Expansion and characterization of cells from surgically removed intervertebral disc fragments in xenogen-free medium.
Low back pain due to degeneration of intervertebral disc (IVD) is a major health problem resulting in significant disability as well as adding to the economic burden. Discectomy is a very common procedure done worldwide to relieve this pain. At present all the surgically removed disc tissue is mostly discarded. However, there are reports that state that progenitor cells in the IVD can be grown ex vivo and have the potential to be used for IVD repair and regeneration. We report here that viable cells can be harvested from surgically removed, herniated disc tissue and can be potentially used in cell based therapy. Further, we have successfully replaced xenogenic supplements such as foetal bovine serum with either autologous serum or human platelet lysate for culturing IVD cells from patient's surgically removed disc tissue, without loss of any cell characteristics, including cell surface markers, growth factor secretion in the conditioned medium and osteogenic and chondrogenic differentiation potential in vitro. The present work will not only contribute to overcoming some of the major barriers in carrying out human clinical trials, but also provide a cheap, alternate source of proteins and growth factors for growing IVD cells ex vivo for therapy.


Serial changes in the white matter diffusion tensor imaging metrics in moderate traumatic brain injury and correlation with neuro-cognitive function.
Diffuse axonal injury (DAI) that follows traumatic brain injury (TBI) is thought to be a major contributor to neurocognitive dysfunction that sometimes follows TBI. Conventional magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and neuropsychological tests (NPT) were performed on 38 TBI patients [hemorrhagic DAI (H-DAI, n=8), non-hemorrhagic (Nh-DAI, n=7), with no apparent DAI on conventional MRI (NA-DAI, n=23)] with a Glasgow Coma Scale score ranging between 9 and 13. The fractional anisotropy (FA) and mean diffusivity (MD) were quantified from different regions of the corpus callosum (CC), and peri-ventricular white matter (PWM) within 5-14 days and 6 months following TBI. Patients in all three groups showed decreased FA in the anterior limb of the internal capsule (ALIC) and the posterior limb of the internal capsule (PLIC), while the genu of the CC showed a decrease in the H-DAI group during the early period following TBI that persisted 6 months later, which appeared to be consistent with axonopathy. In patients without abnormalities on conventional MRI and DTI in the initial phase, a significant decrease in FA and increase in MD were observed in a few regions of the CC at 6 months, which was suggestive of demyelination/gliosis. The changes in FA and MD in the CC and PWM at 6 months follow-up showed significant correlation with some of the NPT performed in the three groups. DTI demonstrates axonopathy in the acute stage, as well as at secondary stages, at 6 months post-injury in the CC and PWM in regions of normal-appearing white matter on conventional MRI.


Native mitral valve fungal endocarditis caused by Aspergillus fumigatus: A case report.
Aspergillus endocarditis is a rare fungal infection associated with a poor prognosis. Most cases of Aspergillus endocarditis involve prosthetic valves, with native valve involvement being rarely reported. A 53-year-old asian female patient presented with fever, chills, dyspnea, generalized fatigue, and significant weight loss one month after undergoing left lower lobectomy for a pulmonary abscess. Echocardiogram showed a large mobile vegetation with a broad base on the anterior leaflet of the mitral valve, resembling atrial myxoma. Despite negative blood cultures, circulating DNA of Aspergillus fumigatus was detected by metagenome Next Generation Sequencing, prompting the initiation of empiric antifungal therapy with voriconazole. Emergency surgery, involving thorough debridement and mitral valve replacement, was successfully performed. Indefinite fungal suppression therapy with oral voriconazole is continued to mitigate the risk of recurrence. The patient survived with no signs of Aspergillus disease recurrence for four years. Diagnosis of Aspergillus endocarditis requires a high index of suspicion and is often delayed due to consistently negative results from blood cultures. Non-culture-based methods, particularly metagenome Next-Generation Sequencing, play a crucial role in early diagnosis and therapeutic decision-making. Surgical debridement and valve replacement are imperative for survival in cases of Aspergillus endocarditis. Voriconazole should be considered the primary fungicidal agent for its treatment. Moreover, lifelong fungal suppression therapy is strongly recommended for all survivors to ensure long-term survival and minimize the risk of recurrence. Despite grim prognosis associated with Aspergillus endocarditis, patients can attain long-term survival through meticulous surgical debridement and lifelong antifungal therapy.


Functional Interactions between BM88/Cend1, Ran-binding protein M and Dyrk1B kinase affect cyclin D1 levels and cell cycle progression/exit in mouse neuroblastoma cells.
BM88/Cend1 is a neuronal-lineage specific modulator with a pivotal role in coordination of cell cycle exit and differentiation of neuronal precursors. In the current study we identified the signal transduction scaffolding protein Ran-binding protein M (RanBPM) as a BM88/Cend1 binding partner and showed that BM88/Cend1, RanBPM and the dual specificity tyrosine-phosphorylation regulated kinase 1B (Dyrk1B) are expressed in mouse brain as well as in cultured embryonic cortical neurons while RanBPM can form complexes with either of the two other proteins. To elucidate a potential mechanism involving BM88/Cend1, RanBPM and Dyrk1B in cell cycle progression/exit, we transiently co-expressed these proteins in mouse neuroblastoma Neuro 2a cells. We found that the BM88/Cend1-dependent or Dyrk1B-dependent down-regulation of cyclin D1 is reversed following their functional interaction with RanBPM. More specifically, functional interaction of RanBPM with either BM88/Cend1 or Dyrk1B stabilizes cyclin D1 in the nucleus and promotes 5-bromo-2'-deoxyuridine (BrdU) incorporation as a measure of enhanced cell proliferation. However, the RanBPM-dependent Dyrk1B cytosolic retention and degradation is reverted in the presence of Cend1 resulting in cyclin D1 destabilization. Co-expression of RanBPM with either BM88/Cend1 or Dyrk1B also had a negative effect on Neuro 2a cell differentiation. Our results suggest that functional interactions between BM88/Cend1, RanBPM and Dyrk1B affect the balance between cellular proliferation and differentiation in Neuro 2a cells and indicate that a potentially similar mechanism may influence cell cycle progression/exit and differentiation of neuronal precursors.


Monocyclicity in the Function of the Erythroid Hematopoietic Lineage in Teleost Fish Exemplified by Platichthys Flesus (Linnaeus, 1758).
The erythroid lineage was studied in the flounder-gloss (Platichthys flesus Linnaeus, 1758) during the annual cycle. The erythrocyte count in the blood was determined along with the contents of immature erythroid forms (basophilic and polychromatophilic normoblasts) in the head kidney (pronephros) and the blood. Cell proliferative activity was inferred from the [3H]thymidine inclusion in circulating immature erythrocytes. Irregularity was observed in erythropoiesis occurring in flounder-gloss hematopoietic tissue. Intense production of erythroid mass was mainly associated with a post-spawning period. This was evident from an increase in the contents of immature erythroid forms in the pronephros and circulating blood and an increase in their proliferative activity. The changes were associated with peculiarities of the erythroid system organization, which precludes regular production of erythropoietin in the kidney in teleost fish.


p53-Dependent and -independent transactivation by the E6 protein of human papillomavirus type 16.
The mechanism by which the E6 protein of human papillomavirus type 16 (HPV-16) transactivates heterologous virus promoters has not been established. In this study, the involvement of p53-mediated transcriptional repression in transactivation by the HPV-16 E6 protein was examined using several virus promoters. HPV-16 E6 transactivated the TATA box-containing simian virus 40 early promoter and the Rous sarcoma virus long terminal repeat in p53-containing cells but not in p53-deficient cells. In contrast, the adenovirus E2 promoter was transactivated both in p53-containing and p53-deficient cells. These results indicate that the transactivation activity of the HPV-16 E6 protein is mediated by p53-dependent and promoter-specific p53-independent pathways.


Endurance training improves fitness and strength in patients with Becker muscular dystrophy.
Studies in a dystrophinopathy model (the mdx mouse) suggest that exercise training may be deleterious for muscle integrity, but exercise has never been studied in detail in humans with defects of dystrophin. We studied the effect of endurance training on conditioning in patients with the dystrophinopathy, Becker muscular dystrophy (BMD). Eleven patients with BMD and seven matched, healthy subjects cycled 50, 30 min sessions at 65% of their maximal oxygen uptake (VO(2max)) over 12 weeks, and six patients continued cycling for 1 year. VO(2max), muscle biopsies, echocardiography, plasma creatine kinase (CK), lower extremity muscle strength and self-reported questionnaires were evaluated before, after 12 weeks and 1 year of training. Endurance training for 12 weeks, improved VO(2max) by 47 +/- 11% and maximal workload by 80 +/- 19% in patients (P < 0.005). This was significantly higher than in healthy subjects (16 +/- 2% and 17 +/- 2%). CK levels did not increase with training, and number of central nuclei, necrotic fibres and fibres expressing neonatal myosin heavy chain did not change in muscle biopsies. Strength in muscles involved in cycle exercise (knee extension, and dorsi- and plantar-flexion) increased significantly by 13-40%. Cardiac pump function, measured by echocardiography, did not change with training. All improvements and safety markers were maintained after 1 year of training. Endurance training is a safe method to increase exercise performance and daily function in patients with BMD. The findings support an active approach to rehabilitation of patients with BMD.


Unveiling hidden ferrimagnetism and giant magnetoelectricity in polar magnet Fe2Mo3O8.
Magnetoelectric (ME) effect is recognized for its utility for low-power electronic devices. Largest ME coefficients are often associated with phase transitions in which ferroelectricity is induced by magnetic order. Unfortunately, in these systems, large ME response is revealed only upon elaborate poling procedures. These procedures may become unnecessary in single-polar-domain crystals of polar magnets. Here we report giant ME effects in a polar magnet Fe2Mo3O8 at temperatures as high as 60 K. Polarization jumps of 0.3 μC/cm(2), and repeated mutual control of ferroelectric and magnetic moments with differential ME coefficients on the order of 10(4) ps/m are achieved. Importantly, no electric or magnetic poling is needed, as necessary for applications. The sign of the ME coefficients can be switched by changing the applied "bias" magnetic field. The observed effects are associated with a hidden ferrimagnetic order unveiled by application of a magnetic field.


