL) and 215 as follicular lymphoma (FL). PFS and OS were markedly improved in the rituximab group compared with the non-rituximab group in patients with DLBCL (both P < 0.001) and in patients with FL (P < 0.001 and P = 0.003 respectively). Rituximab, when used for remission induction therapy, significantly improved the clinical outcome of the mature B cell lymphoma patient in actual clinical practice.


[Synthesis and pharmacologic study of new esters of naproxen with derivatives of N-oxyethylpiperazine].
The preparation of naproxen esters with N,N'-dioxyethylpiperazine and derivatives of N-oxyethylpiperazine with various substituents on the nitrogen is described. Study of analgesic-antiinflammatory properties in comparison with a reference compounds has shown that in most of the new compounds analgesic activity (phenylquinone) is preserved whereas antiinflammatory activity (carrageenin) is generally reduced. The diester with N,N'-dioxyethylpiperazine (MG 28136) proved most interesting, showing clear pharmacological activity and very low toxicity.


What affects mortality after the operative management of hepatic abscess?
Historically, the operative mortality associated with hepatic abscess was >50%. More recently, patients have been treated with percutaneous drainage; however, those failing conservative management are treated operatively. Our aim was to evaluate the outcome of operation for hepatic abscess in those failing conservative treatment or in those presenting as a surgical emergency. This was a retrospective review of patients undergoing operation for hepatic abscess at the Mayo Clinic, Rochester, Minnesota from 1990 to 2003. Of 288 patients diagnosed with hepatic abscesses, 32 required operation. Percutaneous drainage was the initial treatment in 15 (47%). The remaining 17 were initially managed with operation. Operative indication was septic shock (41%), failed nonoperative management (31%), and failure to make a diagnosis (28%). Operation was drainage (62%) or resection (38%). The morbidity and mortality rates were 41% and 15.6%, respectively. Factors associated with increased operative mortality were shock (p=0.04), INR > 1.5 (p=0.03), WBC >15 000 (p=0.04), AST > 150 U/L (p=0.01), alkaline phosphatase >500 U/L (p=0.03), positive blood cultures (p=0.03), total bilirubin >2.0 mg/dl (p<0.01), multiple abscesses (p=0.01), and second operation (p<0.001). Factors not associated were extent of resection (p>0.10), peritonitis (p>0.10), intensive care admission (p>0.10), polymicrobial infection (p>0.10), and blood transfusion (p>0.10). Operative intervention is avoided in 89% of patients with hepatic abscess. Septic shock is the most common reason for operation. Patients with septic shock, INR>1.5, WBC>15 000, AST>150 U/L, total bilirubin >2.0 mg/dl, positive blood cultures, or alkaline phosphatase >500 U/L have increased mortality when undergoing operation for hepatic abscess.


A Review of Recent Innovations in Cartilage Regeneration Strategies for the Treatment of Primary Osteoarthritis of the Knee: Intra-articular Injections.
The pathology of primary osteoarthritis (OA) begins with structural cartilage damage, which initiates a self-propagating inflammatory pathway that further exacerbates cartilage deterioration. Current standard of care for knee primary OA involves treating the inflammatory symptoms to manage pain, which includes intra-articular (IA) injections of cortisone, an anti-inflammatory steroid, followed by a series of joint-cushioning hyaluronic acid gel injections. However, these injections do not delay the progression of primary OA. More focus on the underlying cellular pathology of OA has prompted researchers to develop treatments targeting the biochemical mechanisms of cartilage degradation. Researchers have yet to develop a United States Food and Drug Administration (FDA)-approved injection that has been demonstrated to significantly regenerate damaged articular cartilage. This paper reviews the current research on experimental injections aimed at achieving cellular restoration of the hyaline cartilage tissue of the knee joint. Narrative review. The authors conducted a narrative literature review examining studies on primary OA pathogenesis and a systematic review of non-FDA-approved IA injections for the treatment of primary OA of the knee, described as "disease-modifying osteoarthritis drugs" in phase 1, 2, and 3 clinical trials. New treatment approaches for primary OA investigate the potential of genetic therapies to restore native cartilage. It is clear that the most promising IA injections that could improve treatment of primary OA are bioengineered advanced-delivery steroid-hydrogel preparations, ex vivo expanded allogeneic stem cell injections, genetically engineered chondrocyte injections, recombinant fibroblast growth factor therapy, injections of selective proteinase inhibitors, senolytic therapy via injections, injectable antioxidant therapies, injections of Wnt pathway inhibitors, injections of nuclear factor-kappa β inhibitors, injections of modified human angiopoietin-like-3, various potential viral vector-based genetic therapy approaches, and RNA genetic technology administered via injections.


Multidrug-resistant Enterobacteriaceae from indoor air of an urban wastewater treatment plant.
Wastewater treatment plants (WWTPs) have been recognized as sources of bioaerosols that may act as vehicles for dissemination of pathogens and multidrug-resistant (MDR) bacteria. The occurrence of MDR Enterobacteriaceae in indoor air of an urban WWTP was investigated. A possible airborne contamination with extended-spectrum beta-lactamase (ESBL) and carbapenemase-producing Enterobacteriaceae was also explored. Fourteen of 39 Enterobacteriaceae isolates were MDR. These isolates were found at all sampling sites, mainly at the secondary sedimentation settings. The highest levels of resistance were detected in three different species: Enterobacter cloacae, Escherichia coli, and Citrobacter freundii. Furthermore, one of the airborne E. coli isolates was phenotypically characterized as an ESBL producer. Additionally, five isolates showed non-susceptibility to at least one carbapenem tested. The presence of genes encoding relevant beta-lactamase types in these ESBL-producing and carbapenem-resistant Enterobacteriaceae isolates was investigated by PCR. Results showed amplification for bla CTX-M and bla OXA. These findings are relevant both in terms of occupational/public health and of environmental dissemination of MDR bacteria.


Risk factors for accelerated atherosclerosis in renal transplant recipients.
The factors responsible for atherosclerosis in renal transplant recipients are not known. In the present study, cardiovascular disease was investigated in 403 patients who received 464 kidney transplants during a 10-year period. Among those who had no clinical evidence of vascular disease at the time of transplantation, atherosclerotic complications developed in 15.8 percent during the post-transplant follow-up period (46.1 +/- 36.2 months). Pre- and post-transplant vascular diseases were closely linked. However, after taking pre-transplant vascular disease into account, multivariate analysis showed that a number of known risk factors (age, sex, diabetes, cigarette smoking, hypertension, and serum cholesterol) were independently associated with post-transplant vascular disease. In addition, the number of acute rejection episodes (all treated with high doses of corticosteroids) was also independently linked to vascular disease. These results suggest that an increased prevalence of known risk factors, and events linked to allograft rejection, explain the high incidence of cardiovascular disease in renal transplant recipients.


