Sleep disorders in children after treatment for a CNS tumour.
The long-term survival of children with a central nervous system (CNS) tumour is improving. However, they experience late effects, including altered habits and patterns of sleep. We evaluated the presence and type of sleep disorders and daytime sleepiness in these children, and its associations with clinical characteristics and daily performance (fatigue and psychosocial functioning). In a cross-sectional study at the outpatient clinic of the Emma Children's Hospital AMC (February-June 2010), sleep, fatigue and psychosocial functioning were analysed in 31 CNS tumour patients (mean age: 11.8years; 20 boys) and compared with 78 patients treated for a non-CNS malignancy (mean age: 9.7years; 41 boys) and norm data. Questionnaires applied were the Sleep Disorder Scale for Children, the Epworth Sleepiness Scale, the Pediatric Quality of Life Inventory, and the Strengths and Difficulties Questionnaire. Sleeping habits and endocrine deficiencies were assessed with a self-developed questionnaire. Increased somnolence was found in CNS tumour patients compared with those with a non-CNS malignancy (8.8±2.8 versus 7.5±2.7; P<0.05). Both patient groups reported more problems (P<0.01) than the norm with initiating and maintaining sleep. No specific risk factors were identified for a sleep disorder in CNS tumour patients, but their excessive somnolence was correlated with lower fatigue related quality of life (QoL) (r=-0.78, P<0.001) and worse psychosocial functioning (r=0.63, P<0.001). In conclusion, children treated for a CNS tumour have increased somnolence, significantly increasing fatigue and worsening daily functioning. Further investigation should focus on possibilities to improve sleep quality and diminish fatigue.


Dental technician's pneumoconiosis. A report of two cases.
Diagnosis of pneumoconiosis was made in 2 dental technicians presenting with interstitial lung disease. The occupational origin of inhaled dust was confirmed by mineralogic analyses, which disclosed mainly large amounts of chromium-cobalt-molybdenum particles originating from Vitallium prostheses, but also showed abrasives (silica and silicon carbide) and asbestos in 1 patient. The presence of Vitallium and its chemical stability in bronchoalveolar lavage and lung several years after cessation of exposure confirm the resistance of this alloy to corrosion by body fluids. This contrasts with the high solubility of cobalt described in cobalt or hard metal disease. We suggest that dental technician's pneumoconiosis is a complex pneumoconiosis distinct from silicosis, asbestosis, or hard metal disease and that Cr-Co-Mo alloys play a role in its pathogenesis.


Biological reactivity of hypochlorous acid: implications for microbicidal mechanisms of leukocyte myeloperoxidase.
Oxidative degradation of biological substrates by hypochlorous acid has been examined under reaction conditions similar to those found in active phagosomes. Iron sulfur proteins are bleached extremely rapidly, followed in decreasing order by beta-carotene, nucleotides, porphyrins, and heme proteins. Enzymes containing essential cysteine molecules are inactivated with an effectiveness that roughly parallels the nucleophilic reactivities of their sulfhydryl groups. Other compounds, including glucosamines, quinones, riboflavin, and, except for N-chlorination, phospholipids, are unreactive. Rapid irreversible oxidation of cytochromes, adenine nucleotides, and carotene pigments occurs when bacterial cells are exposed to exogenous hypochlorous acid; with Escherichia coli, titrimetric oxidation of cytochrome was found to coincide with loss of aerobic respiration. The occurrence of these cellular reactions implicates hypochlorous acid as a primary microbicide in myeloperoxidase-containing leukocytes; the reactivity patterns observed are consistent with the view that bactericidal action results primarily from loss of energy-linked respiration due to destruction of cellular electron transport chains and the adenine nucleotide pool.


Making Research Results Relevant and Useable: Presenting Complex Organizational Context Data to Nonresearch Stakeholders in the Nursing Home Setting.
The success of evidence-based practice depends on clearly and effectively communicating often complex data to stakeholders. In our program of research, Translating Research in Elder Care (TREC), we focus on improving the quality and safety of care delivered to nursing home residents in western Canada. More specifically, we investigate associations among organizational context, the use of best practices and resident outcomes. Our data are complex and we have been challenged with presenting these data in a way that is not only intuitive, but also useful for our stakeholders. To illustrate a technique of organizing and presenting complex data to nonresearch stakeholders. Using observational data previously collected within the TREC study, we used k-means cluster analysis to categorize nursing home resident care units or facilities within our sample into two distinct groups-those with more favorable contexts (work environment) and those with less favorable contexts. We then produced scatter plots to illustrate group differences between context and various quality indicators among resident care units or facilities. Care aides working on units with more favorable context reported higher use of best practices. When aggregated at the nursing home facility level, facilities with low rates of both urinary tract infections and indwelling catheter use are higher in organizational context. When feeding back these results to stakeholders, we identify their units so that they are able to visually assess their units, both relative to each other and relative to all other units and facilities both within and among provinces. Although we have not formally evaluated this method, we have used it extensively as part of the feedback we provide to stakeholders. As we are examining modifiable aspects of context, the stakeholder can then identify areas for improvement and thus implement a focused plan.


Expert consensus on the rational clinical use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
Two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, have recently been approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. These fully human monoclonal antibodies selectively block PCSK9, thus permitting the low-density lipoprotein (LDL) receptor to effectively recycle to the surface of liver cells. The administration of these antibodies leads to robust LDL cholesterol (LDL-C) lowering by 50-60% on top of maximum hypolipidemic treatment. At least 4 randomized, placebo-controlled studies are under way and will address the question of whether the administration of these PCSK9 inhibitors is associated with a significant reduction of cardiovascular events. Because of the high cost associated with the use of these medications it is very important to consider which patients may gain the most benefit, at least until the results of outcome studies are available. In this Consensus paper, 34 clinicians/scientists define 3 groups of patients that should be currently considered as candidates for the use of these novel drugs. These include: 1a. Adults with established cardiovascular disease and LDL-C≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 1b. Adults with diabetes and established cardiovascular disease or chronic kidney disease or target organ damage and LDL-C ≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 2. Adults with familial hypercholesterolemia (FH) without established cardiovascular disease and LDL-C ≥130 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe (evolocumab is also indicated in children above 12 years with homozygous FH), and 3. Adults at high or very high cardiovascular risk who are statin intolerant and have an LDL-C ≥100 and ≥130 mg/dL, respectively, while on any tolerated hypolipidemic treatment.


Tinnitus diagnosis and therapy in the aged.
We report on a study of tinnitus in more than 400 patients 20 to 80 years old who had suffered from tinnitus for more than one year. Quality of tinnitus, localization, frequency range, severity, masking and residual inhibition effects show no age dependence. The possible causes of tinnitus, is onset and duration and factors that increase or reduce tinnitus also show no age dependence. Regarding the grade of annoyance judged from a subjective scaling, younger patients seen to suffer more from tinnitus than do older subjects, who seem to compensate their tinnitus more often. With regard to the different therapeutic methods used in this study (transtympanal electrostimulation, iontophoresis, biofeedback, tinnitus masker, hearing aid), the stable benefit over more than one year experienced by those patients fitted with a hearing aid was encouraging for young and old subjects. In both groups, about 3% of the patients could be successfully equipped with a tinnitus masker. Independent of age, the improvement by the other methods is less than 1%. Our results show that sufficient prognostic data on the efficiency of a therapeutic method cannot be perceived from the different tinnitus measurements for either the young or the old subjects.


Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice.
Ghrelin is an important orexigenic peptide that not only exerts gastroprokinetic but also immunoregulatory effects. This study aimed to assess the role of endogenous and exogenous ghrelin in the pathogenesis of colitis and in the disturbances of gastric emptying and colonic contractility during this process. Dextran sodium sulphate colitis was induced for 5 days in (i) ghrelin(+/+) and ghrelin(-/-) mice and clinical and histological parameters were monitored at days 5, 10 and 26 and (ii) in Naval Medical Research Institute non-inbred Swiss (NMRI) mice treated with ghrelin (100 nmol kg(-1)) twice daily for 5 or 10 days. Neural contractility changes were measured in colonic smooth muscle strips, whereas gastric emptying was measured with the (14)C octanoic acid breath test. Inflammation increased ghrelin plasma levels. Body weight loss, histological damage, myeloperoxidase activity and IL-1beta levels were attenuated in ghrelin(-/-) mice. Whereas absence of ghrelin did not affect changes in colonic contractility, gastric emptying in the acute phase was accelerated in ghrelin(+/+) but not in ghrelin(-/-) mice. In agreement with the studies in ghrelin knockout mice, 10 days treatment of NMRI mice with exogenous ghrelin enhanced the clinical disease activity and promoted infiltration of neutrophils and colonic IL-1beta levels. Unexpectedly, ghrelin treatment decreased excitatory and inhibitory neural responses in the colon of healthy but not of inflamed NMRI mice. Endogenous ghrelin enhances the course of the inflammatory process and is involved in the disturbances of gastric emptying associated with colitis. Treatment with exogenous ghrelin aggravates colitis, thereby limiting the potential therapeutic properties of ghrelin during intestinal inflammation.


The spectrum of spontaneous mutations in a Saccharomyces cerevisiae uracil-DNA-glycosylase mutant limits the function of this enzyme to cytosine deamination repair.
Uracil-DNA-glycosylase has been proposed to function as the first enzyme in strand-directed mismatch repair in eukaryotic organisms, through removal of uracil from dUMP residues periodically inserted into the DNA during DNA replication (Aprelikova, O. N., V. M. Golubovskaya, T. A. Kusmin, and N. V. Tomilin, Mutat. Res. 213:135-140, 1989). This hypothesis was investigated with Saccharomyces cerevisiae. Mutation frequencies and spectra were determined for an ung1 deletion strain in the target SUP4-o tRNA gene by using a forward selection scheme. Mutation frequencies in the SUP4-o gene increased about 20-fold relative to an isogenic wild-type S. cerevisiae strain, and the mutator effect was completely suppressed in the ung1 deletion strain carrying the wild-type UNG1 gene on a multicopy plasmid. Sixty-nine independently derived mutations in the SUP4-o gene were sequenced. All but five of these were due to GC----AT transitions. From this analysis, we conclude that the mutator phenotype of the ung1 deletion strain is the result of a failure to repair spontaneous cytosine deamination events occurring frequently in S. cerevisiae and that the UNG1 gene is not required for strand-specific mismatch repair in S. cerevisiae.