Accuracy and Quality of YouTube Videos as a Source of Information on Vitiligo.
Vitiligo is a skin condition characterized by patchy depigmentation in the skin, affecting not just the physical well-being of patients, but also the mental, emotional, and social aspects of their lives. Social media provides a platform where patients can interact and share experiences, and for physicians and experts to disseminate knowledge on the disease. This study aimed to evaluate the accuracy and overall quality of vitiligo-related content on YouTube. Thirty videos were screened by relevance according to the inclusion criteria. Videos were categorized as either healthcare or non-healthcare sources, and viewer engagement ratio was calculated for each. Three independent vitiligo experts rated the content using the following assessment tools: DISCERN, Accuracy in Digital-health Instrument (ANDI), and Global Quality Scale (GQS). Lastly, Cronbach's alpha was used to estimate the inter-rater reliability and consistency. Most of the screened videos came from health-care sources (57%). Non-healthcare sources achieved a slightly higher viewer engagement ratio, although the difference is not statistically significant (p = 0.23). DISCERN score was low overall in most videos. However, DISCERN score was higher for health-care sources as compared to non-healthcare sources (30.5 ± 9.4 vs 22.7 ± 4,2, p = 0.009). Scores of ANDI and GQS were higher for health-care sources but not statistically significant. There was a good internal consistency in DISCERN rating among the evaluators (0.86). Our study shows a low overall accuracy and quality of YouTube videos on vitiligo. It is recommended that health-care sources improve their information material in terms of quality and viewer engagement, as very little can be done to prevent non-healthcare sources in publishing their own videos. Efforts in educating the public on making distinction between evidence and non-evidence-based claims should also be taken.


Clinical potential of introducing next-generation sequencing in patients at relapse of acute myeloid leukemia.
Relapse of acute myeloid leukemia (AML) remains a major determinant of outcome. A number of molecularly directed treatment options have recently emerged making comprehensive diagnostics an important pillar of clinical decision making at relapse. Acknowledging the high degree of individual genetic variability at AML relapse, next-generation sequencing (NGS) has opened the opportunity for assessing the unique clonal hierarchy of individual AML patients. Knowledge on the genetic makeup of AML is reflected in patient customized treatment strategies thereby providing improved outcomes. For example, the emergence of druggable mutations at relapse enable the use of novel targeted therapies, including FLT3 inhibitors or the recently approved IDH1/2 inhibitors ivosidenib and enasidenib, respectively. Consequently, some patients may undergo novel bridging approaches for reinduction before allogeneic stem cell transplantation, or the identification of an adverse prognostic marker may initiate early donor search. In this review, we summarize the current knowledge of NGS in identifying clonal stability, clonal evolution, and clonal devolution in the context of AML relapse. In light of recent improvements in AML treatment options, NGS-based molecular diagnostics emerges as the basis for molecularly directed treatment decisions in patients at relapse.


Molecular dynamics simulations of certain RGD-based peptides from Kistrin provide insight into the higher activity of REI-RGD34 protein at higher temperature.
To determine the bioactive conformation required to bind with receptor aIIbb3, the peptide sequence RIPRGDMP from Kistrin was inserted into CDR 1 loop region of REI protein, resulting in REI-RGD34. The activity of REI-RGD34 was observed to increase at higher temperature towards the receptor aIIbb3. It could be justified in either way: the modified complex forces the restricted peptide to adapt bioactive conformation or it unfolds the peptide in a way that opens its binding surface with high affinity for receptor. Here, we model the conformational preference of RGD sequence in RIPRGDMP at 25 and 42 °C using multiple MD simulations. Further, we model the peptide sequence RGD, PRGD and PRGDMP from kistrin to observe the effect of flanking residues on conformational sampling of RGD. The presence of flanking residues around RGD peptide greatly influenced the conformational sampling. A transition from bend to turn conformation was observed for RGD sequence at 42 °C. The turn conformation shows pharmacophoric parameters required to recognize the receptor aIIbb3. Thus, the temperaturedependent activity of RIPRGDMP when inserted into the loop region of REI can be explained by the presence of the turn conformation. This study will help in designing potential antagonist for the receptor aIIbb3.


Assessing the impact of radiation-induced changes in soft tissue density ∕ thickness on the study of radiation-induced perfusion changes in the lung and heart.
Abnormalities in single photon emission computed tomography (SPECT) perfusion within the lung and heart are often detected following radiation for tumors in∕around the thorax (e.g., lung cancer or left-sided breast cancer). The presence of SPECT perfusion defects is determined by comparing pre- and post-RT SPECT images. However, RT may increase the density of the soft tissue surrounding the lung∕heart (e.g., chest wall∕breast) that could possibly lead to an "apparent" SPECT perfusion defect due to increased attenuation of emitted photons. Further, increases in tissue effective depth will also increase SPECT photon attenuation and may lead to "apparent" SPECT perfusion defects. The authors herein quantitatively assess the degree of density changes and effective depth in soft tissues following radiation in a series of patients on a prospective clinical study. Patients receiving thoracic RT were enrolled on a prospective clinical study including pre- and post-RT thoracic computed tomography (CT) scans. Using image registration, changes in tissue density and effective depth within the soft tissues were quantified (as absolute change in average CT Hounsfield units, HU, or tissue thickness, cm). Changes in HU and tissue effective depth were considered as a continuous variable. The potential impact of these tissue changes on SPECT images was estimated using simulation data from a female SPECT thorax phantom with varying tissue densities. Pre- and serial post-RT CT images were quantitatively studied in 23 patients (4 breast cancer, 19 lung cancer). Data were generated from soft tissue regions receiving doses of 20-50 Gy. The average increase in density of the chest was 5 HU (range 46 to -69). The average change in breast density was a decrease of -1 HU (range 13 to -13). There was no apparent dose response in neither the dichotomous nor the continuous analysis. Seventy seven soft tissue contours were created for 19 lung cancer patients. The average change in tissue effective depth was +0.2 cm (range -1.9 to 2.2 cm). The changes in HU represent a <2% average change in tissue density. Based on simulation, the small degree of density and tissue effective depth change is unlikely to yield meaningful changes in either SPECT lung or heart perfusion. RT doses of 20-50 Gy can cause up to a 46 HU increase in soft tissue density 6 months post-RT. Post-RT soft tissue effective depth may increase by 2.0 cm. These modest increases in soft tissue density and effective depth are unlikely to be responsible for the perfusion changes seen on post-RT SPECT lung or heart scans. Further, there was no clear dose response of the soft tissue density changes. Ultimately, the authors findings suggest that prior perfusion reports do reflect changes in the physiology of the lungs and heart.


Active suppression of immunoglobulin allotype synthesis. II. Transfer of suppressing factor with spleen cells.
The mechanism of chronic allotype suppression in (SJL x BALB/c)F(1) mice has been investigated by means of cell transfer studies. These mice are phenotypically negative for serum Ig-1b, the paternal allotype determinant on gammaG(2a) immunoglubulin, as a result of perinatal exposure to maternal anti-Ig-1b. When spleen or bone marrow (B) cells from suppressed mice were injected into irradiated BALB/c "indicator" hosts, detectable levels of Ig-1b were demonstrated in the sera of a majority of the recipients early after transfer. These results indicate that Ig-1b-producing cells or their precursors are present in the lymphoid tissues of suppressed mice, even though they are not expressed. Within 5-7 wk, it was no longer possible to detect Ig-1b in the sera of these hosts, although cells producing another paternal allotype (Ig-4b) were shown to persist. Control BALB/c mice, injected with spleen and B cells from normal mice, continued to produce high levels of immunoglobulin carrying this allotype. The disappearance of serum, Ig-1b occurred most frequently in the recipients of suppressed spleen cells. Similar results were obtained using a mixture of spleen cells from normal and suppressed mice. Ig-1b production in the recipient mice ceased within a few weeks, even though the majority of cells in the mixture were obtained from normal (nonsuppressed) donors. The data are interpreted as evidence that chronic allotype suppression in mice is actively maintained by cells which are resident in the lymphoid tissues, splenic cells being the most effective. These cells are capable of proliferating in a new host and exerting their suppressive influence on Ig-1b-producing cells and/or their precursors.


Colorectal cancer.
Colorectal cancer is the leading cause, after lung cancer, of death from cancer in Australia. About 50% of colorectal cancers are attributed to dietary factors and about 15%-20% to genetic factors, including high risk familial syndromes. The most common presenting symptoms are rectal bleeding (left-sided cancers) and iron-deficiency anaemia (right-sided cancers). Patients with suggestive symptoms should have a digital rectal examination, followed by sigmoidoscopy and biopsy if a rectal lesion is suspected, or colonoscopy if colon cancer is suspected. Treatment of most colorectal cancers is segmental resection with a wide resection margin; the role of adjuvant therapy is still being refined. Screening with annual (or biennial) faecal occult blood tests is recommended for people over 50 years without symptoms and with average or slightly above average risk; more intensive, earlier screening is recommended for those with greater risk.


Spacer devices for metered dose inhalers.
Spacer devices are attachments to the mouthpieces of pressurised metered dose inhalers (pMDIs), and range from tube spacers with a volume of <50 mL to holding chambers with a volume of 750 mL. Compared with a pMDI alone, spacers minimise coordination difficulties, reduce oropharyngeal deposition and often increase lung deposition. Spacers may not improve the clinical effect in patients able to use a pMDI properly, but may allow maintenance dosages of bronchodilators and corticosteroids to be reduced. Correct use of spacer devices is important, especially achieving control over electrostatic charge accumulation on the walls of plastic devices. In patients with severe acute asthma or severe chronic obstructive pulmonary disease, a pMDI plus large volume spacer may be a viable alternative to a nebuliser for delivering large bronchodilator doses. Although the addition of a spacer to every pMDI would not be justified, the use of large volume spacers has been recommended for any inhaled asthma drug in young children, and as a means of reducing systemic bioavailability of inhaled corticosteroids in adults and children alike.


Hyperventilation and cold-pressor stress echocardiography combined with automated functional imaging non-invasively detected vasospastic angina.
A 47-year-old male presented with chest discomfort while sleeping. The patient was suspected of having vasospastic angina (VSA) and underwent hyperventilation and cold-pressor stress echocardiography. No chest pain, ECG changes or decreased wall motion was found. However, automated function imaging (AFI) showed decreased peak systolic strain at the apex and postsystolic shortening at both the apex and inferior wall, which was not found before the test. The provocation test revealed 99% stenosis in the right coronary artery #2 at a dose of 50 μg acetylcholine and 90% stenosis in the left coronary artery #8 at a dose of 100 μg. The patient was thus diagnosed as having VSA. The present case demonstrates the usefulness of AFI combined with hyperventilation and cold-pressor stress echocardiography as a screening examination for VSA.


