Comparison of the Clinical Value of the Geriatric Nutritional Risk Index and Prognostic Nutritional Index as Determinants of Survival Outcome in Patients with Gastric Cancer.
Background: The geriatric nutritional risk index (GNRI) is an important determinant of overall survival (OS) in patients with stage I-III gastric cancer (GC) across all ages; however, its value as a determinant of disease-free survival (DFS) is unclear. Moreover, the prognostic values between the GNRI and prognostic nutritional index (PNI) remains unclear. Methods: We retrospectively evaluated the value of the GNRI and PNI as determinants of OS and DFS in patients with stage I-III GC who underwent curative-intent gastrectomy. Cox regression analysis was used for evaluating the determinants of survival outcomes. The discriminative capacity of the prognostic model was determined using the concordance index (C-index), and then C-indices of related models were compared. Results: Data from 450 patients were analyzed. The median patient age was 60 years (range: 26-92 years). In total, 276 (61.3%) patients had stage I cancer, 83 (18.4%) had stage II cancer, and 91 (20.2%) had stage III cancer. Multivariate Cox regression analysis revealed that age, type of gastrectomy (TOG), T stage, tumor-node-metastasis (TNM) stage, and GNRI were determinants of OS. These five covariates constituted the GNRI model for the OS. In addition, multivariate analysis revealed that age, TOG, TNM stage, and GNRI were determinants of DFS. These four covariates constituted the GNRI model for DFS. When constructing the PNI model for OS (comprising age, TOG, T stage, TNM stage, and PNI), and PNI model for DFS (including age, TOG, TNM stage, and PNI), the C-indices of the GNRI and PNI models were nearly equal for OS (0.818 and 0.818, respectively; p=0.909) and DFS (0.805 and 0.808, respectively; p=0.653). Using the GNRI models, nomograms for predicting OS and DFS were established. When validating the nomograms using calibration curves, the predicted survival closely matched the actual survival rate. Conclusion: The GNRI and PNI were important determinants of both OS and DFS in patients with GC across all ages. In addition, the effects of the GNRI model on OS and DFS were similar to those of the PNI model.


The role of macrophages in the periodontal regeneration using Emdogain gel.
Emdogain gel is clinically used as a periodontal regenerative material. However, the mechanism of the regeneration has not been completely elucidated. Although many studies have focused on the regenerative effect of Emdogain on connective tissue attachment and alveolar bone, the role of macrophages and the expression of growth factors remains unclear in the regeneration stimulated by Emdogain gel in vivo. The aim of this study was to investigate the effect of Emdogain gel on the expression of cytokines and growth factors by macrophages in vivo using a newly devised rat experimental periodontitis model. Rat experimental periodontitis was induced by elevating a full-thickness gingival flap and ligating silk threads around the first molars of the mandible. At 14 d after inducing experimental periodontitis, Emdogain gel or propylene glycol alginate was applied to the furcation area. The rats were killed 7 and 14 d after treatment with propylene glycol alginate or Emdogain gel. The expression of cytokines and growth factors, and the regeneration of periodontal tissue, were examined by histochemical and immunohistochemical methods. Fourteen days after the induction of periodontitis, the resorption of alveolar bone at furcation was observed and cytokines such as interleukin-1beta, transforming growth factor-beta1, receptor activator of nuclear factor-kappaB ligand, receptor activator of nuclear factor-kappaB and osteoprotegerin were found. In the Emdogain-treatment group, the formation of new acellular cementum and, more remarkably, recovery of the bone, were observed. The new bone formation ratio in the Emdogain treatment group was significantly higher than that of the propylene glycol alginate treatment group. Although the expression of cytokines such as interleukin-1beta, transforming growth factor-beta1, receptor activator of nuclear factor-kappaB ligand and receptor activator of nuclear factor-kappaB was very low, bone morphogenetic protein-2- and bone morphogenetic protein-4-expressing macrophages were observed close to the root, and bone morphogenetic protein-4-expressing macrophages were mainly observed close to the bone surface at the furcation in the Emdogain-treatment group. These results suggest that wound-healing macrophages may express bone morphogenetic protein and play an important role in the regeneration of periodontal tissue at the furcation following the application of Emdogain gel.


Molecular characterization of infectious bursal disease viruses from Pakistan.
Since the first report of infectious bursal disease in Pakistan in 1987, outbreaks have been common even in vaccinated flocks. Despite appropriate administration of vaccines, concerns arise if the circulating strains are different from the ones used in the vaccine. Here, we sequenced the hypervariable region (HVR) of the VP2 gene of circulating strains of infectious bursal disease virus (IBDV) originating from outbreaks (n = 4) in broiler flocks in Pakistan. Nucleotide sequencing followed by phylogeny and deduced amino acid sequence analysis showed the circulating strains to be very virulent (vv) and identified characteristic residues at position 222 (A), 242 (I), 256 (I), 294 (I) and 299 (S). In addition, a substitution at positions 221 (Q→H) was found to be exclusive to Pakistani strains in our analysis, although a larger dataset is required to confirm this finding. Compared to vaccine strains that are commonly used in Pakistan, substitution mutations were found at key amino acid positions in VP2 that may be responsible for potential changes in neutralization epitopes and vaccine failure.


Genetic variation in the Renin-Angiotensin system and progression of diabetic nephropathy.
The impact of polymorphisms in the genes coding for angiotensinogen (M235T), ACE (ID), and angiotensin II type 1 receptor (A(1166)-->C) on decline in GFR and doubling of s-creatinine or development of ESRD in patients with type 1 diabetes and diabetic nephropathy (DN) was tested. From 1985, all patients (n = 169) who had established diabetic nephropathy and were treated with angiotensin-converting enzyme inhibition (ACE-I) were identified consecutively at Steno Diabetes Center. Patients were followed for a median of 6 yr (range, 3 to 15 yr), with nine (range, three to 29) measurements of GFR ((51)Cr-EDTA). In a Cox proportional hazards model corrected for other risk factors, the D allele (ACE/ID) was associated with time to doubling of s-creatinine/ESRD (rate ratio, 1.81 per allele; 95% confidence interval, 1.09 to 3.03; P = 0.02). A new interaction hypothesis was generated demonstrating that the following variables were associated with accelerated decline in GFR: albuminuria (estimate, 2.12 ml/min per yr per 10-fold increase in albuminuria; P < 0.001), mean BP (estimate, 0.88 ml/min per yr per 10 mmHg; P = 0.02), hemoglobin A(1c) (estimate, 0.54 min/min per yr per 1%; P = 0.02), and number of M (M235T)/D (ID)/A (A(1166)-->C) alleles (estimate, 0.45 ml/min per yr per allele; P = 0.049). Number of M/D/A alleles also influenced time to doubling of s-creatinine or ESRD. In this study of patients with type 1 diabetes, the D allele of the ACE/ID polymorphism in addition to nongenetic risk factors independently accelerated progression of DN during ACE-I. Interaction between polymorphisms in the renin-angiotensin system also influenced the loss of kidney function. This new genetic interaction model needs to be confirmed in future studies.


Lifetime benefits of early detection and treatment of diabetic kidney disease.
Diabetic kidney disease (DKD) is a frequent complication of diabetes with potentially devastating consequences that may be prevented or delayed. This study aimed to estimate the health and economic benefit of earlier diagnosis and treatment of DKD. Life expectancy and medical spending for people with diabetes were modeled using The Health Economics Medical Innovation Simulation (THEMIS). THEMIS uses data from the Health and Retirement Study to model cohorts of individuals over age 50 to project population-level lifetime health and economic outcomes. DKD status was imputed based on diagnoses and laboratory values in the National Health and Nutrition Examination Survey. We simulated the implementation of a new biomarker identifying people with diabetes at an elevated risk of DKD and DKD patients at risk of rapid progression. Compared to baseline, the prevalence of DKD declined 5.1% with a novel prognostic biomarker test, while the prevalence of diabetes with stage 5 chronic kidney disease declined 3.0%. Consequently, people with diabetes gained 0.2 years in life expectancy, while per-capita annual medical spending fell by 0.3%. The estimated cost was $12,796 per life-year gained and $25,842 per quality-adjusted life-year. A biomarker test that allows earlier treatment reduces DKD prevalence and slows DKD progression, thereby increasing life expectancy among people with diabetes while raising healthcare spending by less than one percent.


Skin cell proliferation stimulated by microneedles.
A classical wound may be defined as a disruption of tissue integrity. Wounds, caused by trauma from accidents or surgery, that close via secondary intention rely on the biological phases of healing, i.e., hemostasis, inflammation, proliferation, and remodeling (HIPR). Depending on the wound type and severity, the inflammation phase begins immediately after injury and may last for an average of 7-14 days. Concurrent with the inflammation phase or slightly delayed, cell proliferation is stimulated followed by the activation of the remodeling (maturation) phase. The latter phase can last as long as 1 year or more, and the final healed state is represented by a scar tissue, a cross-linked collagen formation that usually aligns collagen fibers in a single direction. One may assume that skin microneedling that involves the use of dozens or as many as 200 needles that limit penetration to 1.5 mm over 1 cm(2) of skin would cause trauma and bleeding followed by the classical HIPR. However, this is not the case or at least the HIPR phases are significantly curtailed and healing never ends in a scar formation. Conversely dermabrasion used in aesthetic medicine for improving skin quality is based on "ablation" (destruction or wounding of superficial skin layers), which requires several weeks for healing that involves formation of new skin layers. Such procedures provoke an acute inflammatory response. We believe that a less intense inflammatory response occurs following microneedle perforation of the skin. However, the mechanism of action of microneedling appears to be different. Here we review the potential mechanisms by which microneedling of the skin facilitates skin repair without scarring after the treatment of superficial burns, acne, hyperpigmentation, and the non-advancing periwound skin surrounding the chronic ulcerations of the integument.


