Altered transition state for the reaction of an RNA model catalyzed by a dinuclear zinc(II) catalyst.
The cyclization of 2-(hydroxypropyl)-4-nitrophenyl phosphate (HpPNP) catalyzed by the dinuclear zinc complex of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane (1) proceeds by a transition state that is different from that of the uncatalyzed reaction. Kinetic isotope effects (KIEs) measured in the nucleophilic atom and in the leaving group show that the uncatalyzed cyclization has a transition state (TS) with little phosphorus-oxygen bond fission to the leaving group ((18)k(lg) = 1.0064 +/- 0.0009 and (15)k = 1.0002 +/- 0.0002) and that nucleophilic bond formation occurs in the rate-determining step ((18)k(nuc) = 1.0326 +/- 0.0008). In the catalyzed reaction, larger leaving group isotope effects ((18)k(lg) = 1.0113 +/- 0.0005 and (15)k = 1.0015 +/- 0.0005) and a smaller nucleophile isotope effect ((18)k(nuc) = 1.0116 +/- 0.0010) indicate a later TS with greater leaving group bond fission and greater nucleophilic bond formation. These observed nucleophile KIEs are the combined effect of the equilibrium effect on deprotonation of the 2'-hydroxyl nucleophile and the KIE on the nucleophilic step. An EIE of 1.0245 for deprotonation of the hydroxyl group of HPpNP was obtained computationally. The different KIEs for the two reactions indicate that the effective catalysis by 1 is accompanied by selection for an altered transition state, presumably arising from the preferential stabilization by the catalyst of charge away from the nucleophile and toward the leaving group. These results demonstrate the potential for a catalyst using biologically relevant metal ions to select for an altered transition state for phosphoryl transfer.


[The pro-angiogenesis effect of Pitavastatin in the Klotho gene-knockout mice].
To discuss the effect of Pitavastatin on angiogenesis in vivo and its mechanism in Klotho heterozygous deficient mice. The heterozygous deficient Klotho mice (kl +/-) and wild mice (kl +/+) from the same litter were used to establish the animal model of hind-limb ischemia and grouped into control and Pitavastatin group, respectively. Hind-limb blood flow was evaluated using Laser Doppler perfusion imager (LDPI) before treatment and after operation of hind-limbs. The capillaries in muscle of limbs were counted by means of CD-31 labeled immuno-fluorescence. The phosphorylation of Akt (Protein kinase B) in cells was measured by direct immunohistochemical technique. The expression of vascular endothelial growth factors (VEGFs) in muscle of limbs was assessed using Western blotting. After treatment of Pitavastatin, the blood flow in ischemic limbs of the Kl +/- and wild mice improved obviously, the ratio of blood flow area in ischemic limb to that in non-ischemic limb increased and the density of capillaries increased in ischemic limbs of the Kl +/- and wild mice. Pitavastatin enhanced the phosphorylation of Akt and the expression of VEGF in ischemic limbs of the Kl +/- and wild mice. Pitavastatin has the pro-angiogenesis effect in vivo and the VEGF-p-Akt-NO pathway may be involved in the mechanism of the effect of Pitavastatin.


Associations of Conifer-Infesting Bark Beetles and Fungi in Fennoscandia.
Bark beetles (Coleoptera, Scolytinae) have a widespread association with fungi, especially with ophiostomatoid fungi (Ascomycota) that cause blue staining of wood, and in some cases, serious tree diseases. In Fennoscandia, most studies of these fungi have focused on economically important bark beetle species and this is likely to have led to a biased view of the fungal biodiversity in the region. Recently, the associations between fungi and bark beetles in Fennoscandia have been shown to be more diverse than previously thought. Furthermore, they form complex and dynamic associations that are only now beginning to emerge. This review examines the current knowledge of the rather poorly known interactions between bark beetles, fungi and their conifer host trees in Fennoscandia. The diversity of ophiostomatoid species is discussed and the possible factors that influence the assemblages of fungal associates are considered for all species that are known to occur in the region. For many ophiostomatoid species found in Fennoscandia, little or nothing is known regarding their pathogenicity, particularly if they were to be transferred to new environments. We, therefore, draw attention to the possible threats of timber trade and climate change-induced invasions of new habitats by bark beetles and the fungi that can be moved along with them.


Generation of Hierarchically Ordered Structures on a Polymer Film by Electrohydrodynamic Structure Formation.
The extensive applications of hierarchical structures in optoelectronics, micro/nanofluidics, energy conservation, etc., have led to the development of a variety of approaches for their fabrication, which can be categorized as bottom-up or top-down strategies. Current bottom-up and top-down strategies bear a complementary relationship to each other due to their processing characteristics, i.e., the advantages of one method correspond to the disadvantages of the other, and vice versa. Here we propose a novel method based on electrohydrodynamic structure formation, aimed at combining the main advantages of the two strategies. The method allows the fabrication of a hierarchically ordered structure with well-defined geometry and high mechanical durability on a polymer film, through a simple and low-cost process also suitable for mass-production. In this approach, upon application of an electric field between a template and a substrate sandwiching an air gap and a polymer film, the polymer is pulled toward the template and further flows into the template cavities, resulting in a hierarchical structure with primary and secondary patterns determined by electrohydrodynamic instability and by the template features, respectively. In this work, the fabrication of a hierarchical structure by electrohydrodynamic structure formation is studied using numerical simulations and experimental tests. The proposed method is then employed for the one-step fabrication of a hierarchical structure exhibiting a gradual transition in the periodicity of the primary structure using a slant template and a flat polymer film, which presents an excellent performance on controllable wettability.


[Early use of CT in the management of acute diverticulitis of the colon].
To assess the early use of CT for the diagnosis, staging, and management of acute diverticulitis. A prospective study of 102 patients with a clinical diagnosis of acute diverticulitis of the left colon. Acute diverticulitis was initially divided into 3 clinical stages. Patients were restaged according to CT findings into stages I, IIa, IIb, and III. Diagnosis was subsequently confirmed intraoperatively or by colonoscopy or barium studies. 102 patients (52 females and 50 males, mean age of 59.4 (SD + 14.96 years)) were included; 84 (82.35%) patients with a clinical diagnosis of acute diverticulitis were confirmed to suffer this disease for a diagnostic error of 17.65% (n=18). Acute diverticulitis was diagnosed by CT in 84.3% (n=86). CT had a sensitivity of 100% and a specificity of 88.9%. CT changed clinical stage for 38% of patients because of understaging in 13% and of overstaging in 25%. When stages II and III were analyzed separately, 60 and 50% were overstaged, respectively. The reclassification of patients according to CT results had a significant impact on treatment. Early clinical staging with CT avoids diagnostic clinical errors in 17.65% of patients. CT changes the initial clinical staging of acute episodes in 38% of cases, thus avoiding unnecessary delays in surgery for severe cases, and unnecessary surgeries for mild cases.


Bilateral cystoid macular edema with giant retinal achromic patch in a patient with tuberous sclerosis.
Retinal astrocytic hamartoma is the most common retinal finding in tuberous sclerosis and has been reported in association with cystoid macular edema. A retinal achromic patch is the second most common retinal finding in tuberous sclerosis. The authors report the first case of bilateral cystoid macular edema in which one the eyes does not have an identifiable retinal astrocytic hamartoma. They also describe a new retinal finding in tuberous sclerosis termed giant retinal achromic patch.


[A model of retinal ischemia: clinicofunctional and histological studies].
A new procedure is proposed for the experimental simulation of retinal ischemia, which develops the latter of the preset area and depth. The clinical and morphofunctional characteristics of retinal ischemia are given. Simulation of retinal ischemia via the photocoagulation effect of argon laser on the rabbit great retinal vessels demonstrated an inflammatory reaction, followed by occlusion and the development of ischemia in the blood-supplied retinal layers, vascular endothelial damage at the site of laser coagulation. There was a persistent (as long as 3 weeks) impairment in retinal electrogenesis with two-phase changes in the amplitude of a- and b-waves on an electroretinogram and in the hypoxia index b/a. Histological studies showed that evolving ischemia afflicted the internal retinal layers, primarily involving the layer ofganglionic cells and nerve fibers, which was also attended by a significant reduction in the level of venous outflow and, thus, it was of mixed (arteriovenous) nature.


COVID-19 Interconnectedness: Health Inequity, the Climate Crisis, and Collective Trauma.
The COVID-19 pandemic brings to the forefront the complex interconnected dilemmas of globalization, health equity, economic security, environmental justice, and collective trauma, severely impacting the marginalized and people of color in the United States. This lack of access to and the quality of healthcare, affordable housing, and lack of financial resources also continue to have a more significant impact on documented and undocumented immigrants. This paper aims at examining these critical issues and developing a framework for family therapists to address these challenges by focusing on four interrelated dimensions: cultural values, social determinants of health, collective trauma, and the ethical and moral responsibility of family therapists. Given the fact that family therapists may unwittingly function as the best ally of an economic and political system that perpetuates institutionalized racism and class discrimination, we need to utilize a set of principles, values, and practices that are not just palliative or after the fact but bring forth into the psychotherapeutic and policy work a politics of care. Therefore, a strong call to promote and advocate for the broader continuum of health and critical thinking preparing professionals to meet the challenges of health equity, as well as economic and environmental justice, is needed. The issues discussed in this paper are specific to the United States despite their relevance to family therapy as a field. We are mindful not to generalize the United States' reality to the rest of the world, recognizing that issues discussed in this paper could potentially contribute to international discourse.


Filling the Gaps in Antagonist CCR5 Binding, a Retrospective and Perspective Analysis.
The large number of pathologies that position CCR5 as a central molecular determinant substantiates the studies aimed at understanding receptor-ligand interactions, as well as the development of compounds that efficiently block this receptor. This perspective focuses on CCR5 antagonism as the preferred landscape for therapeutic intervention, thus the receptor active site occupancy by known antagonists of different origins is overviewed. CCL5 is a natural agonist ligand for CCR5 and an extensively studied scaffold for CCR5 antagonists production through chemokine N-terminus modification. A retrospective 3D modeling analysis on recently developed CCL5 mutants and their contribution to enhanced anti-HIV-1 activity is reported here. These results allow us to prospect the development of conceptually novel amino acid substitutions outside the CCL5 N-terminus hotspot. CCR5 interaction improvement in regions distal to the chemokine N-terminus, as well as the stabilization of the chemokine hydrophobic core are strategies that influence binding affinity and stability beyond the agonist/antagonist dualism. Furthermore, the development of allosteric antagonists topologically remote from the orthosteric site (e.g., intracellular or membrane-embedded) is an intriguing new avenue in GPCR druggability and thus a conceivable novel direction for CCR5 blockade. Ultimately, the three-dimensional structure elucidation of the interaction between various ligands and CCR5 helps illuminate the active site occupancy and mechanism of action.


