[Calcitonin prescriptions: an estimate of the expenditure due to inadequate prescription].
The use of calcitonin is very common in patients diagnosed with osteoporosis. The objective of this study was to determine the percentage of adequate prescriptions of calcitonin for patients with osteoporosis and to estimate the costs due to inadequate prescription. Observational study. Four pharmacies in Osona County (Barcelona) were randomly selected. During two time periods, July-September and November-December of 1994, all women filling prescriptions for calcitonin in any of the eight pharmacies were invited to participate in the study. Adequate and inadequate prescription of calcitonin was determined based on the patient's clinical record. Justifiable and non-justifiable prescriptions were then determined after implementing a protocol and reviewing X-rays of the spine. Forty-eight women agreed to participate (participation rate: 68%). In the first analysis, 58.3% (95% CI: 43-72) of prescriptions were determined to be inadequate whereas in the second analysis 29.2% (95% CI: 17-44) were considered non-justifiable. Chronic back pain was associated with non-justifiable prescription of calcitonin (odds ratio: 5.2; 95% CI: 1.3-33.4). In the best of situations, the excess in annual spending due to inadequate prescription was estimated at 13 million pesetas for Osona County, 1,300 million for Catalonia, and 4,300 million for Spain. Between one-third and one-half of patients prescribed calcitonin in the study area apparently do not need it. Many cases of chronic back pain are being treated as osteoporosis without being properly studied. The costs derived from this incorrect practice are important. This study highlights the need for better practices in the diagnosis of osteoporosis.


Antioxidant activity and total phenolic content of ethanolic extract of pomegranate peels, juice and seeds.
Pomegranate (Punica granatum L.) is extensively cultivated in Middle East especially in Iran. For centuries, this fruit has been used in Iranian herbal medicine. Pomegranate peel, seed and juice contain considerable amounts of phenolic compounds and have antioxidant activity. Pomegranate peels, juice and seeds from three regions of Natanz, Shahreza, and Doorak were obtained. Antioxidant activity, total phenolic, flavonoids, and flavonols contents of pomegranate peels, seeds and juices extracts were analyzed. The β-carotene bleaching test and Folin-Ciocalteu method were applied in this study. The pomegranate peel extract showed high levels of antioxidant activity in comparison to seeds and juices. Doorak peel by 58% had the highest antioxidant activity among two other peels. Total phenolics, flavonoids, and flavonols contents of pomegranate peel were evaluated much more higher than seeds and juices. The significant positive correlation between antioxidant activity and total phenolics was reported. According to achieved results, high antioxidant capacity of pomegranate especially peel, had shed light to use them as natural food preservatives.


Unmixing coral fluorescence emission spectra and predicting new spectra under different excitation conditions.
An algorithm was developed that uses prototype spectra and least-squares minimization to unmix the relative contributions of individual pigments to the composite fluorescence emission spectrum of reef corals. Field measurements indicated that it was necessary to include allowance for spectral shift of the wavelength peak of the prototype emission spectra. The unmixed spectra are used to predict the shape and amplitude of composite spectra that would be expected under different excitation conditions. We found that, for cases in which the pigments occur singly or with significant spectral separation, it is necessary to consider the properties of the excitation light sources, only, to make accurate predictions. In cases with spectral overlap the contribution of interpigment coupling cannot be neglected.


Transport vesicle docking: SNAREs and associates.
Proteins that function in transport vesicle docking are being identified at a rapid rate. So-called v- and t-SNAREs form the core of a vesicle docking complex. Additional accessory proteins are required to protect SNAREs from promiscuous binding and to deprotect SNAREs under conditions in which transport vesicle docking should occur. Because access to SNAREs must be regulated, other proteins must also contain specificity determinants to accomplish delivery of transport vesicles to their distinct and specific membrane targets.


Typical and atypical MR imaging features of intracranial epidermoid tumors.
We categorized the MR imaging characteristics of intracranial epidermoid tumors. MR images from 23 cases of intracranial epidermoid tumors were reviewed retrospectively. Signal intensities of tumor relative to surrounding structures were noted, as were the internal architecture of the tumors and the presence and degree of hydrocephalus. Seventeen (74%) of 23 cases of intracranial epidermoid tumors were revealed as slightly hyperintense relative to CSF on T1-weighted MR images. Nineteen (95%) of 20 cases were hyperintense relative to CSF on proton density-weighted MR images. Fifteen (65%) of 23 cases were isointense to CSF on T2-weighted MR images, whereas the remaining eight cases (35%) were hyperintense to CSF on T2-weighted MR images. One (4%) of 23 cases showed signal intensity that was isointense to CSF on all pulse sequences. Fifteen (65%) of 23 cases showed heterogeneous signal characteristics on either T1-weighted or proton density-weighted MR images, or both. Eight (35%) of 23 cases showed a rim of hyperintensity on proton density-weighted MR images. Five (33%) of the 15 cases that received gadolinium showed rim enhancement. Five (22%) of 23 cases were multilocular, with different regions of tumors showing highly variable imaging characteristics. Two (9%) of 23 cases showed high signal intensity on T2-weighted MR images in the adjacent brain parenchyma. Two (9%) of 23 cases showed mild hydrocephalus. Six (43%) of 14 tumors that either originated in or secondarily involved the cerebellopontine angle also extended into the ipsilateral Meckel's cave. On T1-, proton density-, and T2-weighted MR images intracranial epidermoid tumors usually showed heterogeneous signal intensity that was hyperintense to CSF. On all spin-echo pulse sequences epidermoid tumors with signal characteristics isointense to CSF were unusual. Hydrocephalus, even in the setting of marked displacement and compression of the brainstem, was not usually seen on MR imaging. Meckel's cave was often involved secondarily with epidermoid tumors that involved the cerebellopontine angle.


Insulin biosynthesis and secretion.
Studies are presented which support the concept that a cell membrane localized glucoreceptor system is involved in the insulin secretory response to glucose and that the specific stimulation of insulin synthesis by glucose reflects effects at both the transcriptional and posttranscriptional level. After 48 hours of fasting the insulin secretory response to glucose is markedly reduced. This reduction is overcome by 24 hours of refeeding carbohydrate, but notprotein or fat, and is blocked by refeeding in the presence of an inhibitor of RNA synthesis. Although these studies clearly demonstrate an inducible glucoreceptor system, they do not permit conclusions regarding either its composition or location in the beta-cell. Phloridzin, a glycoside with a high affinity for glucose-carrier systems in plama membranes, stimulated basal insulin secretion sixfold. A large number of plant lectins were tested for ability to stimulate insulin release from isolated islets, and only mushroom lectin did so. The lectin concentration producing half-maximal hormone releaseis 3 x 10-7, a value in good agreement with the dissociation constant forlectin binding. Glucose stimulated insulin sythesis in isolated rat islets was determined to be partially inhibited by actinomycin D. The posttranscriptional effect was determined to be increased initiation of total islet mRNAas well as proinsulin mRNA. To futher quantitate the effect of glucose on proinsulin mRNA, immunoprecipitation of proinsulin synthesizing polysomes was accomplished. It appeared that proinsulin is synthesized on a mRNA accommodating six to eight ribosomes, and the size of the proinsulin mRNA is 10-11 S on sucrose gradients. This unexpectedly large size of the proinsulin mRNA is discussed.


Diagnosing Preclinical Cardiac Dysfunction in Swiss Childhood Cancer Survivors: Protocol for a Single-Center Cohort Study.
Cardiovascular disease is the leading nonmalignant cause of late deaths in childhood cancer survivors. Cardiovascular disease and cardiac dysfunction can remain asymptomatic for many years, but eventually lead to progressive disease with high morbidity and mortality. Early detection and intervention are therefore crucial to improve outcomes. In our study, we aim to assess the prevalence of preclinical cardiac dysfunction in adult childhood cancer survivors using conventional and speckle tracking echocardiography; determine the association between cardiac dysfunction and treatment-related risk factors (anthracyclines, alkylating agents, steroids, cardiac radiation) and modifiable cardiovascular risk factors (abdominal obesity, hypertension); investigate the development of cardiac dysfunction longitudinally in a defined cohort; study the association between cardiac dysfunction and other health outcomes like pulmonary disease, endocrine disease, renal disease, quality of life, fatigue, strength and endurance, and physical activity; and gain experience conducting a clinical study of childhood cancer survivors that will be extended to a national, multicenter study of cardiac complications. For this retrospective cohort study, we will invite ≥5-year childhood cancer survivors who were treated at the University Children's Hospital Bern, Switzerland with any chemotherapy or cardiac radiation since 1976 and who are ≥18 years of age at the time of the study for a cardiac assessment at the University Hospital Bern. This includes 544 childhood cancer survivors, of whom about half were treated with anthracyclines and/or cardiac radiation and half with any other chemotherapy. The standardized cardiac assessment includes a medical history focusing on signs of cardiovascular disease and its risk factors, a physical examination, anthropometry, vital parameters, the 1-minute sit-to-stand test, and echocardiography including 2-dimensional speckle tracking. We will invite 544 eligible childhood cancer survivors (median age at the time of the study, 32.5 years; median length of time since diagnosis, 25.0 years) for a cardiac assessment. Of these survivors, 300 (55%) are at high risk, and 244 (45%) are at standard risk of cardiac dysfunction. This study will determine the prevalence of preclinical cardiac dysfunction in Swiss childhood cancer survivors, inform whether speckle tracking echocardiography is more sensitive to cardiac dysfunction than conventional echocardiography, and give a detailed picture of risk factors for cardiac dysfunction. The results will help improve primary treatment and follow-up care of children with cancer. ClinicalTrials.gov NCT03790943; https://clinicaltrials.gov/ct2/show/NCT03790943. DERR1-10.2196/17724.