Sources of Mycobacterium avium complex infection resulting in human diseases.
Human disease caused by organisms in the Mycobacterium avium complex occur virtually worldwide. A 20-year ongoing study conducted in Western Germany has been analyzed to elucidate the ecologic and epidemiologic characteristics of these infections in man. Organisms included in this investigation have been cultured from man, from domestic and wild animals and fowl, and from a variety of environmental sources. In addition to the usual taxonomic studies of these bacilli, infrasubspecific typing by seroagglutination has enabled identification of 3 distinct serogroups: the classical Mycobacterium avium strains (serovars avium 1, 2, and 3), the intermediate group (avium serovars 4, 5, 6, 8, 9, 10, and 11), and the less frequently encountered organisms, the 11 remaining avium serovars (7 and 12 through 21). Analysis of the number of strains in each of the 3 serogroups, derived, respectively, from man, from animals, and from the environment, has enabled us to draw some conclusions regarding reservoirs and sources of human infection with these agents.


[Regulatory issues of biologically active supplements in Armenia].
Since 1996 by Drug and Medical Technology Agency of the Ministry of Health of the Republic Armenia there has been a record of biologically active supplements, and up to now it numbers 61 products. There has been created a database on biologically active supplements containing relevant information on producers, composition of the product, indications for applying etc. There have been cited some data on examining biologically active supplements and on criteria of such products appraisal. The parameters of not approved Dietary supplements Applications are included and the requirements for Dietary supplements Labels are described in it. There has been cited the division of registration biologically active supplements as per active ingredients and recommendations on use. According to the results of special questionnaire for the Yerevan policlinic doctors, there have been analyzed the spreading area and dynamics biologically active supplements prescription Also there has been estimated the adequacy of their prescription and doctors opinion this product.


Human fascioliasis in Egypt: effect of infection and efficacy of bithionol treatment.
The present study was conducted on 14 patients with established fascioliasis. The effect of infection on the haematological and biochemical parameters was determined and the liver and gall bladder were studied by ultrasonography. Bithionol was given in the dose of 30 mg kg-1 body weight every other day for 5 doses. The therapeutic efficacy was assessed by egg and eosinophilic counts and quantitative estimation of antibody titres by indirect haemagglutination test. Results revealed that fascioliasis caused normocytic hypochromic anaemia and eosinophilia. Serum bilirubin, ALT and AST were within normal range. Ultrasonography showed a normal echogenic pattern of the liver and gall bladder. One case showed thickness of the gall bladder wall which was tender under the transiducer. Fasciola eggs disappeared completely after the 5th dose giving a cure rate of 100%. Antibody titres reached a normal level at the end of the 3rd month post treatment. Bithionol proved to be a potent fasciolicidal drug with minimal side-effects.


Intraoperative echocardiography during congenital heart operations: experience from 1,000 cases.
This article provides an overview of the application of intraoperative echocardiography during repair of congenital heart defects based on our experience with 1,000 patients. The patients in this study all underwent repair of a congenital heart defect between 1987 and 1994 at Duke University Medical Center. Echocardiography was performed on all patients in the operating room both before and after repair using epicardial or transesophageal imaging (or both). Hospital costs and outcome data were obtained for all patients. Overall, 44 patients (4.4%) underwent intraoperative revision of their repair based on echocardiographic findings. There was an initial learning phase during which 8.5% of repairs needed to be revised. With experience, the number of revisions fell to as low as 3% to 4%, but need for revision continued to occur throughout the series. Thirty-nine patients (88.6%) had a successful revision. It was not possible for the surgeon to predict the need for a revision based on his confidence in the repair: in 2.6% of patients thought by the surgeon to have a good repair, intraoperative echocardiography revealed the need for operative revision. The average cost for patients who return to the operating room during their hospitalization for revision of a repair is significantly greater than for those whose repairs are revised before they leave the operating room ($94,180.28 +/- $33,881.63 versus $21,415.79 +/- $8,215.74). There were no significant complication attributable to intraoperative echocardiography. In an era where complete repair of congenital heart defects is emphasized, intraoperative echocardiography provides information that can guide successful operative revision so that babies leave the operating room with optimal results.


High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma.
Hodgkin lymphoma (HL) is one of the most common malignancies in young adults and has become curable for the majority of patients, even in advanced stage. After first-line therapy, 15% to 20% do not respond to treatment and relapse. For those patients, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is a frequently used therapy option. To find the best available treatment with HDCT followed by ASCT for patients with relapsed or refractory HL after first-line treatment. We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, and relevant conference proceedings up to January 2013 for randomised controlled trials (RCTs). We also contacted experts for unpublished data. We included RCTs comparing HDCT followed by ASCT versus conventional chemotherapy without ASCT, or versus additional sequential HDCT (SHDCT) followed by ASCT. We also included RCTs with different HDCT regimens before ASCT in patients with relapsed or primary refractory HL after any first-line therapy. Two review authors (MR, NS) independently selected relevant studies, extracted data and assessed trial quality. We used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS), and we calculated risk ratios (RR) for the other outcomes. We presented all measures with 95% confidence intervals (CI).We assessed the quality of evidence using GRADE methods. Our search resulted in 1663 potentially relevant references, of which we included three trials with 14 publications, assessing 398 patients. Overall, we judged the quality of the trials as moderate. The trials were all reported as randomised controlled and open-label. We included two RCTs assessing the effect of HDCT followed by ASCT compared with conventional chemotherapy in a meta-analysis. The number of studies was very low, therefore, the quantification of heterogeneity was not reliable. We included one further RCT (one assessing additional SHDCT followed by ASCT versus HDCT followed by ASCT), which was not compatible with our meta-analysis. For this trial, we performed further analyses.Two trials showed a non-statistically significant trend that HDCT followed by ASCT compared to conventional chemotherapy increases OS (HR 0.67; 95% CI 0.41 to 1.07; P value = 0.10, 157 patients, moderate quality of evidence). However, the increase in PFS was statistically significant for people treated with HDCT followed by ASCT (HR 0.55; 95% CI 0.35 to 0.86; P value = 0.009, 157 patients, moderate quality of evidence). Adverse events were reported in one trial only and did not differ statistically significant between the treatment arms. We were not able to draw conclusions regarding treatment-related mortality (TRM) because of insufficient evidence (RR 0.61; 95% CI 0.16 to 2.22; P value = 0.45, 157 patients, moderate quality of evidence).For the second comparison, SHDCT plus HDCT followed by ASCT versus HDCT followed by ASCT there was no difference between the treatment arms regarding OS (HR 0.93; 95% CI 0.5 to 1.74; P value = 0.816, three-year OS: 80% SHDCT versus 87% HDCT, 241 patients), or PFS (HR 0.87; 95% CI 0.58 to 1.30; P value = 0.505, 241 patients). Seven patients died in the SHDCT arm and one in the HDCT arm due to increased toxicity of the treatment. Adverse events were increased with SHDCT plus HDCT followed by ASCT after two cycles of dexamethasone plus high-dose cytarabine plus cisplatin (DHAP) (88% SHDCT versus 45% HDCT, 223 patients, P value < 0.00001). Overall, more statistically significant World Health Organization (WHO) grade 3/4 infections occurred with SHDCT (48% SHDCT versus 33% HDCT; P value = 0.002, 223 patients). The currently available evidence suggests a PFS benefit for patients with relapsed or refractory HL after first-line therapy, who are treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. In addition, data showes a positive trend regarding OS, but more trials are needed to detect a significant effect.Intensifying the HDCT regime before HDCT followed by ASCT did not show a difference as compared to HDCT followed by ASCT, but was associated with increased adverse events.


Primary Uterine Alveolar Soft Part Sarcoma in a Postmenopausal Woman: Histopathologic and Immunohistochemical Characteristics of a Rare Case.
Primary uterine alveolar soft part sarcoma (ASPS) is a rare, indolent mesenchymal malignancy with less than 40 patients documented in the literature. We report an example of ASPS in a 61-year-old postmenopausal woman. Macroscopically, the uterus showed multiple nodular masses. Microscopic examination revealed tumor arranged in nests and alveolar pattern. The tumor cells were moderately to markedly pleomorphic, epithelioid to polygonal, with eccentrically placed nuclei, vesicular chromatin, prominent macro-nucleoli, and moderate to abundant eosinophilic cytoplasm. PAS-positive and diastase-resistant intracytoplasmic crystals were also seen in some tumor cells. On immunohistochemistry, the tumor cells showed diffuse positivity for vimentin and nuclear positivity for TFE3, a surrogate marker for ASPS. These were negative for SMA, desmin, CD10, h-caldesmon, cyclin D1, EMA, Melan A, and CD34. SMARCB1 expression was retained. Based on the histopathology and IHC, a final diagnosis of uterine ASPS was rendered. Knowledge of the characteristic histopathologic and immunohistochemical features can help accurately diagnose such rare tumors. Knowledge of the characteristic histopathologic and immunohistochemical features can help accurately diagnose such rare sarcoma in an uncommon site with an unusual age.


The exocellular beta-lactamase of Streptomyces albus G. Purification, properties and comparison with the exocellular DD-carboxypeptidase.
The exocellular beta-lactamase of Streptomyces albus G has been purified to near protein homogeneity. It consists of one single polypeptide chain of mol.wt. 30 000-31 000, has a rather low isoelectric point (at pH 6.0) and contains less lysine (2.1%) and more half-cystine residues than most beta-lactamases from other Gram-positive bacteria. Penicillins are much better substrates than delta 3-cephalosporins; the catalytic-centre activity of good penicillin substrates is 333-500 s-1. The exocellular, mol.wt. 17 000 DD-carboxypeptidase of S. albus G [previously purified to protein homogeneity; Duez, Frère, Geurts, Ghuysen, Dierickx & Delcambe (1978) Biochem. J. 175, 793-800] behaves as an exceedingly poor beta-lactamase, hydrolysing benzylpenicillin into benzylpenicilloate 5 x 10(-6)-fold less rapidly than does the exocellular beta-lactamase. To all appearances, the beta-lactamase has no bivalent cation requirement whereas, as shown elsewhere [Dideberg, Charlier, Dupont, Vermeire, Frère & Ghuysen (1980) FEBS Lett. 117, 212-214, and Dideberg, Joris, Frère, Ghuysen, Weber, Robaye, Delbrouck & Roelands (1980) FEBS Lett. 117, 215-218], the DD-carboxypeptidase possesses one essential Zn2+ ion per molecule. Peptide 'mapping' and immunological studies suggest that the two Streptomyces enzymes probably have very different structural and mechanistic properties.