CRIP1a inhibits endocytosis of G-protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism.
The excitability of the central nervous system depends largely on the surface density of neurotransmitter receptors. The endocannabinoid receptor 1 (CB1 R) and the metabotropic glutamate receptor mGlu8 R are expressed pre-synaptically where they reduce glutamate release into the synaptic cleft. Recently, the CB1 R interacting protein cannabinoid receptor interacting protein 1a (CRIP1a) was identified and characterized to regulate CB1 R activity in neurons. However, underlying molecular mechanisms are largely unknown. Here, we identified a common mechanism used by CRIP1a to regulate the cell surface density of two different types of G-protein coupled receptors, CB1 R and mGlu8a R. Five amino acids within the CB1 R C-terminus were required and sufficient to reduce constitutive CB1 R endocytosis by about 72% in the presence of CRIP1a. Interestingly, a similar sequence is present in mGlu8a R and consistently, endocytosis of mGlu8a R depended on CRIP1a, as well. Docking analysis and molecular dynamics simulations identified a conserved serine in CB1 R (S468) and mGlu8a R (S894) that forms a hydrogen bond with the peptide backbone of CRIP1a at position R82. In contrast to mGlu8a R, the closely related mGlu8b R splice-variant carries a lysine (K894) at this position, and indeed, mGlu8b R endocytosis was not affected by CRIP1a. Chimeric constructs between CB1 R, mGlu8a R, and mGlu8b R underline the role of the identified five CRIP1a sensitive amino acids. In summary, we suggest that CRIP1a negatively regulates endocytosis of two different G-protein coupled receptor types, CB1 R and mGlu8a R.


Efficacy of switching to infliximab in patients with Crohn's disease with loss of response to adalimumab.
Anti-TNF monoclonal antibodies are a cornerstone in the treatment of Crohn's disease. Prospective data on switching from the subcutaneous and human adalimumab (ADM) to the intravenous and chimeric infliximab (IFX) are scarce. In this prospective, observational, multicentre cohort study we included 21 patients with loss of response to ADM despite at least 4 consecutive weekly injections. Clinical response (CDAI drop≥70 points) and remission (CDAI≤150) were assessed after switching from ADM to IFX after 10 weeks, 6 and 12 months. Predictive factors of response/remission, the need for therapy intensification, discontinuation and safety were investigated. Short-term response and remission (10 weeks) were seen in 57% and 48% respectively. Mid- and long-term clinical response and remission were achieved in 40% and 25% after 6 months and in 45% and 20% after 12 months respectively. At 12 months, 81% still were on IFX. IFX therapy intensification was needed in half of the patients at 6 months and three quarter of patients at 12 months. Undetectable ADM trough levels (despite weekly injections) were a predictive factor for short-term response and remission to IFX. About half of the patients with response at week 10 maintained response at 6 and 12 months. Switching from ADM to IFX can be efficacious in patients with loss of response, in particular in case of undetectable ADM trough levels. The majority of patients however will need IFX therapy intensification during their first year of treatment.


Identification of genetic risk factors based on disease progression derived from longitudinal brain imaging phenotypes.
Neurodegenerative disorders usually happen stage-by-stage rather than overnight. Thus, cross-sectional brain imaging genetic methods could be insufficient to identify genetic risk factors. Repeatedly collecting imaging data over time appears to solve the problem. But most existing imaging genetic methods only use longitudinal imaging phenotypes straightforwardly, ignoring the disease progression trajectory which might be a more stable disease signature. In this paper, we propose a novel sparse multi-task mixed-effects longitudinal imaging genetic method (SMMLING). In our model, disease progression fitting and genetic risk factors identification are conducted jointly. Specifically, SMMLING models the disease progression using longitudinal imaging phenotypes, and then associates fitted disease progression with genetic variations. The baseline status and changing rate, i.e., the intercept and slope, of the progression trajectory thus shoulder the responsibility to discover loci of interest, which would have superior and stable performance. To facilitate the interpretation and stability, we employ ℓ2,1-norm and the fused group lasso (FGL) penalty to identify loci at both the individual level and group level. SMMLING can be solved by an efficient optimization algorithm which is guaranteed to converge to the global optimum. We evaluate SMMLING on synthetic data and real longitudinal neuroimaging genetic data. Both results show that, compared to existing longitudinal methods, SMMLING can not only decrease the modeling error but also identify more accurate and relevant genetic factors. Most risk loci reported by SMMLING are missed by comparison methods, implicating its superiority in genetic risk factors identification. Consequently, SMMLING could be a promising computational method for longitudinal imaging genetics.


A carboxy terminal BMP/TGF-β binding site in secreted phosphoprotein 24 kD independently affects BMP-2 activity.
Secreted phosphoprotein 24 kD (spp24) is a bone matrix protein isolated during attempts to identify osteogenic proteins. It is not osteogenic but performs other important roles in the regulation of bone metabolism, at least in part, by binding to and affecting the activity of members of the BMP/TGF-β family of cytokines. Spp24 exists in a number of forms that preserve the N-terminus and are truncated at the C-terminus. The hypothesized cytokine binding domain is present within the cystatin domain which is preserved in all of the N-terminal products. In this report, we describe a C-terminal fragment that is distinct from the cystatin domain and which independently binds to BMP-2 and TGF-β. This fragment inhibited BMP-2 activity in an ectopic bone forming assay. A shorter C-terminal product did not inhibit BMP-2 activity but improved bone quality induced by BMP-2 and produced increased calcium deposition outside of bone. Spp24 has been used to develop several potential therapeutic proteins. These results provide more information on the function of spp24 and provide other materials that can be exploited for clinical interventions.


Conservative methods for reducing lateral translation postures of the head: a nonrandomized clinical control trial.
Fifty-one retrospective, consecutive patients were compared to twenty-six prospective volunteer controls in a nonrandomized clinical control trial. Both groups had chronic neck pain and lateral head translation posture. For treatment subjects, beginning and follow-up pain scales and anteroposterior (AP) cervical radiographs were obtained after 12.8 weeks of care (average of 37 visits), while the duration was a mean of 12 months for control subjects. Digitized radiographs were analyzed for Risser-Ferguson angles and a horizontal translation distance of C2 from a vertical line through T3. For treatment, patients received the Harrison mirror-image postural methods, which include mechanically assisted manipulation, opposite head posture exercise, and opposite head translation posture traction. While no significant differences were found in the control group subjects' pain scores and AP radiographic measurements, statistically significant improvements were observed in the treatment group subjects' pain scores and lateral translation displacements of C2 compared to T3 (pretrial score: 13.7 mm, posttrial score: 6.8 mm) and in angle measurements.


3DinSight: an integrated relational database and search tool for the structure, function and properties of biomolecules.
Although a large amount of information on the structure, function and properties of biomolecules is becoming available, it is difficult to understand the relationship between them. Thus, we have attempted to create an integrated relational database, search and visualization tool, 3DinSight, to help researchers to gain insight into their relationship. We have gathered data on the structure, function and properties of biomolecules, and implemented them into a relational database system. The structural data contain several subset data such as protein homologues, protein-DNA complex, in order to enable searching within a specific class of data. The functional data include motif sequence and mutation data of proteins. Also, various amino acid properties are implemented as a relational table. The World Wide Web (WWW) interfaces enable users to carry out various kinds of searches among these data. The locations of motif sequences and mutations are automatically mapped on the structure, and visualized in three-dimensional (3D) space by interactive viewers, VRML (Virtual Reality Modeling Language) and RasMol. In the case of VRML, the mapped 3D objects are hyper-linked to the corresponding document data. Also, amino acid properties, linked with structure, functional and mutation sites, can be displayed as graph plots. 3DinSight is freely accessible through the Internet (http://www.rtc.riken.go.jp/3DinSight.h tml). firstname.lastname@example.com


Incidental nonuterine high-grade serous carcinomas arise in the fallopian tube in most cases: further evidence for the tubal origin of high-grade serous carcinomas.
Most nonuterine high-grade serous carcinomas (HGSCs) in women with hereditary breast and ovarian cancer syndrome, due to germline BRCA1/2 mutation, arise in the fimbria of the fallopian tube. However, the site of origin of sporadic HGSC, which is usually widely disseminated at presentation, is not well established. We sought to characterize cases of HGSC discovered incidentally in patients not known to be at high risk, in order to determine the site distribution and possible origin of sporadic HGSC. Incidental microscopic, non-mass-forming cases of serous tubal intraepithelial carcinoma or HGSC in salpingo-oophorectomy specimens in which the tubes and ovaries had been extensively examined were identified. No patients were known or suspected BRCA1/2 mutation carriers. Twenty-one cases were identified (mean age: 57 y). Surgery was for benign disease (n=15), uterine endometrioid adenocarcinoma or atypical hyperplasia (n=3), bladder carcinoma (n=1), or ovarian serous borderline tumor (n=2). In 16 of 21 cases, the lesion was confined to the fallopian tube (unilateral in 14 cases, bilateral in 2). There was serous tubal intraepithelial carcinoma in all cases and invasive HGSC into the underlying lamina propria in 8 of these 16 cases; the invasive focus measured 1.3 cm or less in every case. In the remaining 5 cases, there was fallopian tube mucosal and ovarian involvement; in 2 of these cases, there was also microscopic peritoneal involvement. Sporadic cases of nonuterine HGSC arise in the fallopian tube fimbria in a large majority of cases, providing further evidence for the tubal origin of these neoplasms.


Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival.
We assessed the prognostic impact of genitourinary small cell carcinoma tumor and patient characteristics, and therapy. We retrospectively reviewed the records of 180 patients with genitourinary small cell carcinoma in which patient and tumor characteristics, therapy, followup duration and survival status had been documented. Patient age, sex, primary site, histological features, tumor size, stage, locoregional therapy, systemic chemotherapy and hormonal manipulations were analyzed for association with survival. There were 106 cases of bladder, 60 prostatic, 8 renal and 6 ureteral small cell carcinoma. Median survival was 10.5 months overall, and 7 and 13 months for prostatic and bladder small cell carcinoma, respectively (p <0.0001 log rank analysis). In all cases metastatic disease at presentation (p <0.008, risk ratio 1.9) predicted poor survival on multivariate analysis. Radical surgery (p <0.0001, risk ratio 0.34) and cisplatin chemotherapy (p <0.0001, risk ratio 0.20) were the only factors that predicted improved survival on multivariate analysis. For prostatic small cell carcinoma primary surgical therapy (p <0.012, risk ratio 0.46) was the only parameter that predicted survival on univariate analysis. For bladder small cell carcinoma only cisplatin chemotherapy (p <0.0001, risk ratio 0.15) predicted survival on multivariate analysis. Genitourinary small cell carcinoma has a poor prognosis, which is worse in prostatic than bladder disease. Patient and tumor characteristics were not determinants of survival when prostatic and bladder small cell carcinoma were analyzed individually. For prostatic disease only primary surgical therapy was associated with prolonged survival, while for bladder disease cisplatin chemotherapy was associated with a favorable prognosis. We recommend considering primary surgical therapy for prostatic and cisplatin based chemotherapy for bladder small cell carcinoma.


Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction.
Sleep homeostasis is the process by which recovery sleep is generated by prolonged wakefulness. The molecular mechanisms underlying this important phenomenon are poorly understood. We have previously shown that nitric oxide (NO) generation increases in the basal forebrain (BF) during sleep deprivation (SD). Moreover, both NO synthase (NOS) inhibition and a NO scavenger prevented recovery sleep induction, while administration of a NO donor during the spontaneous sleep-wake cycle increased sleep, indicating that NO is necessary and sufficient for the induction of recovery sleep. Next we wanted to know which NOS isoform is involved in the production of recovery sleep. Using in vivo microdialysis we infused specific inhibitors of NOS into the BF of rats during SD, and found that an inhibitor of inducible NOS (iNOS), 1400W, prevented non-rapid eye movement (NREM) recovery, while an inhibitor of neuronal NOS (nNOS), L-N-propyl-arginine, decreased REM recovery but did not affect NREM recovery. Using immunoblot analysis we found that iNOS was not expressed during the spontaneous sleep-wake cycle, but was induced by prolonged wakefulness (increased by 278%). A known iNOS inducer, lipopolysaccharide, evoked an increase in sleep that closely resembled recovery sleep, and its effects were abolished by 1400W. These results suggest that the elevation of NO produced by induction of iNOS in the BF during prolonged wakefulness is a specific mechanism for producing NREM recovery sleep and that the two NOS isoforms have a complementary role in NREM and REM recovery induction.


Human papillomavirus as a risk factor in oral carcinogenesis: a study using in situ hybridization with signal amplification.
It is still controversial whether human papillomavirus (HPV) can be considered a risk factor in oral carcinogenesis. The aim of this study was to detect HPV DNA in 50 cases diagnosed as oral leukoplakias, with different degrees of epithelial dysplasia, and as oral squamous cell carcinomas, using in situ hybridization with signal amplification (CSA-ISH). HPV DNA was assessed in paraffin sections using CSA-ISH with a wide-spectrum biotinylated DNA probe. In HPV-positive cases, genotyping with specific probes to HPV types 6/11, 16/18 and 31/33 was performed. The overall prevalence of HPV infection was 24%, markedly higher than that found in the control group. Results showed a discrete proportional relationship in the indices found in leukoplakia with no dysplasia, leukoplakia with dysplasia, and squamous cell carcinoma, but this was not statistically significant. When separating the group of leukoplakia by degrees of dysplasia, this relation of proportion was not observed. In genotyping, HPV types 16/18 were the most prevalent, and types 6/11 were only found in groups of mild or no dysplasia. The results suggest that HPV is not likely to play a role in the progression of malignant transformation in oral lesions. Nevertheless, the increased prevalence of HPV infection compared to normal oral mucosa and the fact that high-risk HPV types were the most frequently identified do not allow the exclusion of HPV as a risk factor in oral carcinogenesis.


Moebius syndrome: clinical features, diagnosis, management and early intervention.
Moebius syndrome (MBS) is rare disease characterized by nonprogressive congenital uni- or bi-lateral facial (i. e. VII cranial nerve) and abducens (i. e. VI cranial nerve) palsy. Although the neurological and ophthalmological findings are quite well-known, data concerning the attendant functional difficulties and their changes over time are seldom addressed. In this study we attempt to estimate the prevalence of clinical and functional data in an Italian cohort affected by MBS. The study included 50 children, 21 males and 29 females, aged 1 month to 14 years. The patients entered into a multidisciplinary diagnostic and follow-up protocol that had the specific purpose of detecting clinical and developmental deficits related to MBS. Involvement of the VII cranial nerve (total/partial, bilateral or unilateral) was present in 96 % of patients, and of the VI nerve in 85 %. Two patients were without impairment of the VII nerve and seven patients had no involvement of the VI nerve and were thus classified as Moebius-like because of the involvement of other CNs. Additional affected CNs were numbers III-IV in 16 %, V in 11 %, VIII and X each in 8 %, the XI in 6 %, the IX, most often partially, in 22 %, and the XII in 48 % of cases. Their development was characterized by global delay at one year of age, motor, emotional and speech difficulties at two years of age, a trend toward normalization at three years of age but with weakness in hand-eye coordination, and achieving average results at five years of age. Overall 90 % of children had a normal developmental quotient whereas only 10 % manifested cognitive deficits. Early rehabilitation may enhance the recovery of normal function, particularly in vulnerable areas of development. It is possible that early intervention that integrates sensory and visual information with emotional difficulties can improve the prognosis of the child with MBS.


Leptophilic dark matter from the lepton asymmetry.
We present a model of weak scale dark matter (DM) where the thermal DM density is set by the lepton asymmetry due to the presence of higher dimension lepton violating operators. In these models there is generically a separation between the annihilation cross section responsible for the relic abundance (through lepton violating operators) and the annihilation cross section that is relevant for the indirect detection of DM (through lepton preserving operators). This implies a perceived boost in the annihilation cross section in the Galaxy today relative to that derived for canonical thermal freeze-out, giving a natural explanation for the observed cosmic ray electron and positron excesses, without resorting to a Sommerfeld enhancement. These models motivate continued searches for DM with apparently nonthermal annihilation cross sections. The DM may also play a role in radiatively generating Majorana neutrino masses.


Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour.
This is an update of the original review that was published in The Cochrane Database of Systematic Reviews, 2009, Issue 2. Gestational trophoblastic neoplasia (GTN) are malignant disorders of the placenta that include invasive hydatidiform mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). Choriocarcinoma and invasive hydatidiform mole respond well to chemotherapy: low-risk tumours are treated with single-agent chemotherapy (e.g. methotrexate or actinomycin D), whereas high-risk tumours are treated with combination chemotherapy (e.g. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine)). Various drug combinations may be used for high-risk tumours; however, the comparative efficacy and safety of these regimens is not clear. To determine the efficacy and safety of combination chemotherapy in treating high-risk GTN. For the original review, we searched the Cochrane Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2008), MEDLINE, EMBASE and CBM in May 2008. For the updated review, we searched Cochrane Group Specialised Register, CENTRAL, MEDLINE and EMBASE to September 2012. In addition, we searched online clinical trial registries for ongoing trials. Randomised controlled trials (RCTs) and quasi-RCTs comparing first-line combination chemotherapy interventions in women with high-risk GTN. Two review authors independently collected data using a data extraction form. Meta-analysis could not be performed as we included only one study. We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens. CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high-quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary.


[For which cases should clinicians perform blood purification in the management of acute poisoning? Clinical and pharmacological analyses].
Indications for performing blood purification such as direct hemoperfusion (DHP), hemodialysis (HD) and hemodiafiltration (HDF) in patients with acute poisoning were retrospectively analyzed. Although a quick improvement in consciousness level was achieved by an intensive treatment with DHP for three hours in 27 patients suffering from acute tranquilizer poisoning, a slow but safe recovery was surely obtained in another 111 cases who received general supportive care. The medical costs of patients treated by DHP were 2.07 times greater than those of cases treated by general supportive care. Plasma and urine concentrations of theophylline could be obtained simultaneously during the treatment by DHP. The excretion rate of DHP at 1, 2, 3 and 6 hours after starting DHP ranged from 99.4% to 96.0%. At the end of DHP, the clinical findings markedly improved and sufficient elimination from the body could be obtained. The rebound phenomenon was observed after three hours DHP in one case of acute anilin poisoning and the patient died of fatal fulminant hepatic failure at 9th hospital day. In this case, further DHP was needed. DHP is presently becoming less prevalent due to concerns over such issues as rapid metabolism and elimination efficacy in acute organophosphate and aconitine poisoning. In a case of 23-year old female who took a potentially fatal dose of 100 g of acetaminophen, blood purification was not performed and oral N acetylcysteine antidotal therapy was quite effective in order to prevent hepatic injury. The serum acetaminophen concentration was 287 microg/ml on her admission and the value fell to 28.8 microg/ml after 35 hours. These results indicate that blood purification is not always necessary because of it's poor elimination efficacy in some kinds poisoning. Nevertheless, in severe cases it was quite an effective and useful extracorporeal elimination technique for both improvement of clinical outcome and clearance of poisons. Although it is difficult to draw a definitive conclusion from this study, it is suggested that a rapid and prudent decision should be made as to perform blood purification.