Randomized trial of 10 days of decitabine ± bortezomib in untreated older patients with AML: CALGB 11002 (Alliance).
Novel treatment strategies are needed for older patients with acute myeloid leukemia (AML). This randomized phase 2 trial compared the efficacy and safety of 20 mg/m2 of IV decitabine on days 1 to 10 alone (arm A) with those of 1.3 mg/m2 of subcutaneous bortezomib (arm B) on days 1, 4, 8, and 11 for up to 4 10-day cycles followed by monthly 5-day cycles. Previously untreated AML patients age ≥60 years (excluding those with FLT3 mutations and favorable-risk cytogenetics) without restrictions in performance status (PS) or organ function were eligible. Median age was 72.4 years (range, 60.5-92.3 years); 31 patients (19%) had baseline PS ≥2, 35 (22%) had an antecedent hematological disorder, 58 had (39%) adverse cytogenetics, and 7 (5%) and 23 (14%) had abnormal cardiac or renal function. There were no statistically significant differences in overall survival (OS) or responses between the 2 treatment arms. The overall response rate (complete remission + complete remission with incomplete blood count recovery) was 39% (n = 64), with median OS of 9.3 months. Nineteen responders (31%) underwent allogeneic stem cell transplantation. The most common adverse event was febrile neutropenia, and there were no unexpected toxicities. Adding bortezomib to decitabine did not improve outcomes, but responses were better than those in previous trials using 5-day decitabine cycles. This trial was registered at www.clinicaltrials.gov as #NCT01420926.


[In vitro formation of glycogenolytic enzyme complexes with the sarcoplasmic reticulum in the skeletal muscles of skates and the frog].
Experimental evidence is presented concerning the existence of complexes of glycogenolytic enzymes with sarcoplasmic reticulum (SR) in skeletal muscles of the skates Dasyatis pastinaca and Raja clavata and frog Rana temporaria. At various stages of preparation of kinase of glycogen phosphorylase (KGP) from ectothermic animals, in contrast to rabbit, association of KGP with the SR and glycogen granules persisted in calcium-free medium. Complex of KGP with glycogen phosphorylase and ATPase could be fractionated only during chromatographic procedure on Sepharose 4B, chromatographic pictures being distinctly different from those obtained for rabbit. It may be suggested that activation of KGP by Ca2+ in a multienzyme SR--glycogenolytic complex plays an important role in regulation of glycogenolysis in muscle tissue of skates, since hormonal stimulation of glycogen phosphorylation had not yet been described for these fishes.


Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma.
The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.


A deimmunised form of the ribotoxin, α-sarcin, lacking CD4+ T cell epitopes and its use as an immunotoxin warhead.
Fungal ribotoxins that block protein synthesis can be useful warheads in the context of a targeted immunotoxin. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus that functions by catalytically cleaving a single phosphodiester bond in the sarcin-ricin loop of the large ribosomal subunit, thus making the ribosome unrecognisable to elongation factors and leading to inhibition of protein synthesis. Peptide mapping using an ex vivo human T cell assay determined that α-sarcin contained two T cell epitopes; one in the N-terminal 20 amino acids and the other in the C-terminal 20 amino acids. Various mutations were tested individually within each epitope and then in combination to isolate deimmunised α-sarcin variants that had the desired properties of silencing T cell epitopes and retention of the ability to inhibit protein synthesis (equivalent to wild-type, WT α-sarcin). A deimmunised variant (D9T/Q142T) demonstrated a complete lack of T cell activation in in vitro whole protein human T cell assays using peripheral blood mononuclear cells from donors with diverse HLA allotypes. Generation of an immunotoxin by fusion of the D9T/Q142T variant to a single-chain Fv targeting Her2 demonstrated potent cell killing equivalent to a fusion protein comprising the WT α-sarcin. These results represent the first fungal ribotoxin to be deimmunised with the potential to construct a new generation of deimmunised immunotoxin therapeutics.


Long-term tillage effect on with-in season variations in soil conditions and respiration from dryland winter wheat and soybean cropping systems.
Soil respiration from agricultural soils is a major anthropogenic source of CO2 to the atmosphere. With-in season emission of soil CO2 from croplands are affected by changes in weather, tillage, plant row spacing, and plant growth stage. Tillage involves physical turning of soils which accelerate residue decomposition and CO2 emission. No-tillage lacks soil disturbance and residues undergo slower decomposition at the surface. In this study, we compared with-in season soil conditions (temperature and moisture) and soil respiration from two major crops (soybean and winter wheat) by making high temporal frequency measurements using automated chambers at half-hourly intervals. The experiment lasted for 179 days. Total number of measurements made from conventional and no-tillage soybean and winter wheat plots were 6480 and 4456, respectively. Average flux after the winter-dormancy period of wheat was 37% higher in tilled soil compared to no-till soil. However, average flux during the soybean growing season was 8% lower in conventional till compared to no-till soil. This differential response of soil respiration in wheat and soybean was primarily due to tillage-induced changes in surface characteristics (residue cover) and soil environmental conditions (soil temperature and soil moisture). Results from this study can help elucidate relationships for modeling and assessment of field-scale soil CO2 emissions from dryland wheat and soybean crops grown in sub-tropics.


Postsplenectomy recurrence of idiopathic thrombocitopenic purpura: role of laparoscopic splenectomy in the treatment of accessory spleen.
Idiopatic thrombocytopenic purpura (ITP) is the most common indication for splenectomy. The failure rate of surgery is about 8% and the failure rate after splenectomy is approximately 28% for all patients. When the presence of an accessory spleen is diagnosed, splenectomy is recommended. Laparoscopic approach is considered the first choice. At our Department, between July and November 2011 two patients underwent laparoscopic accessory splenectomy for recurrence of ITP. Both patients had a previously laparoscopic splenectomy. Preoperative Magnetic Resonance (MR) was performed in both the cases revealing the presence of an accessory spleen. The operative time was 105 and 100 minutes respectively. No perioperative complications occured. Hospital stay was four days in both cases. The first patient had a disease free period of two months; the second one of one month. Both patients restarted immunosuppressive therapy. The relapse of thrombocytopenia post-splenectomy can be associated with the presence of an accessory spleen. The laparoscopic accessory splenectomy should be considered the first choice approach. Surgical accessory splenectomy allows a transitory remission of the disease.


Defending Victims of Bullying in Early Adolescence: A Multilevel Analysis.
Adolescents' defending behaviors in school bullying situations is likely determined by individual characteristics, social status variables, and classroom/school contextual factors operating simultaneously in the peer ecology. However, there is little research on defending behavior that utilizes this multilevel approach. This study investigated how students' willingness to defend victims of bullying was affected by feelings of empathy, perceived popularity, and classroom-level perceived prosocial norms. Participants were 1373 adolescents (40% girls, Mage: 14 yrs) from 54 classrooms in six middle schools in South Korea. These youth reported on their feelings of empathy and how prosocial they perceived their classmates to be. Peer-ratings and peer nominations were used to estimate defending behaviors and which students were perceived as popular. Multilevel analyses showed that participants were more likely to defend victims when they had greater empathy and perceived popularity and when classroom-level prosocial norms were higher. The findings have implications for interventions to reduce school bullying and for studying defending behavior in multiple cultural contexts.


Immunoblot analysis of anti-Ureaplasma urealyticum antibody in pregnant women and newborn infants.
The purpose of the present study was to determine the frequency in which antibody reactive to Ureaplasma urealyticum could be detected in a population of pregnant women and newborn infants. Serum samples from a prospective cohort of 80 healthy, U. urealyticum culture-positive and culture-negative pregnant women and a retrospective cohort of 522 infants born at between 25 and 42 weeks of gestation were studied by immunoblot analysis. Cultures of specimens from the lower genital tract were positive for U. urealyticum for 83% of the pregnant women, and serum immunoglobulin G (IgG) antibody which reacted to U. urealyticum was detectable in 93% of the pregnant women. Samples from five women (8%) had increases in the number of anti-U. urealyticum IgG bands over the course of the pregnancy. Samples from four of these five women had corresponding increases in the number of antibody bands present in IgA immunoblots. Six of the 522 samples from newborns or cord blood (1.1%) were positive for anti-U. urealyticum IgA; 5 of these 6 samples were also positive for IgM. The six anti-U. urealyticum IgA-positive infants were distributed as follows; 3 of 67 (4.5%) infants were delivered at 25 to 30 weeks of gestation, 3 of 176 (1.7%) infants were delivered at 31 to 34 weeks of gestation, and 0 of 279 infants were delivered at > or = 35 weeks of gestation. An antibody response to U. urealyticum can be detected in pregnant women and preterm infants and may serve as a marker of infection.


Long-term follow-up and patient satisfaction after surgery for thoracic outlet syndrome.
The purpose of this study was to review the long-term outcomes, particularly patient satisfaction, of patients surgically treated for thoracic outlet syndrome (TOS). All patients who had undergone surgery for TOS at the University of Iowa Hospitals and Clinics between 1988 and 1999 were reviewed. A retrospective chart review of 29 patients (36 operations) was performed. In addition, 20 (69%) of the patients were able to be contacted for a phone survey. There was no operative mortality. Specific neurologic complications occurred in 4/36 operations (11%) including one brachial plexus traction palsy, two phrenic nerve palsies, and one long thoracic nerve palsy. All nerve palsies were either mild or temporary. Mean follow-up was 4 years. On phone survey, 80% of the patients were actively employed. Twenty-seven percent reported that they had an excellent result, 58% reported they had a good result, 8% reported that they had a fair result, and 8% had a poor result. If they had it to do over again, 85% of the patients would have the same surgery again for relief of TOS.


Thioredoxin reductase and its inhibitors.
Thioredoxin plays a crucial role in a wide number of physiological processes, which span from reduction of nucleotides to deoxyriboucleotides to the detoxification from xenobiotics, oxidants and radicals. The redox function of Thioredoxin is critically dependent on the enzyme Thioredoxin NADPH Reductase (TrxR). In view of its indirect involvement in the above mentioned physio/pathological processes, inhibition of TrxR is an important clinical goal. As a general rule, the affinities and mechanisms of binding of TrxR inhibitors to the target enzyme are known with scarce precision and conflicting results abound in the literature. A relevant analysis of published results as well as the experimental procedures is therefore needed, also in view of the critical interest of TrxR inhibitors. We review the inhibitors of TrxR and related flavoreductases and the classical treatment of reversible, competitive, non competitive and uncompetitive inhibition with respect to TrxR, and in some cases we are able to reconcile contradictory results generated by oversimplified data analysis.


