Suppressed endothelin-1 production by FK506 and cyclosporin A in ischemia/reperfusion of rat small intestine.
Endothelin-1 (ET-1), a novel vasoconstrictor, possibly plays a role in the mediation of ischemia/reperfusion (I/R) injury. Tacrolimus (FK506) and cyclosporin A (CsA) were reported to maintain tissue microcirculation of the liver subjected to I/R. This study investigated the effects of these immunosuppressants on intestinal I/R in terms of intestinal tissue microcirculation associated with ET-1. Male S-D rats were pretreated twice with FK506 (0.2 mg/kg), CsA (10 mg/kg) or only saline solution (0.5 mL). The tissue microcirculation in the control was reduced after I/R (29% +/- 10%) accompanied by hypotension, increased tissue ET-1 expression (25.0% +/- 6.4% to 67.9% +/- 5.0% 60 minutes after reperfusion), and increased ET-1 level in the portal blood (3.4 +/- 0.9 to 23.6 +/- 6.1 pg/mL). FK506 suppressed ET-1 expression (27.3% +/- 5.2%, 4.1 +/- 2.2 pg/mL), maintained microcirculation (96% +/- 16%), and blood pressure, reduced histologic damage, and improved survival. CsA had a similar but weaker effect compared with FK506. An additional experiment was performed with BQ485Na (BQ), an ETA receptor antagonist, to evaluate the genuine role of ET-1. BQ showed almost the same effects as FK506. FK506 and CsA, particularly the former, maintain microcirculation and protect the tissue from I/R injury by suppressing the production and release of ET-1.


Validating duplex-PCR targeting ND2 for bovine and porcine detection in meat products.
Food authentication is a mandatory effort to assure the fair-trade. This study developed a duplex polymerase chain reaction (PCR) from the NADH dehydrogenase subunit 2 (ND2) gene to amplify specific segments of a cattle and porcine DNA. A universal forward primer composed of nineteen base pairs (bp) (3'-CCAAACACAACTCCGAAAA-5') and species-specific reverse primers composed of twenty (3'-CCAAACACAACTCCGAAAA-5') and twenty-one (3'-TGGCAAGAATTAGGACGGTTA-5') bp were used to limit the amplified DNA segment for porcine and cattle. The PCR reaction would generate a product with a profile of 168 and 227 bp, respectively. To investigate the accuracy and limit of detection, an in vitro experiment was conducted using simplex and duplex PCR on commercial meatballs randomly purchased from a commercial market in Surakarta, Indonesia. The findings of this study indicated that ND2 could be used as an alternative genetic marker for the identification of porcine and beef species in meat-derived products.


[Effect of euphylline and halidor on several indices of catecholamine and serotonin metabolism in the brains and blood of rats].
Euphylline and galidore did not alter the concentration of catecholamines and serotonin in brain of intact rats, but exhibited opposite effects on metabolism of biogenic amines, if their precursors were administered into animals. Galidore decreased the activity of catechol-O-methyl transferase (COMT) and 5-hydroxytryptophane decarboxylase. Euphylline did not influence the COMT activity but increased the activity of 5-HT-decarboxylase. Both preparations did not alter the monoaminooxidase activity.


A psycho-historical research program for the integrative science of art.
Critics of the target article objected to our account of art appreciators' sensitivity to art-historical contexts and functions, the relations among the modes of artistic appreciation, and the weaknesses of aesthetic science. To rebut these objections and justify our program, we argue that the current neglect of sensitivity to art-historical contexts persists as a result of a pervasive aesthetic–artistic confound; we further specify our claim that basic exposure and the design stance are necessary conditions of artistic understanding; and we explain why many experimental studies do not belong to a psycho-historical science of art.


Protein cysteine sulfinic acid reductase (sulfiredoxin) as a regulator of cell proliferation and drug response.
Sulfiredoxin (Srx) is one of a family of low molecular weight sulfur containing proteins linked with maintenance of cellular redox balance. One function of Srx is the reduction of cysteine sulfinic acid to sulfenic acid in proteins subject to oxidative stress. Other redox active protein families have multiple functions in regulating redox and controlling proliferation/death pathways; increased Srx has been linked with oncogenic transformation. To explore the biological functions of Srx in tumors, we established cell lines that overexpress Srx. Enhanced levels of Srx promoted cell proliferation and enhanced cell death following cisplatin. Srx overexpression triggered an alteration in expression and phosphorylation of cell cycle regulators p21, p27 and p53; stabilized the phosphatase PTEN and, importantly, interacted directly with, and enhanced the activity of, phosphatase PTP1B. In turn, this promoted Src kinase activity by dephosphorylating its inhibitory tyrosine residue (Y530). Srx expression was stimulated by cell exposure to certain growth factors. These data support a role for Srx in controlling the phosphorylation status of key regulatory kinases through effects upon phosphatase activity with an ultimate effect on pathways that influence cell proliferation.


Deterioration of health-related quality of life and fatigue in patients with chronic hepatitis C: Association with demographic factors, inflammatory activity, and degree of fibrosis.
Health-related quality of life (HRQoL) is impaired in patients with chronic hepatitis C. We investigated HRQoL and fatigue in patients with chronic hepatitis C virus (HCV) infection in relation to the degree of fibrosis and inflammation, and controlled for the influence of relevant demographic and medical variables. We conducted a cross-sectional two-center study including 215 outpatients with chronic hepatitis C applying the Short-Form Health Survey (SF-36) and the Fatigue Impact Scale (FIS-D). The contribution to the variability of these psychometric scores was evaluated for the degree of fibrosis as well as viremia, gender, age, mode of transmission, genotype, and ALT. There was a strong negative association between the degree of liver fibrosis and the physical SF-36 summary score (p=0.016). This was independent of the covariate age, also significantly predicting physical HRQoL (p=0.001). The absolute FIS score was significantly increased in patients with advanced fibrosis (p=0.043). In females, mental SF-36 summary score (p=0.007) and fatigue (p=0.017) were significantly more impaired. Our study suggests a significant association of physical aspects of HRQoL and fatigue with the extent of fibrosis. Fibrosis stage should be considered for the identification and management of HCV patients at risk for reduced physical HRQoL.


Management of atrial fibrillation in the emergency department.
Although atrial fibrillation remains the most common cardiac arrhythmia, the treatment and disposition remain varied. An accept-able standard of practice requires an evidence-based approach. This approach has revealed that half of the patients who present with acute atrial fibrillation will convert to sinus rhythm without intervention. In the hemodynamically stable subset, ascertaining the on-set of atrial fibrillation within 48 hours is critical because this period dictates when and if anticoagulation should be instituted and if and where electrical or chemical cardioversion needs be performed. The hemodynamically unstable patient, however, requires emergent cardioversion, irrespective of the chronicity of atrial fibrillation. An evidence-based approach may serve to optimize treatment and obviate the need for unnecessary hospital admissions.


Mistargeting of aggregation prone mitochondrial proteins activates a nucleus-mediated posttranscriptional quality control pathway in trypanosomes.
Mitochondrial protein import in the parasitic protozoan Trypanosoma brucei is mediated by the atypical outer membrane translocase, ATOM. It consists of seven subunits including ATOM69, the import receptor for hydrophobic proteins. Ablation of ATOM69, but not of any other subunit, triggers a unique quality control pathway resulting in the proteasomal degradation of non-imported mitochondrial proteins. The process requires a protein of unknown function, an E3 ubiquitin ligase and the ubiquitin-like protein (TbUbL1), which all are recruited to the mitochondrion upon ATOM69 depletion. TbUbL1 is a nuclear protein, a fraction of which is released to the cytosol upon triggering of the pathway. Nuclear release is essential as cytosolic TbUbL1 can bind mislocalised mitochondrial proteins and likely transfers them to the proteasome. Mitochondrial quality control has previously been studied in yeast and metazoans. Finding such a pathway in the highly diverged trypanosomes suggests such pathways are an obligate feature of all eukaryotes.


Utility of the intraflap perfusion procedure for abdominal free flap in unilateral breast reconstruction.
Heparin prophylaxis for venous thromboembolism can be used in microsurgery. If vein anastomosis is performed before the artery, heparin irrigation into the artery can be performed locally without systematic effect. This study aimed to introduce this "intraflap perfusion procedure" in autologous breast reconstruction. Among the 220 patients with unilateral breast cancer who had received the free abdominal flap, we retrospectively compared those that had undergone the intraflap perfusion procedure (n = 108) and those who did not (n = 112). A 10 mL injection of heparinized physiological saline solution (100 units/mL) was administered into the deep inferior epigastric artery. Intraflap perfusion was performed before, during, and after vein anastomosis, without the vessel clip of the vein. Artery anastomosis was performed without the use of a vein clamp. Further, vein anastomosis was performed tightly to prevent leakage from the vein anastomosis site during artery anastomosis. The rates of superficial inferior epigastric vein (SIEV) superdrainage (18.5% vs. 42.0%, P < 0.001), and intraoperative flap congestion (0.9% vs. 8.0%, P = 0.01) were significantly lower in patients undergoing this procedure. There were no significant differences regarding other factors (age, BMI, laterality, comorbidities, and other operative details). Intraflap perfusion prevented long-term stasis at the venous anastomosis site and capillary level. It could reduce flap congestion. SIEV superdrainage was performed to manage flap congestion, particularly in patients who did not undergo this procedure. Consequently, it can be inferred that this procedure reduces the rate of superdrainage.


Secondary cutaneous Epstein-Barr virus-associated diffuse large B-cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma: a case report and review of literature.
Only a few cases of extranodal Epstein-Barr virus (EBV)-associated B-cell lymphomas arising from patients with angioimmunoblastic T-cell lymphoma (AITL) have been described. We report a case of AITL of which secondary cutaneous EBV-associated diffuse large B-cell lymphoma (DLBCL) developed after the initial diagnosis of AITL. A 65-year-old Chinese male patient was diagnosed as AITL based on typical histological and immunohistochemical characteristics in biopsy of the enlarged right inguinal lymph nodes. The patient initially received 6 cycles of chemotherapy with CHOP regimen (cyclophosphamide, vincristine, adriamycin, prednisone), but his symptoms did not disappear. Nineteen months after initial diagnosis of AITL, the patient was hospitalized again because of multiple plaques and nodules on the skin. The skin biopsy was performed, but this time the tumor was composed of large, polymorphous population of lymphocytes with CD20 and CD79a positive on immunohistochemical staining. The tumor cells were strong positive for EBER by in situ hybridization. The findings of skin biopsy were compatible with EBV-associated DLBCL. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) was then administered, resulting in partial response of the disease with pancytopenia and suppression of cellular immunity. To our knowledge, this is the first case of cutaneous EBV-associated DLBCL originated from AITL in Chinese pepole. We suggest the patients with AITL should perform lymph node and skin biopsies regularly in the course of the disease to detect the progression of secondary lymphomas.