Coping and Prognostic Awareness in Patients With Advanced Cancer.
Purpose Patients' understanding of their illness is key for making informed treatment decisions, yet studies suggest an association between prognostic awareness and worse quality of life (QOL) and mood among patients with advanced cancer. We sought to explore the relationships among prognostic awareness, coping, QOL, and mood in patients with newly diagnosed, incurable cancer. Methods We assessed patients' self-reported health status and treatment goal (Prognosis and Treatment Perceptions Questionnaire), coping (Brief COPE), QOL (Functional Assessment of Cancer Therapy-General), and mood (Hospital Anxiety and Depression Scale) within 8 weeks of incurable lung or GI cancer diagnosis. We used linear regression to examine associations and interaction effects among patients' health status and treatment goal, coping strategies, QOL, and mood. Results Patients who reported a terminally ill health status had worse QOL (unstandardized coefficient [B] = -6.88; P < .001), depression (B = 1.60; P < .001), and anxiety (B = 1.17; P = .007). Patients who reported their oncologist's treatment goal was "to cure my cancer" had better QOL (B = 4.33; P = .03) and less anxiety (B = -1.39; P = .007). We observed interaction effects between self-reported health status and treatment goal and certain coping strategies. Specifically, subgroup analyses showed that greater use of positive reframing was related to better QOL (B = 2.61; P < .001) and less depression (B = -0.78; P < .001) among patients who reported a terminally ill health status. Active coping was associated with better QOL (B = 3.50; P < .001) and less depression (B = -1.01; P < .001) among patients who acknowledged their oncologist's treatment goal was not "to cure my cancer." Conclusion Prognostic awareness is related to worse QOL and mood in patients with newly diagnosed, incurable cancer; however, the use of certain coping strategies may buffer these relationships. Interventions to improve patients' prognostic awareness should seek to cultivate more adaptive coping strategies in order to enhance QOL and mood.


Polyketide synthases in the microbiome of the marine sponge Plakortis halichondrioides: a metagenomic update.
Sponge-associated microorganisms are able to assemble the complex machinery for the production of secondary metabolites such as polyketides, the most important class of marine natural products from a drug discovery perspective. A comprehensive overview of polyketide biosynthetic genes of the sponge Plakortis halichondrioides and its symbionts was obtained in the present study by massively parallel 454 pyrosequencing of complex and heterogeneous PCR (Polymerase Chain Reaction) products amplified from the metagenomic DNA of a specimen of P. halichondrioides collected in the Caribbean Sea. This was accompanied by a survey of the bacterial diversity within the sponge. In line with previous studies, sequences belonging to supA and swfA, two widespread sponge-specific groups of polyketide synthase (PKS) genes were dominant. While they have been previously reported as belonging to Poribacteria (a novel bacterial phylum found exclusively in sponges), re-examination of current genomic sequencing data showed supA and swfA not to be present in the poribacterial genome. Several non-supA, non-swfA type-I PKS fragments were also identified. A significant portion of these fragments resembled type-I PKSs from protists, suggesting that bacteria may not be the only source of polyketides from P. halichondrioides, and that protistan PKSs should receive further investigation as a source of novel polyketides.


Epidemiologic investigation of a Yersinia camp outbreak linked to a food handler.
In July 1981, an outbreak of gastroenteritis occurred at a summer diet camp. Of the 455 campers and staff, 35 per cent developed an illness characterized by abdominal pain, fever, diarrhea, and/or nausea and vomiting. A total of 53 per cent experienced abdominal pain. Seven persons were hospitalized, five of whom had appendectomies. Yersinia enterocolitica serogroup 0:8 was isolated from 37 (54 per cent) of 69 persons examined, including the camp cook and three assistants. An epidemiologic investigation demonstrated that illness was associated with consumption of reconstituted powdered milk and/or chow mein . Y. enterocolitica serogroup 0:8 was subsequently isolated from milk, the milk dispenser, and leftover chow mein . Information obtained during the investigation suggested that the Yersinia had been introduced by a food handler during food-processing procedures.


Sunroot snack bar: Optimization, characterization, consumer perception, and storage stability assessment.
This study reports the evolution of phenolics, inulin content, proximate composition, hardness, and sensory characteristics of an inulin-rich healthy snack bar (The Sunroot Snack Bar) over 90 days of storage in refrigerated and room temperature storage. A response surface methodology (RSM) with a central composite rotatable design was first employed for optimizing the concentrations of sunroot, potato, and oats. The optimum selected concentrations of sunroot, potato, and oat were 53.99, 37.88, and 5 g, respectively, and a quadratic model was found to yield the best fit. Analysis of variance revealed that a higher sunroot content resulted in more firmness of the bar and higher overall acceptability in sensory trials. Sunroot snack bar samples without flavor (control), sunroot snack bar with cheese flavor (S1), and sunroot snack bar with olive flavor (S2) were then tested for sensory, chemical, phytochemicals, and microbial contents among control, S1, and S2 samples over a 90-day shelf-life study. Results showed no significant (p < .05) changes in these contents on addition of flavor. An increase in microbial load and the appearance of a bitter taste after 30 days of fresh sunroot storage were observed. No microbial growth was observed in all sunroot snack bar samples during storage at 4°C, while some microbial growth was observed at 25°C for 90 days. It was inferred that the high-quality shelf life of the sunroot bar was 90 days at 4°C, which was shortened to a month if the bars were preserved at 25°C. There was a significant phenolic and inulin content loss at 25°C compared with 4°C in total phenolic component. Based on the results of sensory evaluation, online questionnaire of customer experience, and cost analysis, this study successfully used sunroot tubers for the production of snack bars as a promising new raw material, which was introduced healthily with a suitable price for such product compared with other products in the market.


Influences of an anticholinergic antiparkinsonian drug, parkinsonism, and psychotic symptoms on cardiac autonomic function in schizophrenia.
The arguments against the use of anticholinergic antiparkinsonian drugs for neuroleptic-induced parkinsonism have been based, in part, on their autonomic side effects. Except for anecdotal case reports, there is little evidence that antiparkinsonian drugs are the main factor causing autonomic dysfunction in schizophrenic patients with parkinsonism. Therefore, in the current study, the separate influences of the anticholinergic antiparkinsonian drug (biperiden), parkinsonism, and psychotic symptoms on cardiac autonomic function were investigated in 48 patients with schizophrenia. Biperiden was discontinued in 33 patients with or without parkinsonism and commenced in 15 patients with parkinsonism. Their parkinsonism and psychotic symptoms were assessed using rating scales, and their cardiac autonomic functions were assessed using the mean R-R interval and 3 methods of analyzing heart rate variability both before and after the change in medication. Consequently, the cardiac autonomic function was not affected by biperiden or the change in parkinsonism. Cardiac vagal function decreased when psychotic symptoms were more pronounced, but cardiac sympathetic function did not show a significant change. Therefore, it appeared that psychotic symptoms played the predominant role in modifying the cardiac autonomic function, implying the existence of autonomic changes associated with cognitive processing and a possible relation between psychotic symptoms and autonomic symptoms in schizophrenia.


Facial expression discrimination varies with presentation time but not with fixation on features: a backward masking study using eye-tracking.
The current study investigated the effects of presentation time and fixation to expression-specific diagnostic features on emotion discrimination performance, in a backward masking task. While no differences were found when stimuli were presented for 16.67 ms, differences between facial emotions emerged beyond the happy-superiority effect at presentation times as early as 50 ms. Happy expressions were best discriminated, followed by neutral and disgusted, then surprised, and finally fearful expressions presented for 50 and 100 ms. While performance was not improved by the use of expression-specific diagnostic facial features, performance increased with presentation time for all emotions. Results support the idea of an integration of facial features (holistic processing) varying as a function of emotion and presentation time.


Speckle contrast of the sum of N partially correlated speckle patterns.
In this paper a general method is presented for calculating the theoretical speckle contrast of a sum of correlated speckle patterns, motivated by the need to suppress the presence of speckle in laser projection displays. The method is applied to a specific example, where correlated speckle patterns are created by sequentially passing light through partially overlapping areas on a diffuser, before being projected onto a screen. This design makes it possible to find a simple expression for the correlation between speckle patterns. When the set of correlations involves symmetry, it is shown that the expression for the speckle contrast becomes simpler. The difference in performance between discretely and continuously varying speckle patterns is also investigated. In an example with speckle reduction by a rotating sinusoidal grating, it is found that continuous variation gives a speckle contrast that is 0.61 times the contrast obtained by discretely summing the maximum number of independent patterns.


High-grade cytomegalovirus antigenemia after hematopoietic stem cell transplantation.
Clinical impact of high-grade (HG) cytomegalovirus (CMV) antigenemia after hematopoietic stem cell transplantation has not been clarified. Therefore, in order to investigate the risk factors and outcome for HG-CMV antigenemia, we retrospectively analyzed the records of 154 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2002 at the University of Tokyo Hospital. Among 107 patients who developed positive CMV antigenemia at any level, 74 received risk-adapted preemptive therapy with ganciclovir (GCV), and 17 of these developed HG-antigenemia defined as > or = 50 positive cells per two slides. The use of systemic corticosteroids at > or = 0.5 mg/kg/day at the initiation of GCV was identified as an independent significant risk factor for HG-antigenemia. Seven of the 17 HG-antigenemia patients developed CMV disease, with a cumulative incidence of 49.5%, which was significantly higher than that in the low-grade antigenemia patients (4%, P<0.001). However, overall survival was almost equivalent in the two groups. In conclusion, the development of HG-antigenemia appeared to depend on the profound immune suppression of the recipient. Although CMV disease frequently developed in HG-antigenemia patients, antiviral therapy could prevent a fatal outcome.


[Brazilian Protocol for Sexually Transmitted Infections 2020: infections that cause urethral discharge].
This article approach infections that cause urethral discharge, theme which is part of the Clinical Protocol and Therapeutic Guidelines for Comprehensive Care for People with Sexually Transmitted Infections, published by the Ministry of Health of Brazil in 2020. These guidelines were prepared based on scientific evidence and validated in discussions with experts. When urethritis is not treated correctly, or when the microorganism develops antimicrobial resistance, it can cause serious and even irreversible health damage. It is noteworthy that the high levels of antimicrobial resistance developed by pathogens that causes urethritis comprises a global emergency in public health. This article presents epidemiological and clinical aspects, recommendations on diagnostic and treatment, and strategies for surveillance, prevention and control actions of infections that cause urethral discharge, with the purpose of contributing with managers and health professionals to care qualification.