Second transcatheter closure for residual shunt following percutaneous closure of patent foramen ovale.
Residual shunt following percutaneous patent foramen ovale (PFO) closure has been described in up to 49% of patients and is associated with recurrent cerebrovascular events. Our aim was to evaluate the safety, feasibility, and midterm outcomes of transcatheter residual shunt closure. From 1994 to July 2016, 2,679 patients underwent transcatheter PFO closure for treatment of presumed paradoxical embolism at our institution. Among them, 100 patients (3.7%) were referred for residual shunt closure. They constituted the study population for which a retrospective analysis of the prospectively gathered procedural data was performed along with prospective acquisition of follow-up data. The indication for initial PFO closure was an ischaemic cerebrovascular event in 85% of the patients. Patients underwent transoesophageal echocardiography (TOE) for PFO diagnosis and again for residual shunt assessment at about six months. All procedures were performed under fluoroscopic guidance only. At the first procedure, 10 different devices had been used. The AMPLATZER PFO Occluder accounted for 54% and the AMPLATZER Cribriform Occluder for 28%. Compared to the whole population (n=2,679), a significantly higher rate of atrial septal aneurysm (58% versus 36%; p=0.024), a larger proportion of shunt grade 3 at baseline (97% versus 78%; p<0.001), and a larger size (≥30 mm) of the first implanted device (47% versus 13%; p<0.001) were observed in the patients with residual shunt. Six patients (6%) experienced a recurrent TIA or ischaemic stroke before the second intervention. Residual shunt closure was successful in all but two patients. A second AMPLATZER PFO Occluder was used in the majority of the repeat interventions (76%). There were no complications. TOE, obtained again after 7±5 months in 88 of the 98 patients with a device in place (90%), showed complete closure in 81%. In eight patients (0.3% of the whole cohort), a third device was implanted, resulting in complete closure in all. Transcatheter residual shunt closure after initial percutaneous PFO closure can be safely performed under fluoroscopic guidance only and achieves complete closure in most patients. The use of larger devices, typically prompted by intricate anatomy, represents a risk factor for shunt persistence and the need for reintervention.


One year in review 2019: psoriatic arthritis.
Psoriatic arthritis (PsA) is an inflammatory arthritis belonging to spondyloarthritides (SpA), a group of rheumatologic diseases characterised bya wide spectrum of different clinical manifestations that tend to associate with various comorbidities and that may significantly compromise the quality of life of patients. Nowadays, it is well known how PsA may manifest in different clinical domains, in particular peripheral articular and periarticular involvement, axial involvement, skin and nail psoriasis. Moreover, the majority of patients with PsA develop comorbidities such as inflammatory bowel diseases, uveitis, but also cardiovascular diseases, psychiatric or pulmonary pathologies. The therapeutical armamentarium of PsA has been enriched during the last years, in relation to an advance in the knowledge of the immunological mechanisms at the basis of the disease; in particular, the future frontier of "personalised medicine" could lead to a further improvement in the quality of care of this group of patients. In this paper we review the literature on PsA of 2019 (Medline search of articles published from 1st January 2019 to 31st December 2019).


A lncRNA TCL6-miR-155 Interaction Regulates the Src-Akt-EMT Network to Mediate Kidney Cancer Progression and Metastasis.
Metastasis is the leading cause of mortality from kidney cancer, and understanding the underlying mechanism of this event will provide better strategies for its management. Here we investigated the biological, functional, and clinical significance of lncTCL6 and its interacting miR-155 in clear cell renal cell carcinoma (ccRCC). We employed a comprehensive approach to investigate the lncTCL6-miR-155-Src/Akt-mediated epithelial-to-mesenchymal transition (EMT) pathway as a novel regulatory mechanism in ccRCC progression. Expression analyses revealed that lncTCL6 is downregulated in ccRCC compared with normal tissues. Overexpression of lncTCL6 in ccRCC cell lines impaired their oncogenic functions, such as cell proliferation and migration/invasion, and induced cell-cycle arrest and apoptosis; conversely, depletion of lncTCL6 rescued these phenotypic effects. Furthermore, lncTCL6 directly interacted with miR-155. Unlike lncTCL6, miR-155 was overexpressed in ccRCC. Stable knockdown of miR-155 phenocopied the effects of lncTCL6 overexpression. Conversely, reconstitution of miR-155 and suppression of lncTCL6 in noncancerous renal cell HK2 induced tumorigenic characteristics. Patients with higher expression of lncTCL6 and lower expression of miR-155 had better survival probability. When overexpressed, lncTCL6 recruited STAU1 and mediated decay of Src mRNA, followed by a marked downregulation of an integrated network of Src target genes involved in migration, invasion, and EMT. However, the interaction between miR-155 and lncTCL6 attenuated the regulatory role of lncTCL6 on Src-mediated EMT. In conclusion, this study is the first report documenting the lncTCL6-miR155-Src/Akt/EMT network as a novel regulatory mechanism in aggressive ccRCC and a promising therapeutic target to inhibit renal cancer. SIGNIFICANCE: This study's investigation of noncoding RNA interactions in renal cell carcinoma identify miRNA-155-lncRNA TCL6-mediated regulation of the Src-Akt-EMT network as a novel mechanism of disease progression and metastasis.


Effects of gastrointestinal hormones on Oddi's sphincter and duodenal myoelectric activity and pancreatobiliary pressure. Studies in the opossum.
Myoelectric activity of Oddi's sphincter and duodenum was correlated with common duct and pancreatic duct pressures in conscious opossums after infusion of the following substances: cholecystokinin, pentagastrin, glucagon, secretin, and acetylcholine. Cholecystokinin and pentagastrin increased and glucagon and secretin decreased the frequency of spike potentials in Oddi's sphincter and the duodenum. Acetylcholine was associated with the largest increase in spike potentials in both Oddi's sphincter and the duodenum. Although there was variation in the number of pressure elevations related to Oddi's sphincter spike potentials, the baseline pressure remained constant during administration of the hormones. Acetylcholine infusion increased the biliary and pancreatic pressures to 29 and 31 mm Hg, respectively. We conclude that gastrointestinal hormones may have an important role in regulating the excretion of bile and pancreatic juice into the duodenum.


Brain imaging and prophylactic therapy in children with migraine: recommendations versus reality.
To determine the concordance between referring physician behavior and published criteria for performance of imaging studies and institution of prophylactic therapy, respectively, in children referred to an academic children's hospital headache clinic. Study design A retrospective review of the records of 106 consecutive patients referred to an academic children's hospital headache clinic. Approximately half of patients referred to the clinic had already had head computed tomography or magnetic resonance imaging ordered by the referring doctor and performed before their clinic appointment. However, using published criteria, only 10% of patients seen in the clinic would have required an imaging procedure before institution of therapy. The referring physician had initiated treatment with daily prophylactic medications for headache in more than 30% of patients before their clinic appointments, of whom 89% were on appropriate medications at age-appropriate and weight-appropriate doses. Half of these children exhibited a positive response to this medication before being seen by the consulting neurologist. However, more than 60% of the children actually met the criteria for recommending prophylactic therapy. Imaging is more frequently obtained and prophylactic therapy less frequently implemented by the referring physician than would be indicated by published recommendations.


Mitochondrial alterations related to programmed cell death in tobacco cells under aluminium stress.
The present investigation was undertaken to verify whether mitochondria play a significant role in aluminium (Al) toxicity, using the mitochondria isolated from tobacco cells (Nicotiana tabacum, non-chlorophyllic cell line SL) under Al stress. An inhibition of respiration was observed in terms of state-III, state-IV, succinate-dependent, alternative oxidase (AOX)-pathway capacity and cytochrome (CYT)-pathway capacity, respectively, in the mitochondria isolated from tobacco cells subjected to Al stress for 18 h. In accordance with the respiratory inhibition, the mitochondrial ATP content showed a significant decrease under Al treatment. An enhancement of reactive oxygen species (ROS) production under state-III respiration was observed in the mitochondria isolated from Al-treated cells, which would create an oxidative stress situation. The opening of mitochondrial permeability transition pore (MPTP) was seen more extensively in mitochondria isolated from Al-treated cells than in those isolated from control cells. This was Ca(2+) dependent and well modulated by dithioerythritol (DTE) and Pi, but insensitive to cyclosporine A (CsA). The collapse of inner mitochondrial membrane potential (DeltaPsi(m)) was also observed with a release of cytochrome c from mitochondria. A great decrease in the ATP content was also seen under Al stress. Transmission electron microscopy analysis of Al-treated cells also corroborated our biochemical data with distortion in membrane architecture in mitochondria. TUNEL-positive nuclei in Al-treated cells strongly indicated the occurrence of nuclear fragmentation. From the above study, it was concluded that Al toxicity affects severely the mitochondrial respiratory functions and alters the redox status studied in vitro and also the internal structure, which seems to cause finally cell death in tobacco cells.


Hemoglobin A0 and alpha-crosslinked hemoglobin (alpha-DBBF) potentiate agonist-induced platelet aggregation through the platelet thromboxane receptor.
Chemically modified hemoglobins are potential oxygen-carrying blood substitutes, but their in vivo administration has been associated with a variety of unexpected side events, including increased platelet reactivity. We studied the effects of hemoglobin A0 (HbA0) and alpha-crosslinked hemoglobin (alpha-DBBF) on platelets in vitro. Neither hemoglobin A0 nor alpha-DBBF activated platelets when added alone, but both proteins potentiated submaximal agonist-induced platelet aggregation without increasing other markers of platelet activation such as serotonin secretion. Only agonists that are known to cause release of platelet arachidonic acid (AA) were potentiated while aggregation induced by ADP, which does not release AA, was not potentiated. Blockade of the thromboxane receptor with SQ-29,548 prevented the HbA0-induced and the alpha-DBBF-induced potentiation suggesting that the AA/thromboxane signaling pathway mediates the interaction of platelets with hemoglobin.