Parameters of Oxidative Stress in Reproductive and Postmenopausal Mexican Women.
In the reproductive phase, women experience cyclic changes in the ovaries and uterus, and hormones regulate these changes. Menopause is the permanent loss of menstruation after 12 months of amenorrhea. Menopause is also linked to a decrease in estrogen production, causing an imbalance in oxidative stress. We aimed to compare the three stages of lipid peroxidation, protein oxidative damage, and total antioxidant capacity (TAC) between reproductive-aged women (RAW) and postmenopausal women (PMW) in Mexico. We carried out a cross-sectional study with 84 women from Mexico City, including 40 RAW and 44 PMW. To determine the oxidative stress of the participants, several markers of lipid damage were measured: dienes conjugates (DC), lipohydroperoxides (LHP), and malondialdehyde (MDA); exposure to protein carbonyl is indicative of oxidative modified proteins, and TAC is indicative of the antioxidant defense system. Biomarkers of oxidative stress were significantly lower in RAW vs. PMW. DC were 1.31 ± 0.65 vs. 1.7 ± 0.51 pmol DC/mg dry weight (p = 0.0032); LHP were 4.95 ± 2.20 vs. 11.30 ± 4.24 pmol LHP/mg dry weight (p < 0.0001); malondialdehyde was 20.37 ± 8.20 vs. 26.10 ± 8.71 pmol MDA/mg dry weight (p = 0.0030); exposure of protein carbonyl was 3954 ± 884 vs. 4552 ± 1445 pmol PC/mg protein (p = 0.042); and TAC was 7244 ± 1512 vs. 8099 ± 1931 pmol Trolox equivalent/mg protein (p = 0.027). PMW display significantly higher oxidative stress markers compared to RAW; likewise, PMW show a higher TAC.


Isoprene emission, photosynthesis, and growth in sweetgum (Liquidambar styraciflua) seedlings exposed to short- and long-term drying cycles.
Isoprene emissions were studied in one-year old sweetgum (Liquidambar styraciflua L.) seedlings during nine drying-rewatering cycles extending over five months. Each drying cycle lasted to the point of leaf wilting. Growth was essentially stopped in response to the first drying cycle, though seedling survival and capacity to recover turgor on rewatering remained high throughout the entire nine cycles. Photosynthetic rates of leaves were inhibited by the drying treatments. Under severe drought, isoprene emission rates of leaves were also inhibited, though isoprene emission was generally less sensitive to drought than photosynthesis. The lower drought sensitivity of isoprene emission compared with photosynthesis resulted in a higher percentage of fixed carbon lost as isoprene as seedlings became more stressed. During the recovery phase of the drying-rewatering cycles, isoprene emission rates in several seedlings were higher than in well-watered control seedlings. Following the ninth drying-rewatering cycle, sustained daily watering resulted in recovery of isoprene emission rates to control values within four days. Photosynthetic rates only recovered to 50% of control values after seven days. We conclude that the mechanisms regulating photosynthetic rate and isoprene emission rate are differentially influenced by limited water supplies. The results are consistent with past studies that predict a protective role for isoprene emission during stress, particularly protection from excessive leaf temperatures during drought.


Factors affecting adenoidectomy for otitis media with effusion (glue ear).
One hundred and fifty-five children suffering bilateral otitis media with effusion (OME) and observed for three months have been followed postoperatively for twelve months. Surgery was randomly allocated into three groups: adenotonsillectomy; adenoidectomy; and no surgery. In all cases unilateral myringotomy and grommet insertion was performed. The contralateral unoperated ear was assessed subsequently for clearance of the effusion. Adenoidectomy produced resolution of the effusion in 31-45% of cases at one year, but tonsillectomy conferred no additional benefit. There was improved resolution in those with longer compared with shorter histories, and in older as opposed to younger children. Assessment of preoperative lateral cephalometric radiographs show improved resolution of the effusion following removal of larger, compared with smaller adenoids, but this effect was only demonstrable for three months. The effect of age was longer-lasting for up to one year postoperatively.


Pressure dependence of intrapulse Raman scattering of single- and few-cycle pulses in gaseous deuterium.
We studied the effect of pressure variation on intrapulse Raman scattering for a single-cycle and few-cycle pulses in a gas cell of a given length filled with gaseous deuterium, in the framework of a new model equation that goes beyond the slowly varying envelope approximation. We show that, for a single-cycle pulse, pressure variation does not have any influence on the pulse spectrum. On the other hand, for a four-cycle pulse, an increase in pressure considerably affects the pulse spectrum and leads to substantial broadening and blueshift of the output pulse spectrum. Also, with increasing pressure, more and more energy is transferred from the red to the blue components.


Pathogenic mechanisms in type 1 diabetes: the islet is both target and driver of disease.
Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4⁺ T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8⁺ T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.


Developing a prioritization matrix for improving breast care--a complex project.
Prioritization is an ongoing challenge for quality management professionals. A previous companion Brief Report described a tool for prioritizing improvement projects (Pelletier, Beaudin, and van Leeuwen, 1999). This tool provides a framework for prioritizing opportunities/solutions for major institutional improvement projects. By separating and categorizing opportunities and solutions and then weighing their importance and impact, the organization can graphically evaluate and then select interventions to initiate.


Effects of mibefradil and verapamil on ischemic-reperfusion in the hearts of guinea pigs with acute renal failure.
Two parameters indicating the ischemic-reperfusion myocardial injury, coronary flow and lactate dehydrogenase (LDH) release rate, were evaluated in guinea pigs with gentamicine-induced acute renal failure (ARF) and compared with those of healthy animals. Isolated Langendorffs hearts were exposed to 50 min of zero-flow global ischemia and 60 min of reperfusion. The influences of calcium channel antagonists (of T- and L-type antagonist mibefradil and of L-type antagonist verapamil) in reperfusion solution were evaluated. Our results showed coronary dilatation and higher LDH release rate in ARF than in control hearts before ischemia. Recovery of coronary flow during reperfusion was better and LDH release rate lower in ARF vs. control hearts. Perfusion with mibefradil and verapamil did not additionally increase coronary flow, however 0.1 microM mibefradil and verapamil decreased LDH release rate during reperfusion in ARF hearts in comparison to control hearts. Our results showed some protective effects of 0.1 microM mibefradil and verapamil on LDH release rate during reperfusion, but not on coronary flow in guinea pigs hearts with ARF.


A Nondestructive Methodology for Determining Chemical Composition of Salvia miltiorrhiza via Hyperspectral Imaging Analysis and Squeeze-and-Excitation Residual Networks.
The quality assurance of bulk medicinal materials, crucial for botanical drug production, necessitates advanced analytical methods. Conventional techniques, including high-performance liquid chromatography, require extensive pre-processing and rely on extensive solvent use, presenting both environmental and safety concerns. Accordingly, a non-destructive, expedited approach for assessing both the chemical and physical attributes of these materials is imperative for streamlined manufacturing. We introduce an innovative method, designated as Squeeze-and-Excitation Residual Network Combined Hyperspectral Image Analysis (SE-ReHIA), for the swift and non-invasive assessment of the chemical makeup of bulk medicinal substances. In a demonstrative application, hyperspectral imaging in the 389-1020 nm range was employed in 187 batches of Salvia miltiorrhiza. Notable constituents such as salvianolic acid B, dihydrotanshinone I, cryptotanshinone, tanshinone IIA, and moisture were quantified. The SE-ReHIA model, incorporating convolutional layers, maxpooling layers, squeeze-and-excitation residual blocks, and fully connected layers, exhibited Rc2 values of 0.981, 0.980, 0.975, 0.972, and 0.970 for the aforementioned compounds and moisture. Furthermore, Rp2 values were ascertained to be 0.975, 0.943, 0.962, 0.957, and 0.930, respectively, signifying the model's commendable predictive competence. This study marks the inaugural application of SE-ReHIA for Salvia miltiorrhiza's chemical profiling, offering a method that is rapid, eco-friendly, and non-invasive. Such advancements can fortify consistency across botanical drug batches, underpinning product reliability. The broader applicability of the SE-ReHIA technique in the quality assurance of bulk medicinal entities is anticipated with optimism.


Diagnostic value of the vascular index measured by superb microvascular imaging for evaluating breast tumors: a meta-analysis.
This meta-analysis aims to assess the accuracy of superb microvascular imaging (SMI) using the vascular index (VI) in the diagnosis of breast tumors. PubMed, Web of Science, Embase, Cochrane Library and Scopus were searched for relevant literature by two researchers until March 14, 2023. The Stata Version 16.0 software was utilized to compute the pooled values for sensitivity (Sen), specificity (Spe), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odd ratios (DOR). Heterogeneity among the included literature was assessed using the I2 statistic and Q test. Conducting influence analysis was used to ensure the robustness of the pooled conclusions and the Deeks' funnel plot asymmetry test to assess publication bias. We also performed the summary receiver operating characteristic (SROC) curve. Six studies included 1200 breast lesions. The ultimate results in the VI of SMI are as follows: The pooled Sen was 0.80 (95% confidence interval(CI), 0.75-0.85), the pooled Spe was 0.68 (95% CI 0.63-0.74), the pooled PLR was 2.54 (95% CI 2.07-3.12), the pooled NLR was 0.29 (95% CI 0.22-0.38), the pooled DOR was 8.91 (95% CI 5.62-14.13), and the area under the SROC (AUC) was 0.81. The application of SMI using VI may have the potential to benefit the patients and represents a valuable quantitative parameter of SMI for the diagnosis of breast neoplasms.


