Benfluorex metabolism complemented by electrochemistry-mass spectrometry.
The hypolipidemic and hypoglycemic drug benfluorex was widely applied to treat type 2 diabetes mellitus and metabolic syndrome in overweight patients since 1976. However, benfluorex was connected to multiple cases of valvular heart disease and pulmonary arterial hypertension later on. Similar adverse drug reactions were previously found to be associated to the structurally related drug fenfluramine, which was attributed to the formation of its N-deethylated metabolite norfenfluramine. Even though norfenfluramine was known to be a common metabolite of fenfluramine and benfluorex, only fenfluramine was withdrawn from European and United States markets in 1997 while benfluorex remained available until 2009. In this work, the metabolism of benfluorex is simulated by an online hyphenation of electrochemistry and mass spectrometry and the observed transformation products are further characterized using liquid chromatography and high-resolution tandem mass spectrometry. Using this approach, norfenfluramine is found to be the main electrochemical transformation product of benfluorex. Considering the knowledge about norfenfluramine toxicity, rapid metabolite screening using electrochemistry hyphenated to mass spectrometry could have been used to predict the potential of benfluorex for adverse drug reactions early on, showcasing the value of electrochemical metabolism mimicry for rapid drug safety evaluation.


Outcomes of Quadriceps Tendon With Patellar Bone Block Anterior Cruciate Ligament Reconstruction in Adolescent Patients With a Minimum 2-Year Follow-up.
The incidence of anterior cruciate ligament (ACL) injury in the adolescent population is increasing. The quadriceps tendon-patellar bone autograft (QPA) has been established as a reliable graft choice for ACL reconstruction in the adult population. To investigate graft failure, ability to return to sport, patient-reported functional outcomes, joint laxity, and subsequent injury among adolescent patients >2 years after primary ACL reconstruction with the QPA. Case series; Level of evidence, 4. Consecutive patients who underwent QPA ACL reconstruction performed by a single surgeon were identified from an existing database. Information available in the database included demographics, concomitant/subsequent injuries, surgical procedures, graft failure, return to sport, and Lachman examination collected by medical record review. Pediatric International Knee Documentation Committee (Pedi-IKDC) and Lysholm scores were collected by telephone or during a clinic visit >2 years postoperatively. The final cohort included 81 of 104 consecutive adolescent patients aged 10 to 18 years (mean ± SD, 15.9 ± 1.7 years at the time of surgery) for whom follow-up information was collected at >2 years after surgery. The cumulative incidence of graft failure within the 36-month follow-up period was 1.2% (95% CI, 0.1%-11.4%). The rate of ipsilateral non-ACL injuries was similar (1.2%; 95% CI, 0.2%-7.6%). Contralateral ACL and non-ACL injuries requiring surgical intervention were documented in 9.8% (95% CI, 4.9%-19.5%). The median Pedi-IKDC score was 94 (interquartile range, 89-98). The median Lysholm score was 99.5 (interquartile range, 89.0-100.0). At 36 months after surgery, 87.9% (95% CI, 81.4%-94.9%) of individuals had returned to play. The quadriceps tendon-patellar autograft is a novel graft that demonstrates excellent stability and favorable patient-reported outcomes. Based on these results, the QPA is a reliable choice for primary ACL reconstruction in adolescent patients.