Electroacupuncture at Qiuxu (GB 40) for treatment of migraine--a clinical multicentral random controlled study.
To observe the therapeutic effects of electroacupuncture (EA) at Qiuxu (GB 40) for treatment of migraine so as to provide clinical evidence for compilation of the Acupoints' Dictionary of the People's Republic of China. 275 migraine patients admitted in 3 hospitals were randomly divided into a treatment group treated by EA at Qiuxu (GB 40), and a control group treated by EA at Tianshu (ST 25). The indexes of the migraine symptoms and the 5-HT level were observed in both the groups before and after treatment. There was a significant difference in VAS score between the two groups of the 3 clinical centers (P<0.01). The therapeutic effects of a 4-week treatment were much better in the treatment group than that of the control group. The 3-month follow-up survey showed that the long-term effects were in favor of the treatment group of the first and third clinical centers, though no significant difference was found in the treatment group of the second clinical center as compared with the control group. The results from the 6-month follow-up survey showed better effects in the treatment group of all the 3 clinical centers. EA at Qiuxu (GB 40) may show effect for migraine.


IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17.
We investigated the influence of cytokines on the expression of RANK ligand (RANKL) in fibroblast-like synoviocytes from RA patients (RA-FLS). RA-FLS were stimulated by IL-6, TNF-alpha, IL-17 and IL-1beta with or without soluble IL-6 receptor (sIL-6R) for 24 h. The expression of RANKL was measured by real-time PCR, western blotting and immunostaining. In proliferation assay, RA-FLS were cultured with cytokines for 3 days. RA-FLS were co-cultured with RAW cell in the presence of IL-6/sIL-6R for 3 days and then NFATc1 mRNA expression in RAW cells was examined. RA-FLS was cultured with parthenolide [PAR, signal transducer and activator of transcription (STAT) inhibitor] or PD98059 (PD, mitogen-activated protein kinase inhibitor) in the presence of IL-6/sIL-6R and then the influence of these drugs on phosphorylation of STAT3 and ERK1/2, and RANKL expression was examined. RANKL expression was induced by IL-6/sIL-6R (but not IL-6 alone) and by IL-1beta. On the other hand, TNF-alpha and IL-17 did not induce RANKL expression, although TNF-alpha, IL-17 or IL-1beta stimulated cell growth and IL-6 production. However, in the presence of sIL-6R, TNF-alpha or IL-17 induced RANKL expression. By the co-culture of RA-FLS, NFATc1 mRNA expression was induced in RAW cells. Finally, IL-6/sIL-6R induced phosphorylation of STAT3 and ERK1/2 in RA-FLS, and was completely inhibited by PAR and PD, respectively. PAR completely inhibited IL-6/sIL-6R-induced RANKL expression, but PD did not. IL-6/sIL-6R directly induced RANKL expression in RA-FLS and it is essential for RANKL induction by TNF-alpha and IL-17. Moreover, RANKL induction by IL-6/sIL-6R is mediated by the janus kinase/STAT signalling pathway.


Improved self-referenced biosensing with emphasis on multiple-resonance nanorod sensors.
We present a novel approach to improve self-referenced sensing based on multiple-resonance nanorod structures. The method employs the maximum likelihood estimation (MLE) alongside a linear response model (LM), relating the sensor response (shifts in resonance wavelengths) to the changes due to surface binding and bulk refractive index. We also provide a solution to avoid repetitive simulations, that have been previously needed to determine the adlayer thickness sensitivity when measuring biological samples of different refractive indices. The finite element method (FEM) was used to model the nanorod structure, and the nanoimprint lithography was employed to fabricate them. The standard deviation of the results based on the MLE method is lower than that associated with the LM results. The method can be applied to an extended number of resonances to achieve a higher accuracy and precision.


Sap transporter mediated import and subsequent degradation of antimicrobial peptides in Haemophilus.
Antimicrobial peptides (AMPs) contribute to host innate immune defense and are a critical component to control bacterial infection. Nontypeable Haemophilus influenzae (NTHI) is a commensal inhabitant of the human nasopharyngeal mucosa, yet is commonly associated with opportunistic infections of the upper and lower respiratory tracts. An important aspect of NTHI virulence is the ability to avert bactericidal effects of host-derived antimicrobial peptides (AMPs). The Sap (sensitivity to antimicrobial peptides) ABC transporter equips NTHI to resist AMPs, although the mechanism of this resistance has remained undefined. We previously determined that the periplasmic binding protein SapA bound AMPs and was required for NTHI virulence in vivo. We now demonstrate, by antibody-mediated neutralization of AMP in vivo, that SapA functions to directly counter AMP lethality during NTHI infection. We hypothesized that SapA would deliver AMPs to the Sap inner membrane complex for transport into the bacterial cytoplasm. We observed that AMPs localize to the bacterial cytoplasm of the parental NTHI strain and were susceptible to cytoplasmic peptidase activity. In striking contrast, AMPs accumulated in the periplasm of bacteria lacking a functional Sap permease complex. These data support a mechanism of Sap mediated import of AMPs, a novel strategy to reduce periplasmic and inner membrane accumulation of these host defense peptides.


Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on 17 beta-estradiol-induced glucose metabolism in MCF-7 human breast cancer cells: 13C nuclear magnetic resonance spectroscopy studies.
The effects of 17 beta-estradiol, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and their combination on the metabolism of [1-13C] glucose were determined in cell suspensions of wild-type MCF-7 human breast cancer cells, by 13C NMR spectroscopy. Preliminary studies showed that, during the 7-hr duration of the NMR experiment, the cells maintained their viability and their aryl hydrocarbon responsiveness. Lactate was the major glucose metabolite detected in these studies, and the rate of lactate formation in the untreated (control) and 17 beta-estradiol (10(-9) M)-treated cells was 60 and 86 fmol/cell/hr, respectively; this represented a 40% increase in lactate formation in the cells treated with 17 beta-estradiol; comparable results were observed for the percentage of glucose converted into lactate. In contrast, TCDD (10(-9) M) did not significantly alter the rate of glucose metabolism or lactate formation. Co-treatment of the cells with 17 beta-estradiol (10(-9) M) plus TCDD (10(-8) to 10(-10) M) showed that TCDD completely inhibited the 17 beta-estradiol-induced metabolism of [13C] glucose to lactate in MCF-7 cells. In contrast, 2,8-dichlorodibenzo-p-dioxin (10(-8) M), a weak aryl hydrocarbon receptor agonist, did not inhibit estrogen-induced glucose-to-lactate metabolism in MCF-7 cells. In addition, it was shown that TCDD caused a significant decrease in 17 beta-estradiol-induced lactate formation within 1 hr after treatment, whereas the induction of monooxygenase activity was not observed until 3 hr after exposure of the cells to TCDD. These data indicate that TCDD-induced 17 beta-estradiol metabolism is not related to the decrease in the rate of conversion of glucose to lactate. These results further define the antiestrogenic responses elicited by TCDD and show that 13C NMR spectroscopy provides a unique method for measuring, in real time, the effects of TCDD on specific metabolic pathways.


Sialyl Lewisx-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.
Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.


Triterpenoids from Gymnema sylvestre and their pharmacological activities.
Because plants are estimated to produce over 200,000 metabolites, research into new natural substances that can be used in the pharmaceutical, agrochemical and agro-industrial production of drugs, biopesticides and food additives has grown in recent years. The global market for plant-derived drugs over the last decade has been estimated to be approximately 30.69 billion USD. A relevant specific example of a plant that is very interesting for its numerous pharmacological properties, which include antidiabetic, anticarcinogenic, and neuroprotective effects is Gymnema sylvestre, used as a medicinal plant in Asia for thousands of years. Its properties are attributed to triterpenoidic saponins. In light of the considerable interest generated in the chemistry and pharmacological properties of G. sylvestre triterpenes and their analogues, we have undertaken this review in an effort to summarise the available literature on these promising bioactive natural products. The review will detail studies on the isolation, chemistry and bioactivity of the triterpenoids, which are presented in the tables. In particular the triterpenoids oxidised at C-23; their isolation, distribution in different parts of the plant, and their NMR spectral data; their names and physico-chemical characterisation; and the biological properties associated with these compounds, with a focus on their potential chemotherapeutic applications.


Transposed-word effects in speeded grammatical decisions to sequences of spoken words.
We used the grammatical decision task (a speeded version of the grammaticality judgment task) with auditorily presented sequences of five words that could either form a grammatically correct sentence or an ungrammatical sequence. The critical ungrammatical sequences were either formed by transposing two adjacent words in a correct sentence (transposed-word sequences: e.g., "The black was dog big") or were matched ungrammatical sequences that could not be resolved into a correct sentence by transposing any two words (control sequences: e.g., "The black was dog slowly"). These were intermixed with an equal number of correct sentences for the purpose of the grammatical decision task. Transposed-word sequences were harder to reject as being ungrammatical (longer response times and more errors) relative to the ungrammatical control sequences, hence attesting for the first time that transposed-word effects can be observed in the spoken language version of the grammatical decision task. Given the relatively unambiguous nature of the speech input in terms of word order, we interpret these transposed-word effects as reflecting the constraints imposed by syntax when processing a sequence of spoken words in order to make a speeded grammatical decision.


New advances in using Raman spectroscopy for the characterization of catalysts and catalytic reactions.
Gaining insight into the mode of operation of heterogeneous catalysts is of great scientific and economic interest. Raman spectroscopy has proven its potential as a powerful vibrational spectroscopic technique for a fundamental and molecular-level characterization of catalysts and catalytic reactions. Raman spectra provide important insight into reaction mechanisms by revealing specific information on the catalysts' (defect) structure in the bulk and at the surface, as well as the presence of adsorbates and reaction intermediates. Modern Raman instrumentation based on single-stage spectrometers allows high throughput and versatility in design of in situ/operando cells to study working catalysts. This review highlights major advances in the use of Raman spectroscopy for the characterization of heterogeneous catalysts made during the past decade, including the development of new methods and potential directions of research for applying Raman spectroscopy to working catalysts. The main focus will be on gas-solid catalytic reactions, but (photo)catalytic reactions in the liquid phase will be touched on if it appears appropriate. The discussion begins with the main instrumentation now available for applying vibrational Raman spectroscopy to catalysis research, including in situ/operando cells for studying gas-solid catalytic processes. The focus then moves to the different types of information available from Raman spectra in the bulk and on the surface of solid catalysts, including adsorbates and surface depositions, as well as the use of theoretical calculations to facilitate band assignments and to describe (resonance) Raman effects. This is followed by a presentation of major developments in enhancing the Raman signal of heterogeneous catalysts by use of UV resonance Raman spectroscopy, surface-enhanced Raman spectroscopy (SERS), and shell-isolated nanoparticle surface-enhanced Raman spectroscopy (SHINERS). The application of time-resolved Raman studies to structural and kinetic characterization is then discussed. Finally, recent developments in spatially resolved Raman analysis of catalysts and catalytic processes are presented, including the use of coherent anti-Stokes Raman spectroscopy (CARS) and tip-enhanced Raman spectroscopy (TERS). The review concludes with an outlook on potential future developments and applications of Raman spectroscopy in heterogeneous catalysis.