Ziprasidone: efficacy, tolerability, and emerging data on wide-ranging effectiveness.
Ziprasidone is the fifth atypical antipsychotic to become available in the US market. This compound is a serotonin-dopamine-receptor antagonist, with greater affinity for the 5-HT(2A) receptor than the dopamine D2 receptor. Similar to aripiprazole, this compound also has agonist activity at the serotonin 5-HT(1A) receptor. This affinity has the potential to have particularly beneficial effects on cognitive and affective abnormalities in schizophrenia. Oral and short-acting intramuscular formulations are available. This compound has recently been approved for the treatment of acute mania as well as for schizophrenia. Ziprasidone is associated with low weight gain and a low potential to change lipid and glucose levels. Long-term tolerability data have indicated that initial concerns regarding QTc (corrected cardiac output) prolongation are not a major issue. Recent data have indicated that this compound has short-term antipsychotic efficacy that is equivalent to other members of the class, also with evidence of cognitive enhancement. Finally, longer term data has indicated that ziprasidone is successful in the prevention of relapse and has sustained cognitive benefits. Several issues remain to be addressed, including the efficacy of once-daily dosing, the need to take the medication with food, and the correct dosing strategy.


Hemodilution and whole body oxygen balance during normothermic cardiopulmonary bypass in dogs.
The purpose of this study was to determine the minimum hematocrit value that can support whole body oxygen consumption during normothermic cardiopulmonary bypass. The effect of hemodilution on peripheral resistance, whole body oxygen delivery, and oxygen consumption was determined over a range of hematocrit values. Measurements were obtained during 38 degrees C cardiopulmonary bypass with progressive normovolemic hemodilution (hematocrit value 40% to 9%) in nine dogs. Dextran 70 (6%) was used as a diluent. Anesthesia consisted of high-dose fentanyl and midazolam. A mean arterial pressure of 60 mm Hg was maintained throughout cardiopulmonary bypass via increases in pump flow. Progressive hemodilution was associated with a decreasing total peripheral resistance. During normothermic cardiopulmonary bypass with a whole blood prime, the whole body oxygen consumption approximated values previously reported in dogs under nonbypass conditions. Oxygen delivery and whole body oxygen uptake were maintained between a hematocrit value of 39% and 25%. Significant decreases for both were seen when the hematocrit value was reduced to 18% and below. A hematocrit level greater than 18% was needed to maintain systemic oxygen delivery and consumption during warm cardiopulmonary bypass. The critical hematocrit value may be higher under bypass than nonbypass conditions because the flow increases that are practical during cardiopulmonary bypass do not approximate those seen in response to hemodilution of the intact circulation. Finally, the critical hematocrit value for the body may be higher than that required for the brain during warm cardiopulmonary bypass.


Metal Artifact Reduction Sequence MRI Abnormalities in Asymptomatic Patients with a Ceramic-on-Polyethylene Total Hip Replacement.
Magnetic resonance imaging (MRI) is a commonly utilized screening modality in patients with a metal-on-metal (MoM) total hip replacement. The prevalence of clinically important fluid collections may be overestimated since these collections have been reported to occur in asymptomatic patients with MoM and other bearing surfaces. The purpose of this study was to determine the frequency and types of MRI-documented adverse local tissue reactions in asymptomatic patients with a ceramic-on-polyethylene (CoP) total hip replacement. Forty-four patients (50 hips) with a minimum 2-year follow-up after total hip arthroplasty with CoP implants and a Harris hip score of >90 were enrolled in this study. The inclusion criteria were the absence of hip pain and the availability of appropriate follow-up radiographs. All patients underwent a metal artifact reduction sequence (MARS) MRI scan to determine the presence of fluid collections in asymptomatic patients with a CoP bearing surface. Fluid collections were observed in 9 (18%) of 50 asymptomatic hips in this cohort. There were 5 hips with intracapsular synovitis, and 2 of these hips had a thickened synovium. Extra-articular fluid collections with direct intracapsular communication were identified in 4 additional hips. Two of these hips had a thickened synovium. No signs of osteolysis or evidence of adverse local tissue reactions were noted on radiographs at the most recent follow-up. This study revealed that fluid collections are not uncommon after total hip arthroplasty with CoP implants. Synovial thickening may be present and is more prevalent than has been reported in previous studies involving metal-on-polyethylene (MoP) bearing surfaces. The clinical importance and natural history of these findings remain unknown. Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Maternal anxiety, risk factors and parenting in the first post-natal year.
The antecedents and consequences of maternal post-natal anxiety have received comparatively less attention than depression despite being one of the most frequently reported mental health difficulties experienced by parents following childbirth. The aim of this study was to extend emerging literature on post-natal anxiety by investigating the prevalence of maternal anxiety symptoms, and its relationship with parenting behaviours (i.e. warmth, hostility) and experiences (i.e. parenting efficacy and satisfaction) within the first post-natal year. The psychosocial risk factors for post-natal anxiety symptoms were also explored. A community sample of 224 Australian mothers of infants (aged 0-12 months) completed a self-report questionnaire. Mothers in the current sample reported significantly more symptoms of anxiety compared with a normative sample. Approximately 18% of mothers reported mild to extremely severe symptoms of anxiety, with a high proportion experiencing co-morbid depressive symptoms. Maternal anxiety was associated with low parenting warmth, involvement, efficacy and satisfaction, and high parenting hostility. Yet, co-morbid depression and anxiety was more strongly associated with these parenting behaviours and experiences than anxiety alone. A range of psychosocial risk factors (e.g. education, sleep, relationship quality) were associated with maternal post-natal anxiety symptoms, providing opportunities for early identification and targeted early intervention.


[Grounds for using cattle as one of reference organisms in the system of environmental protection from radiation].
Taking into consideration the basic principles of environmental protection from radiation as stated in Publication 91 of the International Commission on Radiation Protection (ICRP), we suggest cattle to be included into fauna reference species group. The choice is based upon cattle being a typical representative of specific ecosystems and may serve as an informative biological indicator and comparable with humans for its susceptibility to radiation effects. Cattle will receive some higher radiation doses as compared to humans due to its habitat, also earlier determined physiological and radiation constants for cattle are available. Furthermore, there are some data for the effects of radiation levels more than 10 times as higher than the natural ones upon cattle reproductive function and leucosis infection. Using cattle as one of reference organisms will not complicate considerably the systems for environmental protection against radiation as compared to the ones existing now, that will just modify and supplement them.


Impact of cold and warm ischemia on postoperative recovery of affected renal function after partial nephrectomy.
To determine the influence of warm or cold ischemia on postoperative renal function, we conducted preoperative and postoperative analysis by renal scintigraphy of patients who were undergoing open partial nephrectomy (OPN) and laparoscopic partial nephrectomy (LPN). From May 2005 to February 2010, the preoperative and postoperative renal function was evaluated by 99mTc-mercaptoacetyltriglycine (MAG3) clearance in 37 patients who were treated with OPN (n=13) and LPN (n=24). LPN were achieved via retroperitoneal (RPLPN; n=12) or transperitoneal (TPLPN; n=12) routes. Renal cooling was performed after renal hilar clamping in OPN and RPLPN, but not TPLPN. Renal function was evaluated according to the ratio of affected to contralateral renal MAG3 clearance. Mean ischemic time was 29.5 minutes in OPN, 25.5 minutes in TPLPN, and 50 minutes in RPLPN (P < 0.01); median blood loss was 230 mL in OPN (P < 0.05), 110 mL in TPLPN, and 53 mL in RPLPN. There was no significant difference in postoperative total renal function between the groups. Although ischemic time in RPLPN was longer than in TPLPN, the postoperative recovery of affected renal function from 1 week to 3 months for RPLPN and OPN (cold ischemia) was significantly better than for TPLPN (P < 0.01). Cold ischemia has an advantage of postoperative recovery of affected renal function. If a patient has a risk of renal dysfunction, cold ischemia during renal hilar clamping is recommended to avoiding deterioration.


Five v ten days' therapy with furazolidone for giardiasis.
In previous uncontrolled studies it has been reported that five days' treatment with furazolidone is effective for giardiasis. Efficacy of five v ten days of treatment was evaluated in a prospective, randomized study of 22 children with giardiasis. Eleven of 12 patients (92%) treated for ten days were cured based on clinical and parasitological response; one patient did not tolerate furazolidone and was treated with quinacrine hydrochloride. Only two of ten patients (20%) treated with a five-day regimen were cured. Of the other eight patients, five had prompt relapse of diarrhea after furazolidone treatment was stopped, diarrhea persisted in two, and diarrhea diminished but Giardia persisted in one. Six of eight patients in whom the five-day regimen failed were re-treated with furazolidone for ten days, and five patients were cured. Therapy with furazolidone for less than seven to ten days cannot be recommended for children with giardiasis.


[Physiological patterns of intestinal microbiota. The role of dysbacteriosis in obesity, insulin resistance, diabetes and metabolic syndrome].
The intestinal microbiota is well-known for a long time, but due to newly recognized functions, clinician's attention has turned to it again in the last decade. About 100 000 billion bacteria are present in the human intestines. The composition of bacteriota living in diverse parts of the intestinal tract is variable according to age, body weight, geological site, and diet as well. Normal bacteriota defend the organism against the penetration of harmful microorganisms, and has many other functions in the gut wall integrity, innate immunity, insulin sensitivity, metabolism, and it is in cross-talk with the brain functions as well. It's a recent recognition, that intestinal microbiota has a direct effect on the brain, and the brain also influences the microbiota. This two-way gut-brain axis consists of microbiota, immune and neuroendocrine system, as well as of the autonomic and central nervous system. Emerging from fermentation of carbohydrates, short-chain fatty acids develop into the intestines, which produce butyrates, acetates and propionates, having favorable effects on different metabolic processes. Composition of the intestinal microbiota is affected by the circadian rhythm, such as in shift workers. Dysruption of circadian rhythm may influence intestinal microbiota. The imbalance between the microbiota and host organism leads to dysbacteriosis. From the membrane of Gram-negative bacteria lipopolysacharides penetrate into the blood stream, via impaired permeability of the intestinal mucosa. These processes induce metabolic endotoxaemia, inflammation, impaired glucose metabolism, insulin resistance, obesity, and contribute to the development of metabolic syndrome, type 2 diabetes, inflammarory bowel diseases, autoimmunity and carcinogenesis. Encouraging therapeutic possibility is to restore the normal microbiota either using pro- or prebiotics, fecal transplantation or bariatric surgery. Human investigations seem to prove that fecal transplant from lean healthy individuals into obese diabetic patients improved all the pathological parameters. Wide spread use of bariatric surgery altered gut microbiota and improved metabolic parameters apart from surgery itself. Pathomechanism is not yet completely clarified. Clinicians hope, that deeper understanding of complex functions of intestinal microbiota will contribute to develop more effective therapeutic proceedings against diabetes, metabolic syndrome, and obesity.