Spiral ganglion neuron quantification in the guinea pig cochlea using Confocal Laser Scanning Microscopy compared to embedding methods.
Neuron counting in the cochlea is a crucial but time-consuming operation for which various methods have been developed. To improve simplicity and efficiency, we tested an imaging method of the cochlea, and based on Confocal Laser Scanning Microscopy (CLSM), we visualised Rosenthal's Canal and quantified the spiral ganglion neurons (SGN) within. Cochleae of 8 normal hearing guinea pigs and one implanted with a silicone filament were fixed in paraformaldehyde (PFA), decalcified, dehydrated and cleared in Spalteholz solution. Using the tissue's autofluorescence, CLSM was performed at 100 fold magnification generating z-series stacks of about 20 slices of the modiolus. In 5 midmodiolar slices per cochlea the perimeters of the Rosenthal's Canal were surveyed, representative neuron diameters were measured and the neurons first counted manually and then software-assisted. For comparison, 8 normal hearing guinea pig cochleae were embedded in paraffin and examined similarly. The CLSM method has the advantage that the cochleae remain intact as an organ and keep their geometrical structure. Z-stack creation is nearly fully-automatic and frequently repeatable with various objectives and step sizes and without visible bleaching. The tissue shows minimal or no shrinking artefacts and damage typical of embedding and sectioning. As a result, the cells in the cleared cochleae reach an average diameter of 21 μm and a density of about 18 cells/10,000 μm(2) with no significant difference between the manual and the automatical counts. Subsequently we compared the CLSM data with those generated using the established method of paraffin slides, where the SGN reached a mean density of 9.5 cells/10,000 μm(2) and a mean soma diameter of 13.6 μm. We were able to prove that the semi-automatic CLSM method is a simple and effective technique for auditory neuron count. It provides a high grade of tissue preservation and the automatic stack-generation as well as the counter software reduces the effort considerably. In addition this visualisation technique offers the potential to detect the position and orientation of cochlear implants (CI) within the cochlea and tissue growing in the scala tympani around the CI and at the position of the cochleostomy due to the fact that the implant does not have to be removed to perform histology as in case of the paraffin method.


Competitive PCR to detect eIF4E gene amplification in head and neck cancer.
The protein eukaryotic initiation factor 4E (elF4E) binds to messenger ribonucleic acid (mRNA) as the initial step in protein synthesis. Overexpression of elF4E results in upregulation of specific proteins essential to cell growth and division. Overexpression of elF4E has been found in head and neck squamous cell carcinoma (HNSCC) and breast carcinoma. This study's purpose is to determine whether elF4E overexpression is present and associated with elF4E gene amplification in HNSCC. Competitive polymerase chain reaction (PCR) was performed on eight HNSCC and seven intraoral benign lesions to determine the copy number of elF4E relative to a reference gene, gastrin. Western blots were performed to quantify elF4E protein expression. All eight HNSCC specimens demonstrated significant (p < .005) overexpression of elF4E protein (14.1+/-10.4) and elF4E gene amplification (4.5+/-1.2). Benign tissue did not exhibit elF4E protein overexpression or gene amplification. Overexpression and associated gene amplification of elF4E were present in HNSCC but not in benign tissue. Gene amplification of elF4E may be an important mechanism for elF4E overexpression.


Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer's disease.
We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.


Trends in Prescription and Determinants of Persistence to Antihypertensive Therapy : The PAPEETE Study.
To assess trends in prescriptions, determinants and timing of treatment discontinuation and/or changes in antihypertensive drug therapy in a cohort of hypertensive patients living in Pavia, a city in the north of Italy. The cohort included 61 493 patients aged ≥18 years who received their first antihypertensive drug prescription (monotherapy, fixed or extemporaneous combination) during the period 2003-6. Patients were classified as 'persistent' if 12 months after the beginning of treatment they were still taking a regular therapy (same drug = 'same therapy users', added one or more drugs = 'add-on therapy users', different drug = 'switchers'). Otherwise, they were classified as 'non-persistent' (stopping therapy after the first prescription = 'occasional users'; stopping treatment early = 'stoppers'; taking medicines in an erratic fashion = 'intermittent users'). ACE inhibitors were the most frequently prescribed drugs (22.8%), followed by β-adrenoceptor antagonists (β-blockers) [14.3%], diuretics (13.9%), Ca(2+) antagonists (11.4%) and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) [9.3%]. After 12 months, persistent patients were only 11.2% (same therapy users 6.7%, switchers 3.2%, add-on therapy users 1.3%). Non-persistent patients were 88.8% (35.3% occasional users, 20.6% stoppers, 32.8% intermittent users). Patient-related predictors of persistence were older age, male sex, concomitant treatment with antidiabetic and hypolipidaemic drugs and previous hospitalizations for cardiovascular events. Highest level of persistence was seen in patients starting with ARBs (18.8%), followed by ACE inhibitors (11.4%), β-blockers (11.0%), Ca(2+) antagonists (10.8%) and diuretics (3.0%). Among ARBs, considering separately monotherapy and fixed-combination therapy, highest level of persistence was observed in patients starting with candesartan, irbesartan, valsartan and telmisartan given in monotherapy, and with valsartan and telmisartan given in fixed-dose combination. Persistence to antihypertensive treatment at 12 months is only 11.2%, being the lowest with diuretics (3.0%) and the highest with ARBs (18.8%).


Measurement of peri-prostatic fat thickness using transrectal ultrasonography (TRUS): a new risk factor for prostate cancer.
Study Type - Prognosis (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? ADIPOSE tissue secretes various endocrine and paracrine mediators. Some authors have begun to consider whether peri-prostatic fat (PPF) may interact with the prostate and play a role in carcinogenesis. It has recently been shown that the PPF quantity measured by CT is associated with more aggressive disease in patients undergoing radiation therapy. Our group studied a population not yet diagnosed with prostate cancer. By doing so we were able to identify PPF thickness on transrectal ultrasonography as a risk factor for prostate cancer detection upon biopsy, and as a risk factor for high-grade disease. Our study also raises interesting questions about the underlying mechanisms of the association between PPF quantity and prostate cancer. To determine if the amount of peri-prostatic fat (PPF) on transrectal ultrasonography (TRUS) is a risk factor for incident prostate cancer overall and high-grade prostate cancer (Gleason ≥4). A prospectively maintained database of patients undergoing prostate biopsy at Princess Margaret Hospital for cancer suspicion was used. • All TRUS examinations were retrospectively reviewed upon 'blinding' to outcome. • PPF thickness, measured as the distance between the prostate and the pubic bone, was used as an index of the quantity of PPF. • PPF measurements, together with other prostate cancer risk factors, were evaluated against prostate cancer and high-grade prostate cancer detection upon biopsy with univariable and multivariable logistic regression and area under the receiver operating characteristic curve (AUC) analysis. Of the 931 patients, 434 (47%) were diagnosed with prostate cancer and 218 (23%) were diagnosed with high-grade prostate cancer. • The mean (range) PPF thickness was 5.3 (0-15) mm. • Increasing PPF thickness was associated with prostate cancer and high-grade prostate cancer diagnosis, with graded effect. When adjusting for other variables, the odds of detecting any prostate cancer and high-grade prostate cancer increased 12% (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.02-1.23) and 20% (OR 1.20, 95% CI 1.07-1.34), respectively, for each millimetre increase in PPF thickness. • The AUCs for the association of PPF with prostate cancer and high-grade prostate cancer were 0.58 (95% CI 0.54-0.62) and 0.59 (95% CI 0.55-0.64), respectively. The amount of PPF can be estimated with TRUS and is a predictor of prostate cancer and high-grade prostate cancer at biopsy. To our knowledge, this study is the first to investigate PPF quantity in patients without prior prostate cancer diagnosis.