Imbrication of Anterior Digastric with Advancement of the Posterior Digastric and Its Implications in Neck Aesthetics.
Background: To describe a novel technique to modify the proportional length of the anterior-to-posterior digastric muscles to improve neck aesthetics. Objective: To provide an objective measure to quantify neck rejuvenation and a novel technique to adjust the digastric ratio. Design: We retrospectively compared 52 patients who had neck rejuvenation with or without digastric manipulation. Preoperative and postoperative images were analyzed and compared with computer software using a novel analysis technique to measure the digastric ratio and neck height. Distances between the menton, cervical point (CP), and gonion were measured. Results: The anterior-to-posterior digastric ratio improved an average of 26.5% (p < 0.01) in the new technique group, 15.9% in the control group. Distance of the CP to the inferior edge of the mandible decreased an average of 13.9% using the new technique. Conclusion: The ratio of anterior-to-posterior digastric muscle appears to improve as well as the neck height with manipulation of the digastric muscles.


Pharmacological interference with the cardiac renin-angiotensin system.
Biochemical, pharmacological, and molecular biological data provide evidence for the presence of a cardiac renin-angiotensin system. Tissue angiotensins were demonstrated in all regions of the mammalian heart. Reduction of cardiac angiotensin II formation after oral administration of converting enzyme (CE) inhibitors in nephrectomized animals points to local generation of these peptides. Functional studies in isolated working rat hearts subjected to transient regional ischemia and reperfusion showed that there is aggravation of arrhythmias as well as exhaustion of energy status by angiotensins. This was prevented by CE inhibition and/or perfusion with bradykinin (BK), which in turn could be competitively antagonized with a BK antagonist. Intracoronary infusion of low-dose bradykinin attenuated ischemia-reperfusion injuries and reduced enzyme and lactate release in anesthetized dogs. Oral pretreatment with the CE inhibitor ramipril in rats, in doses that did not affect the elevation of blood pressure caused by aortic constriction, could prevent induction of as well as cause regression of established cardiac hypertrophy. In contrast, pure vasodilation was without effect on cardiac enlargement despite lowering blood pressure, pointing to a possible trophic influence of angiotensin II. Thus, apart from afterload reduction and euvolumia produced by CE inhibition, the outstanding efficacy of this therapeutic approach in congestive heart failure and cardiac hypertrophy and its potential usefulness in myocardial ischemia may also be explained by intracardiac suppression of angiotensin II generation and bradykinin degradation.


Citrinin and endosulfan induced teratogenic effects in Wistar rats.
Dietary exposures to food pollutants such as mycotoxin(s) or pesticide(s) are most significant due to their adverse effects on the production and reproduction in animals and the human population. The present investigation was conducted to evaluate the teratogenic potential of citrinin (CIT) and endosulfan either alone or in combination in pregnant rats during gestational days 6-20. Endosulfan (1 mg kg(-1) body weight, by oral intubation) and CIT (10 mg kg(-1) feed, through diet) when administered either alone or in combination in pregnant rats caused significant teratogenic effects in the developing fetuses. There was no maternal mortality, however, reduced maternal weight gain and number of live fetuses and increased fetal resorptions were recorded in all the treated groups. The fetal body weights and crown to rump lengths were significantly decreased and the per cent gross, visceral and skeletal anomalies were significantly increased in the fetuses of dams of all the treated groups. The internal hydrocephalus, cerebellar hypoplasia, microphthalmia, contracted and notched kidneys, multilobulated liver, dilated renal pelvis, incomplete ossification of skull bones, rib anomalies and sacral and caudal vertebrae agenesis were the important fetal malformations. The occurrence of fetal gross, skeletal and visceral malformations was more severe in the combination group, suggesting an additive interaction of CIT and endosulfan in inducing developmental toxicity in Wistar rats.


Constrained transcription factor spacing is prevalent and important for transcriptional control of mouse blood cells.
Combinatorial transcription factor (TF) binding is essential for cell-type-specific gene regulation. However, much remains to be learned about the mechanisms of TF interactions, including to what extent constrained spacing and orientation of interacting TFs are critical for regulatory element activity. To examine the relative prevalence of the 'enhanceosome' versus the 'TF collective' model of combinatorial TF binding, a comprehensive analysis of TF binding site sequences in large scale datasets is necessary. We developed a motif-pair discovery pipeline to identify motif co-occurrences with preferential distance(s) between motifs in TF-bound regions. Utilizing a compendium of 289 mouse haematopoietic TF ChIP-seq datasets, we demonstrate that haematopoietic-related motif-pairs commonly occur with highly conserved constrained spacing and orientation between motifs. Furthermore, motif clustering revealed specific associations for both heterotypic and homotypic motif-pairs with particular haematopoietic cell types. We also showed that disrupting the spacing between motif-pairs significantly affects transcriptional activity in a well-known motif-pair-E-box and GATA, and in two previously unknown motif-pairs with constrained spacing-Ets and Homeobox as well as Ets and E-box. In this study, we provide evidence for widespread sequence-specific TF pair interaction with DNA that conforms to the 'enhanceosome' model, and furthermore identify associations between specific haematopoietic cell-types and motif-pairs.


Transient changes in flocculonodular lobe protein kinase C expression during vestibular compensation.
Protein kinase C (PKC) is a family of intracellular signal transduction enzymes, comprising isoforms that vary in sensitivity to calcium, arachidonic acid, and diacylglycerol. PKC isoforms alpha, gamma, and delta are expressed by cerebellar Purkinje cells and neurons in the cerebellar nuclei and vestibular nuclei of the Long-Evans rat. In control rats, these PKCs are distributed symmetrically in the flocculonodular-lobe Purkinje cells. Behavioral recovery from vestibular dysfunction produced by unilateral labyrinthectomy (UL) is accompanied by asymmetric expression of PKC isoforms in these regions within 6 hr after UL. These expression changes were localized within parasagittal regions of the flocculus and nodulus. The distribution of PKCalpha, -gamma, and -delta were identical, suggesting that they are coregulated in cerebellar Purkinje cells during this early compensatory period. The pattern of Purkinje cell PKC expression returned to the control, symmetric distribution within 24 hr after UL. It is hypothesized that these regional changes in Purkinje cell PKC expression are an early intracellular signal contributing to vestibular compensation. In particular, regulation of PKC expression may contribute to changes in the efficacy of cerebellar synaptic plasticity during the acute post-UL period.


Interaction of Mycoplasma gallisepticum with sialyl glycoproteins.
The binding of several glycoproteins to freshly grown and harvested cells of Mycoplasma gallisepticum was examined. Only human glycophorin, the major sialoglycoprotein of the erythrocyte membrane, bound tightly as judged by direct binding assays with 125I-labeled glycoproteins. Neuraminidase-treated glycophorin did not bind, suggesting that binding is mediated through sialic acid groups. Although other sialoglycoproteins did not appear to bind M. gallisepticum by direct binding assays, some inhibited the binding of glycophorin. The best inhibitors had a mucin-like structure, with high molecular weights and high sialic acid contents. N-acetylneuraminic acid appeared to be the favored sialic acid structure for binding, but there was no strict specificity for its anomeric linkage. Neuraminidase activity could not be detected on the surface of M. gallisepticum, suggesting that this enzyme is not involved in the mechanism of adherence of sialoglycoproteins. Binding of sialoglycoproteins was time dependent, however, and markedly diminished with increasing ionic strength, but was largely unaffected between pH 4 and 9.


Cutaneous dermal non-neural granular cell tumor is a granular cell dermal root sheath fibroma.
Dermal non-neural granular cell tumor (NNGCT) was first described in 1991 as an S100-negative polypoid non-melanocytic tumor. Although originally introduced in the literature as a primary cutaneous tumor, it was later emphasized that such qualification could not be held until the line of differentiation was clarified. It was also demonstrated that not all cases were polypoid. In the current study we try to further characterize this entity by presenting 5 cases of NNGCT. As expected, not all of them were polypoid. The ages of the patients varied from 10 to 43 (mean age 22). They all were composed of S100-negative granular cells with variable atypia and mitotic figures. None of them recurred in follow-up of up to 12 years (mean 8.2 years). We found evidence of folliculocentricity in 4 cases (in 1 case, this feature could not be investigated because the biopsy was a small shave specimen), that is, tumors were always surrounding, embedding, or following a hair follicle. In some occasions, such features were better demonstrated by immunohistochemistry against the arrector pili muscle. Our cases showed intense immunoexpression of CD10 and CD68. We conclude that NNGCT is morphologically related to the hair follicle and we believe that it is a granular cell dermal root sheath fibroma.


Role of non-muscle myosin light chain kinase in neutrophil-mediated intestinal barrier dysfunction during thermal injury.
Neutrophils and non-muscle myosin light chain kinase (nmMLCK) have been implicated in intestinal microvascular leakage and mucosal hyperpermeability in inflammation and trauma. The aim of this study was to characterize the role of nmMLCK in neutrophil-dependent gut barrier dysfunction following thermal injury, a common form of trauma that typically induces inflammation in multiple organs. Histopathological examination of the small intestine in mice after a full-thickness burn revealed morphological evidence of mucosa inflammation characterized by neutrophil infiltration into the lamina propria, epithelial contraction, and narrow villi with blunt brush borders and loss of goblet cells. Compared with their wild-type counterparts, nmMLCK mice displayed diminished morphological abnormalities. Likewise, intravital microscopic studies showed significant leukocyte adhesion in intestinal microvessels after burn, a response that was blunted in the absence of nmMLCK. Functionally, thermal injury significantly increased the gut lumen-to-blood transport of fluorescein isothiocyanate-dextran (4 kd), and this hyperpermeability was attenuated by either neutrophil depletion or nmMLCK deficiency. Consistent with the in vivo observations, in vitro assays with Caco-2 epithelial cell monolayers revealed a decrease in transcellular electric resistance coupled with myosin light chain phosphorylation, actomyosin ring condensation, and claudin-1 internalization upon stimulation with fMLP (N-formyl-methionyl-leucyl-phenylalanine)-activated neutrophils. Pretreatment of the cells with the MLCK inhibitor ML-7 prevented the tight junction responses. Taken together, the results suggest that nmMLCK plays an important role in neutrophil-dependent intestinal barrier dysfunction during inflammatory injury.