Renal manifestations in hypocomplementic urticarial vasculitis syndrome: Is it a distinct pathology?
Hypocomplementic urticarial vasculitis syndrome (HUVS) is an autoimmune disease characterized by recurrent urticaria, arthritis, and glomerulonephritis (GN). Anti-C1q antibody is the marker of HUVS together with low levels of classical pathway complements which are C2, C3, C4, and C1q. We report a case of a 6-year-old boy who presented with episodes of rashes, injected conjunctiva, abdominal pain, and arthritis, diagnosed as HUVS. He had low C3, low CH50, normal C4, and positive C1q antibody. His urinalysis showed intermittent microscopic hematuria only. One year later, his laboratories showed persistent low C3 and positive Anti-ds DNA. The urinalysis showed hematuria, pyuria, and nephrotic-range proteinuria. Urine protein to creatinine ratio was 101.8 h mg/mmol. Kidney biopsy showed mesangioproliferative GN consistent with the diagnosis of HUVS. The patient was treated initially with prednisolone then azathioprine was added to the regimen. He showed good response with the disappearance of hematuria and proteinuria. Nine months later, he had no skin rashes with normal urinalysis and normal anti-ds DNA antibody. We report a case with HUVS and GN with positive anti-dsDNA antibody that revealed good response to combination of immunosuppressive therapy.


Pregnancy diagnosis in swine: a comparison of the accuracies of mechanical and endocrine tests with return to estrus.
The relative accuracies of various commercially available detection procedures in the evaluation of pregnancy status were evaluated in 51 sows of mixed parity. Sows were mated 1 to 3 times during estrus to one or more boars. A blood sample was obtained from each sow between 19 and 23 days after estrus (first day of estrus = day 1) and again between 26 and 30 days and was analyzed by radioimmunoassay for content of progesterone and estrone sulfate, respectively. Sows were considered pregnant if progesterone concentrations were greater than 5 ng/ml and if estrone sulfate concentrations were greater than 0.5 ng/ml. At daily intervals, sows were exposed to mature, sexually aggressive boars and observed for signs of estrus. Between 31 and 35 days of gestation, sows were evaluated for pregnancy by use of the following mechanical devices: a Doppler ultrasound pregnancy detector fitted with an abdominal probe, the Doppler detector with a rectal probe, an amplitude-depth ultrasound pregnancy detector (diode ruler), and another amplitude-depth ultrasound detector from a different manufacturer (oscilloscope). Relative to the proportion of sows that farrowed, the overall accuracies of the techniques were returns to estrus, 98%; estrone sulfate, 92%; progesterone, 92%; Doppler with rectal probe, 86%; Doppler with abdominal probe, 86%; diode ruler amplitude-depth ultrasound, 73%; and oscilloscope amplitude-depth ultrasound, 86%. Estrus detection resulted in the lowest prevalence of sows that were predicted to farrow, but did not subsequently farrow (false-positive diagnoses) and the lowest prevalence of sows that were not predicted to farrow, but subsequently did farrow (false-negative diagnoses).(ABSTRACT TRUNCATED AT 250 WORDS)


The evolution of the cytoskeleton.
The cytoskeleton is a system of intracellular filaments crucial for cell shape, division, and function in all three domains of life. The simple cytoskeletons of prokaryotes show surprising plasticity in composition, with none of the core filament-forming proteins conserved in all lineages. In contrast, eukaryotic cytoskeletal function has been hugely elaborated by the addition of accessory proteins and extensive gene duplication and specialization. Much of this complexity evolved before the last common ancestor of eukaryotes. The distribution of cytoskeletal filaments puts constraints on the likely prokaryotic line that made this leap of eukaryogenesis.


Left Ventricular Myocardial Dysfunction Evaluation in Thalassemia Patients Using Echocardiographic Radiomic Features and Machine Learning Algorithms.
Heart failure caused by iron deposits in the myocardium is the primary cause of mortality in beta-thalassemia major patients. Cardiac magnetic resonance imaging (CMRI) T2* is the primary screening technique used to detect myocardial iron overload, but inherently bears some limitations. In this study, we aimed to differentiate beta-thalassemia major patients with myocardial iron overload from those without myocardial iron overload (detected by T2*CMRI) based on radiomic features extracted from echocardiography images and machine learning (ML) in patients with normal left ventricular ejection fraction (LVEF > 55%) in echocardiography. Out of 91 cases, 44 patients with thalassemia major with normal LVEF (> 55%) and T2* ≤ 20 ms and 47 people with LVEF > 55% and T2* > 20 ms as the control group were included in the study. Radiomic features were extracted for each end-systolic (ES) and end-diastolic (ED) image. Then, three feature selection (FS) methods and six different classifiers were used. The models were evaluated using various metrics, including the area under the ROC curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE). Maximum relevance-minimum redundancy-eXtreme gradient boosting (MRMR-XGB) (AUC = 0.73, ACC = 0.73, SPE = 0.73, SEN = 0.73), ANOVA-MLP (AUC = 0.69, ACC = 0.69, SPE = 0.56, SEN = 0.83), and recursive feature elimination-K-nearest neighbors (RFE-KNN) (AUC = 0.65, ACC = 0.65, SPE = 0.64, SEN = 0.65) were the best models in ED, ES, and ED&ES datasets. Using radiomic features extracted from echocardiographic images and ML, it is feasible to predict cardiac problems caused by iron overload.


CT Attenuation correction and its impact on image quality of myocardial perfusion imaging in coronary artery disease: A systematic review.
Myocardial perfusion imaging is a non-invasive procedure that plays an integral role in the diagnosis and management of coronary artery disease. With the routine use of computerised tomography attenuation correction (CTAC) in myocardial perfusion imaging still under debate, the aim of this review was to determine the impact of CTAC on image quality in myocardial perfusion imaging. Medline, Embase and CINAHL were searched from the earliest available time until August 2019. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies version 2. Details pertaining to image quality and diagnostic accuracy were analysed, and results summarised descriptively. Three studies with 'unclear' risk of bias and low applicability concerns (1002 participants) from a yield of 2725 articles were identified. Two studies demonstrated an increase in image quality, and one study found no difference in image quality when using CTAC compared to no attenuation correction. Benefits of CTAC for improving image quality remain unclear. Given the potential exposure risk with the addition of CTAC, patient and clinician factors should inform decision making for use of CTAC in myocardial perfusion imaging for coronary artery disease.


Life-long diet restriction failed to retard cognitive aging in Fischer-344 rats.
Although the beneficial effects of diet restriction on longevity and the retardation of many somatic age-related processes are well established, the answer to the question of whether anti-aging effects of diet restriction extend to the brain and cognitive function remains unclear. In the present study, the effects of long-term dietary restriction (60% of ad-libitum calories) on an age-related alteration of memory and sensorimotor function have been investigated in Fischer 344 male rats at four different ages: 6 months, 12 months, 18 months, and 24 months. A major drop in reference memory of DR and AL rats occurred at the age of 18 months. The performance deficits in working memory tasks were observed in both diet groups at the age of 24 months. These results indicate that diet restriction failed to provide protection against age-related deficits in memory. Although DR rats outperformed AL rats in sensorimotor tasks throughout the life-span, the slope of the declining function in DR rats paralleled those of AL rats, suggesting that diet restriction failed to alter the rate of aging in sensorimotor performance, as well.


How I treat patients with a history of heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is a relatively common prothrombotic adverse drug reaction of unusual pathogenesis that features platelet-activating immunoglobulin G antibodies. The HIT immune response is remarkably transient, with heparin-dependent antibodies no longer detectable 40 to 100 days (median) after an episode of HIT, depending on the assay performed. Moreover, the minimum interval from an immunizing heparin exposure to the development of HIT is 5 days irrespective of the patient's previous heparin exposure status or history of HIT. This means that short-term heparin reexposure can be safely performed if platelet-activating antibodies are no longer detectable at reexposure baseline and is recommended when heparin is the clear anticoagulant of choice, such as for cardiac or vascular surgery. The risk of recurrent HIT 1 to 2 weeks after heparin reexposure is ∼2% to 5% and is attributable to formation of delayed-onset (or autoimmune-like) HIT antibodies that activate platelets even in the absence of pharmacologic heparin. Some studies suggest that longer-term heparin reexposure (eg, for chronic hemodialysis) may also be reasonable. However, for other antithrombotic indications that involve patients with a history of HIT (eg, treatment of venous thromboembolism or acute coronary syndrome), preference should be given to non-heparin agents such as fondaparinux, danaparoid, argatroban, bivalirudin, or one of the new direct-acting oral anticoagulants as appropriate.


Childhood obesity and its health consequence in China.
Analyses of data from the representative 2002 National Nutrition and Health Survey were used to assess the likelihood of metabolic complications of overweight and obesity in Chinese children aged 7-17 years. Chinese criteria for body mass index classification were used for overweight and obesity with the 75th percentile US adolescent values for waist circumferences and all the metabolic criteria for blood pressure, lipids, fasting glucose established for US adolescents. Diabetes in 7-12-year-olds was 0.2% and 0.4% in children aged 12-18 years. Prevalences of dyslipidaemia (61.9%), hypertriglyceridaemia (18.2%) and low high-density lipoprotein cholesterol (56.1%) were high and 16.0% of 15-18 years had hypertension. The overall prevalence of the metabolic syndrome was 3.3% with more than half the children having at least one metabolic abnormality and 19.8% having at least two. All the metabolic parameters were significantly elevated in the overweight and obese children except high-density lipoprotein cholesterol. These data emphasize the marked sensitivity of Chinese children to the metabolic complications of overweight and obesity and amplify the need for early preventive measures.