Machine learning-assisted medium optimization revealed the discriminated strategies for improved production of the foreign and native metabolites.
The composition of medium components is crucial for achieving the best performance of synthetic construction in genetically engineered cells. Which and how medium components determine the performance, e.g., productivity, remain poorly investigated. To address the questions, a comparative survey with two genetically engineered Escherichia coli strains was performed. As a case study, the strains carried the synthetic pathways for producing the aromatic compounds of 4-aminophenylalanine (4APhe) or tyrosine (Tyr), common in the upstream but differentiated in the downstream metabolism. Bacterial growth and compound production were examined in hundreds of medium combinations that comprised 48 pure chemicals. The resultant data sets linking the medium composition to bacterial growth and production were subjected to machine learning for improved production. Intriguingly, the primary medium components determining the production of 4PheA and Tyr were differentiated, which were the initial resource (glucose) of the synthetic pathway and the inducer (IPTG) of the synthetic construction, respectively. Fine-tuning of the primary component significantly increased the yields of 4APhe and Tyr, indicating that a single component could be crucial for the performance of synthetic construction. Transcriptome analysis observed the local and global changes in gene expression for improved production of 4APhe and Tyr, respectively, revealing divergent metabolic strategies for producing the foreign and native metabolites. The study demonstrated that ML-assisted medium optimization could provide a novel point of view on how to make the synthetic construction meet the designed working principle and achieve the expected biological function.


Closed circular viral DNA and asymmetrical heterogeneous forms in livers from animals infected with ground squirrel hepatitis virus.
To identify possible intermediates in the replication of ground squirrel hepatitis virus, we characterized the major forms of intracellular virus-specific DNA in the livers of infected ground squirrels. A variety of DNA species were found: covalently closed circular molecules, relaxed circular molecules, and a heterogeneous collection of molecules that migrated ahead of closed circular DNA during agarose gel electrophoresis. The heterogeneous DNA was at least partly single stranded, consisted of minus strands in a greater than eight-fold mass excess of plus strands, and was tightly associated with protein.


Portal venous velocity affects liver regeneration after right lobe living donor hepatectomy.
We investigated whether chronological changes in portal flow and clinical factors play a role in the liver regeneration (LR) process after right donor-hepatectomy. Participants in this prospective study comprised 58 donors who underwent right donor-hepatectomy during the period February 2014 to February 2015 at a single medical institution. LR was estimated using two equations: remnant left liver (RLL) growth (%) and liver volumetric recovery (LVR) (%). Donors were classified into an excellent regeneration (ER) group or a moderate regeneration (MR) group based on how their LR on postoperative day 7 compared to the median value. Multivariate analysis revealed that low residual liver volume (OR = .569, 95% CI: .367- .882) and high portal venous velocity in the immediate postoperative period (OR = 1.220, 95% CI: 1.001-1.488) were significant predictors of LR using the RLL growth equation; high portal venous velocity in the immediate postoperative period (OR = 1.325, 95% CI: 1.081-1.622) was a significant predictor of LR using the LVR equation. Based on the two equations, long-term LR was significantly greater in the ER group than in the MR group (p < .001). Portal venous velocity in the immediate postoperative period was an important factor in LR. The critical time for short-term LR is postoperative day 7; it is associated with long-term LR in donor-hepatectomy.


Feedback-loop between psychotic symptoms and brain volume: A cross-lagged panel model study.
Brain structural changes are known to be associated with psychotic symptoms, with worse symptoms consistently associated with brain volume loss in some areas. It is not clear whether volume and symptoms interfere with each other over the course of psychosis. In this paper, we analyse the temporal relationships between psychosis symptom severity and total gray matter volume. We applied a cross-lagged panel model to a public dataset from the NUSDAST cohorts. The subjects were assessed at three-time points: baseline, 24 months, and 48 months. Psychosis symptoms were measured by SANS and SAPS scores. The cohort contained 673 subjects with schizophrenia, healthy subjects and their siblings. There were significant effects of symptom severity on total gray matter volume and vice-versa. The worse the psychotic symptoms, the smaller the total gray volume, and the smaller the volume, the worse the symptomatology. There is a bidirectional temporal relationship between symptoms of psychosis and brain volume.


Involvement of brain transmitters in the modulation of shock-induced aggression in rats by propranolol and related drugs.
(+/-)Propranolol (1, 3, 10 and 30 mg/kg) exhibited a differential effect on footshock aggression (FSA) in rats. Lower doses (1 and 3 mg/kg) of the drug facilitated FSA, whereas an inhibitory effect was observed with higher doses (10 and 30 mg/kg) of the same. (+)Propranolol (30 mg/kg) and UM-272 (1 and 10 mg/kg) as well as physostigmine (0.1 and 0.5 mg/kg) all produced inhibition of FSA. Similar FSA inhibitory effects were also observed with salbutamol (1 and 5 mg/kg). Pretreatment with atropine and not methylatropine attenuated the anti-aggressive effect of (+/-)propranolol (10 mg/kg) without appreciably altering the facilitatory effect (1 mg/kg) of the drug on FSA. In addition, at the anti-aggressive doses, (+/-)propranolol (10 mg/kg) and UM-272 (10 mg/kg), significantly inhibited brain cholinesterase enzyme activity when compared to saline controls. (+/-)Propranolol (10 mg/kg) also inhibited significantly the aggression induced by reserpine-apomorphine treatment. It is inferred that a central cholinergic and dopaminergic mechanism is involved in the anti-aggressive effect of (+/-)propranolol, whereas the low dose induced facilitation of affective aggression could be attributed to central beta-adrenoceptor blockade.


The evolution of asymmetric photosensitive structures in metazoans and the Nodal connection.
Asymmetries are observed in a great number of taxa in metazoans. More particularly, functional lateralization and neuroanatomical asymmetries within the central nervous system have been a matter of intense research for at least two hundred years. While asymmetries of some paired structures/organs (e.g. eyes, ears, kidneys, legs, arms) constitute random deviations from a pure bilateral symmetry, brain asymmetries such as those observed in the cortex and epithalamus are directional. This means that molecular and anatomical features located on one side of a given structure are observed in most individuals. For instance, in humans, the neuronal tract connecting the language areas is enlarged in the left hemisphere. When asymmetries are fixed, their molecular mechanisms can be studied using mutants displaying different phenotypes: left or right isomerism of the structure, reversed asymmetry or random asymmetry. Our understanding of asymmetry in the nervous system has been widely enriched thanks to the characterization of mutants affecting epithalamus asymmetry. Furthermore, two decades ago, pioneering studies revealed that a specific morphogen, Nodal, active only on one side of the embryo during development is an important molecule in asymmetry patterning. In this review, I have gathered important data bringing insight into the origin and evolution of epithalamus asymmetry and the role of Nodal in metazoans. After a short introduction on brain asymmetries (chapter I), I secondly focus on the molecular and anatomical characteristics of the epithalamus in vertebrates and explore some functional aspects such as its photosensitive ability related to the pineal complex (chapter II). Third, I discuss homology relationship of the parapineal organ among vertebrates (chapter III). Fourth, I discuss the possible origin of the epithalamus, presenting cells displaying photosensitive properties and/or asymmetry in the anterior part of the body in non-vertebrates (chapter IV). Finally, I report Nodal signaling expression data and functional experiments performed in different metazoan groups (chapter V).