[Peculiarities of quality of life in children with chronic gastroduodenitis].
To study quality of life (QL) peculiarities in children with chronic gastroduodenitis, Helicobacter pylori positive, in different stages of the disease. Quality of life in 60 children (average age--13.06 +/- 1.2 years) with chronic gastroduodenitis was investigated with using adopted SF-36 questionnaire in period of exacerbation of the disease, in 6 weeks after treatment and in period of remission (in 6 months after treatment). 22 healthy children (average age--12.74 +/- 1.14 years) had been taken as a comparison group. Quality of life in children with chronic gastroduodenitis in exacerbation period was significantly worse (p < 0.05) than in healthy children. The more affected scores were the Role physical (RP), Bodily pain with the scores of healthy children. Presence astenic signs in period of remission (in 6 months after treatment) led to worsening of quality of life; the scores were the same and partly worse then before treatment. Applying of neurometabolic therapy improved psycho-emotional status and quality of life. Quality of life in children with chronic gastroduodenitis was changed with the period of diseases. Initially low scores had tendency to improvement after treatment. In remission period quality of life was mainly depended on peculiarities of psycho-emotional status. Astenic signs led to worsening of quality of life in children with remission of chronic gastroduodenitis. Neurometabolic treatment in this period improved both psycho-emotional status and quality of life.


The involuting lichenoid plaque.
Progressive involution and subsequent regression of a plaque that showed the characteristic histologic findings of solitary lichen planus-like keratosis were observed in five patients. In each lesion, involution took place during a four- to eight-week period. In four patients, the lesion arose in a preexisting pigmented macule. Evolution into a plaque-like lesion coincided with the development of the inflammatory process. Origin from a preexisting lesion suggests that the lichenoid plaque is not an independent entity but a stage in the involution of the preexisting pigmented macule. The lichenoid inflammatory process resembles a delayed hypersensitivity reaction and seems to represent a cell-mediated rejection reaction.


Bifunctional Peptidomimetic G Protein-Biased Mu-Opioid Receptor Agonist and Neuropeptide FF Receptor Antagonist KGFF09 Shows Efficacy in Visceral Pain without Rewarding Effects after Subcutaneous Administration in Mice.
There is still an unmet clinical need to develop new pharmaceuticals for effective and safe pain management. Current pharmacotherapy offers unsatisfactory solutions due to serious side effects related to the chronic use of opioid drugs. Prescription opioids produce analgesia through activation of the mu-opioid receptor (MOR) and are major contributors to the current opioid crisis. Multifunctional ligands possessing activity at more than one receptor represent a prominent therapeutic approach for the treatment of pain with fewer adverse effects. We recently reported on the design of a bifunctional MOR agonist/neuropeptide FF receptor (NPFFR) antagonist peptididomimetic, KGFF09 (H-Dmt-DArg-Aba-βAla-Bpa-Phe-NH2), and its antinociceptive effects after subcutaneous (s.c.) administration in acute and persistent pain in mice with reduced propensity for unwanted side effects. In this study, we further investigated the antinociceptive properties of KGFF09 in a mouse model of visceral pain after s.c. administration and the potential for opioid-related liabilities of rewarding and sedation/locomotor dysfunction following chronic treatment. KGFF09 produced a significant dose-dependent inhibition of the writhing behavior in the acetic acid-induced writhing assay with increased potency when compared to morphine. We also demonstrated the absence of harmful effects caused by typical MOR agonists, i.e., rewarding effects (conditioned-place preference test) and sedation/locomotor impairment (open-field test), at a dose shown to be highly effective in inhibiting pain behavior. Consequently, KGFF09 displayed a favorable benefit/side effect ratio regarding these opioid-related side effects compared to conventional opioid analgesics, such as morphine, underlining the development of dual MOR agonists/NPFFR antagonists as improved treatments for various pain conditions.


Parasite-Mediated Degradation of Synthetic Ozonide Antimalarials Impacts In Vitro Antimalarial Activity.
The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (∼90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia.


Transgenic mice overexpressing the neurotrophic factor S-100 beta show neuronal cytoskeletal and behavioral signs of altered aging processes: implications for Alzheimer's disease and Down's syndrome.
S-100 beta is a neurotrophic factor released by astroglial cells and localized to chromosome 21, within the region which is considered obligate for Down's syndrome (DS). S-100 beta is increased in the postmortem brains of both DS and Alzheimer's disease. Transgenic mice, produced by insertion of the human gene for S-100 beta, were examined for dendritic development at two ages, using an antibody against microtubule associated protein-2 (MAP-2). At the earliest stages, the density of dendrites within the hippocampus of transgenic animals exceeded that of controls. Also, MAP-2 immunostaining was evident in the region of the cell body. By 1 year of age, the transgenic animals had significant loss of dendrites compared to controls and the number of cells showing cell body staining was further increased. These pathological changes could be indicative of the presence of neurofibrillary tangles and cytoskeletal collapse. Behaviorally, younger transgenic animals could not perform in a learning task as well as controls. Together, these findings suggest that increased S-100 beta in brain may lead to accelerated development, followed by increased aging. The pathological changes may prove useful as an animal model of Down's syndrome and Alzheimer's disease.


Changes in phosphofructokinase and pyruvate kinase in rat brain following thyroidectomy.
Changes in the profile of phosphofructokinase (PFK) and Pyruvate kinase (PK) from rat brain regions were studied following thyroidectomy. A regional variation of thyroidectomy on brain was observed; cerebral hemispheres and cerebellum showed decreased activity of phosphofructokinase and pyruvate kinase. The activity in the brain stem did not change. Administration of triiodothyronine to the thyroidectomized rats restored the activity to near control levels. The results suggest a role of the thyroid hormones in the regulation of glycolysis in brain.


First human use of hybrid synthetic/biologic mesh in ventral hernia repair: a multicenter trial.
Mesh options for reinforcement of ventral/incisional hernia (VIH) repair include synthetic or biologic materials. While each material has known advantages and disadvantages, little is understood about outcomes when these materials are used in combination. This multicenter study reports on the first human use of a novel synthetic/biologic hybrid mesh (Zenapro® Hybrid Hernia Repair Device) for VIH repair. This prospective, multicenter post-market clinical trial enrolled consecutive adults who underwent elective VIH repair with hybrid mesh placed in the intraperitoneal or retromuscular/preperitoneal position. Patients were classified as Ventral Hernia Working Group (VHWG) grades 1-3 and had clean or clean-contaminated wounds. Outcomes of ventral and incisional hernia were compared using appropriate parametric tests. In all, 63 patients underwent VIH repair with hybrid mesh. Most were females (54.0%), had a mean age of 54.8 ± 10.9 years and mean body mass index of 34.5 ± 7.8 kg/m2, and classified as VHWG grade 2 (87.3%). Most defects were midline (92.1%) with a mean area of 106 ± 155 cm2. Cases were commonly classified as clean (92.1%) and were performed laparoscopically (60.3%). Primary fascial closure was achieved in 82.5% with 28.2% requiring component separation. Mesh location was frequently intraperitoneal (69.8%). Overall, 39% of patients available for follow-up at 12 months suffered surgical site events, which were generally more frequent after incisional hernia repair. Of these, seroma (23.7%) was most common, but few (8.5%) required procedural intervention. Other surgical site events that required procedural intervention included hematoma (1.7%), wound dehiscence (1.7%), and surgical site infection (3.4%). Recurrence rate was 6.8% (95% CI 2.2-16.6%) at 12-months postoperatively. Zenapro® Hybrid Hernia Repair Device is safe and effective in VHWG grade 1-2 patients with clean wounds out to 12 months. Short-term outcomes and recurrence rate are acceptable. This hybrid mesh represents a novel option for reinforcement during VIH repair.


HIV-1 binds dynein directly to hijack microtubule transport machinery.
HIV-1 uses the microtubule cytoskeleton to reach the host cell nucleus during replication, yet the molecular basis for microtubule-dependent HIV-1 motility is poorly understood. Using in vitro reconstitution biochemistry and single-molecule imaging, we found that HIV-1 binds to the retrograde microtubule-associated motor, dynein, directly and not via a cargo adaptor, as has been previously suggested. We found dynein's tail domain binds to a novel interface on the HIV-1 capsid lattice. Further, we use an engineered encapsulin system to demonstrate that multiple dynein motors tethered to rigid cargoes, like HIV-1 capsids, display reduced motility, distinct from the behavior of multiple motors on membraneous cargoes. Our results provide a new model of HIV-1 trafficking wherein HIV-1 'hijacks' the dynein transport machinery for microtubule motility, establishing a new model of viral trafficking by directly co-opting host dynein motors.


Annexins V and XII alter the properties of planar lipid bilayers seen by conductance probes.
Annexins are proteins that bind lipids in the presence of calcium. Though multiple functions have been proposed for annexins, there is no general agreement on what annexins do or how they do it. We have used the well-studied conductance probes nonactin, alamethicin, and tetraphenylborate to investigate how annexins alter the functional properties of planar lipid bilayers. We found that annexin XII reduces the nonactin-induced conductance to approximately 30% of its original value. Both negative lipid and approximately 30 microM Ca(2+) are required for the conductance reduction. The mutant annexin XIIs, E105K and E105K/K68A, do not reduce the nonactin conductance even though both bind to the membrane just as wild-type does. Thus, subtle changes in the interaction of annexins with the membrane seem to be important. Annexin V also reduces nonactin conductance in nearly the same manner as annexin XII. Pronase in the absence of annexin had no effect on the nonactin conductance. But when added to the side of the bilayer opposite that to which annexin was added, pronase increased the nonactin-induced conductance toward its pre-annexin value. Annexins also dramatically alter the conductance induced by a radically different probe, alamethicin. When added to the same side of the bilayer as alamethicin, annexin has virtually no effect, but when added trans to the alamethicin, annexin dramatically reduces the asymmetry of the I-V curve and greatly slows the kinetics of one branch of the curve without altering those of the other. Annexin also reduces the rate at which the hydrophobic anion, tetraphenylborate, crosses the bilayer. These results suggest that annexin greatly reduces the ability of small molecules to cross the membrane without altering the surface potential and that at least some fraction of the active annexin is accessible to pronase digestion from the opposite side of the membrane.