Intracerebral hemorrhage associated with use of an imported medication.
The importation of medications is strongly discouraged in the United States. However, with the cost of prescription medications on the rise, an increasing number of patients are seeking alternative ways of obtaining drugs. Although medication errors involving imported drugs have been described in the literature, there is little available information on the prevalence of such problems. A 74-year-old woman who had been taking warfarin therapy for >2 years presented to the emergency department with new-onset headache. She was found to have a small subdural hematoma on computed tomography and a prothrombin time >120 seconds. Warfarin was stopped and anticoagulation was corrected with fresh frozen plasma. At follow-up testing, the international normalized ratio (INR) continued to be >2 despite vitamin K therapy and the patient's insistence that she had discontinued warfarin. Further evaluation by a hematologist detected warfarin in the blood. Subsequent inspection of her medications revealed unmarked white tablets labeled "phenytoin" that had been dispensed by a pharmacy in another country. The INR normalized after these tablets were discarded and a new prescription for phenytoin was started. Application of the Naranjo scale to this case suggested a high likelihood of an adverse drug reaction (ADR). Potential causes of the ADR included the placement of warfarin in a bottle mislabeled "phenytoin" and contamination of phenytoin with warfarin. Obtaining medications from pharmacies in or by mail order from other countries means that patients miss the opportunity to ask questions and receive counseling from a pharmacist. Physicians and pharmacists should inspect patients' medications to ensure product legitimacy and confirm that the indications, dispensing, and labeling are accurate.


A replication study examining novel common single nucleotide polymorphisms identified through a prostate cancer genome-wide association study in a Japanese population.
Five novel prostate cancer risk loci were identified in a recent genome-wide association study (GWAS) of Japanese persons (Takata et al., Nat Genet. 2010;42(9):751-754). Those authors proposed that apart from population-specific linkage disequilibrium patterns, limitations of GWAS single nucleotide polymorphism (SNP) prioritization and/or study design could explain the lack of identification of these loci in GWAS previously conducted among Caucasians. Thus, the authors undertook a replication study in 1,357 prostate cancer patients and 1,403 healthy Australian males of European descent (2004-2008). The rs12653946 SNP at 5p15 was found to be significantly associated with prostate cancer risk (odds ratio = 1.20, 95% confidence interval: 1.07, 1.34; P = 0.002). On the basis of linkage disequilibrium calculations, the rs12653946 SNP represents an independent locus, distinct from the previously identified TERT-CLPTM1L cancer nexus region. Further, analysis from AceView (Thierry-Mieg and Thierry-Mieg, Genome Biol. 2006;7(suppl 1):S12) indicated that rs12653946 falls within the intron of a testis-expressed gene strongly predicted to translate a conceptual 8.1-kilodalton protein named tojy.aApr07. The authors' findings suggest that follow-up of apparently ethnicity-specific risk associations are warranted in order to highlight risk-associated loci for experimental studies and for incorporation into future risk prediction models for prostate cancer.


The trajectory of chronic pain: can a community-based exercise/education program soften the ride?
The entire primary care record of six patients attending a community-based education/exercise self-management program for chronic noncancer pain (YMCA Pain Exercise/Education Program [Y-PEP]) was reviewed. Medical visits, consultations and hospital admissions were coded as related or unrelated to their pain diagnoses. Mood disruption, financial concerns, conflicts with employers/insurers, analgesic doses, medication side effects and major life events were also recorded. The 'chronic pain trajectory' resembled a roller coaster with increased health care visits at the time of initial injuries and during 'crises' (reinjury, conflict with insurers/employers, failed back-to-work attempts and life events). Visits decreased when conflicts were resolved. Analgesic doses increased during 'crises' but did not fall after resolution. After attending Y-PEP, health care use fell for four of six patients and two returned to work. Primary care physicians need to recognize the functional limitations and psychosocial complications experienced by their chronic pain patients. A program such as Y-PEP may promote active self-management strategies resulting in lowered health care use.


Polyvinyl alcohol-Fricke hydrogel and cryogel: two new gel dosimetry systems with low Fe3+ diffusion.
Two new Fricke dosimeter gel systems with low diffusion rates have been developed for 3D radiation dosimetry purposes. Both systems consist of a solution of 20% (by weight) polyvinyl alcohol (PVA) in a 50 mM H2SO4 solution with 0.4 mM ferrous ammonium sulphate and xylenol orange (FX). The difference in the two gels is the way that the gelation process was initiated: either by bringing the temperature to (a) +5 degrees C or (b) -20 degrees C before returning them to room temperature. These gels are termed 'hydrogel' and 'cryogel', respectively. The hydrogel is optically transparent, and can be used with either optical or MRI detection methods for dosimetric imaging. The cryogel is rubbery in texture but opaque, so its internal Fe3+ concentration can only be measured with MRI. The hydrogel's optical attenuation coefficient is linear (r2 = 0.99) with dose from 0 to 20 Gy with a sensitivity of 0.106 cm(-1) Gy(-1) (at 543 nm). In terms of MR relaxation rate, the dose response for both the hydrogel and cryogel was linear (r2 = 0.99) with a sensitivity of 0.020 s(-1) Gy(-1) (at 1.5 T). The Fe3+ diffusion coefficient (at 20 degrees C) was measured to be 0.14 mm2 h(-1), which is significantly lower than similar preparations reported for porcine gelatin or agarose. The PVA-FX gels can be stored for long periods of time before exposure to radiation, since the auto-oxidation rate was 10 times less than that of gelatin-Fricke recipes. The new gels developed in this work are a significant improvement on previous Fricke gel systems.


Enzyme concentrations in tissues.
Apparent enzyme concentrations in cells and in mitochondria are calculated from data available in the literature. These values are 10(-6) to 10(-5) moles per kilogram of tissue. It is pointed out that these concentrations are much higher than those used in enzymatic studies in vitro. Metabolic interpretations of experiments in vitro should consider this additional departure from conditions in vivo.


Changes of Cerebrospinal Fluid Peptides due to Tauopathy.
Alzheimer's disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model for tauopathy expressing human truncated tau protein (aa 151-391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography - matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation.


Prostate disease risk factors among a New Zealand cohort.
Prostate cancer is a leading public health burden worldwide, and in New Zealand it is the most commonly registered cancer and the third leading cause of cancer deaths among males. Genetic variability and its associations with diet, demographic and lifestyle factors could influence the risk of this disease. The single nucleotide polymorphisms (SNPs) within a group of antioxidant genes and related markers were tested between patient and control cohorts, adjusted for significant differences between basic lifestyle and demographic characteristics. Increasing age, smoking and low serum selenium levels were significantly associated with an increased risk for prostate disease. Alcohol consumption increased the glutathione peroxidase (GPx) activity. A significant reduction in alcohol consumption was recorded with prostate disease. Three SNPs, namely GPx1 rs1050450, SEL15 rs5845 and CAT rs1001179, were significantly associated with prostate disease risk. A cumulative risk of prostate cancer was noted with 6 risk alleles. A lower GPx activity was recorded with prostate disease compared to the controls. However, the GPx1 rs1050450 allele T in association with prostate cancer recorded a significantly higher GPx activity compared to the controls. These data point to a possibility of identifying individuals at risk of prostate cancer for better management purposes.


Psychodynamic features in borderline personality disorder identified by a subliminal test, the Defense Mechanism Test.
Twenty-seven psychiatric inpatients, diagnosed according to DSM-III and the Diagnostic Interview for Borderline (DIB), and 7 healthy controls were tested with the Defense Mechanism Test (DMT), a test of subliminal perception based on psychoanalytic theory. In the test a specific stimulus is presented subliminally in a tachistoscope and the patient's perceptual distortions are registered. Patients with borderline personality disorder (BPD) were compared with patients with other personality disorders, patients with schizophrenic disorders and healthy controls. Specific perceptual distortions were identified among patients with BPD. Some individual DMT signs correlated with some deviant behaviors as identified by the DIB. The findings supported the psychodynamic validity of the concept of borderline personality disorder. It is concluded that DMT is a promising research instrument that provides an empirical approach to crucial psychodynamic phenomena.


Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes.
Shwachman-Diamond syndrome is a congenital bone marrow failure disorder characterized by debilitating neutropenia. The disease is associated with loss-of-function mutations in the SBDS gene, implicated in ribosome biogenesis, but the cellular and molecular events driving cell specific phenotypes in ribosomopathies remain poorly defined. Here, we established what is to our knowledge the first mammalian model of neutropenia in Shwachman-Diamond syndrome through targeted downregulation of Sbds in hematopoietic stem and progenitor cells expressing the myeloid transcription factor CCAAT/enhancer binding protein α (Cebpa). Sbds deficiency in the myeloid lineage specifically affected myelocytes and their downstream progeny while, unexpectedly, it was well tolerated by rapidly cycling hematopoietic progenitor cells. Molecular insights provided by massive parallel sequencing supported cellular observations of impaired cell cycle exit and formation of secondary granules associated with the defect of myeloid lineage progression in myelocytes. Mechanistically, Sbds deficiency activated the p53 tumor suppressor pathway and induced apoptosis in these cells. Collectively, the data reveal a previously unanticipated, selective dependency of myelocytes and downstream progeny, but not rapidly cycling progenitors, on this ubiquitous ribosome biogenesis protein, thus providing a cellular basis for the understanding of myeloid lineage biased defects in Shwachman-Diamond syndrome.