Insulin-Like Growth Factor-1 Receptor Is Differentially Distributed in Developing Cerebellar Cortex of Rats Born to Diabetic Mothers.
Insulin-like growth factor-1 (IGF-1) has an important role in development of the central nervous system (CNS). Maternal diabetes is associated with a higher risk of developmental abnormalities in their offspring including motor dysfunction and learning deficits. The present study aimed to investigate the effects of maternal diabetes on the distribution pattern of IGF-1 receptor (IGF-1R) in the developing rat cerebellar cortex. Wistar female rats were maintained diabetic from a week before pregnancy through parturition, and male offspring was killed at P0, P7, and P14. In spite of P0, there was a significant increase in the total cerebellar volume in the pups born to diabetic mothers. In diabetic group, the IGF-1R+ granular cell densities in internal granular (IGL) and molecular (ML) layers were increased at P0. Moreover, the number of positive granular and Purkinje cells in the IGL of diabetic neonates' cerebellum was reduced in comparison with the control group at P7 and P14. There were no differences either in volume or in the number of IGF-1R+ cells in the layers of the cerebellar cortex between the insulin-treated diabetic group and controls. Our data indicate that diabetes in pregnancy strikingly influence the localization of IGF-1R in the developing cerebellar cortex.


Habitat complexity and sex-dependent predation of mosquito larvae in containers.
Studies in aquatic systems have shown that habitat complexity may provide refuge or reduce the number of encounters prey have with actively searching predators. For ambush predators, habitat complexity may enhance or have no effect on predation rates because it conceals predators, reduces prey detection by predators, or visually impairs both predators and prey. We investigated the effects of habitat complexity and predation by the ambush predators Toxorhynchites rutilus and Corethrella appendiculata on their mosquito prey Aedes albopictus and Ochlerotatus triseriatus in container analogs of treeholes. As in other ambush predator-prey systems, habitat complexity did not alter the effects of T. rutilus or C. appendiculata whose presence decreased prey survivorship, shortened development time, and increased adult size compared to treatments where predators were absent. Faster growth and larger size were due to predator-mediated release from competition among surviving prey. Male and female prey survivorship were similar in the absence of predators, however when predators were present, survivorship of both prey species was skewed in favor of males. We conclude that habitat complexity is relatively unimportant in shaping predator-prey interactions in this treehole community, where predation risk differs between prey sexes.


Cytogenetic and clinical studies in five cases of inv dup(15).
Inv dup(15) is a clinically significant bisatellited derivative of chromosome 15. Five unrelated patients with this abnormality are described and compared with ten confirmed and nine suspected cases in the literature. Mental and developmental retardation, hypotonia, behavioral disturbances, seizures, abnormal dermatoglyphics, and mild somatic anomalies were the most consistent findings. The extra chromosomes in our patients were identified with the aid of various techniques, including distamycin A/DAPI banding. A comparison of satellite polymorphisms suggested that the rearrangements frequently arose by meiotic nonsister chromatid exchange and second-division nondisjunction. A maternal origin was indicated in two cases, and parental ages were distinctly elevated.


Maternity Care in Russia: Issues, Achievements, and Potential.
In this review, we provide basic facts about maternity care services within the health care system in Russia. We give a short overview of such key aspects as the demographic situation, reproductive behaviour, regulatory framework for providing health care for women and children, maternal and perinatal mortality, and the availability of medical personnel. In 2012, Russia began registration of births in accordance with the WHO recommendations (births with weight ≥ 500 g at ≥ 22 weeks' gestation). Introduction of this new registration system increased the completeness and quality of the collected information and expanded possibilities for future international comparative assessments. A three-level system of specialized medical care has been introduced in Russia for women and newborns during pregnancy, childbirth, and the postpartum period. In 2014, the system included 1942 state (public) maternity hospitals providing 20 obstetric beds per 10 000 women aged 15 to 49 years. More than 100 perinatal centres (level III) are currently functioning in the country, with 32 new perinatal centres planned to open by 2016. The total number of obstetrician-gynaecologists in Russia is approximately 44 000, providing a ratio of 5.7 specialists per 10 000 women. The total number of midwives is 62 000, providing a ratio of 8.1 midwives per 10 000 women. In recent years we have succeeded in optimizing the maternity care system by increasing its accessibility and quality. This was achieved through qualitative and quantitative progress in the training of neonatologists, the development of intensive care technologies and neonatal critical care, capacity building of medical-genetic services and counselling, prenatal diagnosis, and the standardization of health care with data collection.


Schedule-dependent effect of d-amphetamine on pausing by pigeons.
Two pigeons were exposed to a multiple schedule of grain reinforcement where key-pecks were reinforced according to a fixed ratio schedule in the presence of one stimulus and a fixed interval schedule in another stimulus. The fixed interval was adjusted to match average interreinforcer time for the fixed ratio schedule. d-Amphetamine decreased overall rate of responding in the fixed ratio schedule -- primarily by increasing pausing, especially just after a change from the fixed interval component. Rate of responding in the fixed interval schedule was increased for one bird and little affected for the other bird by d-Amphetamine. Again, changes in pausing primarily determined rate change. Since pausing was differently affected, a schedule-dependent rather than rate-dependent effect was indicated.


Using Artificial Intelligence to extract information on pathogen characteristics from scientific publications.
Health risk assessment of environmental exposure to pathogens requires complete and up to date knowledge. With the rapid growth of scientific publications and the protocolization of literature reviews, an automated approach based on Artificial Intelligence (AI) techniques could help extract meaningful information from the literature and make literature reviews more efficient. The objective of this research was to determine whether it is feasible to extract both qualitative and quantitative information from scientific publications about the waterborne pathogen Legionella on PubMed, using Deep Learning and Natural Language Processing techniques. The model effectively extracted the qualitative and quantitative characteristics with high precision, recall and F-score of 0.91, 0.80, and 0.85 respectively. The AI extraction yielded results that were comparable to manual information extraction. Overall, AI could reliably extract both qualitative and quantitative information about Legionella from scientific literature. Our study paved the way for a better understanding of the information extraction processes and is a first step towards harnessing AI to collect meaningful information on pathogen characteristics from environmental microbiology publications.