Prognostic and Immune Infiltration Signatures of GIMAP Family Genes in Clear Cell Renal Cell Carcinoma.
Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor of the urinary system characterized by abundant immunocytes infiltration. The impact of guanosine triphosphatases (GTPases) of immunity-associated proteins (GIMAPs) on the tumor immune microenvironment (TIME) and prognosis of ccRCC is unclear. The expression of GIMAPs in ccRCC was determined through multiple datasets (ONCOMINE, TCGA and UALCAN). The relationship between GIMAP family members was analyzed through Spearman correlation analysis. The interaction among the GIMAPs protein was analyzed using STRING. Prognostic values of GIMAPs were evaluated by Survival analysis, Lasso and Cox regression analysis; Prognostic risk model and nomogram were constructed. The correlation between GIMAPs and TIME was explored using TIMER, Cibersort and Pearson correlation analysis. Gene set enrichment analysis (GSEA) was performed to discuss their function and mechanism in ccRCC. GIMAPs were over-expressed in ccRCC and significantly related to overall survival (OS) of the patients. GIMAPs were positively correlated with each other, the risk model based on GIMAPs had good prognostic value in ccRCC. GIMAPs mainly expressed in TIME and were associated with abundant immunocytic infiltration in ccRCC, the risk model also had close correlation with TIME. Our results showed GIMAPs may affect the development of ccRCC by regulating the amount and antitumor activity of immunocytes in TIME. GIMAPs were over-expressed in ccRCC, and their expression levels were significantly related to the OS of patients and immunocytic infiltration in TIME. GIMAPs are potential therapeutic targets and prognostic biomarkers for ccRCC.


The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin.
Evidence is available from animal and human studies that protein traffic through the glomerular capillary has a pathogenetic role in subsequent renal damage and that angiotensin-converting enzyme (ACE) inhibitors appear superior to other drugs in lowering proteinuria and the rate of renal function decline. This study compares the effect of ACE inhibition or angiotensin II (AngII) receptor blockade on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis randomized to receive enalapril (20 mg/d) or irbesartan (100 mg/d) for 28 d in a double-blind study with two parallel groups. This study also evaluated whether addition of indomethacin (75 mg twice a day) to each of the two treatments resulted in a more potent antiproteinuric effect. Enalapril alone reduced total protein excretion (61% change from baseline) and fractional clearance of albumin without changes in GFR and minor elevation in renal plasma flow. Also, patients randomized to receive the AngII receptor antagonist irbesartan for 28 d had lower proteinuria (55% change from baseline) and fractional clearance of albumin at the end of the treatment period with similar renal hemodynamic changes. When indomethacin was added to enalapril treatment, a further significant reduction in urinary proteins and fractional albumin clearance was observed. In patients given irbesartan, the addition of indomethacin further reduced proteinuria and fractional clearance of albumin. The combined therapy with enalapril or irbesartan and indomethacin did not significantly affect GFR and renal plasma flow compared with baseline. These findings indicate that in patients with IgA glomerulonephritis the antiproteinuric effect of blocking AngII activity by either ACE inhibitors or AngII receptor antagonists is potentiated by indomethacin, an effect that occurred without impairment of renal function.


Genetic causes and clinical management of pediatric interstitial lung diseases.
Interstitial lung disease (ILD) in children (chILD) is an umbrella term for a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and implicates genetic contributors. The purpose of this review is to provide updated information on the molecular defects associated with the development of chILD. Currently, the main mutations are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3, and NKX2-1. In addition, pulmonary alveolar proteinosis is associated with mutations in CSF2RA, CSF2RB, and MARS, and specific auto-inflammatory forms of chILD implicate STING and COPA disorders. The relationships between the genetic defects and the disease expression remain poorly understood, with no genotype-phenotype correlations identified so far. Although targeted therapies are emerging, the management strategies are still largely empirical, relying mostly on corticosteroids. Genetic factors play an important role in chILD, and the ongoing development of novel technologies will rapidly broaden the genetic landscape of chILD. Therefore, in the coming years, it is expected that newly identified molecular defects and markers will help predicting disease courses and tailoring individual therapies.


FT-IR and 2D-IR spectroscopic studies on the effect of ions on the phase separation behavior of PVME aqueous solution.
Thermosensitive phase transition behavior of poly(vinyl methyl ether) (PVME) in an aqueous solution and the effect of inorganic ions on the coil-globule transition have been investigated by Fourier transform infrared (FT-IR) spectroscopy with attenuated total reflection (ATR) accessory. ATR-IR spectra of PVME aqueous solution indicate that in water-PVME-inorganic salts system, the phase separation temperature of PVME aqueous solution decreased with the increase of ion concentration and the increase of anion electronegativity. Meanwhile, two-dimensional infrared (2D-IR) measurements have been made to clarify the microcosmic conformational changes of PVME during the coil-globule transition. Results show that the conformation changes of main chains occur earlier than those of ether groups during heating. Furthermore, the 2D correlation spectroscopy of PVME aqueous solution during heating and the increase of concentration of potassium chloride have been studied. The features of 2D-IR spectra during heating did not change compared to the features of PVME aqueous solution during the increase of concentration of potassium chloride. This result implies that, although the addition of inorganic ions shifts the phase separation temperature, it does not alter the internal mechanism of the coil-globule transition of PVME.


Can diffusion-weighted MRI determine complete responders after neoadjuvant chemoradiation for locally advanced rectal cancer?
We aimed to prospectively determine if analyzing pre- and post-chemoradiotheraphy (CRT) changes in the signal intensity (SI) and apperent diffusion coefficient (ADC) values from diffusion-weighted magnetic resonance imaging (DW-MRI) can accurately predict complete responders for locally advanced rectal cancer. Thirty patients (mean age, 54.3 years) with locally advanced rectal cancer who underwent neoadjuvant CRT and subsequent surgery were included in this study. All patients were evaluated pre- and post-CRT by standardized turbo spin echo and DW-MRI. Pre- and post-CRT tumor and normal rectal wall SI (which were gradually scored as very high, high, intermediate, low, and no signal) and ADC values were recorded. Tumor SIs were decreased in all of the patients that had a therapy response. However, complete tumor SI loss was only seen in two (22.2%) of nine patients with a pathological complete response, while it regressed to low and/or intermediate SI levels in the remaining seven patients (77.8%). Post-CRT ADC values of rectal tumors were significantly higher from the preCRT ADC values (P < 0.0001; Z=-9.39). However, post-CRT ADC values from the complete and partial/no response patient groups were not significantly different (P = 0.071; Z=-1.99). In re-staging of rectal tumors by DW-MRI, an increase in ADC values and decrease in SIs can predict therapy response but cannot unequivocally determine a complete response.


Heating of an Aortic Stent for Coarctation Treatment During Magnetic Particle Imaging and Magnetic Resonance Imaging-A Comparative In Vitro Study.
To evaluate heating of a redilatable stent for the treatment of aortic coarctation in neonates and small children in the new imaging modality magnetic particle imaging and established magnetic resonance imaging. The cobalt-chromium stent (BabyStent, OSYPKA AG, Rheinfelden, Germany) has a stent design which allows for redilatation and adjustment of the diameter from 6 to 16 mm for a use in aortic coarctation. The stent loses its radial integrity while opening at predetermined breaking points at a diameter of 14 mm or 16 mm, respectively. We measured the temperature increase in the stent at different diameters during 7-min magnetic particle imaging and magnetic resonance imaging scans with fiber optic thermometers under static conditions surrounded by air. In magnetic particle imaging, stents with diameters from 6 to 16 mm were tested while in magnetic resonance imaging only stents with diameters of 6 mm and 14 mm were investigated exemplarily. In magnetic particle imaging, the measured temperature differences increased up to 4.7 K with growing diameters, whereas the opened stents with discontinuous struts at 14 and 16 mm showed only minimal heating of max. 0.5 K. In contrast to magnetic particle imaging, our measurements showed no heating of the stents during magnetic resonance imaging under identical conditions. The BabyStent did show only slight heating in magnetic particle imaging and no detectable temperature increase in magnetic resonance imaging.


Sensory and memory stimulation as a means to care for individuals with dementia in long-term care facilities.
The primary objective of this study was to identify and further examine the facilitators and barriers of utilizing sensory and memory stimulation as a means to care for individuals with dementia who live in long-term care settings. The authors conducted a literature review of 30 academic articles found using the databases such as CINAHL, PubMed, and Academic Search Ultimate from the past 15 years. Facilitator and barrier themes were found within each article and analyzed for their relevance to sensory and memory stimulation therapies and their effects on individuals with dementia. The most common facilitator was improved communication. The top three barriers were access, staff training, and mixed results. Reminiscence therapy appears to provide a person-centered method of care for those who otherwise have problems communicating. These implementations will be more effective if they have the support of staff and management. The authors conclude that sensory and memory stimulation therapies have the potential to help improve many dementia-specific issues for individuals living in long-term care settings.