Physalin B from Physalis angulata triggers the NOXA-related apoptosis pathway of human melanoma A375 cells.
Melanoma is a lethal form of skin cancer that can metastasize rapidly. While surgery and radiation therapy provide palliative therapy for local tumor growth, systemic therapy is the mainstay of treatment for metastatic melanoma. However, limited chemotherapeutic agents are available for melanoma treatment. In this study, we investigated the anti-melanoma effect of physalin B, the major active compound from a widely used herb medicine, Physalis angulata L. This study demonstrated that physalin B exhibits cytotoxicity towards v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma A375 and A2058 cells (the IC50 values are lower than 4.6 μg/ml). Cytotoxicity is likely resulted from apoptosis since the apoptotic marker phosphatidylserine are detected immediately under physalin B treatment and apoptotic cells formation. Further examination revealed that physalin B induces expression of the proapoptotic protein NOXA within 2 h and later triggers the expression of Bax and caspase-3 in A375 cells. These results indicate that physalin B can induce apoptosis of melanoma cancer cells via the NOXA, caspase-3, and mitochondria-mediated pathways, but not of human skin fibroblast cells and myoblastic cells. Thus, physalin B has the potential to be developed as an effective chemotherapeutic lead compound for the treatment of malignant melanoma.


Metformin and AICAR regulate NANOG expression via the JNK pathway in HepG2 cells independently of AMPK.
NANOG, a marker of stemness, impacts tumor progression and therapeutic resistance in cancer cells. In human hepatocellular carcinoma (HCC), upregulation of NANOG is associated with metastasis and a low survival rate, while its downregulation results in a lower colony formation rate and enhanced chemosensitivity. Metformin, an agent widely used for diabetes treatment, and AICAR, another AMP-activated protein kinase (AMPK) activator, have been reported to inhibit the growth of several types of cancer. Although inhibitory effects of metformin on NANOG in pancreatic cancer cells and of AICAR in mouse embryonic stem cells have been described, the underlying molecular mechanisms remain uncertain in HCC. In this study, we used the HepG2 cell line and found that metformin/AICAR downregulated NANOG expression with decreased cell viability and enhanced chemosensitivity to 5-fluorouracil (5-FU). Moreover, metformin/AICAR inhibited c-Jun N-terminal kinase (JNK) activity, and blockade of either the JNK MAPK pathway or knockdown of JNK1 gene expression reduced NANOG levels. The upregulation of NANOG and phospho-JNK by basic fibroblast growth factor (bFGF) was abrogated by metformin/AICAR. Additionally, although transient upregulation of NANOG within 2 h of treatment with metformin/AICAR was concordant with both JNK and AMPK activation, increased NANOG expression with activation of JNK was also observed following AMPK inhibition with compound C. Taken together, our data suggest that metformin/AICAR regulate NANOG expression via the JNK MAPK pathway in HepG2 cells independently of AMPK, and that this JNK/NANOG signaling pathway may offer new therapeutic strategies for the treatment of HCC.


The human RD protein is closely related to nuclear RNA-binding proteins and has been highly conserved.
We have isolated cDNA clones encoding the human RD protein, which is closely related to several known nuclear RNA-binding proteins. The RD protein contains a 60-amino acid (aa) tract consisting almost entirely of alternating basic and acidic aa, (RD)n, primarily arginine (Arg; R) and aspartic acid (Asp; D). The protein also contains an 'RNP sequence domain'. Arg-rich tracts and the RNP sequence domain are both features of nuclear RNA-binding proteins. However, we have been unable to detect RNA-binding by the human RD protein. The very strong evolutionary conservation of the mammalian RD protein aa sequence suggests that it plays an important role in the cell.


Isolation of neuronal plasma membranes from the crayfish Procamburus clarkii, with an aqueous two phase polymer system followed by sucrose density gradient centrifugation.
An aqueous two phase polymer system (Dextran-polyethyleneglycol system was developed for isolation of plasma membrane fraction from nerves of the crayfish, Procamburus clarkii. The polymer system effectively reduced both mitochondrial and endoplasmic reticulum marker enzyme activity from a crude membrane fraction. The similar enrichment of (Na+ + K+)-ATPase (ATP phosphohydrolase, EC 22.214.171.124) was shown by the polymer system as well as by the sucrose density gradient centrifugation. The purified plasma membrane fraction (PM) was obtained using the polymer system followed by sucrose density gradient centrifugation. The PM fraction had a high specific activity of (Na + K+)-ATPase of up to 17 times that in the homogenate, with smaller contamination by mitochondria and endoplasmic reticulum enzyme activities than any other membrane fraction. Electron micrographs of the PM fraction also supported the above evidences. The protein recovered from the PM fraction amounted to 1.1% of the total protein in the homogenate. The specific activity of acetylcholinesterase (acetylcholine hydrolase, EC 188.8.131.52) in the membrane fractions was less increased than that of (Na+ + K+)-ATPase. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis suggested that polypeptide chains of estimated molecular weight 115,000 and 31,000 were enriched in the plasma membranes of the crayfish nerves.


SPONTANEOUS CLOSURE OF MYOPIC MACULAR HOLE TWICE WITHOUT POSTERIOR VITREOUS DETACHMENT.
To present a case of a myopic macular hole that spontaneously closed twice in the presence of a broadly adherent posterior hyaloid membrane. Case report. A 49-year-old man with high myopia and pseudophakia had a full-thickness macular hole in the left eye. The hole spontaneously closed in all retinal layers before the elective surgery, but the macular hole recurred one month later. The hole started sealing again spontaneously after one month, leaving a defect in the outer retinal layers. Four months later, the outer layer defect sealed and a lamellar macular hole developed. Throughout the course, the posterior hyaloid membrane remained parallel to the macular surface. The macular morphology and the patient's vision remained stationary at the 2-year follow-up. This case demonstrated that myopic macular holes can form and seal repeatedly with a broadly adherent posterior hyaloid membrane. Although bridging phenomenon was the common sign indicating the initiation of the two hole closures, different patterns of tissue regeneration ensued.


Contraception.
Contraception counseling and provision are vital components of comprehensive health care. An unplanned pregnancy can be particularly challenging for patients with chronic illness. Internal medicine physicians are uniquely positioned to assess pregnancy readiness and provide contraception, as they often intersect with pregnancy-capable patients at the moment of a new diagnosis or when providing ongoing care for a chronic medical condition. A shared decision-making counseling approach engages patients, ensures patient-centered care, and supports their choice of a contraceptive method that aligns with their reproductive plans and medical needs.


Early urinary complications of fractures of the pelvis.
The occurrence, relation to a particular type of fracture of the pelvis and the possible mechanism of early urinary complications were studied in 186 consecutive patients with fracture of the pelvis. Eighty-eight patients (47.3%) showed early urinary complications. These complications were minor in 73 patients (83.0%; 32.9% of all pelvic features) and major in 15 (17.0%; 8.1% of all pelvic fractures). The former comprised retention of urine in 41 patients (33.0%; 15.6% of all pelvic fractures), haematuria in 29 patients (33.0%; 15.6% of all pelvic fractures), and oliguria in three (3.4%; 1.6% of all pelvic fractures). The latter comprised rupture of the posterior urethra in nine patients (10.2%; 4.8% of all pelvic fractures), rupture of the bladder in five (5.7%; 2.7; of all pelvic fractures), and combined injury to the bladder and posterior urethra in one (1.1%; 0.5% of all pelvic fractures). These complications were common in relation to run-over and collision accidents. The common pelvic fracture encountered in these patients was the Type III and the individual pelvic fracture was that of both pubic rami on one or both sides; fractures of the acetabulum and posterior segment of the pelvis were next in frequency. On the other hand, fractures of a single ischial ramus or wing of the ilium were not commonly encountered. Fractures with intact pelvic ring were associated with only 9.1% of these complications; all were minor.


Comparison between multi-echo T2* with and without fat saturation pulse for quantification of liver iron overload.
To test a magnetic resonance image (MRI) technique that uses an additional pulse in multi-echo T2* sequence that works to suppress the fat signal, in subjects with liver iron overload and concomitant presence of fat in the liver, which have been revealed as a major drawback that compromises the correct iron quantification by MRI. Fifty magnetic resonance images of the liver (1.5T scanner) of individuals with blood ferritin increases were retrospectively reviewed for the presence of steatosis, using the sequence in and out of phase, and iron overloading, using two sequences T2 * multi-echo: one standard and other with additional fat suppression pulse. T2 * values and their standard deviations were analyzed statistically. Our results showed that a significantly lower standard deviation of T2* values is obtained when the fat saturation pulse is applied in patients with steatosis. We found that modulation of fat signal on liver iron overload resulted in a different categorization of some patients. In one case, the patient was re-classified within normal levels of liver iron. Our findings may contribute to a better measure of liver iron overload with relevant implications for patient treatment and care.


Structure and luminescence properties of a well-known macrometallocyclic trinuclear Au(I) complex and its adduct with a perfluorinated fluorophore showing cooperative anisotropic supramolecular interactions.
The structure and luminescence properties of a well-known trinuclear Au(i) imidazolate complex are determined for the first time along with its interaction with the organic π acid perfluoronaphthalene in the solid state and solution.


