Effect of some new cAMP analogs on cAMP-dependent protein kinase isoenzymes.
1. Ten new cAMP analogs were synthesized by replacing the purine ring with with indazole, benzimidazole or benztriazole and/or their nitro and amino derivatives. 2. Each analog proved effective in activating cAMP-dependent protein kinase I (PK-I) purified from rabbit skeletal muscle and cAMP-dependent protein kinase II (PK-II) from bovine heart and chasing 8-[3H]cAMP bound to regulatory subunits in the half-maximal effective concentrations of 2 x 10(-8)-8 x 10(-6) M. 3. The N-1-beta-D-ribofuranosyl-indazole-3'5'-cyclophosphate(I) proved a very poor chaser and activator of both isoenzymes, but when indazole was attached at its N-2 to ribose (IV) or when its H at C-4 (equivalent to the position of amino-group in adenine) was substituted by an amino-(III) or especially nitro-group (II) its efficiency was dramatically increased. 4. Analogs containing benztriazole ring proved as powerful as cAMP irrespective of the presence of substituents (VII-X). 5. Benzimidazole derivatives with amino-(VI) or nitro-group (V) activated PK-II 3 and 20 times better than PK-I. 6. Attaching of ribose to N-2 of indazole or benztriazole increased the affinity to PK-II 10 and 4 times, respectively. 7. Chasing efficiency of cAMP analogs at half-saturating [3H]cAMP tended to correlate with activating potency only for PK-I but at saturating [3H]cAMP concentration for both isoenzymes. 8. On the basis of synergistic activation with 8-Br-cAMP a site 2-selective binding of nitro-benzimidazole (V) and unsubstituted benztriazole (VII) derivatives to PK-II is suggested.


[Effect of the UV irradiation of autologous blood on the humoral link in the immune response of patients with chronic inflammatory processes].
Autotransfusions of blood exposed to UV radiation for chronic inflammatory disease were found to normalize immunoglobulins (Ig) and immune complexes (IC) serum levels. A linear and invert correlations were revealed for large IC--IgG, IgM concentration, and small IC--IgM concentration, respectively.


Microsurgery in the hypercoagulable patient: review of the literature.
Improved techniques in microvascular surgery over the last several decades have led to the increased use of free tissue transfers as a mode of reconstructing difficult problems with a high success rate. However, undiagnosed thrombophilias have been associated with microsurgery free flap failures. We present a case of successful free tissue transfer in a patient with lupus anticoagulant and review the literature.


Prediction of Breast Cancer Histological Outcome by Radiomics and Artificial Intelligence Analysis in Contrast-Enhanced Mammography.
To evaluate radiomics features in order to: differentiate malignant versus benign lesions; predict low versus moderate and high grading; identify positive or negative hormone receptors; and discriminate positive versus negative human epidermal growth factor receptor 2 related to breast cancer. A total of 182 patients with known breast lesions and that underwent Contrast-Enhanced Mammography were enrolled in this retrospective study. The reference standard was pathology (118 malignant lesions and 64 benign lesions). A total of 837 textural metrics were extracted by manually segmenting the region of interest from both craniocaudally (CC) and mediolateral oblique (MLO) views. Non-parametric Wilcoxon-Mann-Whitney test, receiver operating characteristic, logistic regression and tree-based machine learning algorithms were used. The Adaptive Synthetic Sampling balancing approach was used and a feature selection process was implemented. In univariate analysis, the classification of malignant versus benign lesions achieved the best performance when considering the original_gldm_DependenceNonUniformity feature extracted on CC view (accuracy of 88.98%). An accuracy of 83.65% was reached in the classification of grading, whereas a slightly lower value of accuracy (81.65%) was found in the classification of the presence of the hormone receptor; the features extracted were the original_glrlm_RunEntropy and the original_gldm_DependenceNonUniformity, respectively. The results of multivariate analysis achieved the best performances when using two or more features as predictors for classifying malignant versus benign lesions from CC view images (max test accuracy of 95.83% with a non-regularized logistic regression). Considering the features extracted from MLO view images, the best test accuracy (91.67%) was obtained when predicting the grading using a classification-tree algorithm. Combinations of only two features, extracted from both CC and MLO views, always showed test accuracy values greater than or equal to 90.00%, with the only exception being the prediction of the human epidermal growth factor receptor 2, where the best performance (test accuracy of 89.29%) was obtained with the random forest algorithm. The results confirm that the identification of malignant breast lesions and the differentiation of histological outcomes and some molecular subtypes of tumors (mainly positive hormone receptor tumors) can be obtained with satisfactory accuracy through both univariate and multivariate analysis of textural features extracted from Contrast-Enhanced Mammography images.


Simultaneous pancreas-kidney transplantation: analysis of rejection.
The 3-year data concerning the occurrence of rejection episodes (RE) are reported herein. Two hundred five simultaneous pancreas-kidney (SPK) transplantations were performed from May 1998 to September 2000, including 103 patients randomly assigned to tacrolimus (Tac) and 102 to cyclosporine microemulsion (CsA-ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil (MMF), and short-term corticosteroids. After a follow-up of 3 years, acute rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving CsA ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93% and 90%, respectively) and in most cases were treated with corticosteroids (88% and 90%). Actuarial rejection-free graft survival was not significantly different between the two groups (54% and 44% at 3 years posttransplant). In a multivariate analysis, HLA compatibility (P = .003) and graft vessel extension (P = .0005) had a significant influence on rejection-free survival. Rejection influenced pancreatic graft survival (P = .01) and pancreatic graft loss owing to rejection influenced patient survival (P = .02). In the intent-to-treat analysis of early rejection, first moderate-to-severe episodes (1 of 40 versus 12 of 47; P = .004) and refractory episodes (2 of 40 versus 10 of 47; P = .03) were significantly lower with tacrolimus than with CsA ME. Pancreatic graft survival was worse among late rejectors (53%) than nonrejectors (86%; P = .002). In addition, serum creatinine was highest in late rejectors. In conclusion, Tac-based immunosuppressive therapy shows advantages over CsA ME in terms of the severity of acute rejection episodes among patients undergoing SPK transplantation.


Advising Medical Students for the Match: A National Survey of Pediatrics Clerkship Directors.
To describe the role and perspectives of pediatrics clerkship directors (CDs) who provide advice to students who apply to Pediatrics residency training programs. We developed a survey based on previous studies and data from the 2012 National Residency Matching Program- Program Director (NRMP-PD) survey. Topics included CDs roles and confidence in advising, perspectives on applicants' competitiveness, and resources used to inform advising practice. This survey was disseminated as part of the 2013 Council on Medical Student Education in Pediatrics annual survey. CDs from 63 (45%) Liaison Committee for Medical Education-accredited medical schools in the United States responded. All CDs had some advising role, and most (68%) served in a formal advising capacity. Most (58%) also participated in the intern selection process at their institution. Those with formal advising roles were not significantly more confident in their advising than those without formal roles. CDs relied heavily on subjective resources and most did not use the NRMP-PD survey data. Despite this, the perspectives of CDs were similar to those of program directors based on the most recent NRMP-PD survey. Pediatrics CDs uniformly serve in advising capacities and have perspectives that compare favorably with those of program directors. Despite this concordance, the high reliance on subjective resources and the frequency in which CDs participate in intern selection raises concern. The results of this study have several implications for key stakeholders in the residency selection process.


Clinical, genetic and magnetic resonance findings in an Italian patient affected by L-2-hydroxyglutaric aciduria.
L-2-Hydroxyglutaric aciduria (L-2-HGA) is a neurometabolic disease characterized by the presence of elevated levels of 2-hydroxyglutaric acid in the plasma, cerebrospinal fluid and urine. Clinical features in this inherited condition consist of mental deterioration, ataxia and motor deficits with pyramidal and extrapyramidal symptoms and signs. L-2-HGA is caused by mutations in the L-2-HGDH gene which most probably encodes for a L-2-hydroxyglutarate dehydrogenase, a putative mitochondrial protein converting L-2-hydroxyglutarate to alphaketoglutarate. Here, we report a pathogenic nonsense mutation in the L-2-HGDH gene found for the first time in an Italian patient affected by L-2-HGA, reinforcing the previously described phenotype of this rare metabolic disease and confirming the data indicating that mutations in the L-2-HGDH gene cause L-2-HGA.


Sex as a Biological Variable in Cardiovascular Diseases: JACC Focus Seminar 1/7.
Sex and gender influence all aspects of cardiovascular health and disease-including epidemiology, pathophysiology, diagnosis, clinical manifestation, disease progression, and response to treatment-in complex and interrelated ways. Sex-based and gender-based differences have been identified in risk and presentation of cardiovascular diseases (CVDs); however, failure to address sex and gender as key variables in CVD research and reporting and limited understanding of differences have contributed to disparities in risk assessment, prevention, diagnosis, treatment, and outcomes. Improved consideration of both sex and gender in all phases of the biomedical research continuum, along with educational and training curricula focused on the role of sex and gender in CVD, are needed to provide targeted therapies and improve cardiovascular health outcomes for all.


Cell-cell adhesion via the ECM: integrin genetics in fly and worm.
Integrins are essential for the development of the two genetically tractable invertebrate model organisms, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Just two integrins are present in C. elegans: one putative RGD binding integrin alphapat-2betapat-3, corresponding to Drosophila alphaPS2betaPS and vertebrate alpha5beta1, alphaVbeta1 and alpha8beta1, and one putative laminin binding integrin alphaina-1betapat-3, corresponding to Drosophila alphaPS1betaPS and vertebrate alpha3beta1, alpha6beta1 and alpha7beta1. In this review, the function of this minimal set of integrins during the development of these two invertebrates is compared. Despite the differences in bodyplan and developmental strategy, integrin adhesion to the extracellular matrix is required for similar processes: the formation of the link that translates muscle contraction into movement of the exoskeleton, cell migration, and morphogenetic interactions between epithelia. Other integrin functions, such as regulation of gene expression, have not yet been experimentally demonstrated in both organisms. Additional proteins have been characterised in each organism that are essential for integrin function, including extracellular matrix ligands and intracellular interacting proteins, but so far different proteins have been found in the two organisms. This in part represents the fact that the characterisation of the full set of interacting proteins is not complete in either system. However, in other cases different proteins appear to be used for similar functions in the two animals. The continued use of genetic approaches to identify proteins required for integrin function in these two model organisms should lead to the identification of the minimal set of conserved components that form integrin adhesive structures.