Interaction of pleuromutilin derivatives with the ribosomal peptidyl transferase center.
Tiamulin is a pleuromutilin antibiotic that is used in veterinary medicine. The recently published crystal structure of a tiamulin-50S ribosomal subunit complex provides detailed information about how this drug targets the peptidyl transferase center of the ribosome. To promote rational design of pleuromutilin-based drugs, the binding of the antibiotic pleuromutilin and three semisynthetic derivatives with different side chain extensions has been investigated using chemical footprinting. The nucleotides A2058, A2059, G2505, and U2506 are affected in all of the footprints, suggesting that the drugs are similarly anchored in the binding pocket by the common tricyclic mutilin core. However, varying effects are observed at U2584 and U2585, indicating that the side chain extensions adopt distinct conformations within the cavity and thereby affect the rRNA conformation differently. An Escherichia coli L3 mutant strain is resistant to tiamulin and pleuromutilin, but not valnemulin, implying that valnemulin is better able to withstand an altered rRNA binding surface around the mutilin core. This is likely due to additional interactions made between the valnemulin side chain extension and the rRNA binding site. The data suggest that pleuromutilin drugs with enhanced antimicrobial activity may be obtained by maximizing the number of interactions between the side chain moiety and the peptidyl transferase cavity.


Probiotics modulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebo-controlled trial.
Early host-microbe interaction provides important maturational stimuli for the developing immune system. The role of prenatal microbial contact remains elusive. Our aim was to investigate whether microbes in placenta or amniotic fluid affect fetal innate immune gene expression during late pregnancy and whether innate immune gene expression profiles in the placenta and the fetal gut may be modulated by dietary supplementation with specific probiotics. Altogether 43 pregnant women were randomized to receive (1) Bifidobacterium lactis, (2) B. lactis in combination with Lactobacillus rhamnosus GG (LGG) or (3) placebo for 14 days before elective cesarian section at full term in a double-blind clinical trial. Bacteria in amniotic fluid and placenta were detected by quantitative (q)PCR. The expression of Toll-like receptor (TLR)-related genes in the placenta and meconium samples was assessed by qPCR. Gene expression patterns in meconium were interpreted to reflect immune physiology in the fetal gut. The study was completed by 29 mother-infant pairs. Bacterial DNA was detected in all placenta samples. Microbial DNA in amniotic fluid and placenta was associated with changes in TLR-related gene expression in the fetal intestine. Maternal probiotic supplementation significantly modulated the expression of TLR-related genes both in the placenta and in the fetal gut. Microbial contact in utero is associated with changes in fetal intestinal innate immune gene expression profile. Fetal and placental immune physiology may be modulated by maternal dietary intervention using specific probiotics.


Mobile Technology in Allergic Rhinitis: Evolution in Management or Revolution in Health and Care?
Smart devices and Internet-based applications (apps) are largely used in allergic rhinitis and may help to address some unmet needs. However, these new tools need to first of all be tested for privacy rules, acceptability, usability, and cost-effectiveness. Second, they should be evaluated in the frame of the digital transformation of health, their impact on health care delivery, and health outcomes. This review (1) summarizes some existing mobile health apps for allergic rhinitis and reviews those in which testing has been published, (2) discusses apps that include risk factors of allergic rhinitis, (3) examines the impact of mobile health apps in phenotype discovery, (4) provides real-world evidence for care pathways, and finally (5) discusses mobile health tools enabling the digital transformation of health and care, empowering citizens, and building a healthier society.


[Chronic Kidney Disease:Key Points for Intraoperative and Postoperative Management].
Chronic kidney disease( CKD) is a challenge in cardiac surgery in elderly patients, making intraoperative and postoperative management critical. Although sodium glucose co-transporter 2( SGLT2) inhibitors have nephroprotective effects, it's important to discontinue them three days before surgery and resume them when food intake is possible. Nephroprotective perioperative management of CKD stage 3-4 patients requires different approaches at each stage, with blood pressure control and nutritional counseling being key. For patients with CKD stage 5, postoperative management includes circulatory management in the intensive care unit and assessment of the need for and timing of hemodialysis. Continuous renal replacement therapy( CRRT) is common, but recently the use of multiple dialysis modalities (multimodal approach) has increased. This multimodal approach, which aims to avoid CRRT trauma, may contribute to improved outcomes.


Quantification of the Geranium Essential Oil, Palmarosa Essential Oil and Phenylethyl Alcohol in Rosa damascena Essential Oil Using ATR-FTIR Spectroscopy Combined with Chemometrics.
Rosa damascena essential oil is an essential oil that has the greatest industrial importance due to its unique quality properties. The study used ATR-FTIR (attenuated total reflectance-Fourier transform infrared) spectroscopy coupled with chemometrics of PLSR (partial least squares regression) and PCR (principal component regression) for quantification of probable adulterants of geranium essential oil (GEO), palmarosa essential oil (PEO) and phenyl ethyl alcohol (PEOH). Hierarchical cluster analysis was performed to observe the classification pattern of Rosa damascena essential oil, spiked samples and adulterants. Rosa damascena essential oil was spiked with each adulterant at concentrations of 0-100% (v/v). Excellent R2 (regression coefficient) values (≥0.96) were obtained in all PLSR and PCR cross-validation models. The SECV (standard error of cross-validation) values ranged between 0.43 and 4.15. The lowest SECV and bias values were observed in the PLSR and PCR models, which were built by using the raw FTIR spectra of all samples. Hierarchical cluster analysis through Ward's algorithm and Euclidian distance had high potential to observe the classification pattern of all adulterated and authentic samples. In conclusion, the combination of ATR-FTIR spectroscopy with multivariate analysis can be used for rapid, cost-effective, easy, reliable and high-throughput detection of GEO, PEO and PEOH in Rosa damascena essential oil.


Three Neocallimastix patriciarum esterases associated with the degradation of complex polysaccharides are members of a new family of hydrolases.
Acetylesterase and cinnamoyl ester hydrolase activities were demonstrated in culture supernatant of the anaerobic ruminal fungus Neocallimastix patriciarum. A cDNA expression library from N. patriciarum was screened for esterases using beta-naphthyl acetate and a model cinnamoyl ester compound. cDNA clones representing four different esterase genes (bnaA-D) were isolated. None of the enzymes had cinnamoyl ester hydrolase activity, but two of the enzymes (BnaA and BnaC) had acetylxylan esterase activity, bnaA, bnaB and bnaC encode proteins with several distinct domains. Carboxy-terminal repeats in BnaA and BnaC are homologous to protein-docking domains in other enzymes from Neocallimastix species and another anaerobic fungus, a Piromyces sp. The catalytic domains of BnaB and BnaC are members of a recently described family of Ser/His active site hydrolases [Upton, C. & Buckley, J.T. (1995). Trends Biochem Sci 20, 178-179]. BnaB exhibits 40% amino acid identity to a domain of unknown function in the CelE cellulase from Clostridium thermocellum and BnaC exhibits 52% amino acid identity to a domain of unknown function in the XynB xylanase from Ruminococcus flavefaciens. BnaA, whilst exhibiting less than 10% overall amino acid identity to BnaB or BnaC, or to any other known protein, appears to be a member of the same family of hydrolases, having the three universally conserved amino acid sequence motifs. Several other previously described esterases are also shown to be members of this family, including a rhamnogalacturonan acetylesterase from Aspergillus aculeatus. However, none of the other previously described enzymes with acetylxylan esterase activity are members of this family of hydrolases.


Violence against children in Afghanistan: Concerns and opportunities for positive change.
Violence against children (VAC) in Afghanistan is a serious issue in the context of many decades of conflict and poverty. To date, limited studies have explored the extent of VAC in Afghanistan and the settings where VAC takes place. To understand (i) the extent of VAC, (ii) settings where VAC takes place, (iii) parental forms of VAC and (iv) regional differences, an interview administered cross-sectional survey was employed among a community sample of 145 children and 104 parents living within Kabul, Torkham, and Jalalabad. Demographic information was collected as well as items from the International Child Abuse Screening Tool (ICAST-CH). In this study, 71% of children reported experiencing physical violence is some form in the past year. Home was the most likely location of violence. The overwhelming majority of parents reported using physical violence as a discipline method. Parents who attained higher levels of education and had more skilled occupations used violence less as a discipline method. However, consistent with international research, children cited their parents as their preferred source of support in situations of violence. Interestingly, parents did not see violent forms of discipline as more effective than non-violent strategies. The results offer a disturbing yet 'on the ground' insight into VAC in Afghanistan from the experience of children and parents. The results have important implications for programming design and provide a focus for stopping and preventing VAC in Afghanistan and similar contexts.


Alterations of municipal solid waste incineration residues in a landfill.
Fresh municipal solid waste incineration residues (MSWIR) and a drilling core of 2-10 years old landfilled MSWIR were investigated to determine the alterations due to weathering in a landfill. Physical and geochemical properties and transformations of major components and heavy metals were analyzed for fresh and landfilled residues. Carbonates and hydroxides (10-12vol%) as major mineralogical compositions in the 8-10 years weathered MSWIR were observed by modal analysis of thin sections. Three step sequential extractions indicated that reducible phases, mainly the Fe, Al and Mn hydroxides increased with depth in the landfill. A pH controlled leaching test (including availability test and pH dependent leaching test) was then conducted. Results indicated lower concentrations of leachable contents at pH values from 6 to 10 for the four elements (Pb, Zn, Al and Fe) in the 8-10 years landfilled residues than in the fresh and 1-2 years landfilled residues. This means that 8-10 years weathered MSWIR became more stable than fresh landfilled residues. The reasons for the stabilization of these elements might be the hydration of Al and Fe during weathering in the landfill, which then results in the heavy metals adsorptions of these minerals.