HIV-1/HSV-2 co-infected adults in early HIV-1 infection have elevated CD4+ T cell counts.
HIV-1 is often acquired in the presence of pre-existing co-infections, such as Herpes Simplex Virus 2 (HSV-2). We examined the impact of HSV-2 status at the time of HIV-1 acquisition for its impact on subsequent clinical course, and total CD4+ T cell phenotypes. We assessed the relationship of HSV-1/HSV-2 co-infection status on CD4+ T cell counts and HIV-1 RNA levels over time prior in a cohort of 186 treatment naïve adults identified during early HIV-1 infection. We assessed the activation and differentiation state of total CD4+ T cells at study entry by HSV-2 status. Of 186 recently HIV-1 infected persons, 101 (54%) were sero-positive for HSV-2. There was no difference in initial CD8+ T cell count, or differences between the groups for age, gender, or race based on HSV-2 status. Persons with HIV-1/HSV-2 co-infection sustained higher CD4+ T cell counts over time (+69 cells/ul greater (SD = 33.7, p = 0.04) than those with HIV-1 infection alone (Figure 1), after adjustment for HIV-1 RNA levels (-57 cells per 1 log(10) higher HIV-1 RNA, p<0.0001). We did not observe a relationship between HSV-2 infection status with plasma HIV-1 RNA levels over time. HSV-2 acquisition after HIV-1 acquisition had no impact on CD4+ count or viral load. We did not detect differences in CD4+ T cell activation or differentiation state by HSV-2+ status. We observed no effect of HSV-2 status on viral load. However, we did observe that treatment naïve, recently HIV-1 infected adults co-infected with HSV-2+ at the time of HIV-1 acquisition had higher CD4+ T cell counts over time. If verified in other cohorts, this result poses a striking paradox, and its public health implications are not immediately clear.


Evaluation of INSTAND e.V.'s external proficiency testing program for tetanus and diphtheria antitoxin detection: Lessons for assessing levels of immunoprotection.
The aim of this study was to evaluate the development and status quo of the quality of high throughput in vitro diagnostic testing for tetanus and diphtheria antitoxin antibody (ATX) concentrations based on external quality assessment (EQA) data. We analyzed manufacturer-specific data of 22 EQA surveys-each for the detection of tetanus and diphtheria ATX-to check the diagnostic strength of the corresponding in vitro diagnostic systems. While the results were mostly well aligned, individual surveys showed widely dispersed ATX concentrations. The medians of manufacturer collectives deviated from the overall median by up to 8.9-fold in the case of diphtheria ATX and by up to 3.5-fold in the case of tetanus ATX. Such a distribution in the results is particularly critical in the cut-off range for immunity and may lead to an incorrect assessment of vaccination status. These results were surprising as there are International Standards for both ATX; however, the results may be linked to the high ATX concentration of the reference material, which deviates considerably from clinically significant concentrations. To increase the accuracy and diagnostic strength of both assays, we recommend a recalibration of the test systems and verification of their traceability to the International Standards.


Alloimmunization with cultured human stomach cancer cell lines and the establishment of human-human hybridomas producing monoclonal antibodies.
Alloimmunization with the cultured human stomach cancer cell lines MKN-45 and MKN-28 was conducted and human-human hybridomas were established. Living MKN-45 cells (10(7) cells per injection) were injected monthly 34 times into one of the authors (K.K.) over 2 years and living MKN-28 cells (10(7) cells per injection) were co-injected 14 times after the 20th injection of MKN-45 alone. Cultured stomach cancer cells injected subcutaneously into K.K.'s forearm were rejected completely, although they grew transiently at the injection site. All the injections were made voluntarily at the direction of K.K. himself. Two human-human hybridomas producing monoclonal antibodies reactive with MKN-45 and MKN-28 cells, respectively, were separated from a hybridoma of human B-lymphoblastoid cell line named HO 323/WIL2-NS and lymphocytes in K.K.'s peripheral blood. One cell line of the hybridoma FMK-H3 produced IgM-type monoclonal antibody, and the other line, EMK-F7, produced IgG-type antibody. These two human-human monoclonal antibodies were highly reactive with MKN-45 and MKN-28 cells, weakly reactive with MKN-74 stomach cancer cell line, and not reactive with the other stomach cancer cell lines tested (MKN-1, MKN-7, TMK-1, NUGU-2, NUGC-3, NUGC-4 and KATO-III).


[Cyclosporine A improves the nuclear entry of hepatitis B virus core protein in HepG2.2.15 cells].
The present aimed to observe the effect of phosphatase inhibitor cyclosporine A on the subcellular location and on expression of HBcAg in HepG2.2.15 cells. Thirty micrograms/ml of cyclosporine A (CSA) was added into HepG2.2.15 cell culture system and on days 2 and 4 HBcAg and HBsAg were respectively stained with fluorescent immunocytochemistry and observed under confocal microscope. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling method. HBcAg was mostly expressed in cytoplasm in the control HepG2.2.15 cells. After 2 days CSA administration of the expression of HBcAg and HBsAg in cytoplasm significantly decreased and the signals of HBcAg in nucleus increased , whereas the HBcAg was still mainly expressed in nucleus in about 1/4 of the cells. Cell apoptosis was observed in about 30% of the cells. CSA improves the nuclear entry of core protein. The increase of HBcAg in nucleus was likely to be related with it's phosphorylation and cell aging or apoptosis.


Unilateral hyperostosis frontalis interna. Case report.
The authors describe a case of atypical unilateral prominent hyperostosis frontalis interna in a 50-year-old Japanese woman with psychiatric symptoms. Radiological, computerized tomographic, operative, and histological findings of this rare case are presented.


Individualization of cancer treatment from radiotherapy perspective.
Radiotherapy is today used in about 50% of all cancer patients, often in multidisciplinary approaches. With major advance in radiotherapy techniques, increasing knowledge on tumor genetics and biology and the continuous introduction of specifically targeted drugs into combined radio-oncological treatment schedules, individualization of radiotherapy is of high priority to further improve treatment outcomes, i.e. to increase long-term tumor cure and/or to reduce chronic treatment toxicity. This review gives an overview on the importance of predictive biomarkers for the field of radiation oncology. The current status of knowledge on potential biomarkers of tumor hypoxia, tumor cell metabolism, DNA repair, cancer stem cells and biomarkers for combining radiotherapy with inhibition of the epidermal growth factor receptor using monoclonal antibodies is described.


Tetraalkyl Hydroxymethylene-bisphosphonate and Dialkyl 1-Diphenylphosphinoyl-1-hydroxy-ethylphosphonate Derivatives by the Pudovik Reaction and Their Rearranged Products.
The reaction of diethyl α-oxoethylphosphonate and diethyl oxobenzylphosphonate with diethyl phosphite, dimethyl phosphite, and diphenylphosphine oxide affords, depending on the substrates and conditions (nature and quantity of the amine catalyst, temperature, and solvent), the Pudovik adduct and/or the corresponding >P(O)-CH-O-P(O)< product formed by rearrangement. The nature of the substituent on the central carbon atom (a methyl or phenyl group) influences the inclination for the rearrangement. The asymmetric products (either adducts or rearranged species) with different P(O)Y functions (Y = RO or Ph) exhibit interesting NMR features.


Quantifying the reproduction of Bacillus thuringiensis HD1 in cadavers and live larvae of Plutella xylostella.
The Bacillus cereus group comprises a range of micro-organisms with diverse habits, including gut commensals, opportunistic pathogens and soil saprophytes. Using quantitative microbiological methods we tested whether Bacillus thuringiensis (Bt) could reproduce in cadavers of Plutella xylostella killed by Bt, or in the gut of live insects, or be transmitted vertically from females to their offspring. We also tested whether diverse Bt strains could grow in high nutrient broth at a pH similar to that in the larval midgut. Low levels of reproduction were found in insect cadavers but there was no evidence of vertical transmission, or of significant reproduction in live insects. Four strains of B. thuringiensis var. kurstaki and one of B. thuringiensis var. tenebrionis were found to be capable of growth at high pH. Greater spore recovery rates in frass were found in hosts that were resistant or tolerant of infection. We concluded that that spores recovered in frass represent, in general, an ungerminated fraction of ingested inoculum and that germination rates are reduced in unsuitable hosts.


[Effects of DL-difluoromethylornithine on the cell surface charge of Ehrlich ascitic cancer during different phases of the mitotic cycle].
Difluoromethylornithine (DFMO)-induced polyamide deficiency has been studied for its effect on the electrophoretic mobility of the Ehrlich ascitic cells in G1, S and G2 phases of the mitotic cycle. The DFMO treatment alters the pattern of the electrophoretic mobility distribution of Ehrlich ascite cells. The most profound changes of the electrophoretic mobility pattern are observed in G1-phase and at the S phase beginning. Exogenic polyamines decrease the electrophoretic mobility of cancer cells, which is accompanied by restoration of the initial pattern of the electrophoretic mobility distribution.


Editorial Commentary: Cam Femoroacetabular Impingement Requires Dynamic Assessment of Beta-Angle (Femoroacetabular Excursion Angle) and Consideration of Femoral and Acetabular Version: Cam Impingement in Patients With Acetabular or Femoral Retroversion May Warrant Greater Osteoplasty.
Radiographs, magnetic resonance imaging, and computed tomography scans have been commonly used to evaluate femoroacetabular impingement (FAI) and are well accepted forms of surgical planning. Assessing and addressing both the femoral and acetabular sides result in a combination of "one-sided" treatments that, in sum, net a successful treatment of FAI. However, combining one-sided approaches may not consider the dynamic interaction of the femoral head with the acetabulum. Elevated alpha angles alone can be indicative of a cam-type lesion without necessitating the presence of functional FAI. The presence of a cam-type lesion on lateral radiographs, as suggested by a positive alpha angle, does not necessitate a decrease in clearance between the femoral head and acetabular rim as measured by the beta angle. Assessment of the beta angle, or femoroacetabular excursion angle, has the potential to address dynamic nature of FAI more accurately by directly measuring the degree of clearance between the femoral head and acetabulum. In addition, a comprehensive assessment of physical examination findings, particularly range of motion, as well as a summation of acetabular and femoral version (as measured by the McKibbin Index), are required. Cam-type of FAI poses a larger challenge in the patient with acetabular or femoral retroversion, which may warrant greater and more localized osteoplasty, distally, during hip arthroscopy.