Modulation of interleukin-8 activity by gingipains from Porphyromonas gingivalis: implications for pathogenicity of periodontal disease.
Gingipains are the major cysteine proteinases synthesized by Porphyromonas gingivalis which, in soluble form, are able to initially convert IL-8 (77 amino acid residues) to a more potent species truncated at the amino terminus, followed by slow degradation and destruction of chemokine biological activity. In contrast, the same enzymes when associated with bacterial outer-membrane blebs (vesicles), instantly degrade this chemokine. This division of enhancing and inactivating activity between soluble and membrane-bound gingipains can cause the compartmentalization of pro- and anti-inflammatory reactions to distal and proximal positions from bacterial plaque, respectively, which may explain why, despite the massive neutrophil accumulation at periodontitis sites, there is no elimination of infection.


Effects of prenatal exposure to different colors on offsprings mood.
There is much evidence indicating that depression is influenced by the levels of neurotransmitters such as dopamine, GABA and adrenaline. The current study we designed to investigate the effect of exposure of pregnant rats to different colors on neurotransmitters level, as indicators of mood disorders in off springs. Five groups of pregnant female Wistar rats (eight rats in each group) were enrolled in this study. Dopamine, adrenaline and GABA concentration in sera of rats were measured using ELISA. The colors black and red elevated the GABA levels in serum and CSF while the colors green and blue decreased the GABA levels. The colors black and red also decreased the sera and CSF levels of dopamine compared to the control group. The concentration of adrenaline was increased following exposure to the colors black, red and blue but decreased only following color green exposure. These results showed serious changes in neurotransmitter levels due to exposure to different colors which can be translated as mood and behavior changes. It can be concluded that exposure during pregnancy can lead to postpartum behavioral changes even at adulthood and such changes can be made by colors.


Phylogenetic analysis of type I polyketide synthase and nonribosomal peptide synthetase genes in Antarctic sediment.
The modular polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) have been found to be involved in natural product synthesis in many microorganisms. Study on their diversities in natural environment may provide important ecological insights, in addition to opportunities for antibacterial drugs development. In this study, the PKS and NRPS gene diversities in two coast sediments near China Zhongshan Station were studied. The phylogenetic analysis of amino acid (AA) sequences indicated that the identified ketosynthase (KS) domains were clustered with those from diverse bacterial groups, including Proteobacteria, Firmicutes, Planctomycetes, Cyanobacteria, Actinobacteria, and some uncultured symbiotic bacteria. One new branch belonging to hybrid PKS/NRPS enzyme complexes and five independent clades were found on the phylogenetic tree. The obtained adenylation (A) domains were mainly clustered within the Cyanobacteria and Proteobacteria group. Most of the identified KS and A domains showed below 80 and 60% identities at the AA level to their closest matches in GenBank, respectively. The diversities of both KS and A domains in natural environmental sample were different from those in sewage-contaminated sample. These results revealed the great diversity and novelty of both PKS and NRPS genes in Antarctic sediment.


Anaplerotic reactions in tumour proliferation and apoptosis.
Our aim in this commentary is to provide evidence that certain oxoacids formed in anaplerotic reactions control cell proliferation/apoptosis. In tumour cells with impaired Krebs cycle enzymes, some anaplerotic reactions do compensate for the deficit in oxoacids. One of these, oxaloacetate, derived from the transamination of asparagine but not of aspartate, is decarboxylated 4-fold more efficiently in polyoma-virus transformed cells than in their non-transformed counterparts. The deamidation of asparagine, in the cell culture medium, to aspartate by asparaginase decreases asparagine transamination and inhibits concomitantly the growth of asparaginase-sensitive lymphoma cells, suggesting a causal relationship between asparagine transamination and growth. Another oxoacid that can provide ATP when metabolised in mitochondria, but by the branched-chain oxoacid dehydrogenase complex (BCOADC), is 2-oxobutanoate. It has two origins: (a) deamination of threonine, and (b) cleavage of cystathionine, a metabolite derived from methionine. 2-Oxobutanoate in the presence of insulin promotes growth in G1/S arrested cells. But methionine also gives rise to another substrate of BCOADC, 4-methylthio-2-oxobutanoate (MTOB), which is synthesised exclusively from methylthioadenosine (MTA) by the action of MTA phosphorylase. In Met-dependent tumour cells with defective MTA phosphorylase, 2-oxobutanoate production would exceed that of MTOB. Further, BCOADC also has 3-fold greater affinity for 2-oxobutanoate than for MTOB; hence, the deficiency in 3-methylthio propionyl CoA, the final product of MTOB decarboxylation, would be exacerbated. Methional, the transient metabolic precursor in 3-methylthio propionyl CoA biosynthesis, is apoptogenic for both normal and bcl(2)-negative transformed cells in culture. Investigations of other causal relationships between the genes/enzymes mediating the homeostasis of anaplerotic oxoacids and cell growth/death may be worthwhile.


[Providing nursing care for migrants: feedback from experience in Greece].
During the 2015 migration crisis in Europe, medical NGOs played a key role in caring for migrant people. Nursing practice during humanitarian crises is characterized by many challenges. Shared experience of a primary care nurse with migrants in Greece.


Vorticity in lower urinary tract can be assessed and associates with urinary tract morphology in men.
The aim of this study is to develop a method to evaluate the fluid dynamics of urine flow in the lower urinary tract (LUT), especially that of vorticity. This investigation included three sub-studies to demonstrate urine flow in the entire LUT. First, we attempted to observe vorticity generation in the urinary bladder during spontaneous voiding using transabdominal color Doppler ultrasonography (CDUS). Second, we performed transrectal CDUS to evaluate the vorticity of urine flow in the prostatic urethra. Patients with prostate cancer were enrolled before robotic surgery and divided into the vorticity and non-vorticity groups based on CDUS findings for comparisons of longitudinal urethral diameter and prostatic urethral angle. Third, the vorticity of the voided urine stream was observed using a high-speed video-camera. Micturition was done in a standing position while synchronously monitored for urine flow using uroflowmetry. Vorticity formation could be dynamically demonstrated in the urinary bladder and prostatic urethra using CDUS. The prostatic urethral angle of the vorticity group was more than that of the non-vorticity group. High-speed video recording could clearly capture vorticity and spiral shape generation in voided urine. The distance from the external urethral orifice to the first twist changed in accordance with urine flow rate. In a series of sub-studies, this investigation proved vorticity generation in the LUT and voided urine. Vorticity was detectable in the LUT and in voided urine using CDUS and a high-speed video-camera. Vorticity generation might be associated with urethral morphology.


Efficacy of two insertions of 100-minute releasing quinacrine hydrochloride pellets for non-surgical female sterilization.
Extensive research has been undertaken to develop a simple method of non-surgical female sterilization. Zipper and associates identified quinacrine hydrochloride as a drug likely to produce tubal occlusion when placed into the uterus. Zipper's early work with a solution of quinacrine led to the development of quinacrine pellets, a delivery system that was designed to bring the quinacrine into prolonged contact with the tubal ostia through extended uterine retention. Three transcervical uterine insertions of 10-minute releasing quinacrine hydrochloride pellets performed at monthly intervals have produced a 12-month pregnancy rate of 3.3 per 100 women. The ultimate goal is to develop an effective, single insertion procedure, but the performance of the quinacrine pellets in occluding tubes has necessitated more than one insertion. FHI developed a 100-minute extended release pellet system with the expectation that more prolonged drug exposure would produce a higher rate of tubal closure. A study of the 100-minute releasing pellet system has been conducted in Santiago, Chile. Two monthly insertions in 112 women has resulted in a 12-month pregnancy rate of 2.0 per 100 women. Postprocedure problems occurring within the first year were reported by 13% of the women; most were minor and transitory.