C-Type natriuretic peptide and natriuretic peptide receptors are expressed by smooth muscle cells in the neointima after percutaneous coronary intervention.
Understanding restenosis after percutaneous coronary intervention (PCI) remains a challenge. Neointimal proliferation is the main cause of restenosis. C-Type natriuretic peptide (CNP) plays a role in relaxation and growth inhibition of vascular smooth muscle cells (SMCs); the effects depend on the presence of specific natriuretic peptide receptors (NPRs) consisting of NPR-A, NPR-B, and NPR-C. To test the hypothesis that CNP and NPRs may be involved in restenosis, we immunohistochemically studied the expression of CNP and NPRs during the post-PCI healing process; 10 sites after PCI obtained at autopsy and 14 atherectomy specimens obtained from restenotic sites were investigated. Frozen sections were stained with antibodies against CNP, NPRs, SMCs, macrophages, and endothelial cells. Within 2 months after PCI, most neointimal SMCs expressed CNP and NPR-A. The expression of CNP and NPR-A in these neointimal SMCs decreased from 6 months onward. In contrast, NPR-C was strongly expressed in neointimal SMCs from 1 to 9 months after PCI. In atherectomy specimens, most neointimal SMCs showed weak positivity for CNP and NPR-A, but NPR-C was strongly expressed in the neointimal SMCs. These findings strongly suggest that a paracrine and autocrine system of CNP and NPRs may be important in controlling neointimal growth after PCI in humans.


Measurement of amniotic fluid interleukin-6 using commercial kits.
The association between increased amniotic fluid interleukin-6 (IL-6) concentrations and preterm labor has received increasing attention. Several research groups have evaluated this association using commercial IL-6 kits, which principally use the sandwich-enzyme-immunoassay method, and were originally created to measure IL-6 in plasma, serum, or culture media. We evaluated commercial kits for the determination of IL-6 in amniotic fluid. Seven commercial kits were used to determine IL-6 concentrations in three amniotic fluid samples which were obtained from patients with clinical chorioamnionitis during labor and five from normal pregnancies at mid-trimester. Amniotic fluid IL-6 values differed significantly with some having over a 50-fold discrepancy and the recovery of known IL-6 added to amniotic fluid ranged from 12 to 123%. However, by all kits we were able to identify that amniotic fluid from patients with chorioamnionitis contained significantly higher IL-6 concentrations than those from normal mid-trimester pregnancies. Our data indicate that standardization of the method for measuring IL-6 in amniotic fluid is desirable for the comparison of values from various laboratories.


Saccharin stimulates the "deterrent" cell in the blowfly: behavioral and electrophysiological evidence.
In the attempt to gain more information on the mechanisms underlying bitter and/or sweet taste reception, we have investigated the responses of labellar chemosensilla in the blowfly Protophormia terraenovae to Na-saccharin, as compared to sweet stimuli (sucrose or fructose) and bitter stimuli (denatonium benzoate or amiloride). Electrophysiological and behavioral results indicate that the sweetener Na-saccharin inhibits the "sugar" cell in the labellar taste sensilla of the blowfly P. terraenovae. In multichoice preference tests, flies ingested more of the solutions containing sugar to those with sugar+Na-saccharin. This finding is in good agreement with the spike frequency reduction observed for the "sugar" cell activity. Analysis of the spike discharges also shows a positive dose-response for the "deterrent" cell following stimulation with Na-saccharin and denatonium benzoate. Flies drank any of the Na-saccharin solutions, regardless of their concentration, less than water, thus indicating a weak deterring effect on water drinking. The prevailing activation of the "deterrent" cell by stimulation with Na-saccharin is not directly coupled with a coherent behavioral output. Cross adaptation was found to occur between responses to Na-saccharin and denatonium benzoate or amiloride regardless of the order of adapting stimuli. In the case of sweet stimuli, cross adaptation occurred when the adapting stimulus was Na-saccharin, but it did not when the adapting stimuli were sucrose or fructose. Addition of Na-saccharin to both sugars significantly depressed the spike firing frequency, while an increase was observed with denatonium benzoate or amiloride.


Possible relation of hemin-induced HO-1 expression to the upregulation of VEGF and BDNF mRNA levels in rat C6 glioma cells.
Glial cells are generally considered to contribute to retaining the integrity of neural function through the protection of neuronal cells against neurodegenerative insults and also expected to play a potential role in the protection of cerebrovascular systems from various toxic insults of hemorrhaged blood, thus proposing a possible implication of glial cells in the recovery of brain function from the damage caused by cerebral hemorrhage. Based on this hypothetical idea, the direct effect of hemin on the expression of genes encoding heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) in glial cells was examined using rat C6 glioma cells as an in vitro model system. Hemin elevated both HO-1 and VEGF mRNA levels in the glioma cells at the concentration causing no critical damage to the cells, and the elevation of BDNF mRNA levels was also observed by exposing the cells to hemin under the same conditions. Furthermore, the elevation of VEGF and BDNF mRNA levels induced by hemin was blocked by pretreatment of the cells with the agents inhibiting not only HO-1 gene expression but also its enzymatic activity. These pharmacological studies indicate that hemin can induce the enhancement of VEGF and BDNF gene expression probably through the mechanism mediated by HO-1 activity in the glioma cells, proposing the possibility that glial cells are capable of contributing to the recovery of brain function from the damage caused by cerebral hemorrhage through the production of neurogenic and angiogenic factors.


A modified form of the St Thomas' Hospital (STH) classification to improve cochlear implantation outcomes.
re-evaluation and modification of the St Thomas' Hospital (STH) classification to improve cochlear implantation outcomes. STUDY DEIGN: a prospective cohort study. children (n = 20) between 2 to 8 years old who received a unilateral cochlear implant, all had difficult round window visibility and/or accessibility for electrode insertion. 10 had a round window insertion through the endoscopic assisted cochlear implantation and the remaining 10 had the same insertion using the retro-facial approach. THE SURGERY: two alternative techniques were used to overcome the difficult cases of round window electrode insertion: 1Endoscopic assisted cochlear implantation 2Transmastoid retro-facial approach RESULTS: both techniques proved to be effective and practical to overcome cases with difficult round window visibility and/or accessibility for electrode insertion. Round window insertion is associated with superior cochlear implantation outcomes, so we recommend a new modification to the STH classification to bypass the cochleostomy insertion.


Tracing the cellular origin of cancer.
Although many genes that lead to different types of cancer when mutated have been identified, the cells that initiate tumour formation following accumulation of these mutations have, until recently, remained elusive. This review explores how mouse genetic lineage-tracing experiments that allow the expression of oncogenes and/or the deletion of tumour suppressor genes in defined cell lineages have been instrumental in defining the cellular origin of different solid tumours in mouse models for various human cancers.


Trends in the use of neoadjuvant chemotherapy for low-grade serous ovarian cancer in the United States.
To describe trends in neoadjuvant chemotherapy (NACT) use for low-grade serous ovarian carcinoma (LGSOC) and to quantify associations between NACT and extent of cytoreductive surgery. We identified women treated for stage III or IV serous ovarian cancer in a Commission on Cancer accredited program between January 2004-December 2020. Regression models were developed to evaluate trends in NACT use for LGSOC, to identify factors associated with receipt of NACT, and to quantify associations between NACT and bowel or urinary resection at the time of surgery. Demographic and clinical factors were used for confounder control. We observed 3350 patients who received treatment for LGSOC during the study period. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to an annual percent change of 7.2% (95% CI 5.6-8.9). Increasing age (rate ratio (RR) 1.15; 95% CI 1.07-1.24), and stage IV disease (RR 2.66; 95% CI 2.31-3.07) were associated with a higher likelihood of receiving NACT. For patients with high-grade disease, NACT was associated with a decrease in likelihood of bowel or urinary surgery (35.3% versus 23.9%; RR 0.68, 95% CI 0.65-0.71). For LGSOC, NACT was associated with a higher likelihood of these procedures (26.6% versus 32.2%; RR 1.24, 95% CI 1.08-1.42). NACT use among patients with LGSOC has increased from 2004 to 2020. While NACT was associated with a lower rate of gastrointestinal and urinary surgery among patients with high-grade disease, patients with LGSOC receiving NACT were more likely to undergo these procedures.


Recent advances in natural phthalides: Distribution, chemistry, and biological activities.
Phthalides, an important class of bioactive natural products, are widely distributed in plants, fungi, lichens, and liverworts. Amon them, n-butylphthalide, a phthalide monomer, has been approved to cure ischemic stroke. Owing to their good bioactivities in anti-microbial, anti-inflammatory, anti-tumor, anti-diabetic, and other aspects, a large number of researches have been conducted on phthalides from nature materials. In recent years, hundreds of novel natural phthalides were obtained. This review provides profiles of the advances in the distribution, chemistry, and biological activities of natural phthalides in 2016-2022.


Effects of statins on brain tumors: a review.
Evidence from preclinical studies suggests that the competitive HMG-CoA reductase (HMGCR) inhibitors universally known as 'statins,' in addition to being powerful drugs that reduce cholesterol and improve cardiovascular risk, also have promising antitumor properties. Statins appear to enhance the treatment outcome of various cancers before and concurrent with other cancer treatment interventions. Glioblastoma multiforme (GBM), a particularly invasive cerebral tumor associated with high mortality, holds a poor median overall survival (OS) of around one year after surgical resection followed by concurrent radiation and chemotherapy. Recently, statins have increasingly appeared as potential adjuvant drugs for the treatment of GBM because of their potential to suppress cell growth, survival, migration, metastasis, inflammation, angiogenesis, and promote apoptosis during both in vitro and in vivo studies. However, the clinical outcomes of statins on the survival of patients with GBM are still controversial. This study aims to review and address some of the documented effects of statin drugs when focusing entirely on cancer treatment, especially GBM, including concurrent statin therapy with chemotherapeutic agents.


Human genomic sequences corresponding to murine CD3 eta-related transcripts: lack of conservation or expression of homologous human products.
We have cloned and sequenced human genomic DNA homologous to exons 9 and 10 of the CD3 zeta/eta/theta locus. Although there are open reading frames within the human sequences corresponding to the translated portions of murine exons 9 and 10, we find no evidence of conservation of the encoded polypeptide product. Furthermore, using oligonucleotides derived from these homologous sequences, we are unable to detect human CD3 eta- or CD3 theta-like transcripts by polymerase chain reaction amplification of reverse-transcribed RNA from a variety of human lymphoid tissues. Despite the absence of evidence for conservation of human CD3 eta and CD3 theta, there is a surprising degree of similarity between human and murine nucleotide sequences, not only for exons 9 and 10 (78% and 70%, respectively), but also for the 9/10 intron (71%). A possible mechanism for this conservation is discussed.