Predictors of Severe Acute Respiratory Syndrome Coronavirus 2 Seropositivity Before Coronavirus Disease 2019 Vaccination Among Children 0-4 Years and Their Household Members in the SEARCh Study.
Estimates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in young children and risk factors for seropositivity are scarce. Using data from a prospective cohort study of households during the pre-coronavirus disease 2019 (COVID-19) vaccine period, we estimated SARS-CoV-2 seroprevalence by age and evaluated risk factors for SARS-CoV-2 seropositivity. The SARS-CoV-2 Epidemiology and Response in Children (SEARCh) study enrolled 175 Maryland households (690 participants) with ≥1 child aged 0-4 years during November 2020-March 2021; individuals vaccinated against COVID-19 were ineligible. At enrollment, participants completed questionnaires about sociodemographic and health status and work, school, and daycare attendance. Participants were tested for SARS-CoV-2 antibodies in sera. Logistic regression models with generalized estimating equations (GEE) to account for correlation within households assessed predictors of individual- and household-level SARS-CoV-2 seropositivity. Of 681 (98.7%) participants with enrollment serology results, 55 (8.1%; 95% confidence interval [CI], 6.3%-10.4%) participants from 21 (12.0%) households were seropositive for SARS-CoV-2. Among seropositive participants, fewer children than adults reported being tested for SARS-CoV-2 infection before enrollment (odds ratio [OR] = 0.23; 95% CI, .06-.73). Seropositivity was similar by age (GEE OR vs 0-4 years: 1.19 for 5-17 years, 1.36 for adults; P = .16) and was significantly higher among adults working outside the home (GEE adjusted OR = 2.2; 95% CI, 1.1-4.4) but not among children attending daycare or school. Before study enrollment, children and adults in this cohort had similar rates of SARS-CoV-2 infection as measured by serology. An adult household member working outside the home increased a household's odds of SARS-CoV-2 infection, whereas a child attending daycare or school in person did not.


Reevaluating concepts of apical dominance and the control of axillary bud outgrowth.
A large amount of diversity of architectural form is found among flowering plants, and an important aspect of this diversity is the wide variation, ranging from simple to complex, found among branching patterns in plant shoot systems. Historically, the control of bud outgrowth has been attributed to the presence of a growing shoot apex. The term "apical dominance" is used to indicate that the shoot tip exerts an inhibitory control over proximal axillary buds. Through decapitation and/or hormone manipulation experiments, this inhibition has been attributed to the phytohormones auxin and cytokinin. Recent studies with mutants demonstrating increased branching indicate important additional roles for organs apart from those in the shoot tip and for signals other than cytokinin and auxin. This chapter provides a critical review of branching with an emphasis toward bud outgrowth in a developmental context. This review provides a detailed synopsis of physiological, genetic, and molecular studies and approaches for the investigation of branching regulation in plants.


Regulation of proto-oncogene Orai3 by miR18a/b and miR34a.
Store Operated Ca2+ Entry (SOCE) mediated by Orai channels is a ubiquitous Ca2+ influx pathway that regulates several cellular functions. We have earlier reported that Orai3, the mammalian specific Orai1 homolog, plays a critical role in breast cancer progression. More recently, Orai3 was demonstrated to regulate prostate and lung tumorigenesis. Although the tumorigenic potential of Orai3 is associated with increase in its expression, the molecular machinery regulating its expression remains largely unexplored. Here, by performing extensive bioinformatics analysis and functional studies, we identify and characterize micro-RNAs (miRNAs) that regulate Orai3 expression and function. We demonstrate that miR18a and miR18b positively regulate Orai3 whereas miR34a represses Orai3 expression and function. All these miRs exert their effect on Orai3 by virtue of their direct action on Orai3 3'UTR. These miRs provide novel opportunities for targeting Orai3 for better management of cancer. This study further opens up the possibility of targeting specific Orai homologs by different miRs in tissue and disease specific context.


[Contribution of equine therapy in the management of post-traumatic stress disorder].
For several years, animal-mediated therapies have been used in the treatment of psychiatric patients. Post-traumatic stress disorder has the particularity of being generated by an external event in a person a priori free of mental pathology. In this disorder, various so-called targeted psychotherapies have proven to be effective, including equine therapy.


Effect of transurethral resection on serum free/total prostate-specific antigen levels in patients with benign prostatic hyperplasia.
Transurethral resection of the prostate (TURP) can cause elevation of total serum prostate-specific antigen (PSA). However, the effect of these procedures on free PSA and percent free PSA is still unknown. The aim of this study was to investigate the effect of TURP on serum total PSA, free PSA, and free/total (f/t) PSA ratio in patients with benign prostatic hyperplasia (BPH) and to determine the reliability of f/t PSA ratio after such interventions. Fifty-three patients with BPH who underwent TURP because of severe bladder outlet obstruction symptoms were included in this study. All patients underwent digital rectal examination and transrectal ultrasound (TRUS), and routine hematologic (complete blood count) and serum biochemical tests, urine analysis, and a peak urinary flow test were performed. Serum total PSA and free PSA levels were determined 1 hour before and 24 hours after TURP by using enzyme immunometric assay. Preoperative and postoperative free and total PSA and f/t PSA ratio were statistically compared. Although postoperative total PSA and free PSA increased significantly compared with preoperative values (P <0.001 and P = 0.024, respectively), the difference between preoperative and postoperative f/t PSA ratios was not statistically significant (P = 0.103). Finding no significant change in f/t PSA ratio, although there is a significant increase in the serum levels of total and free PSA, suggests to us that f/t PSA ratio may be a more reliable parameter in the early period after such interventions as TURP.


Maximum rate of tension fall during isometric relaxation at end-systolic fiber length in canine papillary muscle.
We measured the characteristics of the decline in tension during isometric relaxation of canine papillary muscle. In the intact heart, relaxation begins with the isovolumic phase, but in experiments on papillary muscle previously reported the isotonic phase preceded the isometric phase during the course of relaxation. In our experiments, however, the isotonic bar was locked at the instant the muscle reached the end-systolic fiber length in order to hold the fiber at the length during the succeeding relaxation process. Therefore, we obtained a relaxation process similar to that occurring in the intact heart. The major results of these experiments are: (1) Maximum rate of the decline in tension (-dT/dtmax) is linearly related to the magnitude of total load. (2) -dT/dtmax is augmented by positive inotropic interventions and diminished by negative inotropic interventions. (3) An increase in preload results in only a slight increase in -dT/dtmax. (4) End-systolic fiber length itself is not a principal determinant of -dT/dtmax. (5) -dT/dtmax divided by total load is independent of the amount of muscle shortening. We, therefore, suggest that -dT/dtmax divided by total load cand be a useful index of the relaxation characteristics of cardiac muscle.


Substitution of psychoactive drugs in pentobarbital-dependent rats.
The substitution of either bromazepam, diazepam, methaqualone, mazindol, nortriptyline or bupropion for pentobarbital, in dependent rats, was assessed using a continuous drug infusion method. Male, Sprague-Dawley rats were made dependent on pentobarbital during 12 days of continuous, intraperitoneal, pentobarbital infusion. On Day 13, pentobarbital was replaced with either saline, vehicle, or one of the drugs of interest and rats were infused for 24 h. On Day 14, all rats were infused, for 24 h, with saline. Changes in both body weight and behavioral indices of withdrawal were assessed during Day 13 and 14. It was observed that bromazepam and methaqualone substituted for pentobarbital in a dose-dependent fashion. Diazepam also substituted in pentobarbital dependent rats but, inexplicably, the low dose of diazepam provided better substitution than did the higher dose. On the other hand, neither mazindol or nortriptyline substituted for pentobarbital and there was a tendency for exacerbation of the withdrawal signs. Finally, it was noted that the low dose of bupropion appeared to decrease the severity of the withdrawal symptoms. The data supports the view that the substitution of compounds for pentobarbital, in dependent rats, is limited to those compounds which, presumably, possess similar mechanisms of action in the CNS.


Consistency of drug-drug and gene-drug interaction information in US FDA-approved drug labels.
To characterize concordance between clinically relevant drug-drug interactions (DDIs) related to CYP2C19, CYP2D6 and CYP2C9 and their analogous gene-drug interactions (GDIs) in US FDA-approved drug labeling. We selected prototypical CYP2C19, CYP2D6 and CYP2C9 inhibitors and abstracted all respective interacting drugs via a tertiary resource used in the clinical setting. We then selected only CYP2C19, CYP2D6 and CYP2C9 metabolism-related DDIs requiring enhanced clinical monitoring, dose adjustment or use of alternative drugs. Labeling and management strategies on DDIs and GDIs were compared. Among the drug labels with DDI information, 73% of them describe the analogous GDI. Of the 65 drug labels, 43 and 17% had specific management recommendations for DDIs and GDIs, respectively. In general, GDI management recommendations were concordant with DDI management recommendations in terms of specific dose adjustments or use of alternative drugs. The FDA has recognized genetic differences in drug metabolism where clinically relevant DDIs trigger dose adjustment or use of alternative drugs.


Subcortical vascular encephalopathy in a normotensive, young adult with premature baldness and spondylitis deformans. A clinicopathological study and review of the literature.
Progressive subcortical vascular encephalopathy (PSVE) usually occurs in elderly individuals, suffering from hypertension. We here describe a male, born of consanguineous parents, who first showed signs of PSVE at the age of 30. Despite the absence of hypertension or known metabolic causes, the degenerative cerebral vascular disease developed progressively. Several cases, surprisingly identical to the one reported here, were traced using Japanese medical records. They are clinically characterized by: early onset of PSVE (at age 25-30), absence of persistent hypertension, diffuse alopecia since youth, spondylitis deformans with early onset, often so severe as to necessitate surgery, and the possible existence of an autosomal recessive transmission. Cases with these features appear to constitute a distinct clinical entity, possibly a new form of premature aging syndrome.


The open artery: beyond myocardial salvage.
Despite the potential limitations, the available data suggest the importance of the open artery as a marker of survival following infarction. Perhaps the most important, although as yet unanswered, question is when is it too late to reopen an artery? Further, is reperfusion by interventional techniques preferable to reperfusion by lytic therapy alone? Although a reduction in mortality has not been demonstrated for thrombolysis beyond 12 hours (other than the Second International Study of Infarct Survival, ISIS-2), improvements in ventricular function (which might translate into a survival benefit) have been demonstrated even for very delayed reperfusion. It is hoped that future work will allow us to answer better when such therapy might be preferable.


Transport activity of human MRP3 expressed in Sf9 cells: comparative studies with rat MRP3.
Multidrug resistance-associated protein 3 (MRP3) was initially cloned as a hepatic transporter induced under cholestatic/ hyperbilirubinemic conditions. In the present study, transport property of human MRP3 (hMRP3) was compared with that of rat MRP3 (rMRP3). Adenosine 5' triphosphate (ATP)-dependent uptake of several organic anions into the membrane vesicles isolated from the Sf9 cells expressing hMRP3 and rMRP3 was measured by rapid filtration technique. ATP-dependent uptake of glucuronide conjugates, glutathione conjugates. and [3H]methotrexate (MTX) was stimulated by infection of cDNAs for hMRP3 and rMRP3. The mean (+/- SE) Km values for the uptake of 17beta estradiol 17beta-D-glucuronide ([3H]E(2)17 betaG) by hMRP3 and rMRP3 were 42.9 +/- 4.3 microM and 33.4 +/- 2.2 microM, respectively. Although the Ki values of glucuronides on the uptake of E217betaG were similar in humans and rats, hMRP3 exhibited higher Ki values toward MTX. In addition, although glycocholate and taurolithocholate 3-sulfate (TLC-S) were transported by both hMRP3 and rMRP3, taurocholate was only transported to a significant degree by rMRP3. Moreover, the inhibitory effect of taurocholate and glycocholate on the transport of E(2)17beta3G was much more potent in rMRP3 compared to hMRP3. Collectively, the substrate specificity of hMRP3 resembles that of rMRP3 although differences were observed, particularly in bile acid transport.