Tumorous conditions of the pediatric hand and wrist: Ten-year experience of a single center.
This study aims to evaluate the distribution and prevalence of pediatric hand tumors and tumor-like lesions according to age and gender. We retrospectively examined the details of hospital records of 646 patients who were operated for hand mass between January 2009 and January 2019 and whose pathological diagnosis was established in the same hospital. A total of 54 patients (18 males, 36 females; mean age 12.07 years; range, 3 month to 17 years) under 18 years of age who had been operated for the wrist or hand mass were included in the study. Out of 54 tumors, 53 were benign (98%) and one was malignant (2%). There were 42 soft tissue tumors (78%) and 12 bone tumors (22%). The most common soft tissue mass was ganglion cyst (n=12). Six out of 12 ganglion cysts were on the dorsal side of hand or wrist and six were on the volar side. The distribution of the tumors according to gender was not statistically significant (p=0.73). We had two recurrences: one patient with giant cell tumor of the tendon sheath and one with palmar fibromatosis. Pediatric hand/wrist masses are mostly benign tumorous conditions. The location of the pathologies may be different from the adults. Diagnosis of the tumor should be established carefully clinically and radiologically while malignant tumors should be kept in mind by both pediatricians and orthopedic surgeons.


The signal sequence receptor, unlike the signal recognition particle receptor, is not essential for protein translocation.
Detergent extracts of canine pancreas rough microsomal membranes were depleted of either the signal recognition particle receptor (SR), which mediates the signal recognition particle (SRP)-dependent targeting of the ribosome/nascent chain complex to the membrane, or the signal sequence receptor (SSR), which has been proposed to function as a membrane bound receptor for the newly targeted nascent chain and/or as a component of a multi-protein translocation complex responsible for transfer of the nascent chain across the membrane. Depletion of the two components was performed by chromatography of detergent extracts on immunoaffinity supports. Detergent extracts lacking either SR or SSR were reconstituted and assayed for activity with respect to SR dependent elongation arrest release, nascent chain targeting, ribosome binding, secretory precursor translocation, and membrane protein integration. Depletion of SR resulted in the loss of elongation arrest release activity, nascent chain targeting, secretory protein translocation, and membrane protein integration, although ribosome binding was unaffected. Full activity was restored by addition of immunoaffinity purified SR before reconstitution of the detergent extract. Surprisingly, depletion of SSR was without effect on any of the assayed activities, indicating that SSR is either not required for translocation or is one of a family of functionally redundant components.


Relationship between DNA cross-links, cell cycle, and apoptosis in Burkitt's lymphoma cell lines differing in sensitivity to nitrogen mustard.
We surveyed 11 Burkitt's lymphoma cell lines for chemosensitivity to nitrogen mustard (HN2) in order to determine whether any simple correlates to cytotoxic response might be revealed. The lines tested varied over a 5-fold range in concentration of HN2 required to inhibit tumor cell growth by 50%. Drug sensitivity correlated neither with continental origin of tumor, growth fraction, presence of Epstein-Barr virus, nor with the precise locations of (8;14) translocation breakpoints. Furthermore, contrary to experience with other cell lines, no simple correlation was found between the HN2 sensitivity of the four most divergent lines (low sensitivity, CA46 and MC116 cells; high sensitivity, Namalwa and JLP119 cells) and exposure to DNA cross-links (area under the DNA cross-linking-versus-time curve). In addition, we found similar extents of gene-specific HN2-induced damage in the native and translocated c-myc alleles of CA46 and JLP119 cells. At equimolar HN2 treatment, CA46 cells exhibited a profound arrest in G2M phase, while JLP119 cells exhibited prolonged S-phase delay. This suggested that despite similar DNA cross-link exposure, JLP119 cells were less able to complete DNA replication while repair was in progress. As cell cycle distribution returned to near normal, JLP119 cells exhibited DNA degradation characterized by oligonucleosome-sized DNA fragments prior to cell membrane disintegration. Our findings indicate that HN2-sensitive Burkitt's lymphoma cells may be more susceptible to delay in S phase for a given frequency of DNA cross-links and that prolongation of S phase correlated with apoptotic cell death.


Extraprostatic extension into periprostatic fat is a more important determinant of prostate cancer recurrence than an invasive phenotype.
Although micrometastasis development correlates closely with the depth of invasion of many tumor types, it is unclear whether invasion into but not through the prostatic pseudocapsule has a negative impact on prognosis, similar to extraprostatic extension. We defined the impact of pseudocapsular invasion on the risk of post-prostatectomy biochemical recurrence. Patients with pT2-3a prostate cancer were identified from a prospectively recorded database. Those with pT2 disease were categorized according to pseudocapsular invasion presence or absence. The impact of pseudocapsular invasion on biochemical recurrence was determined by univariable and multivariable Cox regression analysis. In a cohort of 1,338 patients we identified 595 with organ confined cancer positive for pseudocapsular invasion. Compared to tumors without evidence of invasion, pseudocapsular invasion was positively associated with higher Gleason grade and tumor volume (1.2 vs 1.9 cc, each p<0.001). On univariable analysis there was no difference in biochemical recurrence-free survival between patients with vs without pseudocapsular invasion, although those with extraprostatic extension had significantly lower biochemical recurrence-free survival (p<0.001). This was confirmed on multivariable analysis, which revealed that extraprostatic extension was a significant independent predictor of biochemical recurrence (HR 1.53, p=0.018). The presence of pseudocapsular invasion had no effect (HR 0.81, p=0.33). Pseudocapsular invasion is not a pathological feature associated with an adverse outcome after prostatectomy. Thus, the depth of tumor invasion is not a continuum of risk and access to periprostatic adipose tissue is a more important determinant of disease behavior than an invasive phenotype.


[CME Sonography 101/Answers: Ultrasound of the Musculoskeletal System - Update 2021].
CME Sonography 101/Answers: Ultrasound of the Musculoskeletal System - Update 2021 Abstract. Ultrasound technologies in medicine (and in many other areas of life) continuously undergo enormous technological advances. There is increasing automation in medicine, and this is also true for diagnostic imaging. This article describes the current state of the art in musculoskeletal ultrasound and takes a look into the near future.


Dual Role of the Active Site Residues of Thermus thermophilus 3-Isopropylmalate Dehydrogenase: Chemical Catalysis and Domain Closure.
The key active site residues K185, Y139, D217, D241, D245, and N102 of Thermus thermophilus 3-isopropylmalate dehydrogenase (Tt-IPMDH) have been replaced, one by one, with Ala. A drastic decrease in the kcat value (0.06% compared to that of the wild-type enzyme) has been observed for the K185A and D241A mutants. Similarly, the catalytic interactions (Km values) of these two mutants with the substrate IPM are weakened by more than 1 order of magnitude. The other mutants retained some (1-13%) of the catalytic activity of the wild-type enzyme and do not exhibit appreciable changes in the substrate Km values. The pH dependence of the wild-type enzyme activity (pK = 7.4) is shifted toward higher values for mutants K185A and D241A (pK values of 8.4 and 8.5, respectively). For the other mutants, smaller changes have been observed. Consequently, K185 and D241 may constitute a proton relay system that can assist in the abstraction of a proton from the OH group of IPM during catalysis. Molecular dynamics simulations provide strong support for the neutral character of K185 in the resting state of the enzyme, which implies that K185 abstracts the proton from the substrate and D241 assists the process via electrostatic interactions with K185. Quantum mechanics/molecular mechanics calculations revealed a significant increase in the activation energy of the hydride transfer of the redox step for both D217A and D241A mutants. Crystal structure analysis of the molecular contacts of the investigated residues in the enzyme-substrate complex revealed their additional importance (in particular that of K185, D217, and D241) in stabilizing the domain-closed active conformation. In accordance with this, small-angle X-ray scattering measurements indicated the complete absence of domain closure in the cases of D217A and D241A mutants, while only partial domain closure could be detected for the other mutants. This suggests that the same residues that are important for catalysis are also essential for inducing domain closure.


Psychometric properties of a Dutch translation of the Functionality Appreciation Scale (FAS) among adults in the Netherlands.
The Functionality Appreciation Scale (FAS; Alleva et al., 2017) measures functionality appreciation, the extent to which people appreciate their body for what it is able to do. We translated the FAS to Dutch and evaluated its factor structure and psychometric properties among 471 native Dutch speakers in the Netherlands (255 cisgender women, 204 cisgender men, 8 nonbinary, 1 "other," 3 "rather not say") who were between 18 and 85 years old. Participants completed the Dutch translation of the FAS, followed by questionnaires to assess additional variables of interest (body appreciation, appearance satisfaction, self-esteem, and gratitude). Exploratory factor analysis showed that Dutch FAS scores demonstrated a unidimensional factor structure. Dutch FAS scores demonstrated acceptable internal consistency and construct validity via their positive associations with the additional variables of interest. Dutch FAS scores also demonstrated gender invariance, and women reported higher functionality appreciation than men. Dutch FAS scores evidenced incremental validity for gratitude (but not self-esteem), and were inversely correlated with age and body mass index. Last, 2-week test-retest reliability of the Dutch FAS scores was supported. Overall, these findings provide support that the Dutch FAS is a psychometrically sound instrument to assess functionality appreciation among Dutch speaking adults in the Netherlands.