A tale of 2 epidemics: the intersection between obesity and HIV infection in Philadelphia.
Obesity and HIV infection are ongoing epidemics in the United States. Obesity predisposes to diabetes and cardiovascular disease, which are complications also associated with HIV and/or its treatment. To determine the prevalence and risk factors for overweight and obesity in HIV-infected individuals. Retrospective cross-sectional study in which 1689 patients enrolled in the University of Pennsylvania Center for AIDS Research Adult/Adolescent Database at 1 university hospital clinic, 2 affiliated practices, and 1 Veterans Administration clinic in Philadelphia had demographic, social, and medical data collected prospectively since 1999. Body mass index (BMI) data were available for 1669 HIV-infected subjects: 78% were men, and 60% were African American. The median CD4 count was 381 cells/microL, 47% of subjects had a viral load <400 copies/mL, and 9% of subjects were treatment naive. The prevalence and risk factors for overweight (BMI: 25-29.9 kg/m) and obesity (BMI>or=30 kg/m) in HIV-infected subjects. Obesity and overweight were more prevalent than wasting (14%, 31%, and 9%, respectively; P<0.0005), but they were not more common than in the general population. Although women and men were equally overweight (30% vs. 31%), women were more obese than men (28% vs. 11%; P<0.001). Among women, African American race (odds ratio [OR]=1.8, 95% confidence interval [CI]: 1.1-2.9) and a CD4 count>or=200 cells/microL (OR=2.8, 95% CI: 1.6-4.9) were associated with overweight and obesity. Among men, only a CD4 count>or=200 cells/microL (OR=1.6, 95% CI: 1.04-2.4) was associated with increased BMI. In men and women, smoking was associated with decreased obesity and overweight (OR=0.59, 95% CI: 0.47-0.74 and OR=0.65, 95% CI: 0.43-0.98, respectively). Age, income, employment, education, past or current intravenous drugs, being on HIV treatment, and viral load were not associated with obesity in the multivariate model. There was a positive correlation between BMI and total cholesterol, triglycerides, and glucose. Obesity is more common than wasting in this therapeutic era. Women, particularly those of African American race, are at high risk. Obesity might add to metabolic abnormalities associated with HIV or its treatment and contribute to morbidity, as patients with HIV live longer.


Evaluating lesion segmentation on breast sonography as related to lesion type.
Breast sonography currently provides a complementary diagnosis when other modalities are not conclusive. However, lesion segmentation on sonography is still a challenging problem due to the presence of artifacts. To solve these problems, Markov random fields and maximum a posteriori-based methods are used to estimate a distortion field while identifying regions of similar intensity inhomogeneity. In this study, different initialization approaches were exhaustively evaluated using a database of 212 B-mode breast sonograms and considering the lesion types. Finally, conclusions about the relationship between the segmentation results and lesions types are described.


New insights on cytostatic drug risk assessment in aquatic environments based on measured concentrations in surface waters.
Cytostatic drugs are compounds used to treat cancer, one of the deadliest diseases worldwide with a rising yearly incidence. However, the occurrence and concentrations of a large number of cytostatics in waters and wastewaters are unknown. Thus, this study sought to analyze the concentrations of these compounds in different aquatic environments worldwide to assess the risk that these compounds pose to aquatic organisms. The top five most monitored cytostatics in aquatic environments are fluorouracil, methotrexate, tamoxifen, ifosfamide, and cyclophosphamide. Risk quotients (RQs) based on maximum reported measured concentrations revealed that mycophenolic acid and tamoxifen pose a high risk to aquatic organisms (RQmax ≥ 1) at concentrations observed in surface waters. Moreover, methotrexate and tegafur were categorized as moderate risk compounds, and bicalutamide was found to pose a low risk. Importantly, the available analytical methodologies for the quantification of some cytostatics (e.g., cisplatin, fluorouracil, daunorubicin, imatinib, and mycophenolic acid) in water could not rule out potential risk to aquatic biota, since estimated risks for these compounds using the lowest method detection limits reported in the literature (RQ MDL) were all ≥0.01 (i.e., low risk or higher). Moreover, risks based on predicted concentrations (RQ PEC) were consistently lower than those based on measured concentrations, highlighting the importance of risk assessment based on measured values. Thus, accurate and sensitive analytical methods are crucial to identify and quantify cytostatic exposure in aquatic ecosystems in order to preserve biodiversity and ensure a safer environment.


Viscoelastic testing: Critical appraisal of new methodologies and current literature.
United States Food and Drug Administration (FDA)-approved viscoelastic testing (VET) methodologies have significantly changed in the last 10 years, with the availability of cartridge-based VET. Some of these cartridge-based methodologies use harmonic resonance-based clot detection. While VET has always allowed for the evaluation of real-time clot formation, cartridge-based VET provides increased ease of use as well as greater portability and robustness of results in out-of-laboratory environments. Here we review the use of VET in a variety of clinical contexts, including cardiac surgery, trauma, liver transplant, obstetrics, and hypercoagulable states such as COVID-19. As of now, high quality randomized trial evidence for new generation VET (TEG 6s, HemoSonics Quantra, ROTEM sigma) is limited. Nevertheless, the use of VET-guided transfusion algorithms appears to result in reduced blood usage without worsening of patient outcomes. Future work comparing the new generation VET instruments and continuing to validate clinically important cut-offs will help move the field of point-of-care coagulation monitoring forward and increase the quality of transfusion management in bleeding patients.


Adipose cell size in spontaneously hypertensive rats (SHR).
The size of adipose cells in spontaneously hypertensive rats (SHR) and normotensive controls has been evaluated at 4, 8 and 26 weeks of age. Age-matched groups showed significant differences only in 8-week-old rats, but this can be explained by the lower body weight of SHR. In both groups of animals fat cell size varies with body weight (r = 0.965 in SHR and r = 0.863 in normotensive rats) independent of the stage of hypertension. The regression lines are not significantly different. Thus, no evidence of enlarged adipocytes in SHR has been obtained.


Generation of induced pluripotent stem cells (cmESF-iPS-C5) derived from cynomolgus monkey ear skin fibroblasts (cmESF).
Cynomolgus monkeys, due to their close anatomical, genetic and physiological similarity to humans, have been employed as a popular laboratory non-human primate model over rodents. Primate animal induced pluripotent stem cell (iPSC) have been used to aid on the investigation of autologous regenerative therapies. Here, we reprogrammed cynomolgus monkey ear skin fibroblasts (cmESFs) into iPSCs as a starting material for autologous based study. The resulting cmESF-iPSCs with canonical features of PSCs will advance the development of autologous transplantation.