Interventions to increase adherence to micronutrient supplementation during pregnancy: a systematic review.
Prenatal micronutrient supplements are cost-effective in reducing nutritional deficiencies and adverse pregnancy and birth outcomes. However, poor adherence remains a potential barrier to the successful implementation of these supplementation programs. This systematic review assessed the effectiveness of interventions designed to increase adherence to prenatal micronutrient supplementation. Following the Cochrane Collaboration Methodology, literature searches were conducted in six electronic databases and gray literature (on July 24, 2020), and abstract screening, data extraction, and risk of bias assessment were conducted independently by two reviewers. We included 22 studies. Interventions that resulted in increased adherence were most of the education-based strategies, consumption monitoring by volunteer health workers or family members, SMS reminders, free provision of supplements, a multicomponent intervention with community mobilization, and a participatory action research intervention. In several studies, increased adherence was accompanied by beneficial effects on pregnancy and birth outcomes. Given the heterogeneity of study designs and methods used to define and measure adherence, a meta-analysis was not appropriate. We identified several potentially effective strategies to improve supplementation adherence, which may need to be adapted to specific contexts when considered for program implementation. However, additional high-quality studies are critically needed to effectively guide policies and programs.


Hypophosphataemia and paraesthesias during parenteral nutrition.
Parenteral nutrition was instituted in a malnourished woman with a low serum phosphorus. In spite of a moderate phosphorus intake, the serum phosphorus descended to very low levels before returning to a normal range. Over a three week period she was troubled by paraesthesias, numbness, and a generalised weakness. The cause was thought to be hypophosphataemia.


Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin.
Megaloblastic anemia 1 (MGA1) is an autosomal recessive disorder caused by the selective intestinal malabsorption of intrinsic factor (IF) and vitamin B(12)/cobalamin (Cbl) in complex. Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B(12) receptor, cubilin. By site-directed mutagenesis, mammalian expression, and functional comparison of the purified wild-type and FM1 mutant forms of the IF-Cbl-binding cubilin region (CUB domains 5-8, amino acid 928-1386), we have investigated the functional implications of the P1297L mutation. Surface plasmon resonance analysis revealed that the P1297L substitution specifically increases the K(d) for IF-Cbl binding several-fold, largely by decreasing the association rate constant. In agreement with the binding data, the wild-type protein, but not the FM1 mutant protein, potently inhibits 37 degrees C uptake of iodine 125-IF-Cbl in cubilin-expressing epithelial cells. In conclusion, the data presented show a substantial loss in affinity of the FM1 mutant form of the IF-Cbl binding region of cubilin. This now explains the malabsorption of Cbl and Cbl-dependent anemia in MGA1 patients with the FM1 mutation. (Blood. 2000;96:405-409)


Assessment of visceral organ growth in pigs from birth through 150 kg.
Visceral organs (VO) are essential for their role in the metabolism and distribution of consumed nutrients as well as other life functions in animals. Two experiments were conducted to assess the natural longitudinal changes that the VO undergo from birth through 150 kg body weight (BW). In Experiment 1, a total of 96 crossbred pigs were euthanized at birth (pre-suckle), d 1, 2, 3, 5, 7, 14, 21 (weaning), 22, 23, 24, 26, 28, 42, 49, and 63 of age. In Experiment 2, a total of 48 crossbred pigs were euthanized at 30, 50, 75, 100, 125, and 150 kg of BW. The absolute weight of VO, and the volume and length of the gastrointestinal tract (GIT) were measured. In both experiments, the absolute weight of VO, GIT length, and their volume increased (linear, quadratic, and/or cubic, P < 0.05) as BW and age increased. In Experiment 1, the relative weight of VO (liver, kidney, heart, and lung) decreased after initially increasing within the first week of life (linear, quadratic, and/or cubic, P < 0.05), whereas the relative weight of all VO decreased as BW increased in Experiment 2 (linear and/or quadratic, P < 0.05). The relative length of small intestine decreased and that of large intestine increased as age increased in Experiment 1 (linear and quadratic, P < 0.05), whereas the relative length of the small and large intestine in Experiment 2 were relatively constant at 80% and 20% of the total length of the intestine, respectively. As age and BW increased, the relative volume of the large intestine to the total volume of the GIT increased (linear and/or quadratic, P < 0.05), while the relative volume of the small intestine decreased (linear and/or quadratic, P < 0.05). In conclusion, results showed that both absolute and relative measurements (weight, volume, and length) of VO were dependent on the BW (age) of the pig.


Phenotypic plasticity: A missing element in the theory of vegetation pattern formation.
Regular spatial patterns of vegetation are a common sight in drylands. Their formation is a population-level response to water stress that increases water availability for the few via partial plant mortality. At the individual level, plants can also adapt to water stress by changing their phenotype. Phenotypic plasticity of individual plants and spatial patterning of plant populations have extensively been studied independently, but the likely interplay between the two robust mechanisms has remained unexplored. In this paper, we incorporate phenotypic plasticity into a multi-level theory of vegetation pattern formation and use a fascinating ecological phenomenon, the Namibian "fairy circles," to demonstrate the need for such a theory. We show that phenotypic changes in the root structure of plants, coupled with pattern-forming feedback within soil layers, can resolve two puzzles that the current theory fails to explain: observations of multi-scale patterns and the absence of theoretically predicted large-scale stripe and spot patterns along the rainfall gradient. Importantly, we find that multi-level responses to stress unveil a wide variety of more effective stress-relaxation pathways, compared to single-level responses, implying a previously underestimated resilience of dryland ecosystems.


Community hospitals for the new millennium.
There is a lack of basic information regarding the numbers of and facilities offered by community hospitals. This survey identified 471 community hospitals in the United Kingdom containing 18,579 beds with 20% of general practitioners having admitting rights. The majority of hospitals provide a comprehensive range of rehabilitation services and consultant outpatient clinics. Community hospitals are potentially an important resource in providing intermediate care in the community.


Progressive cytomegalovirus glomerulonephritis - An experimental model.
Although acute infection with murine cytomegalovirus (MCMV) resulted in a transient focal glomerulonephritis characterized by mesangial inclusions, infection of HA/ICR mice given antilymphocyte globulin (ALG) led to progressive glomerulonephritis and renal failure. ALG alone without virus failed to produce progressive renal disease. Mice given both MCMV and ALG developed severe proteinuria and azotemia with glomerular crescents by 30 days. By immunofluorescence, viral antigen was limited to mesangial zones and glomerular axial poles. Granular deposits of rabbit IgG from ALG, mouse IgG, and C3 along the peripheral glomerular capillary walls were first observed 12 days after infection. By electron microscopy, virus was found only in glomerular mesangial cells that resembled macrophages. Intramembranous and subepithelial deposits in peripheral capillary walls were associated with accumulations of polymorphonuclear leukocytes dissecting into glomerular basement membranes. These observations best fit a multiphasic mechanism of glomerular injury initiated by persistent virus in the mesangium, followed by deposits of rabbit IgG from ALG, mouse IgG, and C in the peripheral capillary walls, resulting in an amplified immune-complex-mediated injury. Because other viruses localize within the glomerular mesangium, viruses should be considered potential causes of mesangial injury and progressive glomerulonephritis.


Comparison of sealing ability of ProRoot mineral trioxide aggregate, biodentine, and ortho mineral trioxide aggregate for canal obturation by the fluid infiltration technique.
Adequate seal of the root canal is necessary to prevent recontamination and ensure the long-term clinical success. The aim of this study was to evaluate the sealing ability of ProRoot mineral trioxide aggregate (MTA), Biodentine, and Ortho MTA as the root canal obturation materials using the fluid infiltration method. In this invitro study a total of 66 extracted human mandibular premolars were randomly divided into five groups according to the material used for the root canal obturation. Group I - ProRoot MTA (20 samples), Group II - Biodentine (20 samples), Group III - Ortho MTA (20 samples), Group IV - negative group (3 samples), and Group V-positive group (3 samples). MTA, Biodentine, and Ortho MTA were applied using a cotton-tipped K-file #30 and hand plugger into the root canals of each group. In Group 4 (negative control), no filling material was used. In Group 5 (positive control), a single gutta-percha size #40 was inserted into the root canal without using a sealer. The teeth were mounted and exposed to the fluid infiltrarion system. Statistical analysis was performed using Kruskal-Wallis test the level of significance was set at α = 0.05. Mean values of microleakage in MTA ProRoot, Biodentine and Ortho MTA groups were 1.83 ± 0.62, 1.95 ± 1.27 and 1.72 ± 0.83 μL in 8 minutes. No statistically significant difference was observed between the sealing ability of ProRoot MTA, Biodentine, and Ortho MTA (P = 0.091). Within the limitations of this study, microleakage values were similar to MTA ProRoot, Biodentine, and Ortho MTA using the fluid infiltration technique.


Population diversity: its extent and extinction.
Genetically distinct populations are an important component of biodiversity. This work estimates the number of populations per area of a sample of species from literature on population differentiation and the average range area of a species from a sample of distribution maps. This yields an estimate of about 220 populations per species, or 1.1 to 6.6 billion populations globally. Assuming that population extinction is a linear function of habitat loss, approximately 1800 populations per hour (16 million annually) are being destroyed in tropical forests alone.


Coexistent central and peripheral nervous system involvement in a Charcot-Marie-Tooth syndrome X-linked patient.
A 14-year-old boy with an episode of acute weakness resembling acute demyelinating encephalomyelitis and polyradiculoneuritis after a febrile illness is described. Molecular analysis showed a mutation at codon 164 of the connexin 32 gene. Neuroradiological and neurophysiological follow-up is reported during acute and chronic phases of disease, suggesting that during metabolic stress connexin 32 mutations lead to a loss of normal cellular communication and reversible cell dysfunction in oligodendrocytes and in Schwann cells. These data confirm that altered gating properties of connexin 32 could give rise to acute, transient central and peripheral nervous system symptoms in situations of metabolic stress.