Relationships among Malnutrition, Depression and Quality of Life in Patients with Gynecologic Cancer receiving Chemotherapy.
The purpose of this study was to identify nutritional status, and relationships among malnutrition, depression and quality of life in patients with gynecologic cancer who were receiving chemotherapy. For this study a descriptive cross-sectional design was used. Participants were 111 women who were enrolled and agreed to undergo a face-to-face interviews including administration of the structured questionnaires: Patient-Generated Subjective Global Assessment (PG-SGA), Beck Depression Inventory (BDI), Simplified Nutritional Appetite Questionnaire (SNAQ), and Functional Assessment of Cancer Therapy-General (FACT-G). Mean body mass index was 23.3 and mean body weight was 56.5 kg. Sixty-three (57%) of the 111 patients were malnourished according to the PG-SGA. The malnourished patients showed higher levels of depression and lower quality of life compared to the non-malnourished patients. In addition, malnutrition was associated with BMI level, depression, appetite and quality of life. The findings indicate that the prevalence of malnutrition is high and malnutrition in patients with gynecologic cancer influences depression and adversely affects the quality of life of these women. To improve the patient's quality of life, nutritional assessment and appropriate management is important to decrease malnutrition in patients with gynecologic cancer.


Expression of Components of the Renin-Angiotensin System by the Putative Stem Cell Population Within WHO Grade I Meningioma.
Aim: We have recently demonstrated a putative stem cell population within WHO grade I meningioma (MG) that expressed embryonic stem cell (ESC) markers OCT4, NANOG, SOX2, KLF4 and c-MYC, localized to the endothelial and pericyte layers of the microvessels. There is increasing recognition that the renin-angiotensin system (RAS) plays a critical role in stem cell biology and tumorigenesis. This study investigated the expression of components of the RAS: pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1), and angiotensin II receptor 2 (ATIIR2) on the putative stem cell population on the microvessels of WHO grade I MG. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on WHO grade I MG tissue samples from 11 patients for PRR, ACE, ATIIR1, and ATIIR2. Two of the MG samples subjected to DAB IHC staining underwent immunofluorescence (IF) IHC staining to investigate co-expression of each of these components of the RAS in using combinations of CD34 and ESC marker SOX2 or OCT4. NanoString mRNA expression analysis and Western blotting (WB), were performed on six snap-frozen MG tissue samples to confirm mRNA and protein expression of these proteins, respectively. Results: DAB IHC staining demonstrated expression of PRR, ACE, ATIIR1, and ATIIR2 within all 11 MG tissue samples. WB and NanoString mRNA analyses, confirmed protein and mRNA expression of these proteins, respectively. IF IHC staining showed PRR, ATIIR1 and ATIIR2 were localized to the OCT4+ and SOX2+ endothelium and the pericyte layer of MG while ACE was localized to the OCT4+ endothelium of the microvesels. Conclusion: The novel finding of the expression of PRR, ACE, ATIIR1, and ATIIR2 on the putative stem cell population on the microvessels of WHO grade I MG, suggests that these stem cells may be a potential therapeutic target by manipulation of the RAS.


Stronger endocrine responses after brief psychological stress in women at familial risk of breast cancer.
Recent research has linked exposure to chronic stress to altered acute stress responses and suggests a sensitizing effect of chronic stress leading to a stronger endocrine and cardiovascular response to acute stressors. Substantial evidence indicates that familial breast cancer risk is a chronic life stressor with higher levels of self reported distress. In this study, we investigated whether the endocrine response to a brief psychological stressor was stronger for women at familial risk for breast cancer. Thirty-six women at normal risk of breast cancer (FR- Stress Group) and 17 women at familial risk (FR+ Stress Group) underwent a brief psychological laboratory stress test (speech task and mental arithmetic) over a 15 min period. Thirty women at normal risk not subjected to the stressful task served as controls (FR- Control Group). Plasma epinephrine, norepinephrine and cortisol were measured at baseline, directly after the stress test (15 min) and at 30 min and 45 min post baseline. Heart rate data confirmed the effectiveness of the stress regimen. While there were no significant baseline group differences in the endocrine parameters, the response curves for the familial risk group revealed stronger epinephrine and cortisol reactivity to the stress test, as confirmed by significant group by time interactions. Norepinephrine levels showed a similar pattern, but results did not reach significance. These findings are in line with previous research documenting the facilitating effects of chronic stressors on acute stress response in animals and humans and provide the first evidence in the literature of a heightened endocrine reactivity to acute psychological stress in women at familial risk of breast cancer. The heightened endocrine reactivity to the experimental tasks seen here suggests that these women may experience stronger responses to stressors in their daily lives. According to the recently proposed concept of allostatic load, repeated overly strong stress responses may cumulatively have negative health implications.


"To be healthy to me is to be free": how discourses of freedom are used to construct healthiness among young South African adults.
Healthiness is constructed, in Western culture, as a moral ideal or supervalue. This paper will interrogate the assumption that health and the pursuit of healthiness is always and unquestionably positive, by exploring how discourses of health and freedom interact to reinforce the current inequalities and detract from social transformation. Twenty young South African adults were interviewed about their understandings and experiences of health. These discussions were analysed using Foucauldian discourse analysis. Participants constructed healthiness as facilitating the experience of freedom, while at the same time being dependent on a personal orientation towards freedom (as opposed to merely submitting to dominant health authorities). Freedom discourses also played a role in connecting health to neoliberal discourses idealizing economic productivity and hard work. Participants were able to construct a self that is active, productive, valuable, hopeful, and self-assured when talking about health using discourses of freedom. However, these discourses also functioned to moralise and idealise healthiness, which contributed to blaming poor health on its sufferers. Health/freedom discourses can further reinforce the neoliberal value of individual responsibility by constructing self-improvement and self-work as the solution to ill-health, thereby contributing to victim-blaming and weakening support for public health interventions.


Loco-regional deep hyperthermia combined with intravesical Mitomycin instillation reduces the recurrence of non-muscle invasive papillary bladder cancer.
To compare the therapeutic effects of locoregional deep hyperthermia combined with intravesical chemotherapy with those of intravesical chemotherapy alone in patients with intermediate-/high-risk non-muscle invasive bladder cancer (NMIBC). To evaluate the impact of thermal dose in hyperthermia treatment. We analyzed data retrieved from the medical records of patients with intermediate-/high-risk NMIBC treated with intravesical mitomycin (IM group) or locoregional deep hyperthermia combined with intravesical mitomycin (CHT group) at a single tertiary care hospital between May 2016 and June 2019. The primary and secondary endpoints were the recurrence-free survival rate and progression-free survival rate, respectively. Thermal dose was evaluated and adverse events were also recorded. In total, 43 patients (CHT: 18 patients, IM: 25 patients) were enrolled. The median follow-up durations were 14 and 23 months, respectively. The recurrence rate at 12 months was significantly lower in the CHT group than in the IM group (11.1% vs. 44%, p = .048); this trend persisted at 24 months (CHT: 11.1%, IM: 48%; p = .027). The recurrence-free survival was also significantly higher in the CHT group than in the IM group (p = .028). No tumor recurrence was noted in patients who received a thermal dose of ≥4 CEM43. All adverse events were well tolerated, and there was no treatment-related mortality. Intravesical chemotherapy combined with locoregional deep hyperthermia for intermediate-/high-risk papillary NMIBC can significantly decrease the recurrence rate relative to that observed after intravesical chemotherapy alone.


WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited.
Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.


Expression and localization of CKLFSF2 in human spermatogenesis.
To investigate the expression and subcellular localization of chemokine-like factor superfamily 2 (CKLFSF2) in human testis and its potential role in spermatogenesis. A specific polyclonal antibody against CKLFSF2 was raised. The expression and cellular localization of CKLFSF2 in the seminiferous tubules was checked by immunohistochemistry method. Also, in situ hybridization was applied to localize the mRNA distribution. The EGFP-CKLFSF2 fusion protein was expressed in COS-7 cells to localize its subcellular location in vitro. In addition, the abnormal expression of CKLFSF2 in testes of patients with male infertility was assayed by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry methods. Having a close correlation with spermatogenesis defects, CKLFSF2 was specifically expressed in meiotic and post-meiotic germ cells, which were localized to the endoplasmic reticulum (ER) near the Golgi apparatus. CKLFSF2 could play important roles in the process of meiosis and spermiogenesis, and might be involved in the vesicular transport or membrane apposition events in the endoplasmic reticulum.


The treatment of chronic hepatic encephalopathy.
The neuropsychiatric abnormalities which accompany cirrhosis of the liver vary widely from subclinical impairment of psychometric performance to overt episodic or persistent changes in cerebral function. The pathogenesis of the syndrome is unknown although important rôles are ascribed to circulating gut-derived toxins of nitrogenous origin and to changes in central neurotransmission, particularly of the dopaminergic and GABA-ergic systems. Treatment is, therefore, based on mechanisms to reduce the production and absorption of gut-derived toxins such as decreasing and modifying dietary protein intake, altering the intestinal bacterial flora and bowel cleansing, and on mechanisms designed to modify central neurotransmitter balance either directly by use of dopaminergic agents or benzodiazepine antagonists or indirectly by use of amino-acid mixtures. Some treatment measures, such as use of non-absorbable disaccharides and vegetable protein diets, are known to be efficacious, and are the mainstays of management for all forms of the syndrome. Others are used in more specific circumstances, for example the antibiotic neomycin is effective during acute exacerbations of the syndrome, and the dopamine agonist bromocriptine provides benefit when symptoms are persistent and intractable. Certain treatments such as branched-chain amino acids and the benzodiazepine antagonist, flumazenil, are at present, of unproven value.


Zaprinast and rolipram enhances spatial and emotional memory in the elevated plus maze and passive avoidance tests and diminishes exploratory activity in naive mice.
Phosphodiesterase (PDE) inhibitors in the central nervous system have been shown to stimulate neuronal functions and increase neurogenesis in Alzheimer disease (AD) patients. The aim of this study was to investigate the effects of zaprinast, a PDE5 inhibitor, and rolipram, a PDE4 inhibitor, on learning and memory in elevated plus maze (EPM) and passive avoidance (PA) tests in naive mice. Male Balb-c mice received short-term treatment with zaprinast (3 and 10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) before the acquisition trial of the EPM and PA tests. The exploratory activity of the animals was also investigated in the Hughes box test. Both zaprinast (10 mg/kg) and rolipram (0.1 mg/kg) significantly decreased second-day latency compared to the control group in the EPM test, while only rolipram (0.1 mg/kg) significantly increased second-day latency in the PA test. Both zaprinast (10 mg/kg) and rolipram (0.1 mg/kg) significantly decreased the number of entries to new areas and time spent in new areas in the Hughes box test. Our study revealed that both zaprinast and rolipram enhanced spatial memory in EPM, while rolipram seemed to have more emotional memory-enhancing effects in the PA test compared to zaprinast. Both zaprinast and rolipram diminished exploratory activity in the Hughes box test, which can be attributed to the drugs' anxiogenic effects.