Post-exercise ketosis in post-prandial exercise: effect of glucose and alanine ingestion in humans.
This study examined ketosis in response to 90 min of running before and after the ingestion of 50 g glucose or 50 g L-alanine in thirty-three athletes. Everyone ran 20 km at 07.30 h and then rested, while fasting, till 16.00 h. There were four test groups: 'glucose-before', 'glucose-after', 'alanine-before' and 'alanine-after' according to whether glucose or alanine was ingested at 07.00 h, or 09.00 h. Controls did not ingest either test substance. The control 3-hydroxybutyrate concentration rose from 0.23 +/- 0.03 mmol/l (S.E. of mean) at 07.00 h to 0.74 +/- 0.27 mmol/l at 12.00 h, and 0.94 +/- 0.33 mmol/l at 16.00 h. Glucose ingestion before or after exercise did not influence post-exercise ketosis significantly, despite high insulin: glucagon ratios, low free fatty acid concentrations and hyperglycaemia. Alanine significantly lowered the 3-hydroxybutyrate levels, especially after exercise (to 0.14 +/- 0.07 mmol/l at 12.00 h; P less than 0.05) despite reversed insulin: glucagon ratios. This suggests that hepatic responsiveness to portal hyperglycaemia and the main hormones of metabolism is altered immediately after exercise, presumably to promote muscle glycogen synthesis in preference to liver glycogen synthesis.


Differentiation between Prototheca and morphologically similar green algae in tissue.
Evidence that algae are pathogens was provided by the results of electron microscopic studies of tissues from five cattle and sheep suspected of having green algal infections. Chloroplasts were demonstrated in the algae in each case. Prototheca organisms, considered by some to be achloric mutants of green algae, are causative agents of disease in man and animals and may appear morphologically similar to green algae in tissue. However, electron microscopy showed that chloroplasts were absent in these organisms. Light microscopy revealed not only similarities in size, shape, and mode of reproduction, but also a striking difference between the Prototheca organisms and green algae. Unlike Prototheca, the green algae contained abundant cytoplasmic starch granules that were strongly positive by several staining procedures; these granules, which were PAS-negative following diastase digestion, provide a means of differentiating green algae from Prototheca cells in tissue.


Acute chylous peritonitis: Report of a case.
Acute chylous peritonitis, a rare condition, is defined as an abrupt chylous fluid accumulation in the peritoneal space in the absence of a significant underlying pathology. Diagnosis is difficult due to abrupt onset and accompanying acute abdomen signs. Here we presented the case of a 32-year-old female patient who underwent laparoscopy due to acute abdomen findings and was diagnosed with acute chylous peritonitis. No underlying pathologies were detected, and only irrigation and drainage were applied. She was discharged unproblematically with a low-fat diet and somatostatin administration. No recurrence occurred, and no other pathologies were encountered during her 9-month visit. Chylous fluid accumulation is reported to arise from various etiological factors such as trauma, chronic liver diseases, tuberculosis, filariasis, radiation, abdominal aorta surgery, different peritoneal infection and extended lymph node dissections. We have presented an acute chylous peritonitis case that was admitted with acute abdomen findings and followed up and treated with laparoscopy. In conclusion, this case demonstrates the effectiveness of laparoscopy in acute abdomen cases in which a specific preoperative diagnosis cannot be made. Aspiration of the fluid and drainage comprise a sufficient therapy if a focus cannot be found. Postoperative somatostatin use may be beneficial.


Aromatic glycosides from the flower buds of Lonicera japonica.
Six new glycosides (1-6) have been isolated from the flower buds of Lonicera japonica. Their structures including the absolute configurations were determined by spectroscopic and chemical methods as ( - )-2-hydroxy-5-methoxybenzoic acid 2-O-β-d-(6-O-benzoyl)-glucopyranoside (1), ( - )-4-hydroxy-3,5-dimethoxybenzoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (2), ( - )-(E)-3,5-dimethoxyphenylpropenoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (3), ( - )-(7S,8R)-(4-hydroxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (4), ( - )-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (5), and ( - )-4-hydroxy-3-methoxyphenol β-d-{6-O-[4-O-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (6), respectively.


Antimicrobial, antioxidant, and sun protection potential of the isolated compounds from Spermacoce princeae (K. Schum).
Spermacoce princeae (K. Schum) has been used in the treatment of bacterial skin infections in Uganda. Pharmacological studies revealed that extracts of S. princeae exhibited antibacterial, antioxidant, and sun protection potential. This study aimed at isolating and identifying pure compounds from the extracts based on comprehensive analytical characterization by multiple analytical techniques. The plant samples were extracted by sequential maceration using n-hexane, ethyl acetate, methanol, and distilled water. The compounds were isolated using a combination of chromatographic techniques and their structures were elucidated by multiple spectroscopic techniques. The antibacterial and antifungal activity determination of the isolated compounds was carried out using an agar well diffusion and potato dextrose assay against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Candida albicans, and Aspergillus flavus while the antioxidant activity was screened with the 2,2-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging assay. The sun protection factor was determined using a Shimadzu Ultra Violet-visible (UV-VIS) double beam spectrophotometer between 290 to 320 nm. Eleven compounds; quercetin (1), kaempferol-3-O-rutinoside (2), rutin (3, 12), myo-inositol (4), asperulosidic acid (5), hexadecanoic acid (6), β-sitosterol (7), stigmasterol (8), campesterol (9), ursolic acid (10), and β-sitosterol glucoside (11) were identified in the S. princeae extracts. Compound 2 had good antifungal activity against C. albicans (zone of inhibition, 23.0 ± 0.1 mm). Compound 10 showed antibacterial and antifungal activity against S. aureus, P. aeruginosa, C. albicans, and A. flavus. Compound 2 had a good percentage radical scavenging effect (IC50 = 64.81 µg/ml) and a good sun protection factor (SPF = 26.83). This study reports the first-time isolation and identification of compounds 1 to 11 from S. princeae, which contribute to its antimicrobial, antioxidant, and sun protection potential.


Effect of chloroquine, methylene blue and artemether on red cell and hepatic antioxidant defence system in mice infected with Plasmodium yoelii nigeriensis.
Reactive oxygen species are mediators of tissue injury and are involved in malaria infection. In this study, the status of red cell and hepatic oxidative stress and antioxidant defence indices were investigated during Plasmodium yoelii nigeriensis (P. yoelii) infection, and treatment with chloroquine (CQ), methylene blue (MB) or artemether (ART) in mice. P. yoelii infection caused a significant (p < 0.05) increase in oxidative stress as evidenced by the elevated level of malondialdehyde. This was followed by a significant decrease (p < 0.05) in hepatic antioxidant defence indices, viz. reduced glutathione (GSH) and glutathione-S-transferase (GST). Also, the red cell catalase activity was significantly (p < 0.05) lower in malaria infection, while there was no significant difference (p > 0.05) in the superoxide dismutase (SOD) activity of infected mice when compared to untreated normal. Treatment of infected mice with the three antimalarials showed that the drugs suppressed the parasitaemia in the order CQ > ART > MB. CQ, MB and ART treatment of infected mice caused a significant (p < 0.05) increase in the levels of hepatic GSH and GST. Specifically, CQ, MB and ART increased the levels of hepatic GSH by 108, 124 and 98 %, respectively, at day 6. Also, ART treatment of infected mice significantly (p < 0.05) elevated the red cell SOD level by 200 % at day 3. Taken together, the findings suggest that the antimalarial effect of CQ, MB and ART countered the P. yoelii-induced oxidative stress leading to the elevation of enzymatic and non-enzymatic antioxidants in the host system.


Effects of carvedilol on oxidative stress in human endothelial cells and healthy volunteers.
Carvedilol is a nonselective beta- and alpha(1)-receptor antagonist with additional antioxidant properties in vitro. In this study, we assessed the antioxidative potential of carvedilol in cell culture and in antihypertensive doses in healthy men. In vitro, human cultured endothelial cells were treated with native low-density lipoprotein (LDL), oxidized LDL or tumor necrosis factor (TNF)alpha in the absence and in the presence of carvedilol (40 micro M); 8-iso-prostaglandin (PG)F(2alpha), as parameter of oxidative stress, was determined in the supernatants. In a double-blind, randomized, cross-over study, 17 healthy men received 25 mg carvedilol b.i.d., 100 mg metoprolol b.i.d. or placebo for 6 days. After each treatment, systemic oxidative stress was assessed by measuring urinary excretion of 8-iso-PGF(2alpha) and 2,3-dinor-5,6-dihydro-8-iso-PGF(2alpha), and the plasma concentration of 3-nitrotyrosine by means of gas chromatography-tandem mass spectrometry. In addition, thiobarbituric acid-reactive substances (TBARS) in plasma were assessed using spectrophotometry. Native LDL and oxidized LDL induced 8-iso-PGF(2alpha) production in endothelial cells. Carvedilol significantly reduced this effect (e.g., for oxidized LDL: 2.66+/-0.22 pg vs 1.46+/-0.14 pg 8-iso-PGF(2alpha) per micro g protein, P<0.05). In healthy volunteers, carvedilol and metoprolol markedly decreased blood pressure and heart rate, but had no statistically significant effect on any indicator of oxidative stress measured. Remarkably, a trend toward reduction of urinary isoprostanes and 3-nitrotyrosine in plasma by both active treatments was observed, suggesting a non-specific antioxidative effect by beta blockade. In vitro, the antioxidative potential of carvedilol was confirmed. In healthy men, antihypertensive doses of carvedilol exert no specific inhibition of oxidative stress.