Tuberoeruptive xanthomas: unusual presentation of type V hyperlipoproteinemia.
We report a case of pedal tuberoeruptive xanthomatosis associated with ethanol-induced type Vhyperlipoproteinemia that was controlled with diet, withdrawal from ethanol use, and the fibric acid derivative gemfibrozil.


Obstructive azoospermia secondary to bilateral epididymal cystadenomas in a patient with von Hippel-Lindau.
von Hippel-Lindau (VHL) is a heritable cancer syndrome associated with findings in multiple organ systems. Male patients can be affected by epididymal cystadenomas which are benign tumors localized to the epididymis. While benign, these tumors can cause pain and in very rare circumstances can have an effect on fertility especially when present bilaterally. We present a case of a young man with obstructive azoospermia secondary to bilateral cystadenomas, with a focus on his work-up and management.


The control of compound inflorescences: insights from grasses and legumes.
A major challenge in biology is to understand how organisms have increased developmental complexity during evolution. Inflorescences, with remarkable variation in branching systems, are a fitting model to understand architectural complexity. Inflorescences bear flowers that may become fruits and/or seeds, impacting crop productivity and species fitness. Great advances have been achieved in understanding the regulation of complex inflorescences, particularly in economically and ecologically important grasses and legumes. Surprisingly, a synthesis is still lacking regarding the common or distinct principles underlying the regulation of inflorescence complexity. Here, we synthesize the similarities and differences in the regulation of compound inflorescences in grasses and legumes, and propose that the emergence of novel higher-order repetitive modules is key to the evolution of inflorescence complexity.


The sea urchin (Sphaerechinus granularis) codes different H2B histones to assemble sperm and embryo chromatin.
Histones from sperm and gastrula nuclei of the sea urchin Sphaerechinus granularis were analyzed by three different electrophoretic methods, stained with specific color reactions and compared with one another. The histones of the two cell types showed identical properties in none of the three analytical methods employed but the greatest differences involved the H2B type of histones. H2B from embryo chromatin had properties similar to those of the corresponding molecule from calf thymus. In the sperm chromatin no such molecule was observed but two additional ones were found that differed from embryo H2B in size, charge and specific colour reactions. The differences were such that different genes may be postulated for the synthesis of the H2B histones found in sperm and in embryo.


[Nitrate and nitrite contents in vegetable juice, tea beverage and mineral water on the market].
The contents of nitrate and nitrite in vegetable juice (n = 63), tea beverage (n = 12) and mineral water (n = 15) were measured. The mean contents of nitrate were 0.73 +/- 14.57 mg/100 g, 0.61 +/- 1.12 mg/100 g and 0.25 +/- 0.33 mg/100 g as NO3-, respectively. The contents of the nitrite were 0.03 +/- 0.05 mg/100 g, 0.02 +/- 0.01 mg/100 g and 0.001 +/- 0.001 mg/100 g as NO2-, respectively. The content of nitrate is high in some vegetable juices, and warnings may be necessary for people who drink them frequently.


¹H, ¹³C and ¹⁵N chemical shift assignments for the N-terminal PAS domain of the KCNH channel from zebrafish.
The KCNH channels are voltage-gated potassium channels that play important roles in heart and nerve cells. The N-terminal region of the KCNH channel contains a Per-Arnt-Sim (PAS) domain which is important for the channel gating through interaction with other regions of the channel. To study the solution structure of the N-terminal PAS domain of the KCNH channel from Zebrafish (zNTD), we over-expressed and purified zNTD. We report the resonance assignments for zNTD. The data will allow us to perform structural studies for this domain, which will provide insight into its structural basis for the molecular interaction with other regions of the KCNH channel.


Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels.
Oxidation processes play an important role in atherogenesis. Bilirubin IXalpha is recognised as a potent antioxidant. In the present study, we assessed the role of elevated serum bilirubin levels in the prevention of ischemic heart disease (IHD). The occurrence of IHD was determined in Gilbert syndrome (GS) patients above 40 years (n=50). The diagnosis was based on past medical history and ECG criteria. The occurrence was related to that of the comparable general population (n=2296). Serum biochemistry, including the total antioxidant status was evaluated in the GS subjects, IHD patients (n=38) and control subjects (n=38). The prevalence of IHD in GS subjects (aged 49.7+/-9.0 years) was 2% (0.05-10.7%, 95% confidence interval), compared to 12.1% in a general population (P<0.05). Bilirubin, total antioxidant capacity and high density lipoprotein (HDL) cholesterol were found to be significantly higher in GS subjects compared to control groups (P<0.05). According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD. In the present study, low prevalence of IHD in GS subjects was detected. It may be presumed that chronic hyperbilirubinemia prevent the development of IHD by increasing the serum antioxidant capacity.


Locating Gases in Porous Materials: Cryogenic Loading of Fuel-Related Gases Into a Sc-based Metal-Organic Framework under Extreme Pressures.
An alternative approach to loading metal organic frameworks with gas molecules at high (kbar) pressures is reported. The technique, which uses liquefied gases as pressure transmitting media within a diamond anvil cell along with a single-crystal of a porous metal-organic framework, is demonstrated to have considerable advantages over other gas-loading methods when investigating host-guest interactions. Specifically, loading the metal-organic framework Sc2BDC3 with liquefied CO2 at 2 kbar reveals the presence of three adsorption sites, one previously unreported, and resolves previous inconsistencies between structural data and adsorption isotherms. A further study with supercritical CH4 at 3-25 kbar demonstrates hyperfilling of the Sc2 BDC3 and two high-pressure displacive and reversible phase transitions are induced as the filled MOF adapts to reduce the volume of the system.


Antibacterial bisabolane-type sesquiterpenoids from the sponge-derived fungus Aspergillus sp.
Four new bisabolane-type sesquiterpenoids, aspergiterpenoid A (1), (-)-sydonol (2), (-)-sydonic acid (3), and (-)-5-(hydroxymethyl)-2-(2',6',6'-trimethyltetrahydro-2H- pyran-2-yl)phenol (4) together with one known fungal metabolite (5) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Four of them (1-4) are optically active compounds. Their structures and absolute configurations were elucidated by using NMR spectroscopic techniques and mass spectrometric analysis, and by comparing their optical rotations with those related known analogues. Compounds 1-5 showed selective antibacterial activity against eight bacterial strains with the MIC (minimum inhibiting concentrations) values between 1.25 and 20.0 µM. The cytotoxic, antifouling, and acetylcholinesterase inhibitory activities of these compounds were also examined.


Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia.
Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.


Lengthening osteotomy at the intertrochanteric level with simultaneous correction of angular deformities.
Fixed multiplane deformities around the hip representing a combination of rotational, angular, and leg-length discrepancies are disabling for the patient and pose a challenge for the orthopaedic surgeon. We describe a joint-preserving, one-stage procedure to address these complex problems using an intertrochanteric osteotomy with a step-cut to allow for corrective lengthening, angulation, and rotation. We present our results in nine patients. The aim of this paper is to provide the orthopaedic surgeon with a detailed approach to treating these deformities with reproducible results.


Prostate cancer detection rates of magnetic resonance imaging-guided prostate biopsy related to Prostate Imaging Reporting and Data System score.
Recent studies have shown that multiparametric magnetic resonance imaging and magnetic resonance imaging-guided prostate biopsy in patients with suspected prostate cancer increase detection rate and clinical significance of diagnosed tumors. Purpose of this study is to evaluate the detection rates of prostate cancer for magnetic resonance imaging-guided prostate biopsy related to Prostate Imaging Reporting and Data System score. We included all patients with cancer-suspicious lesions on 3-Tesla multiparametric magnetic resonance imaging-prostate who underwent magnetic resonance imaging-guided prostate biopsy in Haga Teaching Hospital between January 2013 and January 2015. In total, 155 patients were included. In 100 of 155 (65 %) men, MRI-guided prostate biopsy was positive for prostate cancer. No biopsy of PI-RADS 2-lesions was positive. PI-RADS 3- and 4-lesions were, respectively, in 10 and 77 % prostate cancer positive. Biopsies of PI-RADS 5-lesions were in 89 % of the cases positive. The majority of detected cancers (63 %) were Gleason score ≥ 7, and this number increases to 75 % in positive PI-RADS 5-lesions. Magnetic resonance imaging-guided prostate biopsy has a high detection rate of prostate cancer in men with cancer-suspicious lesions on multiparametric magnetic resonance imaging-prostate, and this rate (65 %) increases with the Prostate Imaging Reporting and Data System score (81 % in PI-RADS 4- and 5-lesions).


The Prognostic Relevance of MRI Characteristics in Myxofibrosarcoma Patients Treated with Neoadjuvant Radiotherapy.
To improve local control, neoadjuvant radiotherapy (nRT) followed by surgery is the standard of care in myxofibrosarcoma (MFS) because of its infiltrative growth pattern. Nevertheless, local recurrence rates are high. Data on prognostic factors for poor clinical outcomes are lacking. This retrospective study thus investigates the prognostic relevance of magnetic resonance imaging (MRI) characteristics before and after nRT in 40 MFS patients, as well as their association with disease-free survival (DFS) and overall survival (OS). A vascular pedicle, defined as extra-tumoral vessels at the tumor periphery, was observed in 12 patients (30.0%) pre-nRT and remained present post-nRT in all cases. Patients with a vascular pedicle had worse DFS (HR 5.85; 95% CI 1.56-21.90; p = 0.009) and OS (HR 9.58; 95% CI 1.91-48.00; p = 0.006). An infiltrative growth pattern, referred to as a tail sign, was observed in 22 patients (55.0%) pre-nRT and in 19 patients (47.5%) post-nRT, and was associated with worse DFS post-nRT (HR 6.99; 95% CI 1.39-35.35; p = 0.019). The percentage of tumor necrosis estimated by MRI was increased post-nRT, but was not associated with survival outcomes. The presence of a tail sign or vascular pedicle on MRI could support the identification of patients at risk for poor clinical outcomes after nRT.