Right ventricular filling detected by pulsed Doppler echocardiography during the convalescent stage of inferior wall acute myocardial infarction.
To evaluate right ventricular (RV) diastolic function in patients with inferior wall acute myocardial infarction (AMI), flow velocity patterns of the RV inflow tract were studied in patients with anterior AMI (n = 32), inferior AMI (n = 32) and angina pectoris without left ventricular asynergy (n = 10) using pulsed Doppler echocardiography. Doppler examinations were performed at least 4 weeks after the attack. Twenty-seven healthy persons served as control subjects. Three Doppler variables were measured at the RV inflow tract: the ratio of the late diastolic peak flow velocity due to atrial contraction to the rapid filling peak flow velocity in early diastole (A/E) and the acceleration time and deceleration time of the RV rapid filling wave. A/E in patients with inferior AMI (1.01 +/- 0.24, mean +/- standard deviation) was significantly greater than in those with anterior AMI (0.80 +/- 0.16, p less than 0.001) and angina pectoris (0.79 +/- 0.17, p less than 0.01) and in normal subjects (0.70 +/- 0.17, p less than 0.001). A/E in patients with inferior AMI correlated with the ratio of left ventricular to RV end-diastolic pressure (r = -0.60, p less than 0.05). A/E in inferior AMI with relatively high RV end-diastolic pressure (more than 8 mm Hg, n = 8) was significantly greater than that in those with normal pressure (8 mm Hg or less, n = 9). A/E in patients with proximal right coronary artery occlusion was significantly greater than that in those with distal occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Impact of HIV/AIDS on mothers in southern India: a qualitative study.
The purpose of this study is to explore the perceptions and needs of mothers living with HIV to gain greater insights into the challenges they face in relation to their health seeking behavior, fears around disclosure, and issues related to stigma and discrimination. This qualitative study utilized focus groups consisting of a sample of 60 HIV-infected mothers recruited from a large maternity hospital and STD clinic in Chennai, India. Discrimination by physicians and other health care workers has been a major impediment expressed by mothers living with HIV in accessing quality health care. Mothers living with HIV are increasingly concerned about how and when to disclose their HIV status to their children and the repercussions which could result from disclosure. The findings of this study call for urgent intervention strategies taking into consideration these various concerns and needs of mothers living with HIV and their children.


Principles of care and management in a laboratory animal facility.
The keeping of animals in an enclosed area and their use for scientific work goes back to the beginning of the Christian era. This activity gradually developed into the specific science we know today. Principles of housing, animal care, equipment and management according to which, it is felt a modern animal facility should be designed, equipped and operated, are discussed.


External magnetic fields affect the biological impacts of superparamagnetic iron nanoparticles.
Superparamagnetic iron oxide nanoparticles (SPIONs) are recognized as one of the promising nanomaterials for applications in various field of nanomedicine such as targeted imaging/drug delivery, tissue engineering, hyperthermia, and gene therapy. Besides their suitable biocompatibility, SPIONs' unique magnetic properties make them an outstanding candidate for theranostic nanomedicine. Very recent progress in the field revealed that the presence of external magnetic fields may cause considerable amount of SPIONs' agglomeration in their colloidal suspension. As variation of physicochemical properties of colloidal nanoparticles has strong effect on their biological outcomes, one can expect that the SPIONs' agglomeration in the presence of external magnetic fields could change their well-recognized biological impacts. In this case, here, we probed the cellular uptake and toxicity of the SPIONs before and after exposure to external magnetic fields. We found that the external magnetic fields can affect the biological outcome of magnetic nanoparticles.


Impacts of converting from leaded to unleaded gasoline on ambient lead concentrations in Jakarta metropolitan area.
Total suspended particulate mater (TSP) concentrations were monitored for one year from July 2000 and for one year from April 2003 in Jakarta City. Thirteen elemental TSP components, aluminum (Al), sodium (Na), iron (Fe), lead (Pb), potassium (K), zinc (Zn), titanium (Ti), manganese (Mn), bromine (Br), copper (Cu), chromium (Cr), nickel (Ni), and vanadium (V) were analyzed by a sequential X-ray fluorescence spectrometer. Al, Na, Fe, K, and Pb were major components at most of the sampling locations in 2000. However, only Pb in 2003 dramatically decreased to one tenth. The phase-out of leaded gasoline began on July 1, 2001 in Jakarta City and lead content in gasoline decreased to one tenth, too. The decrease in Pb concentration was a result of the phase-out of leaded gasoline, as lead emissions mainly are exhaust gas from vehicles.