Factors affecting the stability of chitosan/tripolyphosphate micro- and nanogels: resolving the opposing findings.
Micro- and nanogels prepared by ionically crosslinking chitosan with tripolyphosphate (TPP) attract keen interest as potential drug carriers. To achieve their optimal performance, it is essential to control their stability to aggregation and dissolution. Yet, literature on this subject (especially at physiological ionic strength and pH) remains filled with opposing reports. Recently, one of us hypothesized that these conflicting findings might stem from: (1) variations in the chitosan molecular structure; (2) the dissimilar particle concentrations used by the various groups; and (3) occasional overreliance on dynamic light scattering (DLS) as the sole analytical tool. To explore this hypothesis, here we use isothermal titration calorimetry, light scattering and UV-vis spectroscopy to analyze the effects of chitosan degree of deacetylation (DD) and particle concentration on chitosan/TPP particle stability. Their dissolution stability increases with the chitosan DD (due to the stronger chitosan/TPP binding) and when the particles are used at higher concentrations, and evidently depends on the chitosan molecular weight. Conversely, their aggregation stability decreases with the DD, because the chitosan is more prone to TPP bridging and becomes more lyophobic at near-neutral (physiological) pH. We also show how using DLS-derived size distributions as the sole tool for characterizing particle stability can lead to erroneous conclusions. Comparison of these findings to literature experimental conditions reconciles many of the opposing reports and provides essential guidelines for tuning chitosan/TPP particle stability.


Role of the energy sensor AMP-activated protein kinase in renal physiology and disease.
The ultrasensitive energy sensor AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and energy-consuming pathways. AMPK is highly expressed in the kidney where it is reported to be involved in a variety of physiological and pathological processes including ion transport, podocyte function, and diabetic renal hypertrophy. Sodium transport is the major energy-consuming process in the kidney, and AMPK has been proposed to contribute to the coupling of ion transport with cellular energy metabolism. Specifically, AMPK has been identified as a regulator of several ion transporters of significance in renal physiology, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), the Na(+)-K(+)-2Cl(-) cotransporter (NKCC), and the vacuolar H(+)-ATPase (V-ATPase). Identified regulators of AMPK in the kidney include dietary salt, diabetes, adiponectin, and ischemia. Activation of AMPK in response to adiponectin is described in podocytes, where it reduces albuminuria, and in tubular cells, where it reduces glycogen accumulation. Reduced AMPK activity in the diabetic kidney is associated with renal accumulation of triglyceride and glycogen and the pathogenesis of diabetic renal hypertrophy. Acute renal ischemia causes a rapid and powerful activation of AMPK, but the functional significance of this observation remains unclear. Despite the recent advances, there remain significant gaps in the present understanding of both the upstream regulating pathways and the downstream substrates for AMPK in the kidney. A more complete understanding of the AMPK pathway in the kidney offers potential for improved therapies for several renal diseases including diabetic nephropathy, polycystic kidney disease, and ischemia-reperfusion injury.


An animal model for external ear canal inflammation.
To develop an animal model for testing efficacy of anti-inflammatory drugs designed to treat external ear canal (EAC) disease. Histological and morphometric methods were used to characterize EAC inflammation produced by topical application of tetradecanoylphorbol acetate (TPA) in mice. The effects of both single and repeated TPA applications were studied. A treatment trial was performed to evaluate the effects of a ciprofloxacin/hydrocortisone suspension on TPA-induced EAC inflammation. In 10 animals, two bilateral applications of TPA were made, spaced 24 hours apart. Immediately after the second TPA application, otic suspension was applied unilaterally four times over a 48-hour period. The contralateral EACs were left untreated to provide TPA-only controls. Twenty-four hours after a single TPA application, EAC skin showed polymorphonuclear (PMN) leukocyte infiltration, vascular dilation, and thickening of the dermis and epidermis. Dermal and epidermal thickening were more pronounced after two TPA applications and PMN leukocyte infiltration remained high 48 hours after a second TPA placement. After treatment with the otic suspension, PMN leukocyte counts were reduced by an average of 76% relative to EACs that received TPA only. There was also statistically significant reduction of dermal swelling and a trend toward reduced epidermal thickness. Vascular dilation was clearly reduced as well EACs that received four applications of the suspension alone showed no adverse effects compared with those that received saline. TPA-induced inflammation of the mouse EAC provides a suitable model for testing the therapeutic efficacy of anti-inflammatory agents being considered for clinical use.


Mechanism-based management for mucositis: option for treating side effects without compromising the efficacy of cancer therapy.
Mucositis is a major side effect induced by chemotherapy and radiotherapy. Although mucositis is a leading cause of morbidity and mortality in cancer patients, management is largely limited to controlling symptoms, and few therapeutic agents are available for treatment. Since mucositis could be inhibited by the modulation of radiotherapy- or chemotherapy-induced pathways independently of cancer treatment, there is an opportunity for the development of more targeted therapies and interventions. This article examined potential therapeutic agents that have been investigated for the prevention and/or inhibition of mucositis induced by conventional chemotherapy and radiotherapy. They can be classified according to their mechanisms of action: scavenging reactive oxygen species, inhibition of specific cytokine production or inflammation, and inhibition of apoptosis. These early events may be good target pathways for preventing the pathogenesis of mucositis. Considering that both cancer therapy and therapeutic agents for mucositis act on both normal and cancer cells, agents that inhibit mucositis should act through mechanisms that selectively protect normal cells without compromising cancer treatment. Therefore, mechanism-based guidance for the treatment of mucositis is critical to prevent risky treatments for cancer patients and to relieve detrimental side effects effectively from cancer therapy.


Collagen XVIII/endostatin structure and functional role in angiogenesis.
The angiogenesis inhibitor endostatin is a 20 kDA C-terminal fragment of collagen XVIII, a proteoglycan/collagen found in vessel walls and basement membranes. The endostatin fragment was originally identified in conditioned media from a murine endothelial tumor cell line. Endostatin inhibits endothelial cell migration in vitro and appears to be highly effective in murine in vivo studies. The molecular mechanisms behind the inhibition of angiogenesis have not yet been elucidated. Studies of the crystal structure of endostatin have shown a compact globular fold, with one face particularly rich in arginine residues acting as a heparin-binding epitope. It was initially suggested that zinc binding was essential for the antiangiogenic mechanism but later studies indicate that zinc has a structural rather than a functional role in endostatin. The generation of endostatin or endostatin-like collagen XVIII fragments is catalyzed by proteolytic enzymes, including cathepsin L and matrix metalloproteases, that cleave peptide bonds within the protease-sensitive hinge region of the C-terminal domain. The processing of collagen XVIII to endostatin may represent a local control mechanism for the regulation of angiogenesis.


Ultrasound-Guided Diagnosis and Injection of the Lateral Femoral Cutaneous Nerve with an Anatomical Variation.
Meralgia paresthetica (MP) is an entrapment neuropathy of the lateral femoral cutaneous nerve (LFCN). There are many variations in the course of the LFCN. A 55-year-old woman presented with pain and tingling sensations on the anterolateral aspect of her left thigh. Physical examination revealed hypoesthesia of the proximal anterolateral thigh on the left side. During the electrodiagnostic study, sensory nerve action potential of the LFCN could not be obtained on both sides. Through those clinical and electrophysiological findings, we prediagnosed the case as MP and planned to perform diagnostic nerve block. For the injection to perform, ultrasonography was used. During the ultrasonographic evaluation, the left LFCN was visualized lateral to the anterior superior iliac spine (ASIS). Then ultrasound-guided nerve block with 2 cc lidocaine 2% for diagnostic purpose was performed in this region. Immediately after the injection, the patient's complaints relieved completely, and hence the patient was diagnosed as having MP with an LFCN anatomical variation. Two months later her complaints persisted, and ultrasound-guided LFCN injection with 2 mL of lidocaine 2% + 1 cc of betametazone was performed. One month after the second injection, her complaints were relieved markedly and she resumed her daily activities. In conclusion, the course of the LFCN is quite variable. We present a relatively rare anatomical variation of the LFCN, crossing lateral to the ASIS, diagnosed with ultrasonography. Ultrasonography can be performed to visualize the LFCN, especially a nerve with an anatomical variation.


Compound odontoma involving the four quadrants of the jaws: a case report and review of the literature.
Odontomas are the most common odontogenic tumors, representing 70% of all odontogenic tumors. They may present in two specific forms; compound odontoma forms multiple small tooth-like structures, while complex odontoma forms an amorphous calcified mass. In this report, we present a 27-year-old male patient with multiple compound odontoma occupied regions at his jaws. The odontomas involve both alveolar and basal processes of the maxilla and mandible as well as both maxillary sinuses. Converse to conventional recommended treatment, which is surgical excision of the lesion, the management was removal of the lesion and clinical-radiologic followup. The first year's follow-up findings are presented in this case report.


Effect of passive stretching on the immobilized soleus muscle fiber morphology.
The aim of the present study was to determine the effect of stretching applied every 3 days to the soleus muscle immobilized in the shortened position on muscle fiber morphology. Eighteen 16-week-old Wistar rats were used and divided into three groups of 6 animals each: a) the left soleus muscle was immobilized in the shortened position for 3 weeks; b) during immobilization, the soleus was stretched for 40 min every 3 days; c) the non-immobilized soleus was only stretched. Left and right soleus muscles were examined. One portion of the soleus was frozen for histology and muscle fiber area evaluation, while the other portion was used to identify the number and length of serial sarcomeres. Immobilized muscles (group A) showed a significant decrease in weight (44 +/- 6%), length (19 +/- 7%), serial sarcomere number (23 +/- 15%), and fiber area (37 +/- 31%) compared to the contralateral muscles (P < 0.05, paired Student t-test). The immobilized and stretched soleus (group B) showed a similar reduction but milder muscle fiber atrophy compared to the only immobilized group (22 +/- 40 vs 37 +/- 31%, respectively; P < 0.001, ANOVA test). Muscles submitted only to stretching (group C) significantly increased the length (5 +/- 2%), serial sarcomere number (4 +/- 4%), and fiber area (16 +/- 44%) compared to the contralateral muscles (P < 0.05, paired Student t-test). In conclusion, stretching applied every 3 days to immobilized muscles did not prevent the muscle shortening, but reduced muscle atrophy. Stretching sessions induced hypertrophic effects in the control muscles. These results support the use of muscle stretching in sports and rehabilitation.