Comparative Study of Laparoscopic Abdominopelvic and Fallopian Tube Findings Before and After Antitubercular Therapy in Female Genital Tuberculosis With Infertility.
To study the effect of antitubercular treatment (ATT) on the laparoscopic abdominopelvic and fallopian tube findings in female genital tuberculosis (FGBT). Prospective cohort (Canadian Task Force classification II2). Tertiary referral center in northern India. Fifty women with infertility and diagnosed with FGTB on laparoscopy, histopathology findings, or endometrial sampling (acid-fast bacilli culture, granuloma on histopathology, positive polymerase chain reaction). Diagnostic laparoscopy in all women diagnosed with FGTB before and after a 6-month course of ATT (2 months of rifampicin, isoniazid, pyrazinamide, and ethambutol, followed by 4 months of rifampicin and isoniazid). All procedures were performed by the same surgeon between June 2012 and May 2014. The mean patient age was 28.7 years, mean parity was 0.9, and mean body mass index was 23.6 kg/m(2). Infertility was seen in all 50 women (66% primary infertility, 34% secondary infertility), with a mean duration of 6.06 years. Abnormal laparoscopic findings of FGTB included tubercles in the pelvic peritoneum, fallopian tube, and ovary in 27 women (54%) before ATT and in only 1 (2.04%) woman after ATT (p < .001). Caseous nodules and encysted ascites were seen in 4 women (8%) before ATT, and in no women after ATT (p < .001); however, there was no change from before ATT to after ATT in the rate of pelvic adhesions (42% vs 42.5%) and perihepatic adhesions (56% vs 58%). Laparoscopic findings in fallopian tubes included hydrosalpinx (32%), pyosalpinx (4%), beaded tubes (12%), nonvisualization of tube (20%), and tubal blockage on the right side (56%), left side (50%), and both sides (38%) before ATT. Hydrosalpinx, beaded tubes, and nonvisualized tube were seen in 33.4%, 4.1%, and 20.8% cases, respectively, after ATT; however, free spill increased to 52% on the right side and 50% on left side after ATT. ATT improves laparoscopic findings in FGTB with infertility. However, advanced fibrotic lesions (eg, pelvic and perihepatic adhesions, bilateral blocked tubes) do not improve with ATT.


Changes in water intake following pharyngolaryngeal deafferentation in the rat.
The role of afferent information arising from the pharyngolaryngeal region in the regulation of water intake was evaluated in rats. The animals received picric application to the mucosa of either the pharyngolaryngeal or the hard palate region. Water intake of the pharyngolaryngeal treated animals was reduced significantly, while no reduction in water intake was shown in the control and hard palate treated animals.


Cancer-Causative Mutations Occurring in Early Embryogenesis.
Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers. Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring. See related commentary by Liggett and Sankaran, p. 889. This article is highlighted in the In This Issue feature, p. 873.


New Therapeutic Options for Fragile X Syndrome.
The purpose of this review is to provide an overview of current research and clinical practice guidelines in fragile X syndrome (FXS) with regard to therapeutic approaches in the management of this condition. The authors summarize and discuss findings from relevant preclinical studies and results from clinical trials in human subjects with FXS. Additionally, we provide an outline of the basic framework for understanding and providing educational and psychosocial supports for these individuals. Current treatments in FXS are largely symptom based and focused on managing associated psychiatric and behavioral co-morbidities. While data from animal studies has been promising in providing targeted treatments to correct the underlying deficits at the cellular level, there have not been as robust findings in human trials. There are several targeted treatments for FXS currently under development. Individuals with FXS present with several behavioral challenges including anxiety, social withdrawal, ADHD, hyperarousal, self-injury, and aggression. Therapeutic services are often necessary, such as behavioral intervention, speech and language therapy, occupational therapy, and individualized educational support; adjunctive psychopharmacologic treatment is often helpful as well. It is important to address these symptoms and weigh the evidence for the use of medications that target the underlying neurobiology and pathophysiology of the syndrome.


[Cryopreservation of hemopoietic stem cells (author's transl)].
The CFU-S potential of mouse bone marrow, the transplantation capacity of autologous and allogeneic monkey bone marrow and the CFU-C potential of human bone marrow can be cryopreserved without loss of viability. It is critical for an optimal stem cell recovery to avoid an osmotic shock after thawing. The intracellular cryoprotectives glycerol and DMSO which provide a high osmotic pressure should be removed from the thawed cells by a slow stepwise dilution procedure.


An evaluation of the mechanism of scopolamine-induced impairment in two passive avoidance protocols.
The effects of several doses of the centrally-acting muscarinic antagonist, scopolamine, on subsequent learning and memory were examined using two versions of a standard light versus dark passive avoidance paradigm. The first protocol was employed primarily to examine the effects of scopolamine on the acquisition component of learning and memory as subject performance was measured during five successive (repeated) training trials. The second protocol employed a one-trial twenty-four hour retention task in which subjects were given one training trial followed by one testing trial twenty-four hours later. This latter test encompasses acquisition, retention, and recall components of learning and memory. Dose response studies indicated an effective dose range of 0.4-1.2 mg/kg with 0.8 mg/kg producing maximal performance decrement. Differential scopolamine treatment demonstrated that the drug's primary effect was on the acquisition component only under the present experimental protocols. Furthermore, scopolamine was not found to produce state-dependent learning. Animals administered scopolamine before training and testing failed to perform better than animals receiving pre-training administration only.


Impacts of the N-terminal fragment analog of human parathyroid hormone on structure, composition and biomechanics of bone.
Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, and it is a serious threat to human lives. We previously showed that the N-terminal peptide analog of human parathyroid hormone (Pro-Pro-PTH(1-34)) enhanced plasma calcium concentration. In this paper, we study the impact of PTH N-terminal fragment analog on the structure, component, and mechanical properties of the rat bones. Daily subcutaneous injections of Pro-Pro-hPTH (1-34) induces 26.5-32.8% increase in femur bone mineral density (BMD), 23.0-34.2% decrease the marrow cavity or increase in trabecular bone area. The peptide also increases 16.0-59.5%, 28.8-48.2% and 14.0-17.8% of bone components of calcium, phosphorus and collagen, respectively. In terms of mechanic properties, administration of the peptide elevates the bone rigidity by 45.4-76.6%, decreases the flexibility by 23.0-31.6%, and improves modulus of elasticity by 32.8-63.4%. The results suggest that Pro-Pro-hPTH (1-34) has a positive effect on bone growth and strength, and possesses anti-fracture capability, thus a potential candidate for the application for the treatment of osteoporosis.