Educational differences in leisure-time physical inactivity: a descriptive and explanatory study.
In this study we aim to explain educational differences in leisure-time physical inactivity in terms of psychosocial and material factors. Cross-sectional data were obtained from the baseline of the Dutch GLOBE study in 1991, including 2598 men and women, aged 15-74 years. Physical inactivity during leisure time was defined as not participating in any activity, such as sports, gardening, walking or cycling. Psychosocial factors included in the study were coping resources, personality, and stressors. Material factors were financial situation, employment status, and living conditions. Logistic regression models were used to calculate educational differences in physical inactivity. Physical inactivity was more prevalent in lower educational groups. Psychosocial factors related to physical inactivity were locus of control, parochialism, neuroticism, emotional social support, active problem focussing, optimistic and palliative coping styles. Material factors associated with physical inactivity were income, employment status and financial problems. All correlates of physical inactivity were unequally distributed over educational groups, except optimistic and palliative coping. Personality and coping style were the main contributors to the observed educational differences in physical inactivity. That is to say, parochialism, locus of control, neuroticism and active problem focussing explained about half of elevated odds ratios of physical inactivity in the lower educational groups. The material factors, equivalent income and employment status explained about 40% of the elevated odds ratios. Psychosocial and material correlates together reduced the odds ratios of lower educational groups by on average 75%. These results have practical consequences for the design of more effective interventions to promote physical activity. In particular, personality and coping style of risk groups, such as lower educational groups, should be taken into consideration at the future development of these interventions, as well as inequalities in material restrictions related to engaging in physical activity. Supplementary interventions focussing on childhood conditions which, partly, influence both personality and physical inactivity may also contribute to a reduction of socio-economic differences in physical inactivity.


Sodium consumption following lesions surrounding the anteroventral third ventricle.
Consumption of sodium solution was measured in rats with lesions of the anteroventral third ventricle (AV3V) and maintained on sodium deficient chow. Rats with AV3V lesions consumed less sodium than control animals, and increased their sodium consumption following a subcutaneous injection of Formalin. These data indicate that the AV3V ablation alters the nature of the regulatory control of sodium but does not render animals insensitive to plasma sodium levels.


An MRI-compatible foot-loading device for assessment of internal tissue deformation.
It is well known that mechanical forces acting within the soft tissues of the foot can contribute to the formation of neuropathic ulcers in people with diabetes. Presently, only surface measurements of plantar pressure are used clinically to estimate risk status due to mechanical loading. It is currently not known how surface measurements relate to the three-dimensional (3-D) internal stress/strain state of the foot. This article describes the development of a foot-loading device that allows for the direct observation of the internal deformation of foot tissues under known forces. Ground reaction forces and plantar pressure distributions during normal walking were measured in ten healthy young adults. One instant in the gait cycle, when pressure under the metatarsal heads reached a peak, was extracted for simulation in an MR imager. T1-weighted 3-D gradient echo MRI sets were collected as the simulated walking ground reaction force was incrementally applied to the foot by the novel foot-loading device. The sub-metatarsal head soft-tissue thickness decreased rapidly at first and then reached a plateau. Peak plantar pressure measurements collected within the loading device (161+/-75kPa) were lower in magnitude and less focal than pressures measured during walking (492+/-91kPa). This finding implies that although the device successfully applied full peak walking ground reaction forces to the foot, they were not distributed in the same manner as during walking. Although not representative of gait, the data collected from this in vivo mechanical test are suitable for determination of foot tissue material properties or, when combined with finite element modeling, to examine the relationship between surface loading and internal stress.


Blood acetaldehyde response to ethanol ingestion during the reproductive cycle of the female rat.
Acetaldehyde could mediate a number of the toxic effects of alcohol both in females and their offspring. Thus, we assessed the blood acetaldehyde response to ethanol (3 g/kg) at various stages of the female reproductive cycle. Blood levels were low throughout the various phases of the estrous cycle and during most of pregnancy. By contrast, a 4-fold rise in maternal blood acetaldehyde occurred at the end of pregnancy (day 20), continued to increase during lactation (17-fold at day 14) and returned to non-pregnant values after weaning or after pup removal at birth. Both enhanced rate of ethanol oxidation and decreased activity of the low Km aldehyde dehydrogenase in liver mitochondria contributed to the increased acetaldehyde levels. Acetaldehyde was detectable in fetal blood, but only a small fraction of the high maternal values in pregnancy reached the fetus through the umbilical vein. Chronic alcohol administration resulted in decreased fetal size and striking enlargement of the placenta with possible implications for abnormal fetal development. Thus, the high maternal acetaldehyde levels at the end of pregnancy may exert deleterious effects on many maternal organs, including those (such as placenta) which are required for normal fetal development.


Diagnostic performance of real time PCR and MALDI-TOF in the detection of nontuberculous mycobacteria from clinical isolates.
This study aimed to evaluate the performance of real-time PCR (qPCR) and MALDI-TOF for accurate and timely detection of nontuberculous mycobacterium (NTM) from clinical isolates. We collected fifty NTM suspected Mycobacteria Growth Indicator Tube (MGIT) cultures and analysed the diagnostic performance of qPCR and VITEK MS using Line Probe Assay (LPA) GenoType CM (Common Mycobacteria) as gold standard. The qPCR assays targeting 16S rRNA, ITS and IS6110 genes were developed for the identification of NTM and Mycobacterium tuberculosis complex (MTBC). LPA GenoType CM, a PCR technique targeting 23S rRNA gene, followed by reverse hybridization and line probe technology identified 90% of Mycobacterium species including M. fortuitum (16%,n = 8), M. intracellulare (10%,n = 5), M. gordonae (10%,n = 5), M. xenopi (4%,n = 2), M. scrofulaceum (4%,n = 2), Mycobacterium additional species (AS) (32%,n = 16) and MTBC (14%,n = 7), qPCR detected 80% of Mycobacterium species (NTM, 66% (n = 33) and MTBC, 14% (n = 7)) and MALDI-TOF, 52% (M. fortuitum (12%,n = 6), M. intracellulare (10%, n = 5), M. simiae (8%,n = 4), M. gordonae (8%,n = 4), and MTBC (14%,n = 7)). Sensitivity of qPCR and MALDI-TOF was 88.9% and 57.8%, respectively with 100% specificity. The combination of qPCR and MALDI-TOF remains an appropriate test for timely diagnosis of Mycobacterium species. This may eventually assist to detect the cases that may have been missed by phenotypic tests and enhance the NTM diagnosis capability to improve effective patient management.


Effectiveness of kampo medicine (sai-boku-to) in treatment of patients with glossodynia.
The purpose of this study was to evaluate the usefulness of a Kampo medicine (Sai-boku-to) for treatment of patients with glossodynia. Sai-boku-to or an antianxiety drug (diazepam) with vitamin B complex was administered orally for 3 months to each of 200 patients with glossodynia. Clinical examination evaluated the following subjective symptoms: pain, burning sensation, and discomfort. Effectiveness was evaluated as follows: "markedly effective," all 3 symptoms disappeared; "effective," pain improved; "ineffective," no improvement in pain. The effective rates were 70% after 1 month, 85% after 2 months, and 92% after 3 months of administration of Sai-boku-to (the Kampo group) and 74% after 1 month, 71% after 2 months, and 69% after 3 months of administration of the antianxiety drug with vitamin B complex (the control group). No significant side effect was noted in the Kampo group, but sleepiness was recorded in 33 cases in the control group. The results indicate that Sai-boku-to may be a clinically useful medicine for the long-term treatment of patients with glossodynia.


Appearance of adenosine triphosphate in the perfusate from working frog heart.
Frog hearts (Rana pipiens) were perfused in situ with Ringer's solution and the perfusate tested on firefly extract for the presence of ATP. At a normal perfusion pressure of 8 cm. H2O the rate of release of ATP into the perfusate was 8.8 (+/- S.E.1.7) pmoles.min-1. When the workload was increased by raising the perfusion pressure to 12 cm. H2O the rate of release increased to 28.3 (+/- S.E.4.8) pmoles.min-1. The rate of release was found to be proportional to the amount of workload imposed upon the heart. It is postulated that the trigger for release is hypoxia and that the release of ATP from the cardiac cell will augment contractility of the myocardium through its action upon adjacent cells via the P2 purinergic receptor. cells via the P2 purinergic receptor.


The magnetic resonance imaging of infections and inflammatory diseases.
The MR features of inflammatory lesions of the central nervous system are reviewed in this article, and the sensitivity and specificity of MR and CT in the detection of these lesions are compared. The advent of CT dramatically improved the morbidity and mortality of inflammatory disease by facilitating earlier and more accurate diagnosis which, in turn, produced more timely medical and surgical intervention. The efficacy of MR in the evaluation of inflammatory lesions must, therefore, be compared to CT in order to accurately asses its role.


Factors associated with appropriate home management of uncomplicated malaria in children in Kassena-Nankana district of Ghana and implications for community case management of childhood illness: a cross-sectional study.
Home management of uncomplicated malaria (HMM) is now integrated into the community case management of childhood illness (CCM), an approach that requires parasitological diagnosis before treatment. The success of CCM in resource-constrained settings without access to parasitological testing significantly depends on the caregiver's ability to recognise malaria in children under five years (U5), assess its severity, and initiate early treatment with the use of effective antimalarial drugs in the appropriate regimen at home. Little is known about factors that influence effective presumptive treatment of malaria in U5 by caregivers in resource-constrained malaria endemic areas. This study examined the factors associated with appropriate HMM in U5 by caregivers in rural Kassena-Nankana district, northern Ghana. A cross-sectional household survey was conducted among 811 caregivers recruited through multistage sampling. A caregiver was reported to have practiced appropriate HMM if an antimalarial drug was administered to a febrile child in the recommended regimen (correct dose and duration for the child's age). Binary logistic regression was used to determine factors associated with appropriate HMM. Of the 811 caregivers, 87% recognised the symptoms of uncomplicated malaria in U5, and 49% (n = 395) used antimalarial drugs for the HMM. Fifty percent (n = 197) of caregivers who administered antimalarial drugs used the appropriate regimen. In the multivariate logistic regression, caregivers with secondary (OR = 1.71, 95% CI: 1.03, 2.83) and tertiary (OR = 3.58, 95% CI: 1.08, 11.87) education had increased odds of practicing appropriate HMM compared with those with no formal education. Those who sought treatment in the hospital for previous febrile illness in U5 had increased odds of practicing appropriate HMM (OR = 2.24, 95% CI: 1.12, 4.60) compared with those who visited the health centres. Half of caregivers who used antimalarial drugs practiced appropriate HMM. Educational status and utilisation of hospitals in previous illness were associated with appropriate HMM. Health education programmes that promote the use of the current first line antimalarial drugs in the appropriate regimen should be targeted at caregivers with no education in order to improve HMM in communities where parasitological diagnosis of malaria may not be feasible.