Antibody labeling of functional subdivisions in visual cortex: Cat-301 immunoreactivity in striate and extrastriate cortex of the macaque monkey.
We have examined the distribution of immunoreactivity for the monoclonal antibody Cat-301 in visual cortex of the macaque monkey. Remarkably, those portions of striate cortex (V1) and extrastriate cortex that are most immunoreactive for Cat-301 are anatomically interconnected and are dominated by inputs arising from the magnocellular layers of the LGN (which are themselves highly immunoreactive). In particular, we found that a band of Cat-301 labeled neurons known to exist in layer 4 of V1 is centered on the boundary between layers 4C alpha and 4B and thus includes portions of both the primary target of the magnocellular LGN and its subsequent relay through layer 4B. We also demonstrated consistently strong Cat-301 immunoreactivity in all three extrastriate targets of layer 4B: areas V3, MT, and the cytochrome-oxidase (CO) enriched thick stripes of V2. In V2, there was a close correlation between Cat-301 labeling and clusters of cells projecting to MT but not to V4. This was true even in regions where the CO pattern was equivocal or irregular, indicating that Cat-301 is a more reliable marker than CO for the thick-stripe subregions of V2. Finally, we found strong Cat-301 immunoreactivity in at least parts of areas V3A, the MST complex, and the posterior parietal complex, but not in area V4 or inferotemporal cortex. The molecular specificity revealed by this single marker thus correlates with functionally specific subdivisions at each hierarchical level over nearly the entire known extent of the visual pathway in macaques. This supports the notion that these subdivisions form an anatomically, physiologically, and now molecularly distinct pathway known as the M-stream.


Phylogeny and patterns of floral diversity in the genus Piper (Piperaceae).
With ∼1000 species distributed pantropically, the genus Piper is one of the most diverse lineages among basal angiosperms. To rigorously address the evolution of Piper we use a phylogenetic analysis of sequences of the internal transcribed spacers (ITS) of nuclear ribosomal DNA based on a worldwide sample. Sequences from a total of 51 species of Piper were aligned to yield 257 phylogenetically informative sites. A single unrooted parsimony network suggested that taxa representing major geographic areas could potentially form three monophyletic groups: Asia, the South Pacific, and the Neotropics. The position of Pothomorphe was well supported among groups of New World taxa. Simultaneous phylogenetic analysis of an expanded alignment including outgroups suggested that taxa from the South Pacific and Asia formed a monophyletic group, provisionally supporting a single origin of dioecy. Within the Neotropical sister clade, resolution was high and strong bootstrap support confirmed the monophyly of several traditionally recognized infrageneric groups (e.g., Enckea [including Arctottonia], Ottonia, Radula, Macrostachys). In contrast, some of the species representing the highly polytypic subgroup Steffensia formed a clade corresponding to the previously recognized taxon Schilleria, while others were strongly associated with several of the more specialized groups of taxa. The distribution of putatively derived inflorescence and floral character states suggested that both umbellate and solitary axillary inflorescences have multiple origins. Reduction in anther number appears to be associated with highly packaged inflorescences or with larger anther primordia per flower, trends that are consistent with the suppression of later stages of androecial development.


Genome mining of cyanide-degrading nitrilases from filamentous fungi.
A variety of fungal species are known to degrade cyanide through the action of cyanide hydratases, a specialized subset of nitrilases which hydrolyze cyanide to formamide. In this paper, we report on two previously unknown and uncharacterized cyanide hydratases from Neurospora crassa and Aspergillus nidulans. Recombinant forms of four cyanide hydratases from N. crassa, A. nidulans, Gibberella zeae, and Gloeocercospora sorghi were prepared after their genes were cloned with N-terminal hexahistidine purification tags, expressed in Escherichia coli, and purified using immobilized metal affinity chromatography. These enzymes were compared according to their relative specific activity, pH activity profiles, thermal stability, and ability to remediate cyanide contaminated waste water from silver and copper electroplating baths. Although all four were similar, the N. crassa cyanide hydratase (CHT) has the greatest thermal stability and widest pH range of >50% activity. N. crassa also demonstrated the highest rate of cyanide degradation in the presence of both heavy metals. The CHT of A. nidulans has the highest reaction rate of the four fungal nitrilases evaluated in this work. These data will help determine optimization procedures for the possible use of these enzymes in the bioremediation of cyanide-containing waste. Similar to known plant pathogenic fungi, both N. crassa and A. nidulans were induced to express CHT by growth in the presence of KCN.


Media Coverage of the Benefits and Harms of Testing the Healthy: a protocol for a descriptive study.
Much testing in medicine is aimed at healthy people to facilitate the early detection of health conditions. However, there is growing evidence that early detection is a double-edged sword that may cause harm in the form of overdiagnosis. The media can be seen as a major generator of consumer demand for health services. Previous research shows that media coverage tends to overstate the benefits and downplay the harms of medical interventions for the sick, and often fails to cover relevant conflicts of interest of those promoting those interventions. However, little is known about how the benefits and harms of testing the healthy are covered by media. This study will examine the media coverage of the benefits and harms of testing the healthy, and coverage of potential conflicts of interest of those promoting the testing. We will examine five tests: 3D mammography for the early detection of breast cancer; blood liquid biopsy for the early detection of cancer; blood biomarker tests for the early detection of dementia; artificial intelligence technology for the early detection of dementia; and the Apple Watch Series 4 electrocardiogram sensor for the early detection of atrial fibrillation. We will identify media coverage using Google News and the LexisNexis and ProQuest electronic databases. Sets of two independent reviewers will conduct story screening and coding. We will include English language media stories referring to any of the five tests from January 2016 to May 2019. We will include media stories if they refer to any benefits or harms of the test for our conditions of interest. Data will be analysed using categorical data analysis and multinomial logistic regression. No ethical approval is required for this study. Results will be presented at relevant scientific conferences and in peer-reviewed literature.


Differential psychostimulant-induced activation of neural circuits in dopamine transporter knockout and wild type mice.
Dopamine (DA) is a neurotransmitter that has been implicated in a wide variety of psychiatric disorders that include attention deficit-hyperactivity disorder (ADHD), schizophrenia, and drug abuse. Recently, we have been working with a mouse in which the gene for the DA transporter (DAT) has been disrupted. This mouse is hyperactive in the open field, displays an inability to inhibit ongoing behaviors, and is deficient on learning and memory tasks. Psychostimulants such as amphetamine and methylphenidate attenuate the hyperlocomotion of the mutants, but stimulate activity of the wild type (WT) controls. The objective of the present study is to examine the neural basis for the differential responses to psychostimulants in these mice. WT and DAT knockout (KO) animals were given vehicle or methylphenidate, amphetamine, or cocaine and brain sections were immunostained for Fos. In WT mice, methylphenidate induced Fos-like immunoreactivity (Fos-LI) in the mesostriatal and mesolimbocortical DA pathways that included the anterior olfactory nucleus, frontal association cortex, orbitofrontal cortex, cingulate cortex, caudate-putamen, globus pallidus, claustrum, lateral septum, nucleus accumbens, basolateral and central nuclei of the amygdala, bed nucleus of stria terminalis, subthalamic nucleus, substantia nigra, ventral tegmental area, and dorsal raphe. Additional areas of activation included the granular dentate gyrus, Edinger-Westphal nucleus, and periaqueductal gray. While the mutants showed little response in most of these same areas, the anterior olfactory nucleus, caudal caudate-putamen, lateral septum, basolateral and central nuclei of the amygdala, and bed nucleus of stria terminalis were activated. Amphetamine and cocaine produced similar changes to that for methylphenidate, except these psychostimulants also induced Fos-LI in the nucleus accumbens of the KO animals. Since the DAT gene is disrupted in the KO mouse, these findings suggest that dopaminergic mechanisms may mediate the WT responses, whereas non-dopaminergic systems predominate in the mutant. In the mutants, it appears that limbic areas and non-dopaminergic transmitter systems within these brain regions may mediate responses to psychostimulants. Inasmuch as the KO mouse may represent a useful animal model for ADHD and because psychostimulants such as cocaine are reinforcing to these animals, our results may provide some useful insights into the neural mechanisms-other than DA-that may contribute to the symptoms of ADHD and/or drug abuse in human patients.


Current landscape of Oculocutaneous Albinism in Japan.
Oculocutaneous albinism (OCA), which is roughly divided into non-syndromic and syndromic OCA, is a group of autosomal recessive disorders caused by mutations in genes associated with pigmentation. Patients with OCA have hypopigmentation and ocular manifestations such as photophobia, amblyopia, and nystagmus. Hermansky-Pudlak syndrome (HPS), the most common syndromic OCA, is characterized by the additional features of a bleeding tendency and other critical systemic comorbidities such as pulmonary fibrosis and immunodeficiency. NGS-based gene analyses have identified several new causative genes for OCA and have detected rare subtypes of OCA with high accuracy including Japanese patients. In our survey of 190 Japanese OCA patients/families, OCA4 is the most common subtype (25.3%) followed by OCA1 (20.0%), HPS1 (14.7%), and OCA2 (8.4%). Similar to the A481T variant in OCA2, which is associated with a mild form of OCA2 and skin color variation, the c.-492_489delAATG variant located in the promoter region of SLC45A2 has been uniquely identified in Japanese patients with a mild form of OCA4. Further, rare OCA subtypes, including OCA3, HPS2, HPS3, HPS4, HPS5, HPS6, and HPS9, have also been identified in Japanese patients. The clinical characteristics and underlying molecular mechanisms of each subtype of OCA are concisely summarized in this review.


Efficacy of tree trunk coating materials in the control of the apple clearwing, Synanthedon myopaeformis.
The efficacy of trunk treatment with three materials, cotton seed oil, lime and used motor oil, were evaluated for the control of apple clearwing, Synanthedon myopaeformis (Borkhausen) (Lepidoptera: Sesiidae) in an apple orchard during two successive years (2004 and 2005). The weekly total number of adult catches and exuviae was recorded each year. No treatments caused significant reductions in mean numbers of adults caught in bait traps or the exuviae protruding from the barks of tree trunks and thick branches in the first year of the study whereas all of them differed significantly from each other or from water-treated control in the second year (P < 0.05). A comparison of the mean numbers of adult catches and exuviae in both years revealed significant differences between the used motor oil and cotton seed oil treatments (P < 0.05). The lime treatments in both years significantly differed in terms of adult catches, but not exuviae (P<0.05). In the second year, compared with those in water-treated control plots, the mean number of adult catches and exuviae decreased by 81.3% and 88.3% in the used motor oil-treated plots, and by 70.8% and 83.3% in the cotton seed oil-treated plots, respectively. Although population reductions in the lime treatment were significant in the second year, the effect was at a much reduced level in comparison to the two oil treatments. The overall results suggest that used motor oil and cotton seed oil may have potential for the control of apple clearwing.