Models and regressions to describe primary damage in silicon carbide.
Silicon carbide (SiC) and SiC/SiC composites are important candidate materials for use in the nuclear industry. Coarse grain models are the only tools capable of modelling defect accumulation under different irradiation conditions at a realistic time and length scale. The core of any such model is the so-called "source term", which is described by the primary damage. In the present work, classical molecular dynamics (MD), binary collision approximation (BCA) and NRT model are applied to describe collision cascades in 3C-SiC with primary knock-on atom (PKA) energy in the range 1-100 keV. As such, BCA and NRT are benchmarked against MD. Particular care was taken to account for electronic stopping and the use of a threshold displacement energy consistent with density functional theory and experiment. Models and regressions are developed to characterize the primary damage in terms of number of stable Frenkel pairs and their cluster size distribution, anti-sites, and defect type. As such, an accurate cascade database is developed with simple descriptors. One of the main results shows that the defect cluster size distribution follows the geometric distribution rather than a power law.


Understanding oncology nurses' difficulties caring for suicidal people.
Clinical challenges occur when patients consider suicide. Despite improved treatment, people with cancer have an increased risk of suicide. While previous research examined patients' perspectives, this study describes the nurse's perspective of difficulty of caring for suicidal patients. Suicidal ideas constitute common psychiatric complications of cancer, however we know little of the nurse's difficulties in care giving. As part of a larger study of oncology nurses' knowledge, we randomly surveyed 1,200 clinical oncology nurses and 434 returned completed questionnaires (37%). This paper describes content analysis of oncology nurses' narratives about their difficulties responding to suicidal patients. Six categories emerged: religious/other values, uncomfortable feelings, inadequate knowledge, personal experiences, and weight of professional responsibility which made it difficult for most nurses to care for suicidal patients. Some nurses reported they had no difficulties. Care giving is also difficult because the patient's right to choose suicide may conflict with the nurse's professional obligation to prevent suicide.


Postural sensorimotor training versus sham exercise in physiotherapy of patients with chronic non-specific low back pain: An exploratory randomised controlled trial.
Sensorimotor training (SMT) is popularly applied as exercise in rehabilitation settings, particularly for musculoskeletal pain. With insufficient evidence on its effect on pain and function, this exploratory randomised controlled trial investigated the potential effects of SMT in rehabilitation of chronic non-specific low back pain. Two arms received 9x30 minutes physiotherapy with added interventions: The experimental arm received 15 minutes of postural SMT while the comparator arm performed 15 minutes of added sub-effective low-intensity training. A treatment blinded tester assessed outcomes at baseline 2-4 days prior to intervention, pre- and post-intervention, and at 4-week follow-up. Main outcomes were pain and functional status assessed with a 0-100mm visual analogue scale and the Oswestry Disability Questionnaire. Additionally, postural control was analysed using a video-based tracking system and a pressure plate during perturbed stance. Robust, nonparametric multivariate hypothesis testing was performed. 22 patients (11 females, aged 32 to 75 years) with mild to moderate chronic pain and functional limitations were included for analysis (11 per arm). At post-intervention, average values of primary outcomes improved slightly, but not to a clinically relevant or statistically significant extent. At 4-week follow-up, there was a significant improvement by 12 percentage points (pp) on the functional status questionnaire in the SMT-group (95% confidence intervall (CI) = 5.3pp to 17.7pp, p < 0.001) but not in the control group (4 pp improvement, CI = 11.8pp to 19.2pp). However, group-by-time interaction effects for functional status (Q = 3.3, 19 p = 0.07) and pain (Q = 0.84, p = 0.51) were non-significant. Secondary kinematic outcomes did not change over time in either of the groups. Despite significant improvement of functional status after SMT, overall findings of this exploratory study suggest that SMT provides no added benefit for pain reduction or functional improvement in patients with moderate chronic non-specific low back pain. ClinicalTrials.gov NCT02304120 and related study protocol, DOI: 10.1186/1471-2474-15-382.


The search for loci under selection: trends, biases and progress.
Detecting genetic variants under selection using FST outlier analysis (OA) and environmental association analyses (EAAs) are popular approaches that provide insight into the genetic basis of local adaptation. Despite the frequent use of OA and EAA approaches and their increasing attractiveness for detecting signatures of selection, their application to field-based empirical data have not been synthesized. Here, we review 66 empirical studies that use Single Nucleotide Polymorphisms (SNPs) in OA and EAA. We report trends and biases across biological systems, sequencing methods, approaches, parameters, environmental variables and their influence on detecting signatures of selection. We found striking variability in both the use and reporting of environmental data and statistical parameters. For example, linkage disequilibrium among SNPs and numbers of unique SNP associations identified with EAA were rarely reported. The proportion of putatively adaptive SNPs detected varied widely among studies, and decreased with the number of SNPs analysed. We found that genomic sampling effort had a greater impact than biological sampling effort on the proportion of identified SNPs under selection. OA identified a higher proportion of outliers when more individuals were sampled, but this was not the case for EAA. To facilitate repeatability, interpretation and synthesis of studies detecting selection, we recommend that future studies consistently report geographical coordinates, environmental data, model parameters, linkage disequilibrium, and measures of genetic structure. Identifying standards for how OA and EAA studies are designed and reported will aid future transparency and comparability of SNP-based selection studies and help to progress landscape and evolutionary genomics.


The evaluation of the client with acute bacterial rhinosinusitis.
The diagnosis of acute bacterial rhinosinusitis (ABR) remains elusive. Most patients with symptoms of ABR are seen in primary care offices. This article focuses on the presentation of the patient with symptoms of ABR, accurate diagnosis, and pharmacologic treatment. The article also discusses the appropriate referrals for patients who do not respond to conventional treatment.


Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.
Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.


Injuries caused by rubber bullets: a report on 90 patients.
The injuries in 90 patients caused by rubber bullets are described. There was 1 death and 17 people in the series had permanent disabilities or deformities. In 41 patients the injuries necessitated admission to hospital. One fatality outside this series is known. Injuries to the head and neck were frequent and severe.


Within-person, between-person and seasonal variance in nutrient intakes among 4- to 8-year-old rural Zambian children.
Estimates of the components of nutrient intake variation are needed for modelling distributions of usual intake or predicting the usual intake of individuals. Season is a potential source of variation in nutrient intakes in addition to within- and between-person variation, particularly in low- or middle-income countries. We aimed to describe seasonal variation in nutrient intakes and estimate within-person, between-person and other major components of intake variance among Zambian children. Children from rural villages and peri-urban towns in Mkushi District, Zambia aged 4-8 years were enrolled in the non-intervened arm of a randomised controlled trial of pro-vitamin A carotenoid biofortified maize (n 200). Up to seven 24-h dietary recalls per child were obtained at monthly intervals over a 6-month period covering the late post-harvest (August-October), early lean (November-January) and late lean (February-April) seasons (2012-2013). Nutrient intakes varied significantly by season. For energy and most nutrients, intakes were highest in the early lean season and lower in the late post-harvest and late lean seasons. Season and recall on a market day had the strongest effects on nutrient intakes among covariates examined. Unadjusted within- to between-person variance ratios ranged from 4·5 to 31·3. In components of variance models, season accounted for 3-20 % of nutrient intake variance. Particularly in rural settings in low- and middle-income countries, where availability of locally grown, nutrient-rich foods may vary seasonally, studies should include replicates across seasons to more precisely estimate long-term usual intakes.


Electronic reporting improves timeliness and completeness of infectious disease notification, The Netherlands, 2003.
In 2002, the internet based reporting system OSIRIS was introduced in the Netherlands and by the end of that year had fully replaced the paper-based reporting system. The objectives of OSIRIS were to improve timeliness and completeness of surveillance data on infectious diseases reported from regional to national level. We compared the timeliness of infectious diseases reported by the conventional paper-based system in 2001 with those reported by OSIRIS in 2003. Two distinct types of delay were compared: (1) total delay: defined as time between symptom onset and reporting at national level and (2) central delay: defined as time between regional and national reporting. Median delays between both systems were compared using the Wilcoxon Rank Sum-Test. We also compared electronic reports received via OSIRIS in 2003 to those received through the conventional system for 2001 for completeness of specific data fields. The Fisher exact test and the Mantel-Haenzel test with Yates correction were used to determine the significance of proportions of completed data fields in each system. Results showed the median central delay was significantly reduced for all diseases in OSIRIS compared to conventional reporting system. Overall, the median central delay was reduced from 10 days (interquartile range 4) in 2001 to 1 day (interquartile range 1) in 2003. Except for cases of malaria, the total delay, from symptom onset to national reporting, was also significantly reduced. In addition, OSIRIS records contained more complete information than conventional records. In total, in 2003, 92.3% of data field examined were complete compared with 81.3% in 2001. This study documents the benefits of electronic reporting of infectious disease surveillance data in terms of improved timeliness and completeness.


Achieving micron-scale plasticity and theoretical strength in Silicon.
As the backbone material of the information age, silicon is extensively used as a functional semiconductor and structural material in microelectronics and microsystems. At ambient temperature, the brittleness of Si limits its mechanical application in devices. Here, we demonstrate that Si processed by modern lithography procedures exhibits an ultrahigh elastic strain limit, near ideal strength (shear strength ~4 GPa) and plastic deformation at the micron-scale, one order of magnitude larger than samples made using focused ion beams, due to superior surface quality. This extended elastic regime enables enhanced functional properties by allowing higher elastic strains to modify the band structure. Further, the micron-scale plasticity of Si allows the investigation of the intrinsic size effects and dislocation behavior in diamond-structured materials. This reveals a transition in deformation mechanisms from full to partial dislocations upon increasing specimen size at ambient temperature. This study demonstrates a surface engineering pathway for fabrication of more robust Si-based structures.


Harmonics-to-noise ratio estimation with deterministically time-varying harmonic model for pathological voice signals.
The harmonics-to-noise ratio (HNR) and other spectral noise parameters are important in clinical objective voice assessment as they could indicate the presence of nonharmonic phenomena, which are tied to the perception of hoarseness or breathiness. Existing HNR estimators are built on the voice signals to be nearly periodic (fixed over a short period), although voice pathology could induce involuntary slow modulation to void this assumption. This paper proposes the use of a deterministically time-varying harmonic model to improve the HNR measurements. To estimate the time-varying model, a two-stage iterative least squares algorithm is proposed to reduce model overfitting. The efficacy of the proposed HNR estimator is demonstrated with synthetic signals, simulated tremor signals, and recorded acoustic signals. Results indicate that the proposed algorithm can produce consistent HNR measures as the extent and rate of tremor are varied.


Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics.
To determine the prevalence and characterize demographic, clinical, and genetic features of familial Mediterranean fever (FMF) of late onset, all patients experiencing their first FMF attack at age 40 years or more were identified using the computerized registry of our FMF clinic, and then thoroughly interviewed and examined. The control group consisted of 40 consecutive FMF patients, who arrived at the FMF clinic for their regular follow-up visit and were 40 years of age or older at the time of the examination. The severity of the disease in patients and controls was determined using a modified score, developed previously. Mutational analysis in the FMF gene was performed using a commercial kit. Only 20 of 4000 (0.5%) patients had late-onset FMF. These patients were mostly men, of non-North African origin, P < 0.05 compared to controls. All had abdominal attacks and in most these were the only manifestation of their disease, P < 0.001. None had chronic or prolonged manifestations of FMF, for example, amyloidosis, chronic arthritis, or protracted myalgia, P < 0.001. The response to treatment was good despite using low colchicine dose, P < 0.05. The overall severity score indicated a mild disease, P < 0.001. Mutational analysis revealed absence of M694V homozygosity, P < 0.01, compared to our regular FMF population. We conclude that the onset of FMF in a late age defines a milder form of disease with typical clinical, demographic, and molecular genetic characteristics.


[Development of biological psychiatric depression research (author's transl)].
The discovery of the anti-depressive effects of imipramine and the MAO inhibitors, associated with the occasional depressions occurring during reserpine treatment was the starting point of modern research into depression. The concern with the neurochemical actions of these substances led to putting forth the noradrenaline and serotonin hypothesis of depression in the mid-60s. According to this, there is supposed to be a deficiency of noradrenaline and/or serotonin at the nerve endings in depression. This amine deficiency hypothesis has not been proved as yet in spite of intensive neurobiological research. Clinical as well as animal experiments in depressive patients with antidepressive drugs have led to the assumption that, in "endogenous" depression particularly, but also for the antidepressive mechanisms, alpha- and beta-adrenergic receptor changes play an important part.


Overtreatment of asymptomatic bacteriuria: identifying targets for improvement.
Treatment of asymptomatic bacteriuria contributes to antimicrobial overuse in hospitalized patients. Indications for urine culture, treatment, and targets for improvement were evaluated in 153 patients. Drivers of antimicrobial overuse included fever with an alternative source, altered mental status, and leukocytosis, which led 435 excess days of antimicrobial therapy.


Characterization and overexpression of a glycosyl hydrolase family 16 β-agarase Aga0917 from Pseudoalteromonas fuliginea YTW1-15-1.
A gene (aga0917) encoding a putative β-agarase was identified from the genome of Pseudoalteromonas fuliginea YTW1-15-1. The nucleotide sequence analysis revealed that aga0917 had significant homology to the agarase genes of the GH16 family. aga0917 encodes a putative protein of 290 amino acids with an estimated molecular mass of 32.5 kDa, including a 21-amino acid signal peptide. A gene fragment encoding only the putative mature form of Aga0917 (269 amino acids) was overexpressed in Escherichia coli BL21 (DE3) pLysS as a 6 × histine-tagged fusion protein (rmAga0917). The Km, Vmax, and kcat for agarose of rmAga0917 were 39.6 mg/mL, 334 (U/mg) of protein, and 178 (1/s), respectively. According to the results of thin-layer chromatography and mass spectrometry analysis, the main end product from agarose with rmAga0917 was neoagarotetraose, in addition to a small amount of neoagarobiose. Notably, the recombinant protein rmAga0917 showed optimum activity at 60°C and retained approximately 100% agarolytic activity after being kept at 40°C for 1 h and 57% residual activity after incubation at 50°C for 1 h. The rmAga0917 exhibited maximum agarase activity at pH 6.0, and retained more than 80% of activity after incubation over a range of pH 4.0-9.0 for 1 h at 4°C.


Ethnicity-Dependent Effects of Schizophrenia Risk Variants of the OLIG2 Gene on OLIG2 Transcription and White Matter Integrity.
Previous studies have indicated associations between several OLIG2 gene single-nucleotide polymorphisms (SNPs) and susceptibility to schizophrenia among Caucasians. Consistent with these findings, postmortem brain and diffusion tensor imaging studies have indicated that the schizophrenia-risk-associated allele (A) in the OLIG2 SNP rs1059004 predicts lower OLIG2 gene expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients and reduced white matter (WM) integrity of the corona radiata in normal brains among Caucasians. In an effort to replicate the association between this variant and WM integrity among healthy Japanese, we found that the number of A alleles was positively correlated with WM integrity in some fiber tracts, including the right posterior limb of the internal capsule, and with mean blood flow in a widespread area, including the inferior frontal operculum, orbital area, and triangular gyrus. Because the A allele affected WM integrity in opposite directions in Japanese and Caucasians, we investigated a possible association between the OLIG2 gene SNPs and the expression level of OLIG2 transcripts in postmortem DLPFCs. We evaluated rs1059004 and additional SNPs in the 5' upstream and 3' downstream regions of rs1059004 to cover the broader region of the OLIG2 gene. The 2 SNPs (rs1059004 and rs9653711) had opposite effects on OLIG2 gene expression in the DLPFC in Japanese and Caucasians. These findings suggest ethnicity-dependent opposite effects of OLIG2 gene SNPs on WM integrity and OLIG2 gene expression in the brain, which may partially explain the failures in replicating associations between genetic variants and psychiatric phenotypes among ethnicities.


Relationship of depression, disability, and quality of life in Parkinson's disease: a hospital-based case-control study.
Depression, anxiety, cognitive impairment, sleep disturbances are common neuropsychiatric manifestations in Parkinson's disease (PD). To compare the prevalence and severity of depression in PD with a group of patients with other chronic medical illnesses and ascertain the relationship of depression with disability and quality of life in PD. Hospital-based prospective case-control study. Forty-six PD patients and 30 non-PD controls having chronic medical conditions were studied. All were assessed by Beck Depression Inventory (BDI) and Montgomery Asberg Depression Rating Scale (MADRS), World Health Organization Disability Assessment Schedule (WHODAS II) and World Health Organization Quality of Life Scale-Brief Version (WHOQOL-Bref). Statistical Analysis Used : SPSS Version 13.0 was used for analysis which included descriptive tests, independent t test, chi-square test, Fisher's exact test, and Pearson's correlation coefficient. Results : The prevalence of depression was higher and more severe in PD than controls (MADRS: 54.3% vs 23.3%, P<0.01; BDI 49.9% vs 23.4%, P<0.05). PD patients had significantly greater overall disability than controls (36.8±19.4 vs 15.1±15.4; P<0.001), and the difference was observed in all six domains of WHODAS II. PD patients had inferior quality of life than controls in all four spheres of WHOQOL-Bref. In PD, depression correlated positively with various domains of disability (P<0.001) and negatively with quality of life (P<0.001). In summary, the prevalence and severity of depression is significantly higher in PD than can be explained by chronic illness. Depression plays an important role in determining the disability and quality of life.


ESRD management in Africa during the last decade.
This study was initiated under the auspices of the African Association of Nephrology to evaluate end-stage renal disease (ESRD) development by using data collected in 3 successive surveys performed during the last decade. Questionnaires were sent in 2004, 2006, and 2012 to national renal societies and to leading nephrologists. Data were also collected from dialysis supply companies, personal communication, and by using research on Medline, Pubmed, etc. So data could be obtained from 33 countries. During the last decade the total number of nephrologists increased from 1,022 to 2,500 in 33 countries - i.e., an average growth rate of 15% per year. But there are still few hospital units dedicated to renal healthcare. The number of dialysis units increased from 1,200 to 1,600 and the number of dialysis patients (97% on hemodialysis) grew from 36,000 to 87,400 i.e., an average growth rate of 14% per year. Peritoneal dialysis, which covers less than 3% of RRT, increased from 1,300 to 2,400 with a yearly growth rate of 8% but it is still located in few countries. Renal transplant is implemented mainly in public hospitals in 5 North African and 7 sub. Saharan and South African countries. Only 5 countries have sustained programs that perform more than 100 operations per year. During the last decade, several countries improved the quality and quantity of care offered to ESRD patients. It is hoped that there will be a sustained improvement with a greater emphasis on education and development of kidney transplantation.


Establishment of a novel cell line from a rare human duodenal poorly differentiated neuroendocrine carcinoma.
Poorly differentiated neuroendocrine carcinoma of the duodenum (D-NEC) is a rare cancer with poor prognosis. However, a D-NEC cell line has not yet been established to study the disease. We established a cell line, TCC-NECT-2, from the ascites tumor of a 59-year-old male Japanese patient with D-NEC. TCC-NECT-2 was positive for neuroendocrine markers, chromogranin A (CGA), cluster of differentiation 56 (CD56/NCAM), synaptophysin (SYN/p38), and neuron specific enolase (NSE). Cells exhibited retinoblastoma (RB) protein loss. Orthotopic implantation of TCC-NECT-2 cells into nu/nu mice resulted in tumor formation (incidence = 83.3%) with neuroendocrine characteristics, metastasis, and weight loss. BRAFV600E and TP53 mutations and C-MYC gene amplification were also observed in TCC-NECT-2. BRAFV600E-expressing TCC-NECT-2 cells were sensitive to BRAF inhibitor vemurafenib, and especially dabrafenib, in vitro, and were strongly inhibited in a dose-dependent manner. Dabrafenib treatment (30 mg/kg) in a xenograft model for 14 days significantly suppressed tumor growth (percent tumor growth inhibition, TGI% = 48.04). An enhanced therapeutic effect (TGI% = 95.81) was observed on combined treatment of dabrafenib and irinotecan (40 mg/kg). Therefore, TCC-NECT-2, the first reported cell line derived from D-NEC, might serve as a useful model to study the basic biology of D-NEC and translational applications for treatment.