The lipoprotein lipase (LPL) S447X gain of function variant involves increased mRNA translation.
A common gain-of-function LPL variant, LPLS447X, has favorable clinical features and involves a C→G base change at nucleotide 1595 of the LPL cDNA, along with a haplotype, which includes other non-coding SNPs. The mechanism for the LPL gain-in-function is not clear. LPL translation is regulated by epinephrine by an RNA-protein complex, consisting of PKA subunits and an A kinase anchoring protein (AKAP), which targets the 3'UTR. To examine LPL translation of the LPLS447X variant, in vitro translation of LPL mRNA constructs was studied in the presence of cytoplasmic extracts from 3T3-F442A adipocytes treated with/without epinephrine. When the C→G base change at nucleotide 1595 was introduced, LPL mRNA was less susceptible to inhibition by the adipocyte extract. Similarly, a lessened susceptibility to translation inhibition occurred when the complete haplotype was constructed in the full-length 3.6 kb LPL mRNA, when an irrelevant coding sequence was introduced into the LPL mRNA construct, and in response to the use of components of the RNA binding complex (PKA C and R subunits, and KH region of AKAP149). These studies suggest that the LPLS447X gain of function may be due to the base change in the LPL mRNA resulting in a decreased susceptibility to translational inhibition.


[Management and treatment of liver injuries after blunt abdominal trauma].
The liver is involved in about 20% of cases of blunt abdominal trauma. The management of liver trauma has changed significantly in the past three decades towards conservative treatment. Up to 80% of all liver trauma patients can now be successfully treated by nonoperative management. Decisive for this is the adequate screening and assessment of the patient and the injury pattern as well as the provision of the appropriate infrastructure. Hemodynamically unstable patients require immediate exploratory surgery. In hemodynamically stable patients, a contrast-enhanced computed tomography (CT) should be performed. If active bleeding is detected angiographic imaging and embolization should be performed to stop the bleeding. Even after initially successful conservative management of liver trauma, subsequent complications can occur that make surgical inpatient treatment necessary.


Soluble RANKL exaggerates hindlimb suspension-induced osteopenia but not muscle protein balance.
We examined the hypothesis that exaggerating unloading-induced bone loss using a combination of hindlimb suspension (HLS) and exogenous injections of receptor activator of nuclear factor-κB ligand (RANKL) also exaggerates gastrocnemius and quadriceps muscle loss. Forty, male C57Bl/6J mice (16 weeks) were subjected to HLS or normal ambulation (ground control, GC) for 14 days. Mice received three intraperitoneal injections of either human recombinant soluble RANKL or phosphate-buffered saline as control (n = 10/group) at 24 h intervals starting on Day 1 of HLS. GC + RANKL and HLS mice exhibited similar decreases in trabecular bone volume and density in both proximal tibias and distal femurs. However, RANKL affected trabecular number, separation, and connectivity density, while HLS decreased trabecular thickness. The combination of RANKL and HLS exacerbated these changes. Similarly, GC + RANKL and HLS mice saw comparable decreases in cortical bone volume, thickness, and strength in femur midshafts, and combination treatment exacerbated these changes. Plasma concentrations of P1NP were increased in both groups receiving RANKL, while CTX concentrations were unchanged. HLS decreased gastrocnemius weight and was associated with a reduction in global protein synthesis, and no change in proteasome activity. This change was correlated with a decrease in S6K1 and S6 phosphorylation, but no change in 4E-BP1 phosphorylation. Injection of RANKL did not alter gastrocnemius or quadriceps muscle protein metabolism in GC or HLS mice. Our results suggest that injection of soluble RANKL exacerbates unloading-induced bone loss, but not unloading-induced gastrocnemius or quadriceps muscle loss.


Evidence for predictive validity of blood assays to evaluate individual radiosensitivity.
An escalation in standard irradiation dose ensuring improved local tumor control is estimated, but this strategy would require the exclusion of the most sensitive individuals from treatment. Therefore, fast and reliable assays for prediction of the individual radiosensitivity are urgently required. Seven parameters in lymphocytes of 40 patients with leukemia were analyzed before, during, and after total body irradiation (TBI) and in vitro X-ray irradiation. These were: cell proliferation, nuclear damage, activation of cytokines, and numbers of total leukocytes of CD34+ hematopoietic blood stem cells and of CD4+ and CD8+ lymphocytes. Additionally, antioxidative capacity of blood plasma, uric acid, and hemoglobin levels were measured. Blood samples of 67 healthy donors were used as controls. In vivo and in vitro irradiations showed comparable results. A dose-response relationship was found for most parameters. Three parameters were associated with severe acute oral mucositis (Grade 3 or 4 vs. Grade 0 to 2): leukocytes fewer than 6200/microL after 4 Gy TBI, a rate of >19% lymphocytes with reduced DNA and protein content ("necroses") after 4 Gy in vitro irradiation, and a small antioxidative capacity in blood plasma (<0.68 mMol) after 8 Gy TBI. Three simple blood assays were associated with oral mucositis that are posed here hypothetically as an early symptom of enhanced radiosensitivity in leukemic patients: leukocyte count, damaged lymphocyte score, and the antioxidative capacity after exposure.


Effects of parathyroid hormone on the osteoclastic pool, bone resorption and formation in rat alveolar bone.
The osteoclast number and its relation to parathyroid hormone have been studied in rat alveolar bone by quantitative histology and fluorescent labeling. The osteoclast number decreases 60 h after parathyroidectomy and remains constant for the next 132 h. Parathyroid hormone administration to parathyroidectomized animals 96 h after the operation induces an increase in osteoclast number within 12 h to somewhat above those of control animals. The elevated osteoclast counts remain constant for 60 h then rapidly fall over the next 24 h to the level seen in untreated parathyroidectomized animals. As determined by fluorescent labeling, normal alveolar bone resorption and formation were disturbed by parathyroidectomy, such that significant bone formation occurred for only 6 days after surgery, after which a quiescent state followed.


Interaction of oscillatory processes: the effects of subthreshold A.C. current on sinoatrial nodal rhythm.
In this study of interactions occurring within the heart, isolated superfused strips of rabbit atria, containing the sinoatrial (s.a.) node, were subjected to sinusoidal subthreshold current pulses of varied frequencies and intensities. A.C. current from an R.C. oscillator was applied through a Grass stimulation isolation unit, push-pull connection, and non-polarizing (Ag-AgCl-KCl-Tyrode Agar-Agar) electrodes. A Grass polygraph and tachometer were used to record the applied pulses and nodal firing rates; simultaneous magnetic tape recordings were obtained and used for data analysis. Suction electrode recordings and oscilloscope displays were used to determine how the cyclic impulses affected cellular activity. The s.a. nodal rhythm was modified by subthreshold A.C. current applications; when frequencies were low, firing rates of the node were modulated by the A.C. and mean rates were reduced. As frequencies were progressively increased, slow waxings and wanings in heart rate were produced. These periodic fluctuations were not readily correlated with either the A.C. frequency nor the intrinsic nodal rate, but were representative of the difference between the two. As applied current frequency neared the pacemaker's intrinsic rate, a synchronization occurred and the discharges locked in at a specific phase of the applied current alternation. This synchronization maintained during slight further increases in A.C. frequency but above a critical rate this relationship broke down and the waxing and wanings in frequency of pacemaker rate again developed. It was concluded that pacemaker action of the s.a. node is effected by integration of cellular activity through electron coupling.


Chronic effects of nano and microplastics on reproduction and development of marine copepod Tigriopus japonicus.
This study aimed to examine the impact of chronic (30 days) exposure to polystyrene microplastics (PS-MPs) of different sizes (50 nm and 2 µm) and at different concentrations (0.5 μg/L and 100 mg/L) to marine copepod Tigriopus japonicus. Polystyrene microplastics affected survival rates in size- and concentration-dependent manners. The LC50s values of 50 nm and 2 µm PS-MPs were 0.10 mg/L and 3.92 mg/L, respectively. The developmental time was delayed by 50 nm PS-MPs, and Usp expression was downregulated. Reproduction was negatively affected by 2 µm PS-MPs even at environmentally relevant concentrations; however, the expression of Vtg was not altered. The production rates of reactive oxygen species and nitric oxide also increased after exposure to PS-MPs; but this effect was independent of particle size. The expression levels of Cat and Tnf, genes related to oxidative stress and inflammation, respectively, were upregulated by exposure to PS-MPs, independently of particle size. Meanwhile, the level of oxidative stress in T. japonicus was not significantly affected by PS-MPs at environmentally relevant concentrations. This study suggests that nano-sized PS-MPs are not always more toxic than micro-sized PS-MPs, and that oxidative stress is a key factor in determining the toxic effect on T. japonicus at high concentrations.


Oral chronic graft-versus-host disease: report from the International Consensus Conference on clinical practice in cGVHD.
Chronic graft-versus-host disease (cGVHD) is a multi-organ disease that occurs post-hematopoietic stem cell transplantation, with the mouth being one of the most frequently affected organs. In 2009, the German-Austrian-Swiss working party on bone marrow and blood stem cell transplantation held a consensus conference to define clinical management of cGVHD. The consensus conference aimed to summarize the literature on diagnosis and topical treatment options for oral cGVHD and to provide recommendations for clinical practice, including routine dental and oral care as well as monitoring for secondary malignancies and bisphophonate-induced osteonecrosis of the jaw.


Expression of complement regulatory proteins on human natural killer cell subsets.
The cell surface complement regulatory (CReg) proteins CD46, CD55 and CD59 are widely distributed on human leucocytes and protect against complement-mediated damage. To investigate heterogeneity in CReg protein expression by human natural killer (NK) cells, levels were assessed on resting and activated NK cell subsets identified phenotypically on the basis of expression of CD56 and CD158 markers. Levels of all three CReg proteins on CD56+ cells were lower than on T cells (p<0.05). Freshly isolated CD56(bright) cells expressed higher levels of CD55 than CD56dim cells (p<0.05). CD158a+ cells expressed significantly lower levels of both CD46 and CD59, and CD158e+ cells expressed significantly lower levels of CD46, than CD158a(-) CD158e(-) cells, respectively (both p<0.05). Stimulation with PHA did not significantly alter NK cell surface CReg protein levels whereas, following culture with IL-2, CD46 and CD59 were decreased on both CD56bright and CD56dim subsets (p<0.05). In the case of CD59, this was independent of T cells. Only CD46 was significantly downregulated on CD158b+ (GL183+) and CD158e (NKB1+) subsets (p<0.05). However, culture in IL-15 significantly increased levels of all three CReg proteins. These observations that CReg proteins are downregulated on certain NK cell subsets following activation with IL-2 are opposite to previous findings for other leucocyte subpopulations. Activated NK cells may instead use other strategies for protection against complement-mediated damage in a local inflammatory response.