From father to son: transgenerational effect of tetracycline on sperm viability.
The broad-spectrum antibiotic tetracycline is used in animal production, antimicrobial therapy, and for curing arthropods infected with bacterial endosymbionts such as Wolbachia. Tetracycline inhibits mitochondrial translation, and recent evidence indicates that male reproductive traits may be particularly sensitive to this antibiotic. Here, we report the first multi-generation investigation of tetracycline's effects on ejaculate traits. In a study of the pseudoscorpion, Cordylochernes scorpioides, in which siblings were randomly assigned to control and tetracycline treatments across replicate full-sibling families, tetracycline did not affect body size in either sex, female reproduction or sperm number. However, tetracycline-treated males exhibited significantly reduced sperm viability compared to control males, and transmitted this toxic effect of tetracycline on sperm to their untreated sons but not to their F2 grandsons. These results are consistent with tetracycline-induced epigenetic changes in the male germline, and suggest the need for further investigation of transgenerational effects of tetracycline on male reproductive function.


Isolation and characterization of antibodies to Clostridium perfringens epsilon toxin from hyperimmune horse serum.
Antibodies against epsilon toxin were isolated from hyperimmune horse serum by affinity chromatography. Purified epsilon prototoxin covalently bound to Affigel 202 was used as immunosorbent, and antibodies were eluted with 6.0 M guanidine chloride. In a single run 80 mg of antibody could be recovered from a 20 microliter column of immunosorbent. The antibody was shown to belong to the IgG(T) class of immunoglobulins.


Regulation of class I MHC expression in skeletal muscle: deleterious effect of aberrant expression on myogenesis.
Aberrant expression of class I major histocompatibility complex (MHC) occurs on myofibers in inflammatory myopathies. The mechanisms responsible for such expression are unknown. Here we show that class I MHC expression is developmentally regulated during muscle regeneration with significant levels only in myoblasts. Injection of gamma-IFN plasmid leads to muscle inflammation, induction of class I MHC in regenerating, but not mature myofibers, and attenuation of regeneration. Gene transfer of class I MHC in vivo and in vitro also attenuates muscle differentiation. Thus, cytokines may contribute to the pathogenesis of inflammatory myopathies by upregulating class I MHC and leading to deleterious effects on muscle repair.


The human EGF receptor gene: structure of the 110 kb locus and identification of sequences regulating its transcription.
The human epidermal growth factor receptor (EGFR) proto-oncogene is shown to span 110 kb of DNA divided into 26 exons. Analysis of sequences surrounding exon 1 reveals a highly CG rich region which promotes transcription. The activity of the EGF receptor promoter can be modulated by E1A protein and receptor RNA levels increased by stimulation with phorbol ester or fetal calf serum. Promoter activity is assayed by linkage to the chloramphenicol acetyl transferase gene and transfection in three cell lines, with quantitation of plasmid DNA uptake by isolation of a Hirt supernatent from each transfection. Deletion analysis of the CG rich promoter region of the gene and construction of chimeric EGFR/SV40 promoters are used to demonstrate positive transcription elements located both within exon 1 and 5' to the start of transcription. Negative regulation of transcription by sequences within a -140 to +80 region is suggested. Cotransfection experiments suggest a requirement for the interaction of DNA binding protein Sp1 for maximal activity. Finally, derepression of a positive regulatory sequence located in exon 1 during cotransfection experiments is shown. Results are discussed in reference to the multilevel regulation of EGF receptor expression.


Management of anterior encephalocele.
The authors report their experience with anterior encephalocele, comprising 11 congenital and 11 traumatic cases. Unlike occipital encephaloceles, anterior lesions are usually associated with normal mental development. Surgery aims to restore normal anatomy with repair of the defective dura, bone and skin. Indications, surgical methods and outcome are discussed.


Carbohydrate partitioning in relation to whole plant production and water use of Vigna unguiculata (L.) Walp.
Increases in plant biomass are mainly a balance between growth of new leaves and growth of new roots, the new leaves having positive feedback upon the production process and the new roots having positive feedback upon the plant water status. Control of both opposing processes with respect to biomass production may be considered optimal whenever biomass of the plant reaches a maximum without adversely affecting plant water status. This occurs only if all carbohydrates are partitioned into growth of new leaves, unless water uptake is insufficient to meet the additional evaporative demand created by the newly grown leaf area without decreasing the water status of the plant. It is shown by theoretical considerations based upon optimization theory, especially by application of the Pontryagin Maximum Principle, that in this case carbohydrate partitioning is dependent upon the transpiration rate per leaf weight and upon the efficiency of the root at taking up water. Growth of Vigna unguiculata at two levels of air humidity and two levels of water uptake rate by the root was consistent with such a carbohydrate partitioning pattern. Growth of total biomass and its components (leaves, stems, and roots), whole plant transpiration, and the pattern of carbon partitioning were predicted and explained by applying the foregoing principles of optimization in a heuristic model for vegetative growth of an annual.


Investigation of the novelty of latent functionally thermal fluids as alternative to nanofluids in natural convective flows.
This paper presents a detailed comparison between the latent functionally thermal fluids (LFTFs) and nanofluids in terms of heat transfer enhancement. The problem used to carry the comparison is natural convection in a differentially heated cavity where LFTFs and nanofluids are considered the working fluids. The nanofluid mixture consists of Al2O3 nanoparticles and water, whereas the LFTF mixture consists of a suspension of nanoencapsulated phase change material (NEPCMs) in water. The thermophysical properties of the LFTFs are derived from available experimental data in literature. The NEPCMs consist of n-nonadecane as PCM and poly(styrene-co-methacrylic acid) as shell material for the encapsulation. Finite volume method is used to solve the governing equations of the LFTFs and the nanofluid. The computations covered a wide range of Rayleigh number, 104 ≤ Ra ≤ 107, and nanoparticle volume fraction ranging between 0 and 1.69%. It was found that the LFTFs give substantial heat transfer enhancement compared to nanofluids, where the maximum heat transfer enhancement of 13% was observed over nanofluids. Though the thermal conductivity of LFTFs was 15 times smaller than that of the base fluid, a significant enhancement in thermal conductivity was observed. This enhancement was attributed to the high latent heat of fusion of the LFTFs which increased the energy transport within the cavity and accordingly the thermal conductivity of the LFTFs.


Electrophysiologic implications of myocardial stem cell therapies.
Myocardial stem cell therapies are emerging as exciting new experimental strategies for treatment of a variety of cardiovascular disorders. This review describes the electrophysiologic implications associated with these emerging strategies. The electrophysiologic considerations associated with cell therapy for myocardial infarct repair are described from the mechanistic point of view (assessing electromechanical coupling between donor and host cells) and from the therapeutic (possibly preventing malignant ventricular arrhythmias) and potential adverse effects (increasing arrhythmogenesis) points of view. The potential of different stem cell therapy approaches for the treatment of bradyarrhythmias, are discussed. Such therapy includes efforts to generate biologic pacemakers either by genetically modifying mesenchymal stem cells to overexpress the pacemaker current I(f) or by inducing differentiation of human embryonic stem cells into cardiomyocytes having pacemaking properties. The ability of cell therapy using genetically modified cells to modulate the electrophysiologic substrate in an attempt to treat different tachyarrhythmias is described. The potential advantages and shortcomings of each strategy are discussed, as are the obstacles that must be overcome before these exciting strategies can become a clinical reality.


ISAR Consensus Guidelines on Safety and Ethical Practices in In vitro Fertilization Clinics.
What are the Safe and Ethical practices for ART applicable in INDIA? The Indian IVF industry is booming; with mushrooming of assisted reproductive technology (ART) clinics in the country, the need for regulation is immense. The ISAR has taken up this initiative to lead the way forward in establishing practice guidelines for the safe and ethical use of ARTs in our country. These guidelines discuss the points to consider before the starting of an IVF unit, to the designing of the laboratory, the staffing pattern and experience recommendations, laboratory safety guidelines, documentation and patient traceability, gamete traceability, handling biological material, the consumables and media, and different consents and checklists and also propose key performance indicators for the Indian scenario. This is the report of a 2-day consensus meeting where two moderators were assigned to a group of experts to collate information on safe and ethical ivf practices in INDIA. This meeting utilised surveys, available scientific evidence and personal laboratory experience into various presentations by experts on pre-decided specific topics. Expert professionals from ISAR representing clinical and embryology fields. The report is divided in various components including the regulations, the various requirements for an ART center, qualifications and trainings, recommendations on good practices and quality management: the report and recommendations of the expert panel reflect the discussion on each of the topics and try to lay down good practice points for labs to follow. The recommendations are solely based on expert opinion. Future availability of data may warrant an update of the same. These guidelines can help labs across the country to standardise their ART services and improve clinical outcomes. The consensus meeting and writing of the paper was supported by funds from CooperSurgical India.


Preferences for a patient-centered role orientation: association with patient-information-seeking behavior and clinical markers of health.
Few data exist examining how patients' preferred role orientation (patient-centered or provider-centered) is associated with "patient-centered" behavior and clinical markers of health. The purpose of the study is to investigate how patients' preferred role orientation is associated with information-seeking behavior and clinical markers of health in a chronically ill population. Participants were 189 hypertensive patients, at two VA Medical Centers and four community-based clinics, who completed measures of preferred role orientation and medication information seeking. Lab values of patients' blood pressure, LDL cholesterol, and glycosylated hemoglobin A1c were used as clinical markers. Preference for a patient-centered role was associated with seeking medication information from various sources (e.g., the internet [OR = 1.14, 95% CI = 1.05-1.23]) and with the number of sources from which patients obtained information (beta = .21, p = 0.005). However, patient-centered preferences were also associated with higher systolic blood pressure (beta = 0.16, p = 0.04), higher diastolic blood pressure (beta = .15, p = 0.04), and higher LDL cholesterol (beta = 0.17, p = 0.04). There was no association with glycosylated hemoglobin A1c (beta = -0.10, p = 0.36). Patients who preferred a patient-centered role engaged in behavior consistent with their preferences, but had higher blood pressure and less favorable lipid levels. These findings are discussed in terms of the nature and treatment of certain chronic conditions that may explain why a patient-centered role orientation is associated with a less favorable clinical profile in some contexts.