Existence and function of opioid receptors on mammalian pinealocytes.
Previous studies in our laboratories have identified a single population of opioid receptors in bovine pineal gland, which we have chosen to characterize further on pinealocytes isolated from the cow and rat pineal gland. The bovine pinealocytes isolated by trypsinization or mechanical manipulation revealed receptor density (Bmax) values of 206.95 +/- 131.15 and 220.34 +/- 11.80 fmol/mg protein, respectively, and dissociation equilibrium constant (Kd) values of 1.93 +/- 0.48 and 1.96 +/- 0.21 nM, respectively. The rat pinealocytes cultured for 7 days exhibited a [3H]diprenorphine binding site of 56 fmol/10(6) cells. Morphine (100 microM) enhanced the activity of N-acetyltransferase and the level of melatonin in rat pineal gland in culture incubated for 21 hr. The results of these studies suggest that opioidergic receptors exist on pinealocytes and they are involved in stimulating the activity of N-acetyltransferase and the synthesis of melatonin, thereby regulating the physiology of mammalian pineal gland.


Robotic systems for percutaneous needle-guided interventions.
Several groups have developed robotic systems for invasive medical procedures. In this article we will focus on selected robotic systems for percutaneous needle-guided interventions using CT or MR imaging. We present six interventional robotic systems designed to work with imaging modalities such as CT, Cone-beam CT and MRI. The details of each system are given along with any phantom, animal, or human trials performed with each particular robot. Although each of these systems has specific features, they are all of great clinical value since they provide very stable needle guidance -- even for angulated approaches, they may allow access to lesions when the width of the CT- or MR- gantry would limit the access for a biopsy needle or other interventional tools such as thermal ablation probes. Then, such a robot may be able to guide the needle into the most promising region of the lesion without the need for a second contrast injection. Thus, more efficacious characterization and treatment, particularly for lesions that are difficult to target, can be anticipated. Although more research and clinical trials are certainly needed, it is, however, our belief that robotic systems will be an important part of future interventions.


High levels of activin A detected in preeclamptic placenta induce trophoblast cell apoptosis by promoting nodal signaling.
The pregnancy-specific disorder preeclampsia is a major cause of maternal mortality and morbidity. Activin A has been suggested as a potential biomarker of the disease, but whether it plays a role in the pathology of preeclampsia or is just a manifestation of the disease is not fully understood. The objective of the study was to examine the roles of Activin A on placental trophoblast cells under pathological conditions of preeclampsia. Placental and plasma productions of Activin A in healthy pregnant women and preeclamptic patients were compared by using clinical samples obtained from Peking University First Hospital during November 2005 to November 2007. The role of Activin A at pathological doses was investigated in human trophoblast cells. Plasma and placental productions of Activin A were significantly higher in preeclamptic patients when compared with normal pregnant subjects in a Chinese Han population. Treatment of trophoblast cells with high doses of Activin A resulted in a significant increase in cell apoptosis. This effect was blocked not only by silencing Activin A's receptor activin receptor-like kinase 4 but also by knockdown of Nodal's receptor ALK7. Important to note was that Activin A could significantly increase Nodal expression in trophoblast cells, and knockdown of Nodal resulted in evident blockage on Activin A-induced trophoblast cell apoptosis. High levels of Activin A observed in preeclamptic placenta may play a role in the pathogenesis of preeclampsia by inducing excessive apoptosis in placenta indirectly through enhancing Nodal expression.


Effect of the ring size of TMC ligands in controlling C-H bond activation by metal-superoxo species.
Metal-superoxo species play a very important role in many metal-mediated catalytic transformation reactions. Their catalytic reactivity is affected by many factors such as the nature of metal ions and ring size of ligands. Herein, for the first time, we report DFT calculations on the electronic structures of a series of metal-superoxo species (M = V, Cr, Mn, Fe, and Co) with two ring size ligands, i.e., 13-TMC/14-TMC, and a detailed mechanistic study on the C-H bond activation of cyclohexa-1,4-diene followed by the effect of the ring size of ligands. Our DFT results showed that the electron density at the distal oxygen plays an important role in C-H bond activation. By computing the energetics of C-H bond activation and mapping the potential energy surface, it was found that the initial hydrogen abstraction is the rate-determining step with both TMC rings and all the studied metal-superoxo species. The significant electron density at the cyclohex-1,4-diene carbon indicates that the reaction proceeds via the proton-coupled electron transfer mechanism. By mapping the potential energy surfaces, we found that the 13-TMC ligated superoxo with the anti-isomer are more reactive than the 14-TMC superoxo species except for the iron-superoxo species where the 14-TMC ligated superoxo species is more reactive i.e. smaller ring size TMC is more reactive towards C-H bond activation. This is also supported by the structural correlation, i.e., the greater contraction in the smaller ring results in the metal being pushed out of plane along the z-axis, which reduces the steric hindrance. Thus, the ring size can help in designing catalysts with better efficiency for catalytic reactions.


Reversing Alzheimer's disease dementia with clemastine, fingolimod, or rolipram, plus anti-amyloid therapy.
A few anti-amyloid trials offer a slight possibility of preventing progression of cognitive loss, but none has reversed the process. A possible reason is that amyloid may be necessary but insufficient in the pathogenesis of AD, and other causal factors may need addressing in addition to amyloid. It is argued here that drugs addressing myelination and synaptogenesis are the optimum partners for anti-amyloid drugs, since there is much evidence that early in the process that leads to AD, both neural circuits and synaptic activity are dysfunctional. Evidence to support this argument is presented. Evidence is also presented that clemastine, fingolimod, and rolipram, benefit both myelination and synaptogenesis. It is suggested that a regimen that includes one of them plus an anti-amyloid drug, could reverse AD.


Endogenous Biomarkers to Assess Drug-Drug Interactions by Drug Transporters and Enzymes.
Drug-Drug Interactions (DDI) by modulation of drug transporters or drug metabolizing enzymes are common in multi-drug therapy. DDI potential of any new drug is assessed by conducting separate clinical studies using relevant probe substrates, which involves additional resource and cost. Recently, several endogenous compounds have been evaluated as substrates of transporters and enzymes that could be assessed as part of early clinical trials along with the assessment of drug pharmacokinetics, pharmacodynamics and safety studies. This enables an early readout on potential DDIs avoiding or minimally delaying the conduct of definitive DDI studies until later in clinical development. This review describes various endogenous biomarkers reported for drug transporters and metabolizing enzymes with their advantages and limitations. Furthermore, the authors describe strategies to adopt while exploring a new endogenous biomarker, and factors to be considered in selection of biomarkers with the current challenges and opportunities.


Sagittal alignment in operative degenerative lumbar spondylolisthesis: a scoping review.
The benefit of surgical intervention over conservative treatment for degenerative lumbar spondylolisthesis (DLS) patients with neurologic symptoms is well-established. However, it is currently unclear what breadth of available evidence exists on regional and global sagittal alignment in DLS surgery. As such, the purpose of the current study is to conduct a scoping review to map and synthesize the DLS literature regarding the current radiographic assessment of sagittal spinal alignment in DLS surgery. A comprehensive search of the MEDLINE, EMBASE and Cochrane databases from January 1971 to January 2023 was performed for all DLS studies examining sagittal spinal alignment parameters with DLS surgery according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review (PRISMA-ScR) protocol. From 2,222 studies, a total of 109 studies were included, representing 10,730 patients with an average age of 63.0 years old and average follow-up of 35.1 months postoperatively. Among included studies, 93 (85%), were largely published in the last decade and predominantly represented retrospective cohorts 70 (64%) or case series 22 (20%). A common theme among the reporting of radiographic parameters in the included investigations was the assessment of the magnitude and/or maintenance of a radiographic change postoperatively, with 92 (84%) studies reporting these findings. The majority of studies focused on index DLS level [33 (30%) studies] or lumbar spine radiographic imaging [33 (30%) studies] only. Thirty-seven (34%) studies reported spinopelvic parameters, with only 13 (12%) of included studies assessing 36-inch standing lateral radiographs and overall alignment. There is increasing prevalence of investigations assessing sagittal spinal alignment parameters in DLS surgery. Although, there is an increasing prevalence of studies investigating sagittal spinal alignment parameters in DLS surgery the quality of the currently available literature on this topic is of overall low evidence and largely retrospective in nature. Additionally, there is limited analysis of global sagittal spinal alignment in DLS suggesting that future investigational emphasis should prioritize longitudinally followed large prospective cohorts or multi-centre randomized controlled trials. Attempts at standardizing the radiographic and functional outcome reporting techniques across multi-centre investigations and prospective cohorts will allow for more robust, reproducible analyses of significance to be conducted on DLS patients.


[Fluid distribution abnormalities and influence of hemodialysis on fluid distribution in patients on maintenance hemodialysis].
To study the fluid distribution abnormalities in patients on hemodialysis and fluid shift between intracellular and extracellular compartment during hemodialysis (HD). Eighty stable end stage renal disease patients on maintenance hemodialysis were selected. Conventional low flux dialyses at dialysate sodium concentration of 138 mmoL/L were performed for all of the patients. Fresenius polysulphons or Gambro hemophon dialyzers were used. All of the patients showed no clinical signs of over ultrafiltration during HD sessions and dry body weights were considered adequate. Intracellular water (ICW), extracellular water (ECW) and total body water (TBW) were measured and standardized by body weight (nICW, nECW, nTBW) before and after HD sessions. Sixty-seven cases of sex, age and body weight matched normal individuals were used as controls. Bio-impedance spectrum (BIS) analysis (Xitron, Technologies, San Diego, CA, USA) was used in body fluid measurement. Pre and post HD nICW, nECW, and nTBW were compared with these of the controls. There were no differences in age, post-dialysis body weight and body mass index between patients on hemodialysis and the controls. Patients on hemodialysis had less nICW [male (0.28+/-0.05) vs (0.33+/-0.04), P<0.01; female (0.22+/-0.03) vs (0.27+/- 0.04), P<0.001], more nECW [male (0.28+/-0.02) vs (0.25+/-0.02), P<0.001; female (0.25+/-0.03) vs (0.23+/-0.01), P<0.05], and less nTBW [male (0.56+/-0.04) vs (0.58+/-0.05), P<0.05; female (0.47+/-0.05) vs (0.49+/-0.03), P<0.05] compared with the controls. The average ultra-filtration volume was (2.2+/-0.9)L. After dialysis, there was an increase in nICW [male (0.28+/-0.05) vs (0.30+/-0.05), P<0.001; female (0.22+/-0.03) vs (0.25+/-0.03), P<0.001), an decrease in nECW [male (0.28+/-0.02) vs (0.26+/-0.03), P<0.001; female (0.24+/-0.03) vs (0.21+/-0.03), P<0.001],and decrease of ECW/ICW ratio [male (1.06+/-0.30) vs (0.89+/-0.25) P<0.001; female (1.10+/-0.17) vs (0.88+/-0.17) P<0.001] which reached the levels of the normal individuals (0.79+/- 0.10 for male, 0.86+/-0.10 for female]. Our results show that (1) Before HD sessions, patients on HD had less nICW and more nECW; (2) During conventional low flux HD sessions at dialysate sodium concentration of 138 mmoL/L, fluid shifted from extracellular space to intracellular space.(3) nECW and ECW/ICW ratio from normal population are reasonable for evaluation of dry weight in patients on hemodialysis, but nTBW and nICW are not.