Neutrophil Extracellular Traps as a Drug Target to Counteract Chronic and Acute Inflammation.
Neutrophil extracellular traps (NET), extruded decondensated chromatin entangled with neutrophil proteases, have been first identified in neutrophils stimulated with bacteria or phorbol myristate acetate (PMA) via activation of NADPH oxidase and the generation of reactive oxygen species. Although the first findings demonstrated the beneficial role of NET formation by trapping the bacteria and limiting their dissemination, numerous studies in the recent decade revealed the multifunctional aspects of NET formation which manifests itself not only in the context of anti-microbial effect but also as a pathological trigger. Uncontrolled and exaggerated NET formation or inability to digest and remove NET have been reported in thrombosis, auto-immune diseases, cancer or even in infertility. Studies are ongoing to disclose the role of NET in different pathological situations and most importantly, NET regulation via compounds that either interfere with NET formation or target NET components such as DNA or neutrophil proteases. Although the final product of NET formation seems to be quite common i.e. DNA entangled with proteases, stimuli that induce NET have a wide range of varieties and the involved pathways are diverse too. Therefore, in every pathological condition, it is necessary to consider carefully the type of stimulus and the signaling pathways in order to target the disease more specifically. Here we briefly summarize some (out of many) NET triggers/pathways and discuss the potential interventions in the pathological situations.


[The influence of proxy respondents on health perception among older adults: a study based on the Brazilian National Household Survey (1998, 2003) and the cohort study in Bambuí, Minas Gerais State, Brazil].
This study was developed to examine whether the use of a proxy respondent influences the distribution and factors associated with health perception among older adults, as well as the mortality relative risk. The study included 28,943 and 35,040 participants from the Brazilian National Household Survey (PNAD) in 1998 and 2003, respectively, and 1,606 members of the cohort from Bambuí, Minas Gerais, Brazil. The results showed that use of proxy in the PNAD 1998 and 2003 did not modify the distribution of health perception or associated factors. The 5-year mortality rate ratio among cohort participants was higher in direct interviews with seniors (RR = 2.40) as compared to those answered by proxies (RR = 1.28), but the direction of the association was the same. These results indicate that health perception data from the PNAD can be used regardless of who answers the interview and that the association between worse health perception and mortality persisted even when perception was inferred from a proxy.


Clinical manifestations of dengue hemorrhagic fever in Puerto Rico, 1990-1991. Puerto Rico Association of Epidemiologists.
The aim of the study reported here was to demonstrate that dengue hemorrhagic fever occurs in Puerto Rico, that it is underreported, and that this underreporting is due partly to underdiagnosis in hospitals. Surveillance for severe dengue identified 986 hospitalizations for suspected dengue in 1990-1991. At the time, on the basis of available clinical and laboratory data, the surveillance system routinely identified 20 DHF cases, including three with dengue shock syndrome (DSS). Our subsequent review of these 986 patients' hospital records identified 102 whose records supported a clinical diagnosis of DHF (88) or DSS (14). Of the 102, there were 57 with positive virologic or serologic results for dengue and that met the World Health Organization criteria for DHF (fever, hemorrhagic manifestations, thrombocytopenia, and excessive capillary permeability). This group of 57 patients had a mean age of 38 years, contained a preponderance of males (34, 59.3%), included eight cases of DSS, and involved two (3.5%) fatalities (in females 16 and 55 years old). Hemorrhagic manifestations were mild; hemoconcentration, hypoalbuminemia, and elevated aspartate and alanine aminotransferase (AST and ALT) levels were frequently encountered. The median duration of hospitalization was five days. The clinical description of these laboratory-positive DHF cases in Puerto Rico is consistent with previous descriptions of DHF in the medical literature; but the patients' age distribution is similar to the pattern typically found in the Americas (where all age groups tend to be affected), as opposed to Southeast Asia (where mostly younger children are affected). The number of DHF cases identified by our study was nearly three times that reported through the established surveillance system. Our findings indicate that recognition and reporting of DHF by local clinicians needs to be improved.


Bayesian nonparametric dictionary learning for compressed sensing MRI.
We develop a Bayesian nonparametric model for reconstructing magnetic resonance images (MRIs) from highly undersampled k -space data. We perform dictionary learning as part of the image reconstruction process. To this end, we use the beta process as a nonparametric dictionary learning prior for representing an image patch as a sparse combination of dictionary elements. The size of the dictionary and patch-specific sparsity pattern are inferred from the data, in addition to other dictionary learning variables. Dictionary learning is performed directly on the compressed image, and so is tailored to the MRI being considered. In addition, we investigate a total variation penalty term in combination with the dictionary learning model, and show how the denoising property of dictionary learning removes dependence on regularization parameters in the noisy setting. We derive a stochastic optimization algorithm based on Markov chain Monte Carlo for the Bayesian model, and use the alternating direction method of multipliers for efficiently performing total variation minimization. We present empirical results on several MRI, which show that the proposed regularization framework can improve reconstruction accuracy over other methods.


The vidian canal: radiological features in Japanese population and clinical implications.
The vidian canal (VC), a bony tunnel in which the vidian artery and nerve pass, has been widely known as an important landmark to identify the anterior genu of the petrous carotid artery (AGPCA) especially during lateral extended endoscopic endonasal approachs (LEEEAs). The objectives of this study in the Japanese population are to describe the radiological anatomic features and relationships between VC and its surrounding structures, and discuss the clinical implications. We studied 231 high-resolution computed tomography (CT) scans with a slice thickness of 0.5 mm. All the patients had known sellar or parasellar pathologies but without any involvement of VC. The following VC-related parameters were examined: its length, relationship to AGPCA, course from the pterygopalatine fossa to the carotid canal, its position relative to the medial pterygoid plate and pneumatization pattern of the sphenoid sinus. Mean length of VC is 14.6 mm. There is more tendency of straight-running VC compared to other populations. VC locates infero-lateral to AGPCA in all the cases. The protrusion of VC and the paraclival carotid artery to the sphenoid sinus, as well as well-pneumatization of the sinus is also observed more frequently in almost a half of the population. Surgeons who perform LEEEAs in Japanese patients must know these anatomical features. The characteristics particular to Japanese populations may facilitate better identification of VC and exposure to AGPCA intraoperatively.


Evidence for acetyl coenzyme A and cinnamoyl coenzyme A in the anaerobic toluene mineralization pathway in Azoarcus tolulyticus Tol-4.
A toluene-degrading denitrifier, Azoarcus tolulyticus Tol-4, was one of eight similar strains isolated from three petroleum-contaminated aquifer sediments. When the strain was grown anaerobically on toluene, 68% of the carbon from toluene was found as CO2 and 30% was found as biomass. Strain Tol-4 had a doubling time of 4.3 h, a Vmax of 50 micromol x min-1 x g of protein-1, and a cellular yield of 49.6 g x mol of toluene-1. Benzoate appeared to be an intermediate, since F-benzoates accumulated from F-toluenes and [14C]benzoate was produced from [14C]toluene in the presence of excess benzoate. Two metabolites, E-phenylitaconic acid (1 to 2%) and benzylsuccinic acid (<1%), accumulated from anaerobic toluene metabolism. These same products were also produced when cells were grown on hydrocinnamic acid and trans-cinnamic acid but were not produced from benzylalcohol, benzaldehyde, benzoate, p-cresol, or their hydroxylated analogs. The evidence supports an anaerobic toluene degradation pathway involving an initial acetyl coenzyme A (acetyl-CoA) attack in strain Tol-4, as proposed by Evans and coworkers (P. J. Evans, W. Ling, B. Goldschmidt, E. R. Ritter, and L. Y. Young, Appl. Environ. Microbiol. 58:496-501, 1992) for another toluene-degrading denitrifier, strain T1. Our findings support a modification of the proposed pathway in which cinnamoyl-CoA follows the oxidation of hydrocinnamoyl-CoA, analogous to the presumed oxidation of benzylsuccinic acid to form E-phenylitaconic acid. Cinnamic acid was detected in Tol-4 cultures growing in the presence of toluene and [14C]acetate. We further propose a second acetyl-CoA addition to cinnamoyl-CoA as the source of benzylsuccinic acid and E-phenylitaconic acid. This pathway is supported by the finding that monofluoroacetate added to toluene-growing cultures resulted in a significant increase in production of benzylsuccinic acid and E-phenylitaconic acid and by the finding that [14C]benzylsuccinic acid was detected after incubation of cells with toluene, [14C]acetate, and cinnamic acid. Evidence for anaerobic toluene metabolism by methyl group oxidation was not found, since benzylsuccinic acid and E-phenylitaconic acid were not detected after incubation with benzylalcohol and benzaldehyde, nor were benzylalcohol and benzaldehyde detected even in 14C trapping experiments.


Recent developments in optimal experimental designs for functional magnetic resonance imaging.
Functional magnetic resonance imaging (fMRI) is one of the leading brain mapping technologies for studying brain activity in response to mental stimuli. For neuroimaging studies utilizing this pioneering technology, there is a great demand of high-quality experimental designs that help to collect informative data to make precise and valid inference about brain functions. This paper provides a survey on recent developments in experimental designs for fMRI studies. We briefly introduce some analytical and computational tools for obtaining good designs based on a specified design selection criterion. Research results about some commonly considered designs such as blocked designs, and m-sequences are also discussed. Moreover, we present a recently proposed new type of fMRI designs that can be constructed using a certain type of Hadamard matrices. Under certain assumptions, these designs can be shown to be statistically optimal. Some future research directions in design of fMRI experiments are also discussed.