Injuries among infants treated in emergency departments in the United States, 2001-2004.
The objective of this study was to present a detailed examination of unintentional injuries in infants < or = 12 months of age treated in emergency departments. We conducted a retrospective analysis of data for infants < or = 12 months of age from the National Electronic Surveillance System-All Injury Program for 2001-2004. Sample weights provided by the National Electronic Surveillance System-All Injury Program were used to make national estimates. An estimated 1,314,000 injured infants were treated in US emergency departments for nonfatal unintentional injuries during the 4-year period of 2001-2004, approximately 1 infant every 1.5 minutes. Falls were the leading cause of nonfatal unintentional injuries for infants. Overall, the patients were more likely to be male (55.2%) than female (44.8%). Contusions/abrasions were the leading diagnosis overall (26.7%). Contusion/abrasion, laceration, hematoma, foreign-body, and puncture injuries occurred most frequently to the head or neck region. More than one third of fractures (37.2%) were to the arm or hand. Bed was the product most frequently noted as being involved in the injury event for every age except 2 and 12 months (car seat was the most frequently noted product at 2 months of age, and stairs were top ranked at 12 months). Product rank changed markedly as age increased. The influences of the social environment, the physical environment, and products change as infants mature in the first year of life; this was substantiated in our study by the shift in the relative importance of products involved in injuries according to month of age. The concept that aspects of safety must adapt in anticipation of developmental stage is critical.


Long-term relationships between perceived social support and posttraumatic stress after the 2011 Oslo bombing: A three-year longitudinal study.
After traumatic events, social support and posttraumatic stress are interrelated, but little is known about the underlying dynamics behind this association. Levels of social support and posttraumatic stress may change and affect each other over time, but there are also stable time-invariant individual differences in both constructs. The present study aimed to determine the amount of variance explained by stable individual differences in levels of social support and posttraumatic stress across three years, and to determine whether and to what extent social support and posttraumatic stress may affect one another when these stable individual differences are controlled for. We used data from ministerial employees present in the Governmental district during the 2011 Oslo bombing attack (N=255). Data was collected ten months, two years, and three years after the terror attack. Using a random intercept cross lagged panel model (RI-CLPM), we tested the possible directional effects between social support and posttraumatic stress within persons when variance between persons was taken into account. The intraclass correlations of the three measures of posttraumatic stress and social support were.83 and.74, respectively. The remaining variation within persons could not be explained by change in either of these constructs. We have no information on the processes that might have occurred before 10 months after the incident. Our findings indicate that the long-term longitudinal linkage between social support and posttraumatic stress may be best explained by stable individual differences rather than causal processes operating within persons.


Symptomatic spinal cord deformity secondary to a redundant intramedullary shunt catheter. Clinical and radiographic features.
Right arm pain, motor and sensory loss in the right arm and right facial numbness recurred in a 27 year old quadraplegic shortly after a posttraumatic spinal cord cyst (PTSCC) was shunted via a catheter into the adjacent subarachnoid space. Although shunt malfunction was clinically suspected, metrizamide computed tomography (MCT) suggested that redundancy of the catheter had caused deformity of the spinal cord. This hypothesis was confirmed at surgery when intraoperative spinal sonography (IOSS) showed that the spinal cord deformity at C1-C2 disappeared when the catheter was withdrawn. This case shows that new or recurrent spinal cord symptoms may be due to a mechanical deformity of the cord rather than shunt malfunction, that restricting the length of the shunt catheter which is used to decompress PTSCCs is important, and that IOSS is an indispensable tool for visualizing the changes in spinal cord morphology during shunting procedures.


Treatment of hepatitis C in special populations.
Treatment options for hepatitis C virus (HCV) infection have improved significantly in recent years, however, treatment recommendations came from large clinical trials of highly selected patient populations. HCV infection has increased prevalence in African Americans and also in patients who have HIV infection, end-stage renal disease, and hemophilia. This article reviews recent findings from research in these patient groups and examines future directions and treatment trials.


High Percentage of IBD Patients with Indefinite Fecal Calprotectin Levels: Additional Value of a Combination Score.
Monitoring mucosal inflammation in inflammatory bowel disease (IBD) is of major importance to prevent complications and improve long-term disease outcome. The correlation of clinical activity indices with endoscopic disease activity is, however, moderate. Fecal calprotectin (FC) is a better predictor of mucosal inflammation, but values between 100 and 250 µg/g are difficult to interpret in clinical practice. We aimed to evaluate the occurrence of indefinite FC levels in a real-life IBD cohort and study the additional value of a combination of biochemical markers and clinical activity indices. In total, 148 Crohn's disease (CD) and 80 ulcerative colitis (UC) patients visiting the outpatient clinic were enrolled. FC, clinical disease activity scored by the Harvey-Bradshaw index or Simple Clinical Colitis Activity Index, and C-reactive protein (CRP) were assessed. In a subset of patients, endoscopic activity was scored by the simple endoscopic score-Crohn's disease and Mayo endoscopic subscore. Clinical activity index, CRP, and FC were integrated in a combination score and compared with endoscopy. Indefinite FC values were present in 24% of CD and 15% of UC. In the cohort of patients with endoscopy scores available, the combination score predicted endoscopic disease activity in CD with a sensitivity of 83% and specificity of 69% [positive predictive value (PPV) 58%, negative predictive value (NPV) 89%]. In UC, this was 88 and 75% (PPV 93%, NPV 60%). A combination of FC with clinical activity indices or CRP may aid in classifying patients with indefinite disease activity according to FC alone.


Raphanusanin-induced genes and the characterization of RsCSN3, a raphanusanin-induced gene in etiolated radish hypocotyls.
Raphanusanin is a light-induced growth inhibitor involved in inhibition of hypocotyl growth in response to unilateral blue light illumination in radish seedlings. To understand better the role of raphanusanin in growth inhibition, we randomly analyzed raphanusanin-induced genes using a modified DD-RT-PCR (differential display RT-PCR) approach. The differential expression RT-PCR approach resulted in identification of four known candidate genes, of which three encoded functional proteins known to be related to responsiveness to diverse environmental stimuli. One of these genes appeared to be an essential element in the inhibition of hypocotyl growth, and was named RsCSN3 (a homologue of subunit 3 of the COP9 signalosome). During the growth inhibition that was observed within minutes of irradiation, the expression of the RsCSN3 gene was increased by phototropic stimulation, as well as by raphanusanin treatment, suggesting that this gene is involved in light-induced growth inhibition. In addition, down-regulation of the RsCSN3 transcript, that is specifically expressed at 60 min after the onset of stimulation under blue light, green light, and raphanusanin treatment, shows a functional correlation with the phototropic response.


A new combined high-frequency ultrasound-impedance planimetry measuring system for the quantification of organ wall biomechanics in vivo.
The aim was to develop a method for the quantification of the stress-strain distribution of tubular organs in vivo using the porcine duodenum as an experimental model. We placed four electrodes for impedance planimetry and a 20 MHz ultrasound transducer inside an inflatable balloon mounted on a 6 mm-diameter probe for intraluminal use. By means of the ultrasound transducer and the impedance planimetric system, we measured the wall thickness and luminal cross-sectional area of the duodenum. We calculated the luminal radius on the basis of the latter. We validated ultrasonic measurements of wall thicknesses by comparing the former to microscopic measurements of the wall thickness of unstrained duodenal specimens in vitro. Also, we tested whether the magnitude of the applied balloon pressure affected ultrasonic measurements in vitro. The luminal and the outer radius increased non-linearly by a factor of three, rising steeply at low balloon pressures, moderately at higher pressures. The wall thickness decreased as an almost linear function of the applied balloon pressure, resulting in a 50% decrease. The stress-strain distribution calculated on the basis of the balloon pressures, the wall thicknesses and the luminal radii were non-linear. The wall reached a maximum circumferential strain of 1.71 at 6 kPa, corresponding to a stress of 64.8 kPa. Our system enabled us to quantify the stress-strain distribution of the porcine duodenum in vivo, and it may become a valuable tool for future biomechanical investigations of tubular organs in health and disease.


Melatonin down-regulates hTERT expression induced by either natural estrogens (17beta-estradiol) or metalloestrogens (cadmium) in MCF-7 human breast cancer cells.
The goal was to evaluate whether melatonin (Mel) down-regulates hTERT expression induced by 17beta-estradiol (E(2)) or cadmium (Cd) in breast cancer cells. We found that: (a) Mel inhibits E(2) or Cd-induced hTERT transcription in hTERT-Luc transfected MCF-7 cells, (b) Mel significantly reduces E(2)- and Cd-mediated hTERT transactivation triggered by ERalpha in transfected HeLa cells, (c) Mel inhibits hTERT expression induced by E(2) or Cd in MCF-7 cells. Melatonin inhibition of telomerase activity supports a possible role in treatment of estrogen-dependent tumors or carcinogenesis by environmental or occupational exposure to xenoestrogens.


Optimization of autologous stem cell transplantation for systemic sclerosis -- a single-center longterm experience in 26 patients with severe organ manifestations.
Autologous stem cell transplantation (aSCT) for systemic sclerosis (SSc) has been shown to be effective in recent reports. This aggressive approach and the disease itself are associated with a high mortality. We report our experiences in 26 consecutive patients. Between 1997 and 2009, 26 patients were scheduled for aSCT. Our standard transplant regimen consists of cyclophosphamide (CYC) and granulocyte colony-stimulating factor (GCSF) for mobilization and CYC plus antithymocyte globulin for conditioning before the retransfusion of CD34 selected stem cells. The major outcome variable was the response to treatment [reduction of modified Rodnan skin score (mRSS) by 25%] at Month 6. Secondary endpoints were the transplant-related mortality and the progression-free survival. Significant skin and lung function improvement of the mRSS was achieved in 78.3% of patients at Month 6. The overall response rate was 91%, as some patients improved even after Month 6. Three patients died between mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was considered treatment-related (i.e., GCSF or CYC toxicity). Depending on definitions, transplant-related mortality was 4% and treatment-related mortality 11%. Seven patients experienced a relapse during the 4.4 years of followup. The progression-free survival was 74%. Four patients died during followup and the most frequent causes of death were pulmonary and cardiac complications of SSc. aSCT led to significant improvement in most patients with SSc. The procedure requires further optimization; hence we are modifying our screening and treatment strategy. To minimize infectious complications, CYC for mobilization and GCSF were reduced. We intensified our screening for cardiac involvement and modified our conditioning regimen in case of cardiac involvement.