Retromandibular transparotid approach for subcondylar mandibular fractures: A retrospective study.
The aim was to evaluate the effectiveness and complications of retromandibular transparotid approach performed for the reduction of dislocated subcondylar fractures. Fourteen patients with subcondylar mandibular fractures were evaluated (8 male, 6 female, age range 19-43 years). The primary predictor variable in the present study was time (preoperative vs postoperative). The primary outcome variables were inflammatory complication, facial nerve deficit (House and Brackmann classification), and presence of parotid fistula. The secondary outcome variables were occlusal disturbances, maximal interincisal opening (MIO), and temporomandibular joint (TMJ) pain (VAS). Excellent occlusion and function was observed postoperatively. One salivary fistula occurred after surgery but was healed after 3 weeks. No inflammatory complication was observed. Three patients had grade III and one patient had grade II facial nerve deficit, all recovered in 6 weeks. All patients were free of pain and no malocclusion was observed. MIO was ranging from 34 to 58 mm (mean 44.4 mm) after 6 months. The retromandibular transparotid approach is feasible and safe. It facilitates reduction and fixation of subcondylar fractures with functional outcomes and rare complications.


Characterization of the proliferation state in canine mammary tumors by the standardized AgNOR method with postfixation and immunohistologic detection of Ki-67 and PCNA.
Paraffin-embedded tissue sections of 96 surgically removed mammary tumors from female dogs were analyzed for their proliferation state using three different methods. The AgNOR method, originally developed by Ploton and coworkers in 1986, modified and standardized by the AgNOR committee, is an easy, inexpensive silver-staining procedure used to determine cell proliferation and prognosis of various tumors. Due to the standardized staining protocol of the AgNOR method and a postfixation step, results obtained were of excellent quality for image-analysis processing. The growth fraction was evaluated by counting of immunohistologically positive-stained cells for Ki-67 or proliferating-cell nuclear antigen (PCNA). The values determined were, in general, lower with Ki-67 (MIB1) than with PCNA (PC10). Nevertheless, the labeling indices of these antigens correlated significantly (P < 0.001). Though the differences of the means between the tumor groups according to the classification system of the World Health Organization were significant for all three investigated methods (P < 0.001), there was a considerable overlap between the tumor groups concerning all investigated parameters. An exploratory data analysis (multivariate analysis) as performed to evaluate the prognostic relevance of the three methods including further anamnestic, clinical, gross, and histopathologic variables. Besides the histopathologic diagnosis (survival P < 0.001; survival time P < 0.05; reappearance of tumor growth P < 0.05), only the PCNA-labeling index (time until reappearance of tumor growth P < 0.001) was of prognostic significance.


The CORE (Consensus on Relevant Elements) Approach to Determining Initial Core Components of an Innovation.
Identifying an intervention's core components is indispensable to gauging whether an intervention is implemented with fidelity and/or is modified; it is often a multi-stage process, starting with the first stage of identifying an initial set of core components that are gradually refined. This first stage of identifying initial core components has not been thoroughly examined. Without a clear set of steps to follow, interventions may vary in the rigor and thought applied to identifying their initial core components. We devised the CORE (Consensus on Relevant Elements) approach to synthesize opinions of intervention developers/implementers to identify an intervention's initial core components, particularly applicable to innovative interventions. We applied CORE to a peer-based intervention that aids military veterans with post-incarceration community reintegration. Our CORE application involved four intervention developers/implementers and two moderators to facilitate the seven CORE steps. Our CORE application had two iterations, moving through Steps 1 (individual core component suggestions) through 7 (group discussion for consensus), then repeating Steps 4 (consolidation of component definitions) through 7. This resulted in 18 consensus-reached initial core components of the peer-based intervention, down from the 60 that the developers/implementers individually suggested at Step 1. Removed components were deemed to not threaten the intervention's effectiveness even if absent. CORE contributes to filling a critical gap regarding identifying an intervention's initial core components (so that the identified components can be subsequently refined), by providing concrete steps for synthesizing the knowledge of an intervention's developers/implementers. Future research should examine CORE's utility across various interventions and implementation settings.


[Knowledge of primary care physicians, cardiologists from cardiology clinics, internal and cardiology department physicians about chronic heart failure diagnosis and treatment].
Last studies have shown unsatisfactory diagnosis and treatment of chronic heart failure (CHF) patients. The aim of this study was to compare the knowledge of primary care physicians (PCP), cardiologists from cardiology clinics (CARC), internal and cardiology department physicians (INTD and CARD) about CHF diagnosis and treatment. A questionnaire consisting of 23 questions related to above issues was filled out by 153 physicians (64 PCP, 24 CARC, 44 INTD and 21 CARD) from the urban district. Similarly to other physicians, PCP suspected CHF on the ground of ankle oedema (88%), dyspnoea (75%) and basal pulmonary crepitations (44%). Most questioned doctors ordered a chest X-ray (58-86%) to establish the diagnosis. Echocardiography was underused by PCP (19%) in comparison to other doctors (68-86%). Under-utilization of angiotensin converting enzyme inhibitors (ACEI) (-68 to -79%; NS) and, especially, beta-blockers (-35% by PCP to -51% by CARD; p < 0.05) was observed. The recommended target dose of enalapril knew more CARD (52%) and INTD (45%) than PCP (25%) (p < 0.05 and p < 0.01, respectively). The appropriate target dose of carvedilol knew 3% of PCP, 8% of CARC, 9% of INTD and 14% of CARD (PCP vs. CARD; p < 0.01). Most CHF patients from the urban region are diagnosed by PCP and other doctors on the basis of symptoms, signs and a chest X-ray. The misdiagnosis of CHF may depend on the small direct access of PCP to echocardiography. Under-utilization and under-dosing of ACEI and beta-blockers creates the necessity to introduce broad educational programs and some organisational changes (implementation of CHF clinics).


Plasma concentrations of aminoterminal pro atrial natriuretic peptide and aminoterminal pro brain natriuretic peptide in healthy neonates: marked and rapid increase after birth.
The purpose of the study was to examine the possible age dependency of plasma N-terminal pro atrial natriuretic peptide (N-ANP) and N-terminal pro brain natriuretic peptide (N-BNP) levels in healthy term neonates to establish normal ranges for the neonatal period. N-ANP and N-BNP plasma concentrations were measured in peripheral venous (n = 116) and umbilical cord blood (n = 37) in 153 healthy term neonates (mean: 5.1; range: 0-30 days) using an enzyme immunoassay. The neonates were classified into 8 groups according to their age (day of delivery and 1, 2, 3, 4, 5-7, 8-14, and 14-30 days of age). The plasma N-ANP and N-BNP concentration were the highest at the first day of age (96 700; 6912-436 000 and 641; 254-1272 fmol/mL) and were found significantly higher compared with the day of delivery (5680; 1005-16 900 and 221; 58-478 fmol/mL; P < 0,0001). After this marked increase, N-ANP and N-BNP levels decreased steadily and became stable at the fifth (5232; 2691-7353 fmol/mL) and third (246; 110-430 fmol/mL) day of life, respectively. The N-ANP and N-BNP plasma concentrations in healthy neonates showed a marked increase during the first days of age, suggesting that ANP and BNP have physiologic roles in the perinatal circulatory change from fetus to neonate.


Japanese apricot extract (MK615) potentiates bendamustine-induced apoptosis via impairment of the DNA damage response in lymphoma cells.
Bendamustine, a hybrid molecule of a purine analog and alkylator, induces cell death by the activation of apoptosis and the DNA damage response. The agent MK615 is produced from Japanese apricot and contains a number of cyclic triterpenes that exhibit antitumor activities. In the present study, the combined effects of bendamustine and MK615 on lymphoma cells were investigated. The combined compounds synergistically induced apoptosis in all lymphoid cell lines examined. MK615 inhibited the bendamustine-induced phosphorylation of checkpoint kinase 1 and 2. As ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) kinases are key mediators of the DNA damage response, the effects of the combination of bendamustine and ATM/ATR inhibitors (KU-60019 and VE-821) on lymphoma cells were investigated. KU-60019 and/or VE-821 potentiated bendamustine activity in all cell lines tested, but did not affect MK615 activity, suggesting that these inhibitors have the same underlying mechanism of action as that of MK615. The results of the present study suggest that it may be feasible to use ATM/ATR inhibitors in combination with bendamustine for treating malignant lymphoma.


Care coordination and electronic health records: connecting clinicians.
To examine the association between use of electronic health records (EHR) and care coordination. Two surveys, in 2005 and again in 2006, of primary care clinicians working in a prepaid integrated delivery system during the staggered implementation of an EHR system. Using multivariate logistic regression to adjust for clinician characteristics, we examined the association between EHR use and clinicians' perceptions of three dimensions of care coordination: timely access to complete information; treatment goal agreement; and role/responsibility agreement. Compared to clinicians without EHR, clinicians with 6+ months of EHR use more frequently reported timely access to complete information, and being in agreement on treatment goals with other involved clinicians. There was no significant association between EHR use and being in agreement on roles and responsibilities with other clinicians. EHR use is associated with aspects of care coordination involving information transfer and communication of treatment goals.