2-substituted indazolinones: orally active and selective 5-lipoxygenase inhibitors with anti-inflammatory activity.
1. This paper describes the pharmacological profile of ICI207968, a novel, orally-active and selective inhibitor of 5-lipoxygenase. 2. Inhibition of leukotriene B4 (LTB4) synthesis by 2-substituted indazolinones was not directly related to redox potential but was critically dependent on the nature of the N2 substituent. 2-(3-Pyridylmethyl)-indazolinone (ICI207968) combined selectivity and oral potency. 3. In several in vitro systems ICI207968 exhibited similar lipoxygenase inhibitory potency (IC50 values from 1.5 microM to 6.0 microM) and was approximately 300 times less potent against cyclo-oxygenase, as measured by inhibition of prostaglandin E2 (PGE2) synthesis. 4. ICI207968 also produced selective lipoxygenase inhibition following oral administration in the rat. ED50 values of 2.5, 10 and 25 mg kg-1 p.o. for inhibition of LTB4 release from A23187-stimulated blood were obtained 1, 3 and 5 h after dosing. The compound did not inhibit PGE2 synthesis at oral doses up to 300 mg kg-1. 5. Co-administration of ICI207968 with arachidonic acid, into rabbit dermis, potently inhibited both plasma extravasation and polymorphonuclear leucocyte (PMNL) infiltration induced by this inflammatory fatty acid. The anti-inflammatory potency of a number of intradermally administered indazolinones, with similar redox potentials, was related to their inhibitory potency against leukotriene generation in blood. Oral administration of ICI207968 (100 mg kg-1) in the rabbit inhibited ex vivo leukotriene generation in blood and arachidonic acid-induced skin inflammation. 6. These data demonstrate that ICI207968 is an orally active and selective inhibitor of 5-lipoxygenase which has anti-inflammatory properties. IC1207968 will be a valuable agent for clarifying the biological roles of leukotrienes and the therapeutic potential of 5-lipoxygenase inhibitors.


Cholesterol homeostasis and autophagic flux in perifosine-treated human hepatoblastoma HepG2 and glioblastoma U-87 MG cell lines.
Perifosine exerts an antiproliferative effect on HepG2 and U-87 MG cells and also interferes with the transport of cholesterol from the plasma membrane to the endoplasmic reticulum (ER). Recently we demonstrated that exposure of U-87 MG cells to perifosine causes an accumulation of autophagosomes. We have now expanded the study to establish the molecular mechanism by which perifosine interferes with the autophagic process. Using transmission electron microscopy, we report that the treatment of HepG2 and U-87 MG cells with perifosine causes an intense cytoplasmic vacuolization identified as autophagic vesicles. The accumulation of autophagosomes induced by perifosine is due to a blockage of the autophagic flux, thereby affecting cell proliferation. Perifosine also provokes a differential ER stress response in the HepG2 and U-87 MG cell lines. We have also demonstrated a relationship between the deregulation of cholesterol transport and the inhibition of the autophagic flux prompted by perifosine. Thus our findings clearly demonstrate that perifosine impairs the autophagic flux in HepG2 and U-87 MG cells, which is related to defects in intracellular cholesterol transport. Our study is relevant for anticancer therapy because tumour cells exhibit autophagy as a pro-survival mechanism. Further research to identify the precise mechanisms of autophagy maturation and the role of cholesterol may provide new insights into the antiproliferative action of perifosine.


Tuning nanopore surface polarity and rectification properties through enzymatic hydrolysis inside nanoconfined geometries.
Enzyme-catalyzed reactions inside nanoconfined geometries promote sensitive changes in the surface charge polarity and the concomitant permselective transport properties of the single conical nanopores.


The immunoglobulins of carcharhine sharks: a comparison of serological and biochemical properties.
The immunoglobulins of three carcharhine sharks were isolated from serum by means of salt precipitation and gel chromatography. The Galapagos shark (Carcharhinus galapagensis), the sandbar shark (Carcharhinus plumbeus) and the tiger shark (Galeocerdo cuvieri) each contained high molecular weight (18S) and low molecular weight (7S) IgM-like molecules as the major serum immunoglobulins. Both within and between species 18S and 7S immunoglobulins closely resemble each other in antigenic character, polypeptide chain composition, chain mass, amino acid composition, carbohydrate content and amino-terminal sequence. These results suggest that the immunoglobulins of carcharhine sharks have undergone little structural divergence during their evolution.


MRT letter: a fast and easy method for general fluorescent staining of cultured cells on transparent or opaque supports.
Development of cell-based therapy entails the use of different types of materials as support for cultured cells. Some of these materials are opaque. For a general microscope study of cell cultures prepared on transparent supports, Giemsa stain with bright field microscopy is useful. With opaque supports or scaffolds, epifluorescence microscopy is necessary. The method the authors describe uses eosin Y to stain cytoplasm and DAPI to stain nuclei under fluorescence microscopy. This method provides easy and fast fluorescent staining for a general morphological study of cultured cells on transparent or opaque supports.


Immunohistology of thymic nurse cells.
The demonstration of thymic nurse cells (TNC), complexes between stromal cells and thymocytes, in cell suspensions of murine thymuses, prompted us to investigate (1) the relationship of TNC to other thymic stromal cell types defined in situ, and (2) the maturation stage of the enclosed thymocytes. To this purpose we incubated frozen sections of TNC suspensions with various monoclonal antisera directed to T cells and stromal cell types, using immunohistology. This approach enabled us to study antigen expression on the "nursing" cell itself and to analyze the phenotype of the enclosed lymphocytes in cross sections of TNC. The results show that lymphocytes enveloped by TNC express high levels of Thy-1, moderate levels of T200, and variable amounts of Lyt-1. Due to enzymatic degradation Lyt-2 expression could not be studied. The enveloped cells also bear PNA receptors, but no detectable I-A/E antigens. Expression of H-2K antigens on enclosed thymocytes varied from weak to absent. The "nursing" cells react with ER-TR4, a monoclonal antibody which detects cortical epithelial-reticular cells. In addition TNC express I-A/E and H-2K antigens. In contrast, TNC do not react with ER-TR 5 and 7, monoclonal antibodies, which detect medullary epithelial cells and reticular fibroblasts, respectively. TNC do not express the macrophage antigens Mac-1 and Mac-2. We conclude that TNC in vitro represent the in vivo association of epithelial-reticular cells with cortical thymocytes. However, the enclosed thymocytes do not constitute a phenotypically distinct subset of subcapsular or outer cortical cells.


Erratum: Consumption of whole grains and cereal fiber and total and cause-specific mortality: prospective analysis of 367,442 individuals.
This is an Erratum to BMC Medicine 2015, 13:59, highlighting previously undeclared competing interests and including more information in the acknowledgements section.Please see related article: http://www.biomedcentral.com/1741-7015/13/59. The statement in the competing interests should read as follows: This study is funded by unrestricted research fund from NutraSource. Susan Cho is founder and owner of NutraSource and Albert Lee is an employee of NutraSource. The other authors declare that they have no competing interests. The following information should be included in the acknowledgements section: The authors also thank Dr. Yi K Park at National Cancer Institute for her guidance in the study design.


Inhibition by H-7 of the protein kinase C prevents formation of brain edema in Sprague-Dawley CFY rats.
The effect of the protein kinase C enzyme inhibitor H-7 was examined on the brain edema formation evoked by bilateral occlusion of the common carotid arteries in Sprague-Dawley rats of CFY strain. Brain edema was assessed by measurement of water and electrolyte contents of the brain. The results showed that pretreatment with H-7 reduced the extent of brain edema formation in a dose-dependent manner. The fact that H-7 treatment prevented the accumulation of water and certain electrolytes in the brain indicates that the protein kinase C may be activated not only in the neuronal structures but also in the microvessels during ischemia, which can lead directly or via certain calcium-mediated mechanisms to the opening of tight junctions resulting in the development of brain edema.