[Benign tumors of the esophagus].
The authors make an analysis of 30 observations of benign tumors of the esophagus (1979-1989). In 13 patients the tumors were found occasionally during the X-ray endoscopic examination, in 7 patients only the diagnosis was established on the basis of their complains, medical history and findings of an instrumental examination. A histological investigation has diagnosed leiomyoma in 10 patients, polyps in 7 patients and fibroma in 1 patient. Eighteen patients had single tumors, 2 patients had large tumors causing considerable obturation of the esophagus lumen. The endoscopic electroexcision was performed in 12 patients. No complications were noted. Only two patients were operated upon. Tumor enucleation was performed in 1 patients following laparotomy and gastrotomy. The other patient was subjected to resection of the esophagus after Torek followed by plasty of the large intestine. Long-term results were followed-up during 2-10 years. No recurrent tumors were noted. The endoscopic electroexcision of the benign esophageal tumors is the radical operation which is though to be the method of choice, especially for elderly patients with coexistent diseases.


The fine structure of the cilia from ctenophore swimming-plates.
The ctenophore swimming-plate has been examined with the electron microscope. It has been recognized as an association of long cilia in tight hexagonal packing. One of the directions of the hexagonal packing is parallel to the long edge of the swimming-plate and is perpendicular to the direction of the ciliary beat. All the cilia in the swimming-plate are identically oriented. The effective beat in the movement of the swimming-plate is directed towards the aboral pole of the animal, and this is also the side of the unpaired peripheral filament in all the cilia. The direction of the ciliary beat is fixed in relation to the position of the filaments of the cilia. The swimming-plate cilium differs from other types of cilia and flagella in having a filament arrangement that can be described as 9 + 3 as opposed to the conventional 9 + 2 pattern. The central filaments appear in a group of two "tubular" filaments and an associated compact filament. The compact filament might have a supporting function. It has been called "midfilament." Two of the peripheral nine filaments (Fig. 1, Nos. 3 and 8) are joined to the ciliary membrane by means of slender lamellae, which divide the cilium into two unequal compartments. These lamellae have been called "compartmenting lamellae." Some observations of the arrangement of the compartmenting lamelae indicate that they function by cementing the cilia together in lateral rows. The cilia of the rows meet at a short distance from each other, leaving a gap of 30 A only. The meeting points are close to the termini of the compartmenting ridges. An electron-dense substance is sometimes seen bridging the gap. Some irregularities are noted with regard to the arrangement of the compartmenting lamellae particularly at the peripheral rows of cilia. In many cilia in these rows there are small vesicles beneath the ciliary membrane.


Autoimmune pancreatitis presenting a short narrowing of main pancreatic duct with subsequent progression to diffuse pancreatic enlargement over 24 months; natural history of autoimmune pancreatitis.
Initial pancreatogram and natural history of autoimmune pancreatitis (AIP) have not been clarified, and there were few recent studies concerning the association between AIP and intraductal papillary mucinous neoplasm (IPMN). We report an 81-year- old man with AIP associated with IPMN. Although the initial pancreatogram was normal, a short narrowing of the main pancreatic duct (MPD) appeared during a follow-up for IPMN after 6 months, which was highly suggestive of pancreatic cancer. A narrowing of the MPD extended after 15 months, and this progressed to diffuse narrowing of the MPD with an elevation in the serum IgG4 levels after 24 months. Finally, the patient was diagnosed with diffuse-type AIP, according to the Japanese diagnostic criteria 2011 and the International Consensus Diagnostic Criteria. Considering the natural history of AIP, this marked change of the MPD is indicative of this condition. We report a case of AIP presenting with a short narrowing of the MPD with subsequent progression to diffuse pancreatic enlargement during a follow-up for IPMN.


Spray-dried mucoadhesive microspheres: preparation and transport through nasal cell monolayer.
The purpose of this research was to prepare spray-dried mucoadhesive microspheres for nasal delivery. Microspheres composed of hydroxypropyl methylcellulose (H), chitosan (CS), carbopol 934P (CP) and various combinations of these mucoadhesive polymers, and maltodextrin (M), colloidal silicon dioxide (A), and propylene glycol (P) as filler and shaper, were prepared by spray-drying technique. Using propranolol HCl as a model drug, microspheres were prepared at loadings exceeding 80% and yields between 24% and 74%. Bulky, free flowing microspheres that had median particle size between 15 and 23 mum were obtained. Their zeta potential was according to the charge of polymer. Adhesion time of mucoadhesive microspheres on isolated pig intestine was ranked, CS > CP:H > CP > H, while the rank order of swelling was CP > CS > H. Increasing the amount of CP in CP:H formulations increased the percentage of swelling. Infrared (IR) spectra showed no interaction between excipients used except CS with acetic acid. The release of drug from CP and CP:H microspheres was slower than the release from H and CS microspheres, correlated to their viscosity and swelling. Long lag time from the CP microspheres could be shortened when combined with H. The permeation of drug through nasal cell monolayer corresponded to their release profiles. These microspheres affected the integrity of tight junctions, relative to their swelling and charge of polymer. Cell viability was not affected except from CS microspheres, but recovery could be obtained. In conclusion, spray-dried microspheres of H, CS, CP, and CP:H could be prepared to deliver drug through nasal cell monolayer via the opening of tight junction without cell damaging.


Eye movements do not reflect retrieval processes: limits of the eye-mind hypothesis.
This research investigated whether eye movements are informative about retrieval processes. Participants learned facts about persons and locations, and the number of facts (fan) learned about each person and location was manipulated. During a subsequent recognition test, participants made more gazes to high-fan facts than to low-fan facts, and gazes to high-fan facts had a longer duration than gazes to low-fan facts. However, there was no relation between the order in which items were fixated and the relative effect of person or location fan. The effect of person and location fan on gaze duration also did not differ with whether it was the person or location being fixated. A model assuming that the process of retrieval is independent of eye movements was successfully fit to the data on the distribution of gaze durations. According to this model, the effect of fan on number of gazes and gaze duration is an artifact of the longer retrieval times for high-fan facts.


The functional roles of protein glycosylation in human maternal-fetal crosstalk.
The establishment of maternal-fetal crosstalk is vital to a successful pregnancy. Glycosylation is a post-translational modification in which glycans (monosaccharide chains) are attached to an organic molecule. Glycans are involved in many physiological and pathological processes. Human endometrial epithelium, endometrial gland secretions, decidual immune cells, and trophoblasts are highly enriched with glycoconjugates and glycan-binding molecules important for a healthy pregnancy. Aberrant glycosylation in the placenta and uterus has been linked to repeated implantation failure and various pregnancy complications, but there is no recent review summarizing the functional roles of glycosylation at the maternal-fetal interface and their associations with pathological processes. This review aims to summarize recent findings on glycosylation, glycosyltransferases, and glycan-binding receptors at the maternal-fetal interface, and their involvement in regulating the biology and pathological conditions associated with endometrial receptivity, placentation and maternal-fetal immunotolerance. Current knowledge limitations and future insights into the study of glycobiology in reproduction are discussed. A comprehensive PubMed search was conducted using the following keywords: glycosylation, glycosyltransferases, glycan-binding proteins, endometrium, trophoblasts, maternal-fetal immunotolerance, siglec, selectin, galectin, repeated implantation failure, early pregnancy loss, recurrent pregnancy loss, preeclampsia, and fetal growth restriction. Relevant reports published between 1980 and 2023 and studies related to these reports were retrieved and reviewed. Only publications written in English were included. The application of ultrasensitive mass spectrometry tools and lectin-based glycan profiling has enabled characterization of glycans present at the maternal-fetal interface and in maternal serum. The endometrial luminal epithelium is covered with highly glycosylated mucin that regulates blastocyst adhesion during implantation. In the placenta, fucose and sialic acid residues are abundantly presented on the villous membrane and are essential for proper placentation and establishment of maternal-fetal immunotolerance. Glycan-binding receptors, including selectins, sialic-acid-binding immunoglobulin-like lectins (siglecs) and galectins, also modulate implantation, trophoblast functions and maternal-fetal immunotolerance. Aberrant glycosylation is associated with repeated implantation failure, early pregnancy loss and various pregnancy complications. The current limitation in the field is that most glycobiological research relies on association studies, with few studies revealing the specific functions of glycans. Technological advancements in analytic, synthetic and functional glycobiology have laid the groundwork for further exploration of glycans in reproductive biology under both physiological and pathological conditions. A deep understanding of the functions of glycan structures would provide insights into the molecular mechanisms underlying their involvement in the physiological and pathological regulation of early pregnancy. Glycans may also potentially serve as novel early predictive markers and therapeutic targets for repeated implantation failure, pregnancy loss, and other pregnancy complications.


Degradation behavior of soy protein-wheat gluten films in simulated soil conditions.
Films containing soy protein and wheat gluten were exposed to simulated farmland soil mix over a period of 30 days and monitored for degradation. The simulated farmland soil mix (topsoil/sand/Sunshine compost/vermiculite, 59:6:25:10, wt %) was mixed and stored at ambient humidity (48-55%) and temperature (20-24 degrees C); the soil mix was constantly maintained at 15% moisture by weight. Research focused on evaluating the effectiveness of gluten and cysteine additions on biodegradable behavior in the simulated farmland soil conditions. The four types of films, soy protein (S:G 1:0); soy protein with cysteine addition (S:G 1:0 + CYS); soy protein-wheat gluten (S:G 4:1); and soy protein-wheat gluten with cysteine addition (S:G 4:1 + CYS), were prepared at pH 7. 0 for degradation studies. Soy protein-gluten film rapidly degraded with 50% weight loss in about 10 days and with up to 95% weight loss in 30 days. Tensile strength and elongation of all soy protein-gluten films significantly decreased in 3 days. However, cysteine addition delayed the degradation rate of soy protein-gluten films. Soy protein-wheat gluten film disintegrated after 20 days in the simulated farmland soil environment. These results suggest that wheat gluten and cysteine addition to soy protein-based films could delay degradation rates due to their high disulfide contents.