An injectable and active hydrogel induces mutually enhanced mild magnetic hyperthermia and ferroptosis.
Magnetic hyperthermia therapy (MHT) is a promising new modality to deal with solid tumors, yet the low magnetic-heat conversion efficacy, magnetic resonance imaging (MRI) artifacts, easy leakage of magnetic nanoparticles, and thermal resistance are the main obstacles to expand its clinical applications. Herein, a synergistic strategy based on a novel injectable magnetic and ferroptotic hydrogel is proposed to overcome these bottlenecks and boost the antitumor efficacy of MHT. The injectable hydrogel (AAGel) exhibiting a sol-gel transition upon heating is made of arachidonic acid (AA)-modified amphiphilic copolymers. Ferrimagnetic Zn0.4Fe2.6O4 nanocubes with high-efficiency hysteresis loss mechanism are synthesized and co-loaded into AAGel with RSL3, a potent ferroptotic inducer. This system maintains the temperature-responsive sol-gel transition, and provides the capacity of multiple MHT and achieves accurate heating after a single injection owing to the firm anchoring and uniform dispersion of nanocubes in the gel matrix. The high magnetic-heat conversion efficacy of nanocubes coupled with the application of echo limiting effect avoids the MRI artifacts during MHT. Besides the function of magnetic heating, Zn0.4Fe2.6O4 nanocubes combined with multiple MHT can sustain supply of redox-active iron to generate reactive oxygen species and lipid peroxides and accelerate the release of RLS3 from AAGel, thus enhancing the antitumor efficacy of ferroptosis. In turn, the reinforced ferroptosis can alleviate the MHT-triggered thermal resistance of tumors by impairment of the protective heat shock protein 70. The synergy strategy achieves the complete elimination of CT-26 tumors in mice without causing local tumor recurrence and other severe side effects.


Malignant pleural and pericardial effusion in invasive breast cancer: impact of the site of the primary tumor.
Malignant effusion in invasive breast cancer, either pleural or pericardial, is associated with a poor survival rate. We investigated the role of the location of invasive breast cancer in developing malignant pleural or pericardial effusion. Three thousand eight hundred and fifty six women with a history of invasive breast cancer between 1960 and 1994 were analyzed in a retrospective study. Two hundred and six patients (5.34%; group A) developed malignant pleural and/or pericardial fluid as the first visible clinical sign of distant metastasis. A control group of 206 patients (group B) without malignant effusions were matched in terms of clinical and pathological characteristics. The two groups were compared in respect of the location of the primary tumor. Fifty patients in group A (n = 50; 24.2%) had tumors in the inner quadrants, 83 patients (n = 83; 40.3%) in the outer quadrants, and 13 patients (n = 13; 6.3%) in a central location. No data were available for 60 patients (n = 60; 29.1%). In group B, 12 patients (n = 12; 5.9%) had tumors in the inner quadrants, 140 patients (n = 140; 68.0%) in the outer quadrants, 14 patients (n = 14; 6.8%) had centrally located tumors, while no data were available for 40 patients (n = 40; 19.4%). Invasive ductal carcinomas (IDC) located in the inner quadrants were highly significantly associated with increased pleural or pericardial effusion as the first site of distant metastasis (p <or= 0.0001; chi-square tests). IDC in the inner quadrants were associated with a 4-fold higher rate of malignant pleural or pericardial effusions. Further studies will have to determine whether tumor location is a criterion for more aggressive adjuvant therapy.


Anti-lipopolysaccharide activity of histatins, peptides from human saliva.
Histatins are histidine-rich polypeptides secreted in human saliva. They were found to inhibit lipopolysaccharide (LPS)-mediated gelation of Limulus amoebocyte lysate, and to reverse the anti-complement action of LPS or lipid A. Histatins also gave precipitate bands in agarose gels with various LPS. The results indicate that histatins neutralized the activity of LPS by binding to the lipid A moiety of LPS.


The Use of Ultrasound Simulators to Strengthen Scanning Skills in Medical Students: A Randomized Controlled Trial.
This study evaluates the use of ultrasound simulators for retaining and improving ultrasound skills acquired in undergraduate ultrasound training. Fourth-year medical students (n = 19) with prior training in point-of-care sonography for shock assessment were recruited for this study. Students were randomly assigned to a study group (n = 10) that followed an undergraduate ultrasound training curriculum, then used a simulator to complete 2 self-directed practice ultrasound sessions over 4 weeks. The control group (n = 9) followed the same undergraduate ultrasound training curriculum and received no additional access to a simulator or ultrasound training. A blinded assessment of the students was performed before and after the 4-week study period to evaluate their image acquisition skills on standardized patients (practical examination). To evaluate the student's clinical understanding of pathological ultrasound images, students watched short videos of prerecorded ultrasound scans and were asked to complete a 22-point questionnaire to identify their findings (visual examination). All results were adjusted to pretest performance. The students in the study group performed better than those in the control group on the visual examination (80.1% versus 58.9%; P = .003) and on the practical examination (77.7% versus 57.0%; P = .105) after the 4-week study period. The score difference on the postintervention practical examinations was significantly better for the study group compared to the control group (11.6% versus -9.9%; P = .0007). The use of ultrasound simulators may be a useful tool to help previously trained medical students retain and improve point-of-care ultrasound skills and knowledge.


Pars plana vitrectomy combined with phacoemulsification versus pars plana vitrectomy only for treatment of phakic rhegmatogenous retinal detachment: a systematic review and meta-analysis.
To compare the visual, refractive, and anatomical outcomes and incidence of complications between combined pars plana vitrectomy and phacoemulsification (phacovitrectomy) versus pars plana vitrectomy (PPV-only) in phakic eyes with rhegmatogenous retinal detachment (RRD). Two independent reviewers searched MEDLINE, Cochrane Central, and Web of Science to identify relevant articles. Prospective or retrospective studies comparing PPV-only and phacovitrectomy for RRD were included. Recruited studies provided information about at least anatomical success or refractive outcomes. Meta-analysis was performed for single surgery success rate, final best-corrected visual acuity (BCVA), postoperative complications, mean predicted refractive error, and mean absolute predicted refractive error. Seven studies (788 eyes) were selected, including two clinical trials and five retrospective comparative case series. The single surgery success rate was similar in PPV-only and phacovitrectomy groups (risk ratio [RR] = 1.02; 95% confidence interval [CI] 0.95-1.10; P = 0.57). Mean final BCVA was significantly better in the PPV-only group than the phacovitrectomy group (MD = 0.06; 95% CI 0.00-0.12; P = 0.04). The risk of epiretinal membrane formation was significantly higher in eyes that underwent phacovitrectomy than PPV-only (RR = 2.85; 0.95% CI 1.5-5.41; P = 0.001). Phacovitrectomy group showed a more myopic final mean predicted refractive error than PPV-only group (MD = -0.31; 95% CI -0.55--0.07; P = 0.01). There was no significant difference between the two groups regarding the anatomical outcome. Slightly better visual and refractive results were observed in the PPV-only group. However, the results should be interpreted with caution as the majority of included studies were low-quality retrospective studies.


Requirement of multiple lysine residues for the transcriptional activity and the instability of Hes7.
The basic helix-loop-helix (bHLH) gene Hes7 is expressed in an oscillatory manner and regulates the periodic somite formation. Oscillatory expression of Hes7 depends on negative feedback and rapid degradation of the gene products, but the precise mechanisms of how the transcriptional activity and the degradation of Hes7 protein are regulated remain to be analyzed. Here, we found that lysine residues (K22, K52, and K55) in the bHLH domain are essential not only for the instability of Hes7 protein but also for the transcriptional repressor activity. Introduction of lysine-to-arginine mutations into the bHLH domain led to stabilization of Hes7 protein and to abnormalities in either the N box-binding activity or partner preference in heterodimer formation. These results indicate that common amino acid residues are involved in both the transcriptional repressor activity and the instability of Hes7 protein, suggesting of a critical link between the transcription and degradation control.


Validation of the UDI-6 and the ICIQ-UI SF - Croatian version.
Despite the widespread use of UDI-6 and ICIQ-UI SF in Croatia, it remains unknown whether a realiable and valid measure for the population of interest is used. Thus, the aim of this study was to translate, adapt and validate the UDI-6 and the ICIQ-UI SF in Croatia. The study included a total of 232 consecutive patients with urinary incontinence symptoms. The translation to Croatian followed standardized procedure. All participants underwent urodynamic assesment and completed UDI-6 and ICIQ-UI SF questionnaires at inclusion and 2 weeks after to assess test-retest reliability. Cronbach α coefficient was calculated in order to assess internal consistency. Both questionnaires had high internal consistency (Cronbach α for UDI-6 and ICIQ-UI SF was .83 and .85, respectively) and high test-retest reliability (intraclass correlation coefficient .99 for instruments). Strong correlation was found between urodynamic findings and total scores in UDI-6 and ICIQ-UI SF (ρ = 0.88 and 0.89, respectively). Women with stress urinary incontinence (SUI) and detrusor overactivity (DOA) group had significantly higher scores on UDI-6 (Mdn = 33.33 and Mdn = 50, respectively) compared to women with no urodynamic abnormality (Mdn = 0; p < 0.001). Women with no urodynamic abnormality scored significantly lower on ICIQ-UI SF (Mdn = 0; p < 0.001) compared to women with SUI (Mdn = 14) and DOA (Mdn = 16). Women with DOA scored worse on Irritative and Obstructive symptoms when comparing with two other groups (p < 0.001), while women with SUI had significantly worse score on Stress symptoms subscale (p < 0.001). The UDI-6 and ICIQ-UI SF have very good psychometric characteristics and can be used in Croatian urogynecology practice.


Heterogeneity of purified mouse interferons.
A procedure for obtaining highly purified stable interferon from mouse L cells is described. Interferon with a specific activity of 2.5 times 10-8 reference units/mg of protein is composed of 10 to 11 polypeptides. They differ in their molecular size as determined by electrophoresis on polyacrylamide gels containing sodium dodecyl sulfate. The molecular weight range is estimated to be from the smallest at 20, 000 to the largest at 32, 000. At least six of the polypeptides are glycoproteins and each of the polypeptides can be obtained as an apparent homogeneous entity and each has interferon activity.


Insights into Cytochrome P450 Enzyme Catalyzed Defluorination of Aromatic Fluorides.
Density functional calculations establish a novel mechanism of aromatic defluorination by P450 Compound I. This is achieved via either an initial epoxide intermediate or through a 1,2-fluorine shift in an electrophilic intermediate, which highlights that the P450s can defluorinate fluoroarenes. However, in the absence of a proton donor a strong Fe-F bond can be obtained as shown from the calculations.