[Anti-hypertensive Effect of Total Flavonoids of Cydonia oblonga Leaves and Its Mechanism Based on Anti-inflammatory Function].
To study the anti-hypertensive effect of total flavonoids of Cydonia oblonga leaves in spontaneously hypertensive rats, then to preliminarily investigate the mechanism of action based on anti-inflammatory function. Spontaneously hypertensive rats were divided into six groups as spontaneously hypertensive control group (SHR), captopril group (25 mg/kg), Eucommia ulmoides group (30 mg/kg), total flavonoids of Cydonia oblonga leaves low (40 mg/kg), middle (80 mg/kg) and high dose (160 mg/kg) groups. Eight Wistar-Kyoto (WKY) rats were given distilled water as the control. The drugs were given by intragastric administration for 16 weeks, then the contents of IL-1β, IL-6, IL-10, TNF-α and CRP in rats serum were detected. The weight and the blood pressure of rats were measured at 0 min and 2, 4, 6, 8, 10, 12, 14, 16 weeks after drug administrated. Compared with control group, the contents of IL-1β, IL-6, TNF-α and CRP were increased and IL-10 was decreased; Compared with SHR group, the contents of IL-1β,IL-6, TNF-α and CRP were decreased in total flavonoids of Cydonia oblonga leaves groups. Total flavonoids of Cydonia oblonga leaves show an anti-hypertensive activity in spontaneously hypertensive rats and the mechanism is related to the function of anti-inflammatory.


[Selected elements of health status of the Polish population in relation to other European countries in the light of the program "Health for all up to 2000"].
Total mortality from main causes of death (diseases of circulatory system, malignant neoplasms, injuries and poisoning) life expectancy at birth, infant and maternal mortality in Poland in the years 1970-1988 were analyzed on the basis of targets of the regional strategy for "Health for all by the year 2000" (HFA 2000). It seems that it isn't possible to achieve targets concerning mortality by the year 2000. However it is possible to decrease infant and maternal mortality. Standardization of health indicators to european population allows to compare health status of the polish population to other european countries. This comparison shows that situation in Poland is not optimistic.


Caudal fluoroscopy to guide venous access for pacemaker device implantation: should this now be standard practice?
We describe a technique that uses both posterior-anterior and caudal fluoroscopy to achieve venous access for pacemaker device implantation. A significant advantage of this technique is the ability to clearly demarcate both the anatomy of venous drainage and the lung border. We would encourage all centres to adopt this technique as a safe approach to venous access.


Significance of HLA-B[*]51 allele expression in Crohn's disease: a case-control study.
Crohn's disease (CD) and Behçet's disease (BD) are two autoinflammatory diseases that share clinical and pathogenic features. Furthermore, when BD involves the gastrointestinal tract, it is extremely difficult to distinguish endoscopic lesions from CD lesions. HLA-B*51 allele expression is highly associated with BD diagnosis. In this study we analysed HLA-B*51 status in 70 Argentine patients with confirmed CD diagnosis and compared it to our previous Argentine BD cohort, with the aim of finding similarities or differences between these two diseases regarding HLA-B*51 status. This is a multi-centre case-control study, including 70 patients with confirmed CD diagnosis, who underwent HLA-B*51 allele status testing; the results were compared to our previous BD cohort of 34 patients. Among patients with CD, 12.85% were positive for the HLA-B*51 allele, compared with 38.24% patients with BD (OR=0.238; 95% CI=0.089-0.637; p=0.004). Our finding suggests that determination of HLA-B*51 allele status may contribute to the differential diagnosis between CD and BD.


An optimal morphometric method for quantitating wound epithelization.
A new, inexpensive method for quantitative evaluation of reepithelization of shallow split thickness wounds in piglets is described. Wounds, 2.2 X 2.2 cm and 0.4 mm depth are inflicted by an electro-keratome knife in domestic piglets. At a specific time after wounding, the wound area is excised and processed for histology. A computer simulation, based on a randomized systematic sectioning of an entire wound, was used to conclude that only eight sections from the 2.2 X 2.2 cm wound are needed for the final evaluation. The results showed that the above method allows for determination of the epithelization magnitude within +/- 5% at a 95% confidence limit. It was found that in 15 kg piglets 50% epithelization of the above wounds was achieved in 65 hr; however, there exists a great interindividual variability. The rate of epithelization is age dependent and significantly faster in 7 kg body weight piglets than in those weighing 40 kg. The epithelization rate was the same at both the wound edge and the center of the wound, stressing the importance of hair follicles as a source of epithelization.


Three-dimensional molecular distribution in single cells analysed using the digital imaging microscope.
Cellular changes in molecular distribution are believed to underly a wide range of cell functions. In order to investigate changes in molecular distribution in single cells utilizing fluorescent probes we have developed a digital imaging microscope. The system, consisting of both hardware and software, automatically acquires 3-D data sets consisting of optical sections and then processes such data to facilitate the analysis of molecular distribution in single cells. The first major step in processing reverses distortion introduced principally by the optics of the fluorescent microscope. Various procedures for accomplishing this task are compared and a method based on regularization theory is shown to give superior results for several different 3-D images. Following this step features of interest are automatically extracted from 3-D images utilizing an artificial 3-D visual system. This artificial visual system utilize a system of spatial filters to identify regional characteristics of images, the information obtained from these filters being used to identify and characterize clusters of molecules within the image. This information is then utilized to construct a 3-D graphical model of molecular distribution in single cells. Such models are displayed in 3-D and may further analysed utilizing interactive 3-D computer graphics. These methods are illustrated by results obtained regarding alpha-actinin distribution in single smooth muscle cells.


Detection of nanoparticles by single-particle ICP-MS with complete transport efficiency through direct nebulization at few-microlitres-per-minute uptake rates.
Measurement of nanoparticle (NP) concentration and size by single-particle inductively coupled plasma mass spectrometry (spICP-MS) usually requires the use of a NP reference material to determine the loss of NPs and/or ions during their transport from the sample solution to the detection system. The determination of this loss, qualified as nebulization efficiency (ηNebulization) and/or transport efficiency (ηTransport), is time-consuming, costly and lacks reliability. Nebulization of the NPs directly into the plasma (without a spray chamber) results in ηNebulization = 100% and is thus a promising strategy to avoid these calibration steps. In this work, we used the μ-dDIHEN introduction system: a demountable direct injection high-efficiency nebulizer (dDIHEN) hyphenated to a flow-injection valve and a gas displacement pump. For the first time with a continuous flow nebulizer, complete transport efficiency was reached (i.e. ηTransport = 100%). Operated at a very low uptake rate (as low as 8 μL min-1), the μ-dDIHEN accurately and reproducibly determined average diameters of Au-, Ag- and Pt-NPs, in full agreement with their reference values. It was also successfully tested for Au-NPs in complex matrices, such as surface waters. spICP-MS analyses with the μ-dDIHEN sample introduction system only require a dissolved standard calibration to determine NP average diameter (dNPs in nm) and number concentration (NNPs) from the simplified set of equations: [Formula: see text] and [Formula: see text]Graphical abstract.


Protecting neurons.
Brain injury evolves over time, often taking days or even weeks to fully develop. It is a dynamic process that involves immediate oxidative stress and excitotoxicity followed by inflammation and preprogrammed cell death. This article presents a brief overview of mechanisms of neuroprotection in the developing brain. Although the focus is on ischemic injury, the conclusions drawn apply to any type of brain insult-epileptic seizures, trauma, or ischemia. Strategies of neuroprotection include salvaging neurons through the use of targeted pharmacotherapies, protecting neurons through preconditioning, and repairing neurons by enhancing neurogenesis. Drug therapies that dampen the impact of immediate and downstream postinjury events are only modestly effective in protecting the brain from ischemic injury. In experimental models, complete or true protection can be achieved only through preconditioning, a process during which an animal develops tolerance to an otherwise lethal stressor. Although of no clinical use, preconditioning models have provided valuable insight into how repair systems work in the brain. Cumulative evidence indicates that the same genes that are upregulated during preconditioning, those mediating true protection, are also upregulated during injury and repair. Specifically, hypoxic preconditioning and hypoxic-ischemic insult have been shown to induce hypoxia inducible factor-1 (HIF-1) and its target survival genes, vascular endothelial growth factor (VEGF), and erythropoietin (Epo) in rodents. Of particular interest is the upregulation of Epo, a growth factor that may have therapeutic potential in the treatment of ischemic stroke. At this time, however, the postinjury enhancement of neurogenesis appears to offer the best hope for long-lasting functional recovery following brain injury.


Do biased technological advances affect carbon productivity of service sector: Evidence from China.
Increasing carbon productivity is regarded as one of the significant ways to strike a balance between national economic growth and environmental protection. As the proportion of China's service sector in the national economy rises and the severity of environmental pollution increases, the matter of carbon productivity in service sector required to be explored in depth. This paper focuses on the biased technological advances index of China's service sector and its impact on carbon productivity by constructing a two-layer nested CES production function, proposing policy countermeasures to raise service sector's carbon productivity in China, which is of great practical significance in reducing carbon emissions of China's service sector, improve carbon productivity of China's service sector and promote the green transformation and sustainable development of China's service sector. The results are as follows. (1) The average value of the biased technological advances index of services in China is negative, indicating that technological advances of services in China are biased towards non-energy elements. The biased technological advances indexes of China's service sector in the western, middle and eastern regions are also negative, and the index of the eastern region is the smallest, indicating that the technological advances of the service sector in the eastern region are biased towards non-energy elements to the highest extent. (2) There is a negative correlation between the biased technological advances index and carbon productivity of services in China. In the western, middle and eastern regions of China, the bias of technological advances in eastern China has the greatest effect on China's productivity of carbon in service sector. The policy implication is that in order to increase China's services' productivity of carbon, it is essential to reduce the biased technological advances index of China's service sector.


Corrigendum: A feedback regulatory loop involving dTrbd/dTak1 in controlling IMD signaling in Drosophila Melanogaster.
[This corrects the article DOI: 10.3389/fimmu.2022.932268.].