Characterization of strong electromagnetic field confinement on gold nanostructures by apertureless scanning near-field optical microscopy.
We report on the detection of the optical near field of a 1D gold particle array by using an apertureless scanning near-field optical microscope. The strong near-field confinement measured above the grating proves unambiguously the near-field origin of the detected optical signal. Comparing the experiment with theory leads us to assign the optical near field to the first diffracted order of the grating, which is evanescent.


Mortality due to acute adverse drug reactions: opiates and cocaine in Barcelona, 1989-93.
Drug-related deaths have become a major source of premature mortality. This paper presents an analysis of deaths due to acute adverse drug reactions caused by opiates or cocaine in the city of Barcelona over a 5-year period during which figures were stable. Annual mortality rates due to adverse drug reactions of city residents for the 1989-93 period were estimated to be 15.3 per 100,000 people in the 15-49-year age group. Mortality rates for men (25.0) are consistently higher than mortality rates for women (5.8). Mortality rates by age group show different patterns by gender. Males in the 25-29-year group have the highest mortality rate (62.8), almost doubling the rates for the 20-24 (36.1) and 30-34 (33.3)-year groups. The highest differential in age-specific mortality by gender is seen in the 35-39-year age group, where mortality rates for men (21.5) are eight times higher than for women (2.6 per 100,000). The distribution by place of residence, stratifying data across city neighbourhoods and municipal districts displays wide differences between districts in the mean annual rates, ranking between 77.3 and 8.3 per 100,000, a nine-fold magnitude. Differences are even steeper when we break down data by neighbourhood. Although all areas with high adverse drug reactions mortality are areas of low socio-economic level, a more complex association between deprivation and drug use must exist, as other areas with similarly low socio-economic indicators do not suffer from such high mortality. A cross-tabulation of place of residence and district of death shows that for most adverse drug reaction deaths, death takes place in the district of residence but patterns related to districts who attract drug-related deaths and districts who export them may be observed. These results provide new insights into the epidemiology of substance abuse in Barcelona, where it follows patterns that may be similar to those of other major urban areas in Spain, but also in other Southern European countries.


A double-blind study of dothiepin hydrochloride (Prothiaden) and amitriptyline in out-patients with masked depression.
A group of forty patients who presented to their general practitioner with depression or somatic complaints, which were considered to be due to depression, were included in a double-blind trial of dothiepin and amitriptyline. Patient improvement as judged by the Hamilton Rating Scale (HRS) and the Comprehensive Psychopathological Rating Scale (CPRS) indicated that both groups significantly improved over the 6 week period. Only in one comparison, CPRS after 1 week, was there any statistical difference between the groups and in this case dothiepin produced a better response than amitriptyline (p less than 0.05). Statistical analysis of side-effects indicated that the frequency and severity of certain individual side-effects, hypotension, tiredness/sleepiness and dry mouth were significantly less with dothiepin than with amitriptyline at Week 1 (p less than 0.05). The overall incidence and severity of side-effects was also less with dothiepin at all assessments during the trial.


Catalyst-Free Cycloaddition Reaction for the Synthesis of Glyconanoparticles.
A new conjugation method for the immobilization of carbohydrates on nanomaterials was demonstrated simply by mixing perfluorophenyl azide-functionalized silica nanoparticles (SNPs), an amine-derivatized carbohydrate, and phenylacetaldehyde under ambient conditions without any catalyst. The density of carbohydrates on the glyconanoparticles was determined using the quantitative 19F NMR (19F qNMR) technique; for example, the density of d-mannose (Man) on Man-SNPs was 2.5 ± 0.2 × 10-16 nmol/nm2. The glyconanoparticles retained their binding affinity and selectivity toward cognate lectins. The apparent dissociation constant of the glyconanoparticles was measured by a fluorescence competition assay, where the binding affinity of Man-SNPs was almost 4 orders of magnitude higher than that of Man with concanavalin A. Moreover, even with a ligand density of 2.6 times lower than Man-SNPs synthesized by the copper-catalyzed azide-alkyne cycloaddition, the binding affinity of Man-SNPs prepared by the current method was more than 4 times higher.


Coordinated change at the colony level in fruit bat fur microbiomes through time.
The host-associated microbiome affects individual health and behaviour, and may be influenced by local environmental conditions. However, little is known about microbiomes' temporal dynamics in free-living species compared with their dynamics in humans and model organisms, especially in body sites other than the gut. Here, we investigate longitudinal changes in the fur microbiome of captive and free-living Egyptian fruit bats. We find that, in contrast to patterns described in humans and other mammals, the prominent dynamics is of change over time at the level of the colony as a whole. On average, a pair of fur microbiome samples from different individuals in the same colony collected on the same date are more similar to one another than a pair of samples from the same individual collected at different time points. This pattern suggests that the whole colony may be the appropriate biological unit for understanding some of the roles of the host microbiome in social bats' ecology and evolution. This pattern of synchronized colony changes over time is also reflected in the profile of volatile compounds in the bats' fur, but differs from the more individualized pattern found in the bats' gut microbiome.


Dietary omega-3 fatty acids aid in the modulation of inflammation and metabolic health.
This article focuses on the role of omega-3 fatty acids as precursors for lipid signaling molecules known as oxylipins. Although omega-3 fatty acids are beneficial in autoimmune disorders, inflammatory diseases and heart disease, they are generally underrepresented in the American diet. A literature review confirms that the consumption of omega-3 fatty acids - whether in food sources such as walnuts, flax seeds and fatty fish (including salmon and sardines), or in supplements - is associated with decreased morbidity and mortality. This growing body of evidence, including the results of a recent study of patients with kidney disease, highlights the need to measure omega-3 fatty acids and their oxylipin products as markers of metabolic health and biomarkers of disease. In addition, there is substantial evidence of the need to increase the omega-3 fatty acid content of American diets to optimize metabolic health.


A Bayesian deep learning method for freeway incident detection with uncertainty quantification.
Incident detection is fundamental for freeway management to reduce non-recurrent congestions and secondary incidents. Recently, machine learning technologies have made considerable progress in the incident detection field, but many still face challenges in uncertainty quantification due to the aleatoric uncertainty of traffic data and the epistemic uncertainty of model deviations. In this study, a Bayesian deep learning method was proposed for freeway incident detection with uncertainty quantification. A convolutional neural network variant was designed on a Bayesian framework, and mechanisms of Bayes by backpropagation and local reparameterization technics were used to update the weight of the proposed model. The predictive uncertainty of the proposed method was modeled jointly by integrating the aleatoric and epistemic uncertainty. The proposed model was tested on the PORTAL dataset and compared with four benchmark models: standard normal deviate, wavelet neural network, long-short term memory neural network, and convolutional neural network. The results show that the proposed model outperforms the baseline methods in terms of accuracy, detection rate and false alarm rate. Perturbation experiments were used to test the robustness of the model against noise. The results indicated that the aleatoric uncertainty of the model remained almost constant under different noise levels. The proposed method may benefit future studies on uncertainty quantification while using machine learning method in incident management and other fields in intelligent transportation systems.


Inhibitory activities of dietary phenolic compounds on heterocyclic amine formation in both chemical model system and beef patties.
The correlation between radical scavenging capacity and inhibitory activity in PhIP formation of 12 food-derived antioxidative phenolic compounds was investigated. Very poor correlation was found between their radical scavenging activity assessed by Trolox equivalent antioxidant capacity assay and PhIP formation inhibition in a model system. The effects of several of these polyphenols were further evaluated using beef patties. Remarkably, theaflavin 3,3'-digallate, epicatechin gallate, rosmarinic acid, and naringenin were capable of simultaneously reducing the levels of PhIP, MeIQx, and 4,8-DiMeIQx. Moreover, the inhibition of the formation of one of these HAs was not compromised by the inhibition of the formation of another HA. Naringenin, a flavonoid found in many citrus fruits, was found to be the most promising inhibitor in both chemical model system and beef patties, suggesting its great potential for practical application in daily cuisine.


The association between paired basic amino acid cleaving enzyme 4 gene haplotype and diastolic blood pressure.
In a previously identified locus linked to hypertension on chromosome 15q, we identified three blood pressure candidate genes: insulin-like growth factor 1 receptor gene (IGF1R), myocyte specific enhancer factor 2A gene (MEF2A), and paired basic amino acid cleaving enzyme 4 gene (PACE4). In this study, we tested their associations with hypertension using haplotype analysis. A total of 288 unrelated individuals, including 163 high diastolic blood pressure (DBP) subjects and 125 normal DBP subjects were enrolled in this case-control study. Twenty single nucleotide polymorphisms (SNPs) in the three genes were genotyped using polymerase chain reaction followed by restriction enzyme digestion. Haplotype analysis was accomplished in the following stages: (1) pair-wise linkage disequilibrium test among SNPs on the same gene was performed to explore blocks in which recombination is very unlikely to happen; (2) Estimation-Maximization algorithm was applied to estimate haplotype frequencies in each block; (3) the chi-square test was used to examine the specific haplotype difference, and a permutation test was used to examine the overall haplotype profile difference between cases and controls in each block. An estimated haplotype "CCCCG" frequency in the haplotype block on the PACE4 gene was significantly higher in high DBP cases than in controls (P < 0.01). The overall estimated haplotype profile in this block was also significantly different between the cases and the controls (P < 0.001). This association indicates. This study for the first time demonstrated that PACE4 gene may play an important role in the regulation of DBP. This association indicates that variations influencing DBP resides in or near this genomic region.