Measurement of backbone hydrogen-deuterium exchange in the type III secretion system needle protein PrgI by solid-state NMR.
In this report we present site-specific measurements of amide hydrogen-deuterium exchange rates in a protein in the solid state phase by MAS NMR. Employing perdeuteration, proton detection and a high external magnetic field we could adopt the highly efficient Relax-EXSY protocol previously developed for liquid state NMR. According to this method, we measured the contribution of hydrogen exchange on apparent 15N longitudinal relaxation rates in samples with differing D2O buffer content. Differences in the apparent T1 times allowed us to derive exchange rates for multiple residues in the type III secretion system needle protein.


Epidemiological aspects of rheumatoid arthritis patients affected by oral bisphosphonate-related osteonecrosis of the jaws.
This literature review aims to evaluate the epidemiologic profile of patients with rheumatoid arthritis (RA) that developed a bisphosphonate-related osteonecrosis that affect the jaws (BRONJ), including demographic aspects, as well as clinical and therapeutic issues. A search of PUBMED/MEDLINE, Scopus, and Cochrane databases from January 2003 to September 2011 was conducted with the objective of identifying publications that contained case reports regarding oral BRONJ in RA patients. Patients with RA who develop oral BRONJ are usually women above 60 years taking steroids and long-term alendronate. Most of them have osteoporosis, and lesions, triggered by dental procedures, are usually detected at stage II in the mandible. Although there is no accepted treatment protocol, these patients seem to have better outcomes with conservative approaches that include antibiotic therapy, chlorhexidine, and drug discontinuation.


Urologic Management and Complications in Spinal Cord Injury Patients: A 40- to 50-year Follow-up Study.
To assess the management and types of urologic complications in spinal cord injury (SCI) patients and to explore the risk factors for these complications. A total of 43 SCI patients with a median follow-up of 45 (range 40-50) years were included in this retrospective study. All medical charts were reviewed for demographics, urologic complications, and bladder management. Recurrent urinary tract infection (UTI) was noted in all patients, with an average incidence of 6.1 cases per 5 years per person. UTI incidence peaked in the 1st and 10th 5-year intervals. Besides UTI, the most common complications were bladder stone (49%), hydronephrosis (47%), and vesicoureteral reflux (33%). Most complications initially occurred during the first 25 years post injury. Male gender, cervical injury, and condom catheter use were closely related to complications, particularly UTI and renal insufficiency. The bladder managements used for the longest period were condom catheter in men (79%) and clean intermittent catheterization in women (33%), with an average maintenance of 23.6 and 38.0 years, respectively. With long follow-up, a wide and complex range of urologic complications occurred in SCI patients and continued to do so throughout the period of follow-up. A greater risk of urologic complications may be seen with certain factors (male gender, cervical SCI, and condom catheter use); however, all patients with SCI are at risk of urinary complications over time. Thus, even long-term patients who are thought to be "stable" require regular follow-up and surveillance.


Direct site-specific radiolabeling of an Affibody protein with 4-[18F]fluorobenzaldehyde via oxime chemistry.
In this study, we introduce a methodology for preparing 18F-labeled Affibody protein, specifically 18F-Anti-HER2 dimeric Affibody (14 kDa), for in vivo imaging of HER2neu with positron emission tomography (PET). We have used 4-[18F]fluorobenzaldehyde as a synthon to prepare 18F-Anti-HER2 Affibody. Aminooxy-functionalized Affibody (Anti-HER2-ONH2) was incubated with 4-[18F]fluorobenzaldehyde in ammonium acetate buffer at pH 4 in the presence of methanol at 70 degrees C for 15 min. The resulting 18F-labeled Affibody molecule was evaluated as a PET probe in xenograft models expressing HER2. We have successfully prepared 18F-Anti-HER2 dimeric Affibody (14 kDa), N-(4-[18F]fluorobenzylidine)oxime-Anti-HER2 Affibody, [18F]FBO-Anti-HER2, in 26-30% radiochemical yields (decay corrected). High-contrast small-animal PET images with relatively moderate tumor uptake (1.79 +/- 0.40% ID/g) were observed for the 18F-Anti-HER2 Affibody. Site-specific 18F-labeled Affibody against HER2 has been synthesized via chemoselective oxime formation between an aminooxy-functionalized Affibody and 18F-fluorobenzaldehyde. The results have implications for radiolabeling of other affibodies and macromolecules and should also be important for advancing Affibody imaging with PET.