Single-stranded DNA-binding proteins and neuron-restrictive silencer factor participate in cell-specific transcriptional control of the NMDAR1 gene.
Our previous studies revealed that a proximal region of the N-methyl-D-aspartate receptor 1 (NMDAR1) promoter is important for cell-type-specific expression. We have now explored the contributions of several regulatory elements to this specificity. Deletion of the neuron-restrictive silencer element partially relieved the suppression of promoter activity in C6 glioma and HeLa cells. An overlapping G(C/G)G/tandem Sp1-containing region crucial for both basal and nerve growth factor (NGF)-regulated promoter activity specifically bound nuclear proteins on its purine-rich sense strand. A faster migrating complex, single-stranded binding protein complex 1 (SBPC1), was highly enriched in HeLa cells, whereas a slower migrating complex, SBPC2, was enriched in PC12 cells. A high ratio of 2/1 complex correlated with a high level of promoter activity. NGF treatment of PC12 cells reduced SBPC1 but increased SBPC2. Competition experiments showed that the SBPC1 binding required a dG4 sequence and the SBPC2 needed a core of TG3A plus a 5'-flanking sequence. Single-stranded DNA encompassing TG3A and/or dG4 specifically suppressed cotransfected NMDAR1 promoter activity. UV cross-linking studies indicated that a 31.5-kDa protein mainly formed SBPC1, whereas SBPC2 contained several larger proteins. Our results suggest that neuron-restrictive silencer factor and single-stranded DNA-binding proteins may both play a role in cell-type specificity of the NMDAR1 gene, and the latter may also be involved in basal and NGF-regulated activity.


Comparison of efficiency of intravitreal ceftazidime and intravitreal cefepime in the treatment of experimental Pseudomonas aeruginosa endophthalmitis.
In this study, we evaluated the efficiency of cefepime in the treatment of experimental Pseudomonas aeruginosa endophthalmitis. We compared the findings with the standard dose of ceftazidime (1 mg/0.1 ml). Thirty-six New-Zealand White rabbits were divided into 6 equal groups and were treated with different methods (Group 1 = sham, Group 2 = 0.5 mg/0.1 ml cefepime, Group 3 = 1 mg/0.1 ml cefepime, Group 4 = 2 mg/0.1 ml cefepime, Group 5 = 1 mg/0.1 ml ceftazidime, Group 6 = control). The eyes of rabbits in each group were examined clinically on 1 st , 3 rd , and 6 th day of the experiment. At 6 th day, 0.1 ml vitreous humor aspirates were obtained and plated for quantification on the blood agar and the results were expressed as colony-forming unit/ml. Subsequently, the eyeballs were enucleated and the histopathological evaluation was performed. Our findings denoted beneficial effects of cefepime in treatment groups (especially, in Groups 3 and 4). Intravitreal cefepime may be an alternative drug in the treatment of P. aeruginosa endophthalmitis.


Structural and thermodynamic analysis of human PCNA with peptides derived from DNA polymerase-delta p66 subunit and flap endonuclease-1.
Human Proliferating Cellular Nuclear Antigen (hPCNA), a member of the sliding clamp family of proteins, makes specific protein-protein interactions with DNA replication and repair proteins through a small peptide motif termed the PCNA-interacting protein, or PIP-box. We solved the structure of hPCNA bound to PIP-box-containing peptides from the p66 subunit of the human replicative DNA polymerase-delta (452-466) at 2.6 A and of the flap endonuclease (FEN1) (331-350) at 1.85 A resolution. Both structures demonstrate that the pol-delta p66 and FEN1 peptides interact with hPCNA at the same site shown to bind the cdk-inhibitor p21(CIP1). Binding studies indicate that peptides from the p66 subunit of the pol-delta holoenzyme and FEN1 bind hPCNA from 189- to 725-fold less tightly than those of p21. Thus, the PIP-box and flanking regions provide a small docking peptide whose affinities can be readily adjusted in accord with biological necessity to mediate the binding of DNA replication and repair proteins to hPCNA.


Flt23k nanoparticles offer additive benefit in graft survival and anti-angiogenic effects when combined with triamcinolone.
To determine if nanoparticles delivering plasmids expressing Flt23k (an anti-VEGF intraceptor) can enhance murine cornea transplant survival and whether their effect is synergistic with steroid therapy. Biodegradable PLGA Flt23k loaded or blank nanoparticles were prepared using the emulsion solvent evaporation Graft survival, corneal neovascularization, and corneal lymphangiogenesis were compared among the Flt23k nanoparticles, blank nanoparticles, triamcinolone acetonide, and PBS groups following subconjunctival injection in mice that underwent penetrating keratoplasty. Graft survival, corneal neovascularization, and corneal lymphangiogenesis in a group treated with both nanoparticles and steroid therapy were also analyzed. The Flt23k nanoparticle group showed less neovascularization, lymphangiogenesis, and graft failure compared with the PBS control group (P < 0.01). The 2-month graft survival rate was 20% in the Flt23k nanoparticle group with no grafts surviving in the PBS group. When the Flt23k nanoparticle was combined with steroid therapy, a significant increase in graft survival was seen compared with both steroid treatment alone (P < 0.05) and steroid combined with blank nanoparticle treatment (P < 0.05). The 2-month graft survival rate was 91.6% in the combination group compared with 47.6% in the triamcinolone-only group and 42.4% in the triamcinolone plus blank nanoparticle group. Anti-VEGF nanoparticles (Flt23k) have a significant effect on decreasing neovascularization and lymphangiogenesis, resulting in increased graft survival in penetrating keratoplasty. This beneficial effect is synergistically enhanced with steroid treatment.


Suppression of immune response to Listeria monocytogenes: mechanism(s) of immune complex suppression.
We have investigated possible mechanisms underlying immune complex suppression of resistance to Listeria monocytogenes. Inhibition of resistance was found when immune complexes were formed in vivo in immune mice or in nonimmune mice adoptively transferred with specific antibody. Suppression was also found when nonimmune mice were injected with immune complexes preformed in vitro. We investigated the role of complement by decomplementing mice with cobra venom factor purified by high-pressure liquid chromatography. Complete depletion of serum C3 did not eliminate immune complex suppression of resistance to L. monocytogenes, suggesting that complement activation is not required for immune complex suppression. Infection-induced changes in the surface phenotype and functional properties of macrophages from normal and immune complex-suppressed mice were also investigated. Macrophage expression of both H-2K and Ia molecules increased during the response of normal mice to L. monocytogenes. However, these changes were not found in immune complex-suppressed mice. In contrast, membrane interleukin 1 expression was increased in macrophages from suppressed mice compared with macrophages from normal mice. Macrophages from L. monocytogenes-infected normal and immune complex-suppressed mice expressed cytotoxicity against tumor cells in vitro. We conclude that immune complexes do not inhibit resistance to L. monocytogenes by activation of complement or decreasing macrophage cytotoxic activity. Rather, defects in Ia expression by macrophages from suppressed mice might be one component responsible for immune complex suppression of resistance to L. monocytogenes.


Self-efficacy: a mediator of smoking behavior and depression among college students.
Cigarette smoking is a growing problem among adolescents. This correlational study tested theoretical relationships between the dependent variable (smoking behavior) and the independent variables (depression and smoking resistance self-efficacy) in a convenience sample of 364 college students ages 18 to 21 years recruited from a large urban public college. An a priori mediational model tested the role of smoking resistance self-efficacy as a mediator in the relationship between smoking behavior and depression. Findings showed there was a statistically significant positive relationship between depression and smoking behavior (r = 0.122, p = 0.01). There was a statistically significant negative relationship between smoking resistance self-efficacy and smoking behavior (r = -0.744, p = 0.01). Additionally, smoking resistance self-efficacy was a mediator of the relationship between depression and smoking behavior (beta = -0.757, p = 0.001). This study identifies a need for further theory-driven study of the relation of adolescent depression and smoking behavior. The findings of this study have implications for nursing interventions targeted to both current smokers and smoking initiation prevention programs.


Side of dental anomalies and taurodontism as potential clinical markers for cleft subphenotypes.
The aim of this work was to investigate in more detail the dental clinical features that could serve to define subphenotypes of oral clefts. Dental records of oral cleft subjects from a group of 164 cases were examined, and 157 were included in this study. In addition, 65 families with two or more siblings born with clefts and 30 control families were evaluated to determine whether dental phenotypes were sporadic. Type of oral cleft and dental phenotypes (tooth agenesis, supernumerary teeth, taurodontism, dental transposition, and microdontia) outside the cleft area were investigated. Association of dental anomalies with preferential subtypes of cleft (subphenotype) was assessed. A total of 74 subjects presented at least one developmental dental anomaly. Tooth agenesis was the most common dental anomaly (28.6%), followed by taurodontism (15.2%). Supernumerary teeth were associated with cleft palate only (p = .05). The absence of maxillary left lateral incisors was significantly associated with unilateral right cleft lip (p = .02). Bilateral clefts were strongly associated with bilateral dental anomalies (p < 0.001). In the cleft lip and palate group, tooth agenesis was associated with dental transposition (p = .03) and with supernumerary teeth (p = .009). Subjects with oral clefts have a higher risk of tooth agenesis (odds ratio = 3.33; 95% confidence interval, 1.18 to 10.13) and taurodontism (odds ratio = 3.95; 95% confidence interval, 2.28 to 6.82). Tooth agenesis, microdontic upper lateral incisors, and supernumerary teeth were most commonly found in unaffected siblings and parents of children born with clefts in comparison with families with no family history of clefts (p = .01). The preferential associations between specific cleft types with dental phenotypes suggest dental anomalies can be used as clinical markers to define the subphenotype isolated cleft lip and palate.