Biogenesis and Membrane Targeting of Lipoproteins.
Bacterial lipoproteins represent a unique class of membrane proteins, which are anchored to membranes through triacyl chains attached to the amino-terminal cysteine. They are involved in various functions localized in cell envelope. Escherichia coli possesses more than 90 species of lipoproteins, most of which are localized in the outer membrane, with others being in the inner membrane. All lipoproteins are synthesized in the cytoplasm with an N-terminal signal peptide, translocated across the inner membrane by the Sec translocon to the periplasmic surface of the inner membrane, and converted to mature lipoproteins through sequential reactions catalyzed by three lipoprotein-processing enzymes: Lgt, LspA, and Lnt. The sorting of lipoproteins to the outer membrane requires a system comprising five Lol proteins. An ATP-binding cassette transporter, LolCDE, initiates the sorting by mediating the detachment of lipoproteins from the inner membrane. Formation of the LolA-lipoprotein complex is coupled to this LolCDE-dependent release reaction. LolA accommodates the amino-terminal acyl chain of lipoproteins in its hydrophobic cavity, thereby generating a hydrophilic complex that can traverse the periplasmic space by diffusion. Lipoproteins are then transferred to LolB on the outer membrane and anchored to the inner leaflet of the outer membrane by the action of LolB. In contrast, since LolCDE does not recognize lipoproteins possessing Asp at position +2, these lipoproteins remain anchored to the inner membrane. Genes for Lol proteins are widely conserved among gram-negative bacteria, and Lol-mediated outer membrane targeting of lipoproteins is considered to be the general lipoprotein localization mechanism.


Amino acid metabolism in various fractions of rat-brain homogenates with special reference to the effect of ethanol.
1. The increase in brain gamma-aminobutyrate, glutamate and aspartate and the decrease in brain glutamine that occur when ethanol is administered to rats in vivo could be reproduced by incubating brain homogenates from rats pretreated with ethanol. 2. For the demonstration of the effects of pretreatment with ethanol on the metabolism of gamma-aminobutyrate and glutamine, the whole homogenate could be replaced by various supernatant preparations, and even by the soluble protein fraction, which was less active, however. The ;postmitochondrial' sediment could likewise mediate the effects of pretreatment with ethanol. 3. When the brain homogenates from control and ethanol-treated rats were allowed to ;age' at 2 degrees for more than 7 days, the metabolic difference at incubation could no longer be demonstrated. The capacities of the homogenate from the control rats had changed to resemble those of ethanol-treated rats. 4. Data are given on the effects of the incubation time and of the concentration of homogenate.


[Current social workers' task: promoting a life model].
The enactment of Psychiatric Social Workers Act was passed the National Diet in 1997. With this professional certification, psychiatric social workers are expected to help discharging more mental patients. For the further development of community care system, community agencies need to work as equal partners. It is critical to developing a team concept in the time that Japan is implementing case management service for the mentally ill. We should be able to work for the cause and think alike what we are for. Whether Japanese care management service empower the consumers or not depends on what model this service is based on, and whether community agencies and consumers working together. Social workers need to advocate for mental health consumers' choose from available resources, consent to treatment, create natural support networks, feel empowered, and allow themselves to live as an integral part of the community.


Morphologic differentiation of viruses beyond the family level.
Electron microscopy has been instrumental in the identification of viruses by being able to characterize a virus to the family level. There are a few cases where morphologic or morphogenesis factors can be used to differentiate further, to the genus level. These include viruses in the families Poxviridae, Reoviridae, Retroviridae, Herpesviridae, Filoviridae, and Bunyaviridae.


Geographical and experimental contexts modulate the effect of warming on top-down control: a meta-analysis.
Ecologists have extensively investigated the effect of warming on consumer-resource interactions, with experiments revealing that warming can strengthen, weaken or have no net effect on top-down control of resources. These experiments have inspired a body of theoretical work to explain the variation in the effect of warming on top-down control. However, there has been no quantitative attempt to reconcile theory with outcomes from empirical studies. To address the gap between theory and experiment, we performed a meta-analysis to examine the combined effect of experimental warming and top-down control on resource biomass and determined potential sources of variation across experiments. We show that differences in experimental outcomes are related to systematic variation in the geographical distribution of studies. Specifically, warming strengthened top-down control when experiments were conducted in colder regions, but had the opposite effect in warmer regions. Furthermore, we found that differences in the thermoregulation strategy of the consumer and openness of experimental arenas to dispersal can contribute to some deviation from the overall geographical pattern. These results reconcile empirical findings and support the expectation of geographical variation in the response of consumer-resource interactions to warming.


Fast preparation of LiFePO4 nanoparticles for lithium batteries by microwave-assisted hydrothermal method.
Nanomaterial for lithium batteries can decrease mechanical strain upon lithium intercalation/ deintercalation from lattice, and lead to high rate capability. The currently available microwave technology permits the development and implantation of a temperature-controlled microwave-assisted hydrothermal synthesis (TCMH) of nano-sized cathode material for lithium batteries. Unlike in previous reported traditional hydrothermal synthesis of cathode material LiFePO4, the pure phase of LiFePO4 can be simply and rapidly synthesized for 5 minutes in water under hydrothermal treatment with microwave irradiation. The homogeneous effects induced by microwave irradiation could create a uniform seeding condition. The colloid precursor Li3PO4 plays the key role to be the nucleation center for the new phase while the formation energy for LiFePO4 would be decreased during the following microwave irradiation. The as-prepared pristine LiFePO4 without carbon coating are characterized by X-ray diffraction, Raman, scanning and transmission electron microscopy, and tested as the cathode in lithium batteries. The particle sizes of pristine LiFePO4 are dependent on hydrothermal and microwave-assisted hydrothermal condition and the electrochemical performance are relatively determined.


Prospects of medium specific activity (177) Lu in targeted therapy of prostate cancer using (177) Lu-labeled PSMA inhibitor.
Targeted radionuclide therapy using (177) Lu-labeled peptidomimetic inhibitor of prostate specific membrane antigen (PSMA) viz. PSMA-617 is emerging as one the most effective strategies for management of metastatic prostate cancer, which is one of the leading causes of cancer related death. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of therapeutic dose of (177) Lu-PSMA-617 at hospital radiopharmacy using moderate specific activity (177) Lu available at an affordable cost. Extensive radiochemical studies were performed to optimize the required [PSMA-617] / [Lu] ratio and other parameters to formulate 7.4 GBq dose of (177) Lu-PSMA-617. Based on these, 7.4 GBq therapeutic dose of (177) Lu-PSMA-617 was formulated by incubating 160 µg of PSMA-617 with indigenously produced (177) LuCl3 (555 GBq/µg specific activity of (177) Lu) at 90 °C for 30 min. The radiochemical purity of the formulation was 98.3 ± 0.6% (n = 7) which was retained to the extent of >95% after 7 d in normal saline at room temperature and >96% after 2 d in human serum at 37 °C. Preliminary clinical studies showed specific targeting of the agent in the lesion sites and similar physiological distribution as in diagnostic (68) Ga-PSMA-11 PET scans performed earlier. The developed optimized protocol for formulating therapeutic dose of (177) Lu-PSMA-617 could be useful for large number of nuclear medicine therapy clinics across the world having access to moderate specific activity (177) Lu at an affordable cost.


Behavior study of the doped castor bean polymer rod with bioactive glass and hidroxyapatite in mice femur medullary canal.
Purpose To evaluate the polymer doped rods behavior with bioactive glass and hydroxyapatite for possible application as a fracture fixing method. Methods Twenty eight Rattus norvegicus Wistar underwent bone defect for access to the femoral medullary canal and distributed into three experimental groups: group A - doped castor bean polymer with bioactive glass; group B - castor bean polymer and; group C - castor bean polymer doped with bioactive glass and hydroxyapatite. After 15 and 60 evaluation days, the femurs were removed and sent for histology and scanning electron microscopy. Results Initially mild and moderate inflammatory infiltrate is observed that decreases as time goes by, and the presence of connective tissue capsule around the graft in all groups. Regarding the biomaterials resorption little was observed. The implanted rods did not favor the osteoconductive process in the femoral medullary canal which was observed only in the C15 group. Conclusions The association of castor bean polymer, bioactive glass and hydroxyapatite was biocompatible and osteointegrable. The osteoconductive only occurred in the presence of hydroxyapatite and bioactive glass (C15 Group) and little biodegradation was observed.


Effects of penicillin on macromolecular synthesis and surface growth of a tolerant streptococcus as studied by computer reconstruction methods.
Strains of Streptococcus mutans are very susceptible to growth inhibition by benzylpenicillin, but are tolerant to lysis when exposed to even high concentrations of this drug. These properties enabled this study of S. mutans GS-5 surface growth and peptidoglycan, ribonucleic acid, protein, and deoxyribonucleic acid syntheses in the absence of osmotic stabilization. Inhibition of syntheses of peptidoglycan, ribonucleic acid, and protein was dose dependent. Synthesis of peptidoglycan was most susceptible. Substantial but less severe inhibitions of ribonucleic acid and protein syntheses rapidly followed decreased peptidoglycan synthesis, whereas inhibition of deoxyribonucleic acid synthesis was delayed and minimal. Computer-assisted reconstructions of surface growth zones and poles observed in electron micrographs of replicas were performed and indicated that at low concentrations of benzylpenicillin (0.03 micrograms/ml), growth sites reached abnormally large sizes and surface/volume ratios. The observed shifts in surface/volume ratio were attributed to an inhibition of the normal constrictive division mechanism. The poles of these cells also increased in size over those of the controls, but the relatively smaller change in surface/volume ratio confirmed the visual impression that the shape of the poles was much less altered than the shape of the growth sites. As the concentration of benzylpenicillin used was raised from 0.03 to 2 micrograms/ml, the ability of growth sites and poles to enlarge was restricted in a manner that most closely agreed with the extent of inhibition of peptidoglycan (rather than deoxyribonucleic acid, ribonucleic acid, or protein) synthesis. This correlation suggested that increases in cell size may be regulated by the supply of peptidoglycan precursors.