Influence of antimicrobial photodynamic therapy in carious lesion. Randomized split-mouth clinical trial in primary molars.
The literature presents many studies regarding photodynamic antimicrobial therapy (aPDT). However, the great variety of protocols to be used can directly influence its effectiveness in reducing microorganisms. The aim of this randomized split-mouth clinical study was to evaluate the effect of aPDT in the reduction of Streptococcus mutans and their effect on restorations performed. Twenty children between 6 and 8 years old with active caries and dentin cavitation, located on the occlusal surface of homologous primary molars were included. The selective removal of carious tissue was performed in both molars, than one was subsequently restored and the other received aPDT treatment on the affected dentin with low intensity laser (InGaAlP) associated to 0.005% methylene blue photosensitizer before restoration. Dentin collections were performed only in the tooth submitted to aPDT in three moments: before and after selective caries removal and after application of aPDT. The restorations were analyzed after polishing and after 6 months using United States Public Health Service (USPHS) method. Data were analyzed using ANOVA with repeated measures and Bonferroni post-hoc test with a significance level of 5%. There was a significant reduction on the amount of microorganisms after selective caries removal (p = 0.04) and also after the application of aPDT (p = 0.01). The reduction of S. mutans CFU was of 76.4% after caries removal, but associated with aPDT was 92.6%. After 6 months of clinical evaluation, no difference between groups was found for retention, marginal adaptation, color, marginal discoloration, and secondary caries. aPDT can be used as an additional treatment against cariogenic microorganisms after selective caries removal without compromising composite resin restorations.


ULTRASTRUCTURAL DIFFERENCES OF PRESPORES DEVELOPMENTAL STAGES AND MEIOSPORES OF SPECIES OF CLOSELY RELATED MICROSPORIDIA OF GENERA AMBLYOSPORA AND TRICHOCTOSPOREA (AMBLYOSPORIDAE: MICROSPORIDIA) FROM BLOOD-SUKING MOSQUITOES OF THE GENUS AEDES (DIPTERA: CULICIDAE).
Ultrastructure of prespore developmental stages, with emphasis on meiospores, has been examined in closely related genera of Microsporidia, Amblyospora and Trichoctosporea, isolated from larvae adipose tissue of mosquitoes Aedes in order to compare morphology of these parasites. Ultrastructural differences between Amblyospora and Trichoctosporea have been found to concern the secret filling episporal space of sporophorous vesicle, wall of mature spores, the polaroplast and membranes of thin coils of polar tubes. The episporal secret contributes to formation of meiospore wall and its structure is one of key systematic features to be considered in the identification of microsporidia.


Identification of potential genetic Loci and polygenic risk model for Budd-Chiari syndrome in Chinese population.
Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction, posing life-threatening risks in severe cases. Reported risk factors include inherited and acquired hypercoagulable states or other predisposing factors. However, many patients have no identifiable etiology, and causes of BCS differ between the West and East. This study recruited 500 BCS patients and 696 normal individuals for whole-exome sequencing and developed a polygenic risk scoring (PRS) model using PLINK, LASSOSUM, BLUP, and BayesA methods. Risk factors for venous thromboembolism and vascular malformations were also assessed for BCS risk prediction. Ultimately, we discovered potential BCS risk mutations, such as rs1042331, and the optimal BayesA-generated PRS model presented an AUC >0.9 in the external replication cohort. This model provides particular insights into genetic risk differences between China and the West and suggests shared genetic risks among BCS, venous thromboembolism, and vascular malformations, offering different perspectives on BCS pathogenesis.