Saireito (a Chinese herbal drug) decreases inhibitory effect of prednisolone and accelerates the recovery of rat hypothalamic-pituitary-adrenal axis.
Saireito, a saiko agent (a Chinese herbal drug), increases the synthesis and secretion of ACTH by stimulating hypothalamic CRH release. In the present study, we examined the effect of food containing saireito (1.5%) on the recovery of the hypothalamic-pituitary-adrenal axis after treating male rats with prednisolone (PSL, 200 microM) in drinking water for 14 days. Saireito was administered during and after PSL administration. The rats were decapitated at various times after PSL administration. Tail-pinch stress had been applied to some rats. The plasma ACTH response to tail-pinch stress in the PSL + saireito group recovered to the control level on day 1, but that in the group given PSL alone recovered on day 3. The ACTH level in the anterior pituitary and the CRH level in the median eminence of the PSL + saireito group returned to the control level on day 3, and that in the group given PSL alone returned to it on day 5. These results indicate that the administration of saireito reduces the negative feedback effect of PSL on the hypothalamus and pituitary and accelerates the recovery of the hypothalamic CRH and pituitary ACTH level after glucocorticoid treatment.


Milk coagulation and gastric emptying in women experiencing gastrointestinal symptoms after ingestion of cow's milk.
Gastrointestinal symptoms after drinking milk are often attributed to lactose intolerance or cow's milk allergy. However, some individuals without either condition still report gastrointestinal symptoms after drinking milk. This may be caused by gastric emptying (GE) rate or gastric protein coagulation. This study aimed to compare GE rate and protein coagulation after milk consumption between individuals reporting gastrointestinal symptoms and those without symptoms using a novel gastric MRI approach. Thirty women were included in this case-control study, of whom 15 reported gastrointestinal symptoms after drinking milk and 15 were controls. Participants underwent gastric MRI before and up to 90 min after consumption of 250 mL cow's milk. Gastric content volume and image texture of the stomach contents were used to determine GE and changes in the degree of coagulation. GE half-time did not differ between the groups (gastrointestinal symptom group 66 ± 18 min; control group 61 ± 14 min, p = 0.845). The gastrointestinal symptom group reported symptoms from 30 min onwards and rated pain highest at 90 min. The control group reported no symptoms. Image texture analyses showed a significantly higher percentage of coagulum and lower percentage of liquid in the group in the GI symptom group (MD 11%, 95% CI [3.9, 17], p = 0.003). In vitro data suggests that pH and proteolytic enzyme activity influence the coagulum structure. Gastric milk coagulation and emptied fraction of stomach content may differ between individuals experiencing symptoms after milk consumption, possibly due to differences in pH and proteolytic enzyme activity.


Over Troubled Water: An Outbreak of Infection Due to a New Species of Mycobacterium following Implant-Based Breast Surgery.
Mycobacterial infection is a rare complication associated with breast surgery using implants. Over the course of 5 months, one center experienced 12 such cases, 10 of which were linked to a single surgeon. Most presented 3 to 6 weeks postoperatively with clear serous drainage from the incision, minimal local redness, no fever or other systemic signs of infection, and negative standard bacterial cultures. Patients were given empiric broad-spectrum oral antibiotic therapy. In eight cases, implants were removed and exchanged for new devices after irrigation of the pocket with antibiotics; these patients nonetheless experienced recurrent infection, which led to explantation (without immediate exchange for new implants). The last two patients proceeded straight to explantation. Because mycobacteria grow in water, the water supply and air-conditioning system were initially suspected as the source, and both were disinfected. However, this did not stop the outbreak. Eventually, the source was traced to a new species of mycobacteria isolated from a garden hot tub. These bacteria had then been unwittingly transferred to patients during surgery. A Triclosan-containing shampoo effectively ended the outbreak. This series is unique in several respects: the novelty of the pathogen, the heavy colonization of the surgeon, and the mechanism of transmission (the first occurrence of human-to-human mycobacterial transfer published in the plastic surgery literature). Surgeons who perform breast surgery with implants should be aware of the possibility of mycobacterial infection. Proactive culturing of the organism, use of antibiotics, and reoperation are essential to good outcomes.


Isolation of a relatively nontoxic 65-kilodalton protein inclusion from the parasporal body of Bacillus thuringiensis subsp. israelensis.
Ultrastructural studies of the mosquitocidal bacterium Bacillus thuringiensis subsp. israelensis revealed that the parasporal body contained three major inclusion types, designated types 1, 2, and 3, which could be differentiated on the basis of electron opacity and size and, to some extent, shape. The type-2 inclusion, which was of moderate electron density and often appeared as a bar-shaped polyhedral body, was isolated on NaBr gradients from purified parasporal bodies and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transmission electron microscopy, and bioassays against neonate larvae of Aedes aegypti. Purified inclusions averaged 150 to 200 nm by 500 to 700 nm in transverse sections and consisted almost exclusively of a 65-kilodalton (kDa) protein contaminated with minor quantities of 38- and 28-kDa proteins. Lethal concentration values at the 50% level for preparations of the purified parasporal body and the type-2 inclusion were, respectively, 0.66 and 43 ng/ml, indicating that the 65-kDa protein is only slightly toxic to mosquitoes in comparison to the intact parasporal body. Analysis of the type-2 polyhedral inclusion by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and bioassays during different stages of purification demonstrated a positive correlation between the toxicity of the preparation and the degree of contamination with the 28-kDa protein. These results indicate that the 65-kDa protein is not the primary larvicidal toxin, although it may act in conjunction with other parasporal body proteins to produce the high mosquitocidal toxicity characteristic of this bacterium.


Evolutionary shifts to self-fertilisation restricted to geographic range margins in North American Arabidopsis lyrata.
Cross-fertilisation predominates in eukaryotes, but shifts to self-fertilisation are common and ecologically and evolutionarily important. Reproductive assurance under outcross gamete limitation is one eco-evolutionary process held responsible for the shift to selfing. Although small effective population size is a situation where selfing plants could theoretically benefit from reproductive assurance, empirical tests of the role of population size are rare. Here, we show that selfing evolved repeatedly at range margins, where historical demographic processes produced low effective population sizes. Outcrossing populations of North American Arabidopsis lyrata have low genetic diversity at geographic margins, with a signature of post-glacial range expansion in the north and rear-edge isolation in the south. Selfing populations occur at the margins of two genetic groups and never in their interior. These results corroborate small effective population size as the promoter of self-fertilisation and have important implications for our understanding of species turnover, range limits and range dynamics.


Neurofeedback and epilepsy.
Over the past three decades, researchers have examined various behavioral approaches to the treatment of epilepsy. One prominent line of inquiry concerns the effectiveness of neurofeedback, which entails the entrainment of specific electroencephalographic frequencies for the purpose of decreasing seizure frequencies in patients with epilepsy. This article reviews the current literature on the efficacy of neurofeedback in reducing seizure frequency. While it is clear that neurofeedback had a positive effect in most of the studies reviewed, these findings are limited due to multiple confounding factors. In the absence of any rigorously controlled studies, the relationship between neurofeedback and seizure frequency cannot be firmly established. Despite these limitations, the promising role of neurofeedback as a treatment for epilepsy is illustrated.


Acute exercise can improve cardioprotection without increasing heat shock protein content.
The aim of this study was to determine the effects of acute bouts of exercise on myocardial recovery after ischemia and heat shock protein expression. Adult female Sprague-Dawley rats were divided into five groups: 1) 1-day run (1DR; n = 6) and 2) 3-day run (3DR; n = 7), in which rats ran for 100 min at a speed of 20 m/min up a 6 degrees grade for 1 or 3 consecutive days; 3) 1-day cold run (1CR), in which rats ran the same as 1DR but with wet fur at 8 degrees C, which prevented an elevation of core temperature (n = 8); 4) heat shock sedentary (HS), in which rats had their core temperatures raised to 42 degrees C one time for 15 min (n = 5); and 5) sedentary control (n=15). Cardiac function was analyzed 24 h after the last treatment using an isolated, working heart model. Nonpaced hearts were initially perfused under normoxic conditions, then underwent 17 min of global, normothermic (37 degrees C) ischemia, and, finally, were allowed to recover for 30 min under normoxic conditions. The concentration of the 72-kDa heat shock protein (HSP 72) was measured in each left ventricle. Compared with that in the sedentary group, recovery of cardiac output x systolic pressure (CO x SP) was enhanced (P < 0.05) in all treatment groups when the postischemic value was covaried with the preischemic value. No differences in CO x SP were found (P > 0.05) between the following groups: 1DR vs. 3DR, 1DR vs. HS, and 1DR vs. 1CR. Heat shock protein concentration was significantly greater (P < 0.05) than that in the sedentary controls in HS, 1DR, and 3DR groups, but not for 1CR. The concentration of HSP 72 was not significantly correlated with postischemic CO x SP (R2 = 0.197, P > 0.05). We conclude that acute bouts of exercise can produce cardioprotective effects without an elevation of HSP 72.


Why carve out? Determinants of behavioral health contracting choice among large U.S. employers.
Many U.S. employers have carved substance abuse and mental health services out of their medical plans, changing the way millions of people access care. Employers that take this approach contract directly with specialized vendors, bypassing their general health plans. Since carving out may alter access and treatment, there is a need to understand why employers take this approach. This article reviews various hypotheses about why purchasers carve out and tests them using data from a survey of America's largest employers, the Fortune 500 firms. Size is the strongest predictor of an employer's decision to carve out behavioral health once other characteristics are controlled for. Employers that report they value coordination are less likely to carve out, while those that value special expertise are more likely to carve out. Employers are less likely to carve out enrollees in health maintenance organizations (HMOs) than those in other types of plans.