Influence of luminance gradient reversal on simple cells in feline striate cortex.
1. The sensitivity of simple cells to luminance gradient reversal in bar stimuli has been investigated in the striate cortex of lightly anaesthetized cats.2. The influence of segment(s) of one polarity of contrast, partially masking or added end-on to a bar of reversed contrast, was assessed against a stationary textured background (of intermediate average luminance), which was itself without influence on cell behaviour.3. In either configuration, short segments of reversed contrast were suppressive of bar response, to an extent varying with location along the receptive-field axis, but much greater than predictable from length-summation characteristics. Response suppression, even by very short segments, was often total.4. The effects of longer segments, added end-on to a bar of opposite contrast, depended on the extent of length summation exhibited by each cell. With progressive extension of these segments, some recovery of response occurred in a few simple cells with larger receptive fields, but not in small-field simple cells. The behaviour of end-stopped simple cells was comparable in all respects to that of their end-free counterparts, within the length-summation zone; thereafter, invasion of the inhibitory end-zones by bars of either polarity elicited a generalized decline in response.5. Where responsiveness was restored by adding longer segments of opposite polarity, the response peak shifted to the discharge centre appropriate to that polarity.6. All these results were found with either polarity of contrast, i.e. a light bar plus dark segments or the converse.7. Similar results were obtained for motion in either direction across the receptive field; and also for flash-presentation, over either the centre or flanks (whether ;on' or ;off') of the receptive field.8. The effectiveness of contrasting added segments was assessed as a function of location along the receptive-field axis for flash-presented and for moving stimuli. Suppressive effects were greatest over the centre of the receptive field, declining progressively in either direction along its axis, but over greater distances than anticipated from length summation.9. None of the results presented could have been predicted from length-summation characteristics. They are strongly suggestive of gating, rather than linear, antagonistic interactions.


Aerosol generation during general anesthesia is comparable to coughing: An observational clinical study.
Intubation, laryngoscopy, and extubation are considered highly aerosol-generating procedures, and additional safety protocols are used during COVID-19 pandemic in these procedures. However, previous studies are mainly experimental and have neither analyzed staff exposure to aerosol generation in the real-life operating room environment nor compared the exposure to aerosol concentrations generated during normal patient care. To assess operational staff exposure to potentially infectious particle generation during general anesthesia, we measured particle concentration and size distribution with patients undergoing surgery with Optical Particle Sizer. A single-center observative multidisciplinary clinical study in Helsinki University Hospital with 39 adult patients who underwent general anesthesia with tracheal intubation. Mean particle concentrations during different anesthesia procedures were statistically compared with cough control data collected from 37 volunteers to assess the differences in particle generation. This study measured 25 preoxygenations, 30 mask ventilations, 28 intubations, and 24 extubations. The highest total aerosol concentration of 1153 particles (p)/cm³ was observed during mask ventilation. Preoxygenations, mask ventilations, and extubations as well as uncomplicated intubations generated mean aerosol concentrations statistically comparable to coughing. It is noteworthy that difficult intubation generated significantly fewer aerosols than either uncomplicated intubation (p = .007) or coughing (p = 0.006). Anesthesia induction generates mainly small (<1 µm) aerosol particles. Based on our results, general anesthesia procedures are not highly aerosol-generating compared with coughing. Thus, their definition as high-risk aerosol-generating procedures should be re-evaluated due to comparable exposures during normal patient care. The list of aerosol-generating procedures guides the use of protective equipments in hospitals. Intubation is listed as a high-risk aerosol-generating procedure, however, aerosol generation has not been measured thoroughly. We measured aerosol generation during general anesthesia. None of the general anesthesia procedures generated statistically more aerosols than coughing and thus should not be considered as higher risk compared to normal respiratory activities.


Insertion of a structural domain of interleukin (IL)-1 beta confers agonist activity to the IL-1 receptor antagonist. Implications for IL-1 bioactivity.
We showed previously that replacement of Lys-145 in the IL-1 receptor antagonist (IL-1ra) with Asp resulted in an analog (IL-1ra K145D) with partial agonist activity. To identify additional amino acids that affect IL-1 bioactivity, we created second site mutations in IL-1ra K145D. Substitutions of single amino acids surrounding position 145 were made; none of these substitutions increased the bioactivity of IL-1ra K145D. However, the insertion of the beta-bulge (QGEESN) of IL-1 beta at the corresponding region of IL-1ra K145D resulted in a 3-4-fold augmentation of bioactivity. An additional increase in agonist activity was observed when the beta-bulge was co-expressed with a second substitution (His-54 --> Pro) in IL-1ra K145D. We also show that the bioactivity of both IL-1ra K145D and the triple mutant IL-1ra K145D/H54P/QGEESN is dependent on interaction with the newly cloned IL-1 receptor accessory protein.


Ant Olfaction: Smells Like an Insect, Develops Like a Mammal.
A detailed description of olfactory system development in ants reveals that - unlike in Drosophila and as in mammals - olfactory receptors may play a role, providing new insights into the developmental evolution of complex chemosensory systems.


Inflammatory mediators do not stimulate CGRP release if prostaglandin synthesis is blocked by S(+)-flurbiprofen in isolated rat skin.
Nonsteroidal antiinflammatory drugs are well known as antipyretic analgesics, however, their mode of action is not yet fully understood. Besides their cyclooxygenase (COX) blocking effect other action principles are discussed. In the present study we investigated the effects of the flurbiprofen enantiomers on the stimulated release of calcitonin gene-related peptide (CGRP) from the isolated rat skin as an indirect measure of peripheral nociceptor activation and 'neurogenic inflammation'. Stimulation was performed by a combination of inflammatory mediators (bradykinin, serotonin and histamine, all 10(-5) M). In addition, prostaglandin E(2) (PGE(2)) release was determined in order to verify the inhibitory effect of the tested drugs on prostaglandin production. S(+)-flurbiprofen (10(-7) and 10(-6) M), reported as the COX blocking enantiomer, completely blocked basal as well as stimulated PGE(2) release. Under R(-)-flurbiprofen a reduction of basal PGE(2) release was not significant; the stimulated PGE(2) release, was however significantly reduced at 10(-7) M and completely suppressed at 10(-6) M drug concentration. The stimulated CGRP release was not affected by R(-)-flurbiprofen (10(-7) or 10(-6) M). In contrast, S(+)-flurbiprofen - only at 10(-6) M - significantly reduced the inflammatory mediator-induced CGRP release. This reduction could be reversed by co-administration of PGE(2) (10(-5) M) suggesting that the effect was due to COX block and prostanoid deprivation. Although a higher concentration of the effective enantiomer was needed to inhibit stimulated CGRP than PGE(2) release, flurbiprofen seems to exert the antinociceptive/antiinflammatory effects observed by preventing the secondary cutaneous prostaglandin formation that appears necessary to enable activation by inflammatory mediators of the CGRP-releasing nerve fibers.


Drug permeation enhancement, efficacy, and safety assessment of azelaic acid loaded SNEDDS hydrogel to overcome the treatment barriers of atopic dermatitis.
Atopic dermatitis is one of the most widespread chronic inflammatory skin conditions that can occur at any age, though the prevalence is highest in children. The purpose of the current study was to prepare and optimize the azelaic acid (AzA) loaded SNEDDS using Pseudo ternary phase diagram, which was subsequently incorporated into the Carbopol 940 hydrogel for the treatment of atopic dermatitis. The composition was evaluated for size, entrapment efficiency, in vitro, ex vivo, and in vivo studies. The polydispersity index of the optimized preparation was found to be less than 0.5, and the size of the distributed globules was found to be 151.20 ± 3.67 nm. The SNEDDS hydrogel was characterized for pH, viscosity, spreadability, and texture analysis. When compared to the marketed formulation, SNEDDS hydrogel was found to have a higher rate of permeation through the rat skin. In addition, a skin irritation test carried out on experimental animals showed that the SNEDDS formulation did not exhibit any erythematous symptoms after a 24-h exposure. In conclusion, the topical delivery of AzA through the skin using SNEDDS hydrogel could prove to be an effective approach for the treatment of atopic dermatitis.


Evaluation of PLED as a chelating ligand in the preparation of gallium and indium radiopharmaceuticals.
The 68Ga and 111In complexes of PLED (N,N'-dipyridoxylethylenediamine-N,N'-diacetic acid) were prepared and their biodistribution determined as a function of time following i.v. injection into rats. The 68Ga and 111In complexes behaved identically and were rapidly cleared from the blood via the kidneys into the urine. Similar rapid urinary excretion was observed in the gamma images obtained from a stump-tailed macaque injected with 111In-PLED. Paper electrophoresis at pH 7.35 showed a single radioactive peak for 111In-PLED which migrated towards the anode. PLED administered by i.p. injection was found to speed the blood pool clearance of previously administered 67Ga-citrate.


Retroperitoneal hematoma after manual reduction of indirect inguinal hernia.
This report presents the case of a 59-year-old man with sudden severe pain in the right lower abdomen after manually reducing the right indirect inguinal hernia who had bilateral indirect inguinal hernia for 5 years. A subsequent contrast computed tomography scan with contrast of the abdomen and pelvis revealed a significant extensive retroperitoneal hematoma at the abdomen and pelvis of the right side. There was contrast leaked out, which was suspected from inferior epigastric artery. He underwent successful laparotomy. The bleeding ruptured inferior epigastric artery at the interior side of the deep inguinal ring was found, the deep inguinal ring was avulsed, ligature of the inferior epigastric artery and removal of the retroperitoneal hematoma were done, and the patient was discharged from hospital on the seventh postoperative day. This is the first report in the literature on retroperitoneal hematoma caused by manual reduction of indirect inguinal hernia.


Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia.
The MIR-15A/-16-1 tumor suppressor microRNAs (miRNAs) are deleted in leukemic cells from more than 50% of patients with chronic lymphocytic leukemia (CLL). As these miRNAs are also less abundant in patients without genomic deletion, their downregulation in CLL is likely to be caused by additional mechanisms. We found the primary transcripts (pri-miRNAs) of MIR-15a/-16/-15b to be elevated and processing intermediates (precursor miRNAs) to be reduced in cells from CLL patients (22/38) compared with non-malignant B-cells (n=14), indicating a block of miRNA maturation at the DROSHA processing step. Using a luciferase reporter assay for pri-miR processing we validated the defect in primary CLL cells. The block of miRNA maturation is restricted to specific miRNAs and can be found in the cell line MEC-2, but not in MEC-1, even though both are derived from the same CLL patient. In these cells, the RNA-specific deaminase ADARB1 leads to reduced pri-miRNA processing, but full processing efficiency is recovered upon deletion of the RNA-binding domains or nuclear localization of ADARB1. Thus, we show that, apart from genomic deletion or transcriptional downregulation, aberrant processing of miRNA leads to specific reduction of miRNAs in leukemic cells. This represents a novel oncogenic mechanism in the pathogenesis of CLL.