Thiazolidine derivatives: In vitro toxicity assessment against promastigote and amastigote forms of Leishmania infantum and ultrastructural study.
Neglected diseases, such as Leishmaniasis, constitute a group of communicable diseases that occur mainly in tropical countries. Considered a public health problem with limited treatment. Therefore, there is a need for new therapies. In this sense, our proposal was to evaluate in vitro two series of thiazolidine compounds (7a-7e and 8a-8e) against Leishmania infantum. We performed in vitro evaluations through macrophage cytotoxicity assays (J774) and nitric oxide production, activity against promastigotes and amastigotes, as well as ultrastructural analyzes in promastigotes. In the evaluation of cytotoxicity, the thiazolidine compounds presented CC50 values between 8.52 and 126.83 μM. Regarding the evaluation against the promastigote forms, the IC50 values ranged between 0.42 and 142.43 μM. Compound 7a was the most promising, as it had the lowest IC50. The parasites treated with compound 7a showed several changes, such as cell body shrinkage, shortening and loss of the flagellum, intense mitochondrial edema and cytoplasmic vacuolization, leading the parasite to cell inviability. In assays against the amastigote forms, the compound showed a low IC50 (0.65 μM). These results indicate that compound 7a was efficient for both evolutionary forms of the parasite. In silico studies suggest that the compound has good oral bioavailability. These results show that compound 7a is a potential drug candidate for the treatment of Leishmaniasis.


Characterization of different compost extracts using Fourier-transform infrared spectroscopy (FTIR) and thermal analysis.
Compost extract or "compost tea" is a liquid extract of compost obtained by mixing compost and water for a defined period of time. Compost tea contains nutrients and a range of different organisms and is applied to the soil or directly to plants with the principal aim of suppressing certain plant diseases. In addition, the application of compost tea supplies nutrients and organic matter to the soil. Thermal analysis and Fourier transform infrared spectroscopy (FTIR) are two widely applied analytical techniques for establishing the stability of compost, and although numerous studies have evaluated the capacity of compost tea to suppress plant diseases, there are no studies employing these techniques to characterize compost-tea. For the present study, 12 compost extracts were produced under varying conditions in a purpose-built reactor. Two different composts, an stable compost produced from manure and an unstable compost produced from municipal solid waste, respectively, two aeration systems (aerated and non-aerated extracts) and three temperatures (10, 20 and 30 degrees C) were used in these experiments. The extracts were freeze-dried and subsequently analysed, together with the two composts, by means of FTIR and thermal analysis. Extracts produced from high stability compost, independently of the conditions of aeration and temperature, showed very similar results. In contrast, differences among extracts produced from the unstable compost were more noticeable. However, the different conditions of aeration and temperature during the production of the extracts only explained partially these differences, since the transformations undergone by compost over the 3 months that the experiments lasted were also reflected in the composition of the extracts. In spite of everything, extraction process favoured the degradation of easily oxidizable organic matter, which was more abundant in unstable compost. This degradation was more intense for non-aerated processes, probably due to the longer duration of these (10 days) with respect to aerated extractions (2 days). The effect of temperature was not clear in these experiments, although high temperatures could increase micro organism activity and consequently favour the degradation of easily oxidizable organic matter.


Reduced adult survival and increased reproduction in Swedish kestrels.
The decline of the Swedish kestrel population during the 1950s and 1960s is probably caused by a decrease in yearly adult survival rate, from 0.66±0.03 S.E. to 0.48±0.03 S.E.Contrary to what would be expected from generally harmful effects of pesticides on reproduction, brood size increased from 3.4±0.4 S.E. to 4.2±0.2 S.E. during the same period.We found no relationship between brood size and breeding density. The increased reproduction therefore does not seem to be a density-dependent effect of reduced population size. The increase in brood size may rather be an evolved adaptation, selected for by increased