[Reconstruction of transfixing loss of substance from the wing of the nose by composite graft of the controlateral nostril: about three cases].
Reconstruction of the loss of transfixing substance from the nose wing is one of the most difficult procedures in facial plastic surgery. We propose a new technique consisting of a composite graft of the controlateral nostril among patients having an asymmetry of the nostrils. A clinical study was carried out on three patients who had undergone a composite nasal graft. The graft was harvested from the nostril controlateral to the nasal defect then placed at the level of the previously prepared affected nostril. Three patients aged 27, 37 and 39years respectively received a controlateral nasal composite graft for the treatment of transfixing substance loss of the nose wing of less than 1cm. In all three cases, the result was judged to be very satisfactory by the surgeon and by all the patients. The controlateral nasal composite graft is a straightforward, quick and reliable technique to treat small losses of transfixing substance from the nose wing. However, because of an uncertain cicatricial ransom of the donor site, this technique must be compared to the auricular composite graft that is the technique of reference.


Complete mitogenome data from a European specimen of Ostrinia scapulalis (Walker, 1859) (Lepidoptera, Pyraloidea, Crambidae, Pyraustinae).
We present an assembly and annotation of the mitogenome of a European specimen of the Adzuki bean borer, Ostrinia scapulalis (Walker, 1859). The data were obtained by combining WGS data issue of a de novo and a previously published sequence library (Gschloessl et al., 2018). We also provide the phylogenetic positioning of the mitogenome within the Ostrinia genus, the Crambidae family and with more distant Lepidoptera species.


Transcripts homologous to a long repeated DNA element in the human genome.
Using three cloned DNA fragments from a 6.4-kb (kilobase pair) DNA element repeated several thousand times in the human genome (Adams, J. W., Kaufman, R. E., Kretschmer, P. J., Harrison, M. and Nienhuis, A. W. (1980) Nucleic Acids Res. 8, 6113-6128) and DNA/RNA hybridization, we show that transcripts homologous to this DNA family exist in total cellular RNA from human blood cells and from a mouse-human hybrid cell line with one human chromosome, the X. No such transcripts were detected in RNA from rabbit blood or a mouse cell line. For each DNA fragment studied, we found that blood transcripts and X-chromosome transcripts were indistinguishable in electrophoretic mobility and very heterogeneous in length; in addition, prominent hybridization bands were seen at 4.7 and 1.9 kb. Transcription from this DNA family likely occurs from heterogeneous templates. The existence of RNAs smaller than 6.4 kb suggests that part of the repeat unit can be transcribed and/or there exists a cellular mechanism to make these short RNAs from longer precursors. The vast majority of the RNAs homologous to the long repeat are not polyadenylated. In blood RNA there are a few hundred copies of beta-globin mRNA for every transcript homologous to this 6.4 kb repeat.


A study on antisperm antibody in homosexual men.
Using a hemagglutination assay we surveyed antibody distribution to human sperm antigen in a sexually transmitted disease (STD) clinic population and in an AIDS study group. We found no significant difference for the mean antisperm antibody titres between sexually active heterosexual men, women or homosexual men, homosexual men with or without AIDS, and no correlation between T4/T8 lymphocyte ratios and antibody titres in homosexual men. We conclude that levels of antibody to sperm antigens are not significantly greater in homosexual men and antisperm antibody levels do not correlate with the diagnosis of AIDS.


Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy.
We describe a novel type of ribosomopathy that is defined by deficiency in diphthamidylation of translation elongation factor 2. The ribosomopathy was identified by correlating phenotypes and biochemical properties of previously described patients with diphthamide biosynthesis gene 1 (DPH1) deficiencies with a new patient that carried inactivating mutations in both alleles of the human diphthamide biosynthesis gene 2 (DPH2). The human DPH1 syndrome is an autosomal recessive disorder associated with developmental delay, abnormal head circumference (microcephaly or macrocephaly), short stature, and congenital heart disease. It is defined by variants with reduced functionality of the DPH1 gene observed so far predominantly in consanguineous homozygous patients carrying identical mutant alleles of DPH1. Here we report a child with a very similar phenotype carrying biallelic variants of the human DPH2. The gene products DPH1 and DPH2 are components of a heterodimeric enzyme complex that mediates the first step of the posttranslational diphthamide modification on the nonredundant eukaryotic translation elongation factor 2 (eEF2). Diphthamide deficiency was shown to reduce the accuracy of ribosomal protein biosynthesis. Both DPH2 variants described here severely impair diphthamide biosynthesis as demonstrated in human and yeast cells. This is the first report of a patient carrying compound heterozygous DPH2 loss-of-function variants with a DPH1 syndrome-like phenotype and implicates diphthamide deficiency as the root cause of this patient's clinical phenotype as well as of DPH1-syndrome. These findings define "diphthamide-deficiency syndrome" as a special ribosomopathy due to reduced functionality of components of the cellular machinery for eEF2-diphthamide synthesis.


Synergetic effect of gamma irradiation and moisture content on decontamination of sewage sludge.
Samples of concentrated municipal sewage sludge, stored for 2, 4 and 6 months, with moisture contents of 2%, 20%, 40%, 60%, and 80% were exposed to doses of 0, 1, 2, 3, 4 and 5 kilogray (kGy) of gamma irradiation. Immediately after irradiation, total microbial count and bacterial pathogens in sewage sludge were determined. The results indicated that in all tested sewage sludge samples, bacterial pathogens including Enterobacter sp., Klebsiella sp., Salmonella sp., and Escherichia coli were initially detected. All doses of gamma irradiation reduced the total counts of microorganisms. D(10) of total count decreased with increase in the moisture content of the sewage sludge. The lowest lethal dose for tested bacterial pathogens was 5 kGy in air dried sewage sludge. In addition for wet sewage sludge having more than 40% moisture, the lethal dose was 1 kGy, for samples taken at different storage periods 2, 4 and 6 months, and therefore the cost per unit could be decreased to half when wet sewage sludge (about 50% moisture) was used.


Knowledge mapping of early-onset colorectal cancer from 2000 to 2022: A bibliometric analysis.
The incidence of early-onset colorectal cancer (EO-CRC), diagnosed in patients younger than 50 years, has increased in incidence alarmingly over the past few decades, while overall incidence and mortality of colorectal cancer are stabilizing or declining in many high-income countries. These unfavorable changes have raised significant concerns and led to extensive research, resulting in a surge in studies on EO-CRC. Our aim was to obtain a more comprehensive understanding of the current state of this field and to identify prospective research directions by performing a bibliometric analysis of EO-CRC. A total of 1952 papers on EO-CRC published from 2000 to 2022 were identified after a thorough search of the Web of Science Core Collection. The United States dominated this field, with Harvard University contributing the greatest number of papers, while the journal Familial Cancer (n = 52) published the most articles. Cooperation network analysis revealed close internal cooperation among countries, institutions and authors. Based on reference and keyword analysis, high-frequency keywords showed several popular research directions, including epidemiology (incidence, young patients, age of onset, etc.), risk factors (obesity, family history, lynch syndrome, etc.) and molecular characterization (germline mutation, genome wide association, MLH1, etc.). Overall, our research provides an overview of the current status in this field, which we hope will give researchers a comprehensive perspective on the present trends within this domain.


Role of central beta-adrenergic receptors in regulating proinflammatory cytokine responses to a peripheral bacterial challenge.
Elevation of proinflammatory cytokines in the brain have potent effects on altering physiological, behavioral, and cognitive processes. The mechanism(s) by which brain cytokines are induced during a peripheral immune challenge remains unclear since microorganisms/cytokines do not cross the blood-brain barrier (BBB). Recent studies indicate that central beta-adrenergic receptors (beta-ADRs) may mediate brain interleukin-1beta (IL-1) production. This has direct implications for the production of brain cytokines during a peripheral immune response since peripheral pathogens and cytokines rapidly stimulate brainstem catecholamine neurons via peripheral nerves and circumventricular pathways. Studies here examine the role of central beta-ADRs in regulating brain cytokine production following peripheral Escherichia coli (E. coli) challenge. Rats were centrally administered propranolol (beta-ADR antagonist) or vehicle followed by peripheral E. coli or saline and sacrificed 6h later for measurement of cytokines. Pre-treatment with propranolol completely blocked the induction of brain IL-1 following E. coli. Surprisingly, central propranolol also attenuated E. coli-induced peripheral cytokines. To examine whether the attenuated peripheral cytokine response following central propranolol administration was due leakage of propranolol into the general circulation and blockade of peripheral beta-blockade, nadolol (beta-ADR antagonist that does not cross the BBB) was administered peripherally prior to E. coli. Nadolol administration did not block central cytokine production following E. coli, but instead enhanced both peripheral and central proinflammatory cytokine production. Furthermore, central administration of isoproterenol (beta-ADR agonist) results in a time-dependent increase in brain IL-1 production. These data demonstrate central beta-ADRs may play a critical role to induce brain IL-1, while peripheral beta-ADRs inhibit cytokine response to bacterial challenge.


A simplified method for power-law modelling of metabolic pathways from time-course data and steady-state flux profiles.
In order to improve understanding of metabolic systems there have been attempts to construct S-system models from time courses. Conventionally, non-linear curve-fitting algorithms have been used for modelling, because of the non-linear properties of parameter estimation from time series. However, the huge iterative calculations required have hindered the development of large-scale metabolic pathway models. To solve this problem we propose a novel method involving power-law modelling of metabolic pathways from the Jacobian of the targeted system and the steady-state flux profiles by linearization of S-systems. The results of two case studies modelling a straight and a branched pathway, respectively, showed that our method reduced the number of unknown parameters needing to be estimated. The time-courses simulated by conventional kinetic models and those described by our method behaved similarly under a wide range of perturbations of metabolite concentrations. The proposed method reduces calculation complexity and facilitates the construction of large-scale S-system models of metabolic pathways, realizing a practical application of reverse engineering of dynamic simulation models from the Jacobian of the targeted system and steady-state flux profiles.


Pharmacological and behavioral treatment of pediatric migraine and tension-type headache.
The problem concerning the treatment of pediatric headache has been the object of several recent reports. Some of the same medications used to treat adult headache problems are also utilized with children but usually at smaller dosages and in different combinations. The recent application of behavioral approaches, in particular biofeedback, for treatment of children's headaches has been an effective alternative to drugs without the problematic and dangerous side effects of pharmacological treatments. The purpose of this review is to give some indications about the most common pharmacological therapies for migraine and tension-type headache in children, and also to discuss the use of behavioral therapies, in particular biofeedback, as excellent alternatives to drugs.