After more than a decade of soil moisture deficit, tropical rainforest trees maintain photosynthetic capacity, despite increased leaf respiration.
Determining climate change feedbacks from tropical rainforests requires an understanding of how carbon gain through photosynthesis and loss through respiration will be altered. One of the key changes that tropical rainforests may experience under future climate change scenarios is reduced soil moisture availability. In this study we examine if and how both leaf photosynthesis and leaf dark respiration acclimate following more than 12 years of experimental soil moisture deficit, via a through-fall exclusion experiment (TFE) in an eastern Amazonian rainforest. We find that experimentally drought-stressed trees and taxa maintain the same maximum leaf photosynthetic capacity as trees in corresponding control forest, independent of their susceptibility to drought-induced mortality. We hypothesize that photosynthetic capacity is maintained across all treatments and taxa to take advantage of short-lived periods of high moisture availability, when stomatal conductance (gs ) and photosynthesis can increase rapidly, potentially compensating for reduced assimilate supply at other times. Average leaf dark respiration (Rd ) was elevated in the TFE-treated forest trees relative to the control by 28.2 ± 2.8% (mean ± one standard error). This mean Rd value was dominated by a 48.5 ± 3.6% increase in the Rd of drought-sensitive taxa, and likely reflects the need for additional metabolic support required for stress-related repair, and hydraulic or osmotic maintenance processes. Following soil moisture deficit that is maintained for several years, our data suggest that changes in respiration drive greater shifts in the canopy carbon balance, than changes in photosynthetic capacity.


Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) induced by oral metronidazole.
Baboon syndrome is a special form of systemic contact dermatitis to systemic or local administration of contact allergens. Baboon syndrome without known previous cutaneous sensitisation was also described as drug-related baboon syndrome or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). The major drugs causing SDRIFE was beta-lactam antibiotic such as amoxicillin and ampicillin. We report a case of 16-year-old woman who developed pruritic eruptions after oral metronidazole treatment for diarrhea. She was diagnosed SDRIFE according to her clinical and histopathological findings. To our knowledge, our patient is the first case who developed SDRIFE due to metronidazole in the literature.


Impact of antibiotic resistance and of adequate empirical antibiotic treatment in the prognosis of patients with Escherichia coli bacteraemia.
Escherichia coli is the most frequent Gram-negative organism causing bacteraemia. There are few data about prognostic factors of bloodstream infections due to E. coli. In particular, the consequences of antibiotic resistance and of adequate empirical antibiotic treatment on outcome remain broadly unknown. We conducted a retrospective cohort study of patients with E. coli bacteraemia between January 1997 and June 2005 to identify any association between antibiotic resistance, adequacy of empirical antibiotic therapy and mortality. Of 663 patients with E. coli bacteraemia, 36 (5.4%) died. Patients with multidrug-resistant (MDR) E. coli bacteraemia had a significantly lower frequency of correct empirical antibiotic treatment than patients with non-MDR E. coli bacteraemia [relative risk (RR) 0.53; 95% confidence interval (CI) 0.48-0.67], and also had a significantly higher mortality (RR 3.31; 95% CI 1.72-6.36). An association between the number of antibiotics to which E. coli was resistant with adequacy of empirical antibiotic (P < 0.001) and with mortality (P < 0.001) was detected. After adjustment for other significant risk factors and confounders, the inadequacy of empirical antibiotic treatment was associated with an increased mortality (adjusted OR 2.98; 95% CI 1.25-7.11). When the adequacy of empirical treatment was excluded from the model, the presence of MDR E. coli in blood cultures was also associated with the prognosis (adjusted OR 3.11; 95% CI 1.3-7.44). In multivariate analysis, other variables associated with the outcome were age, the presence of severe sepsis or shock, Charlson index score and a non-urinary origin of the bacteraemia. Adequacy of empirical antibiotic treatment is an independent risk factor for mortality in patients with E. coli bacteraemia. MDR E. coli bacteraemia had a worse prognosis due, at least in part, to a lower frequency of correct empirical treatment.


Antibody array in a multiwell plate format for the sensitive and multiplexed detection of important plant pathogens.
The global seed market is considered to be an important industry with a total value of $10,543 million US dollars in 2012. Because plant pathogens such as bacteria and viruses cause a significant economic loss to both producers and exporters, the seed export industry urgently requires rapid, sensitive, and inexpensive testing for the pathogens to prevent disease spreading worldwide. This study developed an antibody array in a multiwell plate format to simultaneously detect four crucial plant pathogens, namely, a bacterial fruit blotch bacterium Acidovorax avenae subsp. citrulli (Aac), Chilli veinal mottle virus (ChiVMV, potyvirus), Watermelon silver mottle virus (WSMoV, tospovirus serogroup IV), and Melon yellow spot virus (MYSV, tospovirus). The capture antibodies specific to the pathogens were immobilized on each well at preassigned positions by an automatic microarrayer. The antibodies on the arrays specifically captured the corresponding pathogens present in the sample extracts. The presence of pathogens bound on the capture antibodies was subsequently detected by a cocktail of fluorescently conjugated secondary antibodies. The limits of detection of the developed antibody array for the detection of Aac, ChiVMV, WSMoV, and MYSV were 5 × 10(5) CFU/mL, 30 ng/mL, 1000 ng/mL, and 160 ng/mL, respectively, which were very similar to those of the conventional ELISA method. The antibody array in a multiwell plate format accurately detected plant pathogens in single and multiple detections. Moreover, this format enables easy handling of the assay at a higher speed of operation.


Preparing to reach: selecting an adaptive long-latency feedback controller.
In a voluntary movement, the nervous system specifies not only the motor commands but also the gains associated with reaction to sensory feedback. For example, suppose that, during reaching, a perturbation tends to push the hand to the left. With practice, the brain not only learns to produce commands that predictively compensate for the perturbation but also increases the long-latency reflex gain associated with leftward displacements of the arm. That is, the brain learns a feedback controller. Here, we wondered whether, during the preparatory period before the reach, the brain engaged this feedback controller in anticipation of the upcoming movement. If so, its signature might be present in how the motor system responds to perturbations in the preparatory period. Humans trained on a reach task in which they adapted to a force field. During the preparatory period before the reach, we measured how the arm responded to a pulse to the hand that was either in the direction of the upcoming field, or in the opposite direction. Reach adaptation produced an increase in the long-latency (45-100 ms delay) feedback gains with respect to baseline, but only for perturbations that were in the same direction as the force field that subjects expected to encounter during the reach. Therefore, as the brain prepares for a reach, it loads a feedback controller specific to the upcoming reach. With adaptation, this feedback controller undergoes a change, increasing the gains for the expected sensory feedback.


Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria.
Podocytes are specialized epithelial cells that play a significant role in maintaining the integrity of the glomerular filtration barrier and preventing urinary protein leakage. We investigated the contribution of protein tyrosine phosphatase Shp2 to lipopolysaccharide (LPS)-induced renal injury. We report increased Shp2 expression in murine kidneys and cultured podocytes following an LPS challenge. To determine the role of podocyte Shp2 in vivo, we generated podocyte-specific Shp2 knockout (pod-Shp2 KO) mice. Following administration of LPS, pod-Shp2 KO mice exhibited lower proteinuria and blood urea nitrogen concentrations than controls indicative of preserved filter integrity. In addition, renal mRNA and serum concentrations of inflammatory cytokines IL-1β, TNFα, INFγ and IL-12 p70 were significantly decreased in LPS-treated knockout mice compared with controls. Moreover, the protective effects of podocyte Shp2 deficiency were associated with decreased LPS-induced NF-κB and MAPK activation, nephrin phosphorylation and attenuated endoplasmic reticulum stress. These effects were recapitulated in differentiated E11 murine podocytes with lentiviral-mediated Shp2 knockdown. Furthermore, Shp2 deficient podocytes displayed reduced LPS-induced migration in a wound healing assay. These findings identify Shp2 in podocytes as a significant contributor to the signaling events following LPS challenge and suggest that inhibition of Shp2 in podocytes may present a potential therapeutic target for podocytopathies.


Frost hardiness of tree species is independent of phenology and macroclimatic niche.
The differences in timing in bud burst between species have been interpreted as an adaptation to late frost events in spring. Thus, it has been suggested that the degree of frost susceptibility of leaves is species-specific and depends on the species' phenology and geographic distribution range. To test for relationships between frost tolerance and phenology as well as between frost tolerance and distribution range across Central European tree species, we studied the frost hardiness of closed buds before bud burst and of freshly opened buds at the time of bud burst. We hypothesized that species with early bud burst and species distributed in eastern and northern areas were more frost tolerant than species with late bud burst and species distributed in western and southern areas. Frost hardiness was estimated by exposing twigs to 11 frost temperatures between -4 °C and -80 °C and by assessing tissue damage by the electrolyte leakage method. In contrast to our hypotheses, neither frost hardiness of closed buds nor frost hardiness of freshly opened buds were related to any variable describing species' macroclimatic niche. Furthermore, frost hardiness of freshly opened buds did not differ among species. Thus, the investigated species with early bud burst take higher risks of frost damage than the species with late bud bursts. These findings indicate that frost hardiness might not play the key role in limiting the geographic distribution ranges previously anticipated.


B lymphocytes promote lymphogenous metastasis of lymphoma and melanoma.
The prognosis of patients with many types of cancers correlates with the degree of metastasis to regional lymph nodes (LNs) and vital organs. However, the mechanisms and route of cancer cell metastasis are still unclear. Previous studies determined that B-cell accumulation in tumor-draining LNs (TDLNs) induces lymphatic sinus growth (lymphangiogenesis) and increases lymph flow, which could actively promote tumor dissemination through the lymphatic system. Using young Eµ-c-Myc mice that feature LN B-cell expansion as hosts for tumor transplants, we show that subcutaneously implanted lymphomas or melanomas preferentially spread to TDLNs over non-TDLNs, thus demonstrating that these tumors initially metastasize through lymphatic rather than through hematogenous routes. In addition, the rate and amount of tumor dissemination is greater in Eµ-c-Myc mice versus wild-type hosts, which correlates with LN B-cell accumulation and lymphangiogenesis in Eµ-c-Myc hosts. The increased lymphatic dissemination in Eµ-c-Myc hosts is further associated with rapid hematogenous tumor spread of subcutaneously implanted lymphomas, suggesting that TDLN metastasis secondarily drives lymphoma spread to distant organs. In contrast, after intravenous tumor cell injection, spleen metastasis of lymphoma cells or lung metastasis of melanoma cells is similar in Eµ-c-Myc and wild-type hosts. These studies demonstrate that the effect of Eµ-c-Myc hosts to promote metastasis is limited to the lymphatic route of dissemination. TDLN B-cell accumulation, in association with lymphangiogenesis and increased lymph flow, thus significantly contributes to dissemination of lymphomas and solid tumors, providing new targets for therapeutic intervention to block metastasis.


Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity.
This study shows that removal of a T cell subpopulation can evoke effective tumor immunity in otherwise nonresponding animals. Elimination of CD25-expressing T cells, which constitute 5-10% of peripheral CD4+ T cells in normal naive mice, elicited potent immune responses to syngeneic tumors in vivo and eradicated them. The responses were mediated by tumor-specific CD8+ CTLs and tumor-nonspecific CD4-8- cytotoxic cells akin to NK cells. Furthermore, in vitro culture of CD25+4+ T cell-depleted splenic cell suspensions prepared from tumor-unsensitized normal mice led to spontaneous generation of similar CD4-8- cytotoxic cells capable of killing a broad spectrum of tumors; reconstitution of CD25+4+ T cells inhibited the generation. In this culture, self-reactive CD25-4+ T cells responding to self peptides/class II MHC complexes on APCs spontaneously proliferated upon removal of CD25+4+ T cells, secreting large amounts of IL-2. The IL-2 thus produced appeared to be responsible for the generation of CD4-8- NK cells as lymphokine-activated killer cells, because direct addition of an equivalent amount of IL-2 to the culture of CD4-8- cells generated similar lymphokine-activated killer/NK cells, whereas coculture of normal CD4-8- cells with CD25-4+ T cells from IL-2-deficient mice did not. Thus, removal of immunoregulatory CD25+4+ T cells can abrogate immunological unresponsiveness to syngeneic tumors in vivo and in vitro, leading to spontaneous development of tumor-specific effector cells as well as tumor-nonspecific ones. This novel way of evoking tumor immunity would help to devise effective immunotherapy for cancer in humans.


[Clinical features and treatment of Wegener's granulomatosis (author's transl)].
Between 1972 and 1978 a total of 16 patients, aged 19 to 70 years, seven of them women, were diagnosed as having Wegener's granulomatosis. The course of the disease in some instances was rapidly progressive, in some protracted. Nine patients have died, three of them within three months. The diagnosis can only be made after intensive ear-nose-throat, medical and histological studies. Early administration of cyclophosphamide seems to influence the course of the disease favourably.


Autism spectrum disorders, risk communication, and the problem of inadvertent harm.
Autism spectrum disorders (ASDs) are an issue of significant and growing importance to the field of public health. The prevalence of ASDs is rising, and these disorders significantly impact the quality of life of affected persons and their families. Though the etiology of ASDs has long been poorly understood, in recent years, studies are revealing genetic and environmental risk information about ASDs, with much more risk information expected to follow from scientific studies currently underway. The availability of this risk information raises questions about whether and how it should be communicated to individuals, families, and the public at large. One ethical issue of particular concern with ASD risk communication is the possibility that it may cause inadvertent harm to risk message recipients. Here we review the emerging picture of ASD risk, discuss some ways in which it may lead to inadvertent harm, and suggest some future directions for risk communication research and practice that might help to address this issue.


Integrating mind and body: Investigating differential activation of nodes of the default mode network.
The default mode network (DMN) is a large-scale brain network tightly correlated with self and self-referential processing, activated by intrinsic tasks and deactivated by externally-directed tasks. In this study, we aim to investigate the novel approach of default mode activation during progressive muscle relaxation and examine whether differential activation patterns result from the movement of different body parts. We employed neuroimaging to investigate DMN activity during simple body movements, while performing progressive muscle relaxation. We focused on differentiating the neural response between facial movements and movements of other body parts. Our results show that the movement of different body parts led to deactivation in several DMN nodes, namely the temporal poles, hippocampus, medial prefrontal cortex (mPFC), and posterior cingulate cortex. However, facial movement induced an inverted and selective positive BOLD pattern in some of these areas precisely. Moreover, areas in the temporal poles selective for face movement showed functional connectivity not only with the hippocampus and mPFC but also with the nucleus accumbens. Our findings suggest that both conceptual and embodied self-related processes, including body movements during progressive muscle relaxation, may be mapped onto shared brain networks. This could enhance our understanding of how practices like PMR influence DMN activity and potentially offer insights to inform therapeutic strategies that rely on mindful body movements.


The relations between ionic and non-ionic diffusion of sulfonamides across the rabbit cornea.
We studied the transcorneal permeability of five carbonic anhydrase inhibitors, with particular attention to the passage of these acidic compounds in their ionized and nonionized forms. Their pKs varied from 5.9 to 8.0, and CHCl3/pH 7.2 buffer partition coefficients from 10(-4) to 25. Solutions of appropriate pH of each compound were applied to the cornea in steady state, and the rates of passage to the anterior chamber for each compound in each form were measured. The rate constants for the ionized forms were surprisingly high, only four- to sevenfold less than those for the uncharged species. Thus these compounds penetrate the cornea in both forms, and the data show that by increasing the pH of solutions, and thereby solubility, the overall rates of accumulation in the eye are increased.


Facility and Geographic Variation in Rates of Successful Community Discharge After Inpatient Rehabilitation Among Medicare Fee-for-Service Beneficiaries.
The Improving Medicare Post-Acute Care Transformation (IMPACT) Act of 2014 mandated a quality measure of successful community discharge for postacute care services. Examining variation in performance nationally can help identify opportunities for improving patient-centered quality of care. To examine US facility-level and geographic variation in rates of successful community discharges after inpatient rehabilitation. This retrospective cohort study of Medicare claims data from December 31, 2013, through October 1, 2015, included 1154 inpatient rehabilitation facilities submitting claims to the Centers for Medicare & Medicaid Services and a total of 487 862 Medicare fee-for-service beneficiaries discharged from inpatient rehabilitation facilities. Analyses were performed from December 8, 2017, through September 11, 2018. Successful community discharge as defined for the Discharge to Community-Post-Acute Care Inpatient Rehabilitation Facility Quality Reporting Program measure. To be considered a successful community discharge, patients had to discharge from the inpatient rehabilitation facility to the community (ie, home or self-care) and remain there without experiencing an unplanned rehospitalization or dying within the following 31 days. Centers for Medicare & Medicaid Services specifications were followed to identify the cohort, define the outcome, and calculate risk-standardized facility and state rates. Among the 487 862 patients included in the cohort, mean (SD) age was 76.4 (10.8) years, and 56.9% were female. The overall rate of successful community discharge after inpatient rehabilitation was 63.7% (95% CI, 63.6%-63.8%). Risk-standardized rates ranged from 42.9% to 83.6% across inpatient rehabilitation facilities. Two hundred sixteen facilities (18.7%) performed significantly better than the mean national rate and 203 (17.6%) performed significantly worse (P < .05). Risk-standardized state rates ranged from 55.9% to 73.3%. Rates were lowest in the Northeast (Massachusetts, 55.9%; New Hampshire, 57.0%) and highest in the West (Oregon, 70.3%; Hawaii, 73.3%). The observed variation suggests opportunities exist for improving this important, patient-centered national quality measure. Future research is needed to identify the aspects of care delivery and the community services and supports that facilitate successful community discharge. These findings can be used to guide care improvement efforts and further improve the consistency and quality of postacute care.


Binaural processing and phonological awareness in Australian Indigenous children from the Northern Territory: A community based study.
Research has found that otitis media (OM) is highly prevalent in Australian Indigenous children, and repeated bouts of OM is often associated with minimal-to-moderate hearing loss. However, what is not yet clear is the extent to which OM with hearing loss impacts auditory signal processing specifically, but also binaural listening, listening in noise, and the potential impact on phonological awareness (PA) - an important, emergent literacy skill. The goal of this study was to determine whether auditory abilities, especially binaural processing, were associated with PA in children from populations with a high incidence of OM, living in a remote Australian Indigenous community in the Northern Territory (NT). Forty-seven 5-12-year-olds from a bilingual school participated in the study. All were tested to determine hearing sensitivity (pure tone audiometry and tympanometry), with PA measured on a test specifically developed in the first language of the children. OM often results in a hearing loss that can affect binaural processing: the Dichotic Digit difference Test (DDdT) was used to evaluate the children's dichotic listening and the Listening in Spatialized Noise-sentences test (LiSN-S) was used to evaluate their abilities to listen to speech-in-noise. Seventeen (36%) and 16 (34%) had compromised middle ear compliance (combined Type-B and -C) in the right and left ear respectively. Six children demonstrated a bilateral mild hearing loss, and another five children demonstrated a unilateral mild hearing loss. Thirty-one children were able to complete the DDdT listening task, whereas only 24 completed the speech in noise task (LiSN-S). Forty-four children (94%) were able to complete the letter identification subtask, comprising part of the PA task. The findings revealed that age was significantly correlated with all tasks such that the older children performed better across the board. Once hearing thresholds were controlled for, PA also correlated significantly with both binaural processing tasks of dichotic listening (r = 0.59, p < 0.001) and listening to speech in noise (r = -0.56, p = 0.005); indicating a potential association between early, emergent literacy and listening skills. The significant correlations between phonological awareness and dichotic listening as well as phonological awareness with listening to speech-in-noise skills suggests auditory processing, rather than hearing thresholds per se, are associated to phonological awareness abilities of this cohort of children. This suggests that the ability to process the auditory signal is critical.