Autonomic failure in neurodegenerative disorders.
Autonomic failure with orthostatic and postprandial hypotension, bowel and bladder disturbances, and sexual dysfunction are frequent, disabling features in patients with the three most prevalent neurodegenerative movement disorders: Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA), and the related neurodegenerative Lewy-body disorder characterized by isolated severe autonomic failure (pure autonomic failure, PAF). All of these disorders have in common the presence of alpha-synuclein in the cytoplasmic precipitates found in neurons in Lewy body disorders or glia in MSA. Autonomic failure with disabling orthostatic hypotension is the clinical hallmark of PAF. It may also be the initial presentation of MSA, making diagnosis difficult. Within a few years, however, MSA patients develop movement disorders, which are differentiated from PD by the paucity of unilateral resting tremor, the lack of response to levodopa, and their rapidly progressive nature, resulting in disability and death in 7 to 8 years. Moderately effective treatment is available for autonomic symptoms, but management of movement disorders remains unsuccessful. Discoveries relevant to physiology and common pathological conditions were initially made in patients with autonomic failure. Meals induce profound hypotension in these patients. Conversely, commonly used nasal decongestants can produce substantial pressor effects. Even 500 mL of water can increase blood pressure by a previously unrecognized sympathetic reflex. Residual sympathetic tone is able to induce sustained supine hypertension in MSA, because it is resolved after ganglionic blockade. These phenomena were not previously recognized because of the buffering capacity of the baroreflex, but were unmasked in autonomic failure patients.


Developing a random forest classifier for predicting the depression and managing the health of caregivers supporting patients with Alzheimer's Disease.
Supporting the caregivers of dementia patients is an important issue in the field of public health. This study established a model for predicting the depression of dementia caregivers while considering the sociodemographic and health science characteristics of South Koreans. The results of this study provided baseline data for developing and applying a caregiver management App. This study analyzed 2,592 adults (⩾ 19 years old; 1154 men and 1438 women) who were caregivers (e.g., family and caregivers) of demented elderly (⩾ 60 years old). The results of developed random forest model showed that gender, subjective health status, disease or accidence experience within the past two weeks, the frequency of meeting a relative, economic activity, and monthly mean household income were the major predictors for the depression of caregivers. The prediction accuracy of the model was better than K-NN and support vector machine. It was proved that the developed random forest-based App for predicting and managing the depression of dementia caregivers used an algorithm that has a high predictive power. It is required to develop a customized home care system that can prevent and manage the depression of the caregiver.


A comparative study of histochemical mapping on the distribution of acid phosphatase and 5-nucleotidase in the forebrain of frog (Rana tigrina).
The four well defined dorsal, lateral, medial and intermediate olfactory tracts of the frog have been studied. During their courses they become intermingled with fibers related to the primordial septum, the primordial hippocampus, the primordial dorsal pallium and the primordial piriform areas. In acid phosphatase preparations all these tracts are completely negative, and, therefore, are not identifiable. However, these tracts have intense staining reaction to 5-nucleotidase throughout their courses. Differences in the distribution of acid phosphatase and 5-nucleotidase are apparent in the hippocampal and anterior commissures. These are negative for acid phosphatase. In 5-nucleotidase preparations the anterior commissure has an intensely positive whereas the hippocampal commissure has a completely negative reaction. The medial septal nucleus is intensely positive for 5-nucleotidase at the anterior hemisphere level. There is a gradual decrease in intensity of staining in this nucleus towards the posterior hemisphere levels so that in the last few sections of the forebrain of the frog the medial septal nucleus is completely unstained or negative. In the acid phosphatase preparations at all levels the medial septal nucleus presents a moderately positive reaction. In 5-nucleotidase preparations, the dorsomedial part of primordial hippocampus is intensely positive whereas the dorsal part of the hippocampus is completely negative. In acid phosphatase preparations, both dorsal and dorsomedial parts of hippocampus are intensely positive. The striatal complex and the lateral septal nucleus are positive for acid phosphatase and negative for 5-nucleotidase. The possible significance of some of these similarities and differences in tracts and nuclei has been considered with reference to the functioning of the various parts. The present histoenzymological preparations have revealed distinct nerve pathways. In some instances clear-cut connections, which had hitherto been unrevealed by neuroanotomical methods, have been demonstrated.


Marijuana: interaction with the estrogen receptor.
Crude marijuana extract competed with estradiol for binding to the estrogen receptor of rat uterine cytosol. Condensed marijuana smoke also competed with estradiol for its receptor. Pure delta 9-tetrahydrocannabinol, however, did not interact with the estrogen receptor. Ten delta 9-tetrahydrocannabinol metabolites also failed to compete with estradiol for its receptor. Of several other common cannabinoids tested, only cannabidiol showed any estrogen receptor binding. This was evident only at very high concentrations of cannabidiol. Apigenin, the aglycone of a flavinoid phytoestrogen found in cannabis, displayed high affinity for the estrogen receptor. To assess the biological significance of these receptor data, estrogen activity was measured in vivo with the uterine growth bioassay, using immature rats. Cannabis extract in large doses exhibited neither estrogenic nor antiestrogenic effects. Thus, although estrogen receptor binding activity was observed in crude marijuana extract, marijuana smoke condensate and several known components of cannabis, direct estrogenic activity of cannabis extract could not be demonstrated in vivo.


A new fracture assessment approach coupling HR-pQCT imaging and fracture mechanics-based finite element modeling.
A new fracture assessment approach that combines HR-pQCT imaging with fracture mechanics-based finite element modeling was developed to evaluate distal radius fracture load. Twenty distal radius images obtained from postmenopausal women (fracture, n=10; nonfracture, n=10) were processed to obtain a cortical and a whole bone model for each subject. The geometrical properties of each model were evaluated and the corresponding fracture load was determined under realistic fall conditions using cohesive finite element modeling. The results showed that the whole bone fracture load can be estimated based on the cortical fracture load for nonfracture (R(2)=0.58, p=0.01) and pooled data (R(2)=0.48, p<0.001) but not for the fracture group. The portion of the whole bone fracture load carried by the cortical bone increased with increasing cortical fracture load (R(2)≥0.5, p<0.05) indicating that a more robust cortical bone carries a larger percentage of whole bone fracture load. Cortical thickness was found to be the best predictor of both cortical and whole bone fracture load for all groups (R(2) range: 0.49-0.96, p<0.02) with the exception of fracture group whole bone fracture load showing the predictive capability of cortical geometrical properties in determining whole bone fracture load. Fracture group whole bone fracture load was correlated with trabecular thickness (R(2)=0.4, p<0.05) whereas the nonfracture and the pooled group did not show any correlation with the trabecular parameters. In summary, this study introduced a new modeling approach that coupled HR-pQCT imaging with fracture mechanics-based finite element simulations, incorporated fracture toughness and realistic fall loading conditions in the models, and showed the significant contribution of the cortical compartment to the overall fracture load of bone. Our results provide more insight into the fracture process in bone and may lead to improved fracture load predictions.


High School Students' Online Learning Ineffectiveness in Experimental Courses During the COVID-19 Pandemic.
Due to the COVID-19 pandemic, online learning has been adopted in all stages of education. This sudden change from traditional learning to 100% online learning may affect students' learning effectiveness, especially in experimental courses. However, there has been little discussion of experimental courses conducted entirely through online learning. To address this gap, the present study investigated factors affecting high school students' online learning ineffectiveness (OLI) in online experimental courses, particularly online science experimental courses. The role of gender was also explored to understand whether it affects participants' OLI. An ANOVA was conducted to analyze the data from a survey of 347 online learners in high schools. The results indicated that the number of online experimental courses and the duration of online hands-on learning were negatively related to the high school students' OLI. Meanwhile, the study found that the high school participants' OLI differed by gender, with female students more likely than males to have OLI in the context of online learning. The results of this study can provide a reference for teachers who conduct online experimental courses and wish to improve their online teaching, not only during the COVID-19 lockdown, but also in other pandemic periods.


PRNP M129V homozygosity in multiple system atrophy vs. Parkinson's disease.
Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown etiology characterized by extrapyramidal, pyramidal, cerebellar, and autonomic dysfunction in any combination. We report a patient with a 4-year history of MSA who developed dementia associated with sporadic Creutzfeldt-Jakob disease (CJD). Our proband was MM homozygous for the M129V polymorphism within the prion protein gene (PRNP), a known risk factor for CJD. We conducted a case-control study to test the hypothesis that homozygosity for the M129V polymorphism of PRNP occurs more frequently in MSA in comparison to Parkinson's disease and healthy volunteers. A total of 63 patients with MSA, 54 age-, race- and gendermatched controls with Parkinson's disease, and 126 matched healthy volunteers were studied. The genotype analysis revealed no significant difference in the codon 129 genotype distribution in MSA as compared to controls. Nonetheless, the frequencies of the MM and VV genotypes were higher in MSA than in Parkinson's disease. Thus, homozygosity, particularly VV homozygosity, at codon 129 of PRNP is associated with MSA compared to a clinically related but pathophysiologically distinct alpha-synucleinopathy. Considering the possibility that the prion protein contributes to the pathogenesis of MSA would require confirmation of these findings in an independent patient population.


Incidence and Significance of Spontaneous ST Segment Re-elevation After Reperfused Anterior Acute Myocardial Infarction - Relationship With Infarct Size, Adverse Remodeling, and Events at 1 Year.
Up to 25% of patients with ST elevation myocardial infarction (STEMI) have ST segment re-elevation after initial regression post-reperfusion and there are few data regarding its prognostic significance.Methods and Results:A standard 12-lead electrocardiogram (ECG) was recorded in 662 patients with anterior STEMI referred for primary percutaneous coronary intervention (PPCI). ECGs were recorded 60-90 min after PPCI and at discharge. ST segment re-elevation was defined as a ≥0.1-mV increase in STMax between the post-PPCI and discharge ECGs. Infarct size (assessed as creatine kinase [CK] peak), echocardiography at baseline and follow-up, and all-cause death and heart failure events at 1 year were assessed. In all, 128 patients (19%) had ST segment re-elevation. There was no difference between patients with and without re-elevation in infarct size (CK peak [mean±SD] 4,231±2,656 vs. 3,993±2,819 IU/L; P=0.402), left ventricular (LV) ejection fraction (50.7±11.6% vs. 52.2±10.8%; P=0.186), LV adverse remodeling (20.1±38.9% vs. 18.3±30.9%; P=0.631), or all-cause mortality and heart failure events (22 [19.8%] vs. 106 [19.2%]; P=0.887) at 1 year. Among anterior STEMI patients treated by PPCI, ST segment re-elevation was present in 19% and was not associated with increased infarct size or major adverse events at 1 year.