Monoamine neurotransmitter interactions and the prediction of antidepressant response.
Clinical studies of monoamine neurotransmitter function in depression have concentrated on individual monoamines without focusing on interactions between monoamine systems. Virtually all modern studies have found significant correlations between monoamine metabolite concentrations in cerebrospinal fluid (CSF). These correlations should in part reflect interactions between central monoamine systems. In the present analysis, CSF had been obtained from depressed patients before (n = 40) and after (n = 36) antidepressant treatment. The patients were grouped based on their response to treatment. Absolute concentrations of CSF monoamine metabolites (homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol) did not differ between the two groups before or after treatment. However, when correlations between metabolites were compared, nonresponders to treatment differed considerably from responders. In responders, as in previously described normal populations, all three metabolites correlated with one another before and after treatment, and treatment-induced changes in metabolite concentrations also correlated with one another. In contrast, metabolites in nonresponders did not correlate with one another before treatment, nor did treatment-induced changes correlate with one another in this group. Furthermore, correlations between treatment-induced changes in metabolites differed significantly between responders and nonresponders, and there was a trend for pretreatment correlations to differ as well. The lack of correlation between monoamine metabolites in nonresponders suggests that interactions between monoamine systems may be disrupted in these individuals. Using CSF metabolite correlations to study neurotransmitter interactions may have clinical relevance and yields information not available from examining neurotransmitters in isolation.


Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss.
In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding α-galactosidase A lead to accumulation of globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are poorly replicating, with little ability to compensate for cell loss. In this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases. Podocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion-a strong prognosticator of adverse renal outcomes in Fabry disease-as well as with decreasing GFR. Given the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.


Molecular ultrasound imaging: current status and future directions.
Targeted contrast-enhanced ultrasound (molecular ultrasound) is an emerging imaging strategy that combines ultrasound technology with novel molecularly-targeted ultrasound contrast agents for assessing biological processes at the molecular level. Molecular ultrasound contrast agents are nano- or micro-sized particles that are targeted to specific molecular markers by adding high-affinity binding ligands onto the surface of the particles. Following intravenous administration, these targeted ultrasound contrast agents accumulate at tissue sites overexpressing specific molecular markers, thereby enhancing the ultrasound imaging signal. High spatial and temporal resolution, real-time imaging, non-invasiveness, relatively low costs, lack of ionising irradiation and wide availability of ultrasound systems are advantages compared to other molecular imaging modalities. In this article we review current concepts and future directions of molecular ultrasound imaging, including different classes of molecular ultrasound contrast agents, ongoing technical developments of pre-clinical and clinical ultrasound systems, the potential of molecular ultrasound for imaging different diseases at the molecular level, and the translation of molecular ultrasound into the clinic.


Theoretical study of vibrational and optical spectra of methylene-bridged oligofluorenes.
We report a systematic characterization of methylene-bridged fluorene oligomers constructed of two, four, six, and eight aromatic rings using time-dependent density functional theory (TDDFT), the ab initio approximate coupled-cluster singles and doubles (CC2) method, and semiempirical spectroscopic Zerner's intermediate neglect of differential overlap method (ZINDO/S). Geometry optimizations have been performed for the ground state and for the first electronically excited state. Vertical excitations and the fluorescence transition from the lowest excited state have been calculated. Computed ground-state geometries and infrared spectra for fluorene are in good agreement with experimental results. The RI-CC2 and ZINDO/S absorption and fluorescence spectra agree very well with the available experimental data for studied fluorene oligomers and for para oligophenylenes films. On the other hand, TDDFT calculations underestimate excitation and fluorescence energies systematically for larger systems (N > 4) in comparison with the above-mentioned results. The effective conjugation length was estimated to 13-14 repeat units. The computed radiative lifetimes for the fluorene molecule show good agreement with experiment within realistic expectations. The decrease of the radiatiave fluorescence lifetime with the increase in the conjugation length has been discussed also.


Characterization of 5-hydroxytryptamine1B receptors in rat spinal cord via [125I]iodocyanopindolol binding and inhibition of [3H]-5-hydroxytryptamine release.
The aim of the present study in rat spinal cord synaptosomes was to compare the pharmacological characteristics of the serotonin (5-HT)1B receptor defined by [125I]iodocyanopindolol [( 125I] ICYP) binding and the 5-HT autoreceptor defined by inhibition of [3H]-5-HT release. In Percoll gradient Fractions 3 and 4 of spinal cord synaptosomes, a single saturable binding site for [125I]ICYP with a maximum binding of 70 and 134 fmol/mg, respectively, was demonstrated in the presence of 30 microM isoproterenol. The Kd of 0.16 nM did not vary between fractions. Competition for [125I]ICYP binding by various 5-HT agonists and antagonists also indicated a single site model based on a Hill coefficient of approximately 1.0. The most potent compounds at displacing [125I]ICYP binding were RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole), 5-carboxyamidotryptamine HCl, 5-methoxytryptamine, 5-HT and CGS 12066B (7-trifluoromethyl-4(4 methyl-1-pyrolo[1,2-a]-quinoxaline malate). [125I]ICYP binding was not altered by compounds with activity at 5-HT1A, 5-HT1C, 5-HT2, 5-HT3 or alpha-2 receptor sites. Similar to the pharmacological characteristics of the 5HT1B site defined by [125I]ICYP, compounds most active at inhibiting 15 mM K(+)-stimulated release of [3H]-5-HT were RU24969 = 5-carboxyamidotryptamine HCl = CGS 12066B greater than 5-methoxytryptamine greater than 5-HT. Compounds with activity at 5-HT1A, 5-HT1C, 5-HT2 or 5-HT3 sites were inactive. A correlation analysis of selective 5-HT1B compounds comparing the pKD for displacement of [125I]ICYP vs. the IC50 for inhibition of [3H]-5-HT release demonstrated the pharmacological similarity of the presynaptic inhibitory 5-HT autoreceptor and the 5-HT receptor site defined by [125I]ICYP binding in spinal cord synaptosomes (r = 0.791, P = .0193). Although [125I]ICYP binding was unaltered, alpha-2 agonists such as clonidine, norepinephrine and UK 14304 [5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) as well as the alpha-2 antagonists rauwolscine and yohimbine also decreased the K(+)-stimulated release of [3H]-5-HT and phentolamine, an alpha-2 antagonist increased release. The action of these alpha-2 compounds to alter [3H]-5-HT release suggests the presence of heteroreceptors localized on 5-HT terminals in the spinal cord. These results point out that [125I]ICYP identifies the 5-HT1B receptor, and affinity of compounds for this site predicts action at the 5-HT1B autoreceptor.(ABSTRACT TRUNCATED AT 400 WORDS)


The mevalonate pathway as a therapeutic target in the Ph-negative chronic myeloproliferative disorders.
The Ph-negative chronic myeloproliferative disorders (CMPDs) polycythaemia vera, essential thrombocytosis and idiopathic myelofibrosis are acquired stem cell disorders, which pathophysiologically are featured by clonal myeloproliferation and accumulation of myeloid cells, the latter being consequent to decreased apoptosis. Myelofibrosis and neoangiogenesis in the bone marrow and spleen are the histopathological hallmarks of idiopathic myelofibrosis but may develop in the other diseases as well. In patients with myelofibrosis elevated levels of circulating CD34+ cells are highly characteristic being partly explained by a proteolytic bone marrow mileu owing to excessive release of various proteases with ensuing extracellular matrix degradation and constitutive mobilisation of CD34+ cells into the peripheral blood. Thrombohaemorrhagic complications are major clinical problems contributing significantly to morbidity and mortality. Based upon in vitro and in vivo studies of the effects of statins (antithrombotic, antiproliferative, antiangiogenic, antiproteolytic) and zoledronic acid (antiproliferative antiproliferative, antiangiogenic, antiproteolytic) this review focusses on the translation of these effects into potential clinical benefits of combinational therapy with these agents in patients with CMPDs.


[Ploidy and liquid-holding recovery in yeasts sensitive to radiation and nitrous acid].
The effects of genome ploidy and posttreatment incubation on inactivation by nitrous acid (NA) were studied in normal, radio- and nitrous acid-sensitive strains of yeast. In normal yeast cells the increase of ploidy (haploid to triploid) resulted in "the protective effect", i.e. haploid cells were the most sensitive, triploid -- the most resistant. This "protective effect" is absent in polyploid yeast homozygous for the xrs1-5 (rad 54) mutation; in this case the NA-sensitivity rises with the increase of ploidy, i.e. haploid cells are the most resistant ones. The effect of liquid holding (LH) after the NA treatment depends on the genetic background and ploidy of treated cells. Posttreatment incubation in buffer has practically no effect on the survival of wild-type Berkeley's yeast strains (1n, 2n, 3n). The highly homozygous haploid strains from Zakharov' collection, both wild type and xrs1-5 mutant, exhibit no LH-recovery too. However the death of wild-type cells drastically rises in LH-condition as the ploidy increases. 24 hours incubation in buffer results in at least a ten-fold decrease in survival of wild type 2n, 3n, 4n cells. The loss of viability is proportional to the time of incubation, but the cell titer being constant. The strains (2n, 3n, 4n) homozygous for the xrs1-5 mutation (rad 54) show considerable LH-recovery. It is supposed that the xrs1-5 mutation results in the derepression of the prereplicative pathway of LH-recovery which eliminates the NA-INDUCED DAMAGE OF DNA.


Human monoclonal antibody that recognizes the V3 region of human immunodeficiency virus gp120 and neutralizes the human T-lymphotropic virus type IIIMN strain.
We describe a human IgG1 monoclonal antibody (N701.9b) derived by Epstein-Barr virus transformation of B cells from a human immunodeficiency virus-seropositive asymptomatic donor. This antibody was shown to recognize the principal neutralizing domain contained within the V3 region of gp120 of the MN strain of human immunodeficiency virus and MN-like strains, as determined by binding to the PB-1 fragment of MN gp120 and to synthetic peptides corresponding to the V3 region of MN and related virus strains. The epitope identified by monoclonal antibody N701.9b was mapped to a segment of V3 containing at least 7 amino acids (amino acids 316-322), which is located in the "tip" and "right" side of the V3 loop of the MN strain. Furthermore, this antibody manifested potent type-specific fusion-inhibitory activity against the MN strain but not against the IIIB or RF virus strains. This antibody also neutralized four virus isolates that had MN-like V3 region sequences and failed to neutralize three other strains containing unrelated V3 region sequences. Our findings confirm that the V3 region stimulates type-specific neutralizing antibody during natural human immunodeficiency virus infection in humans. The potential clinical use of this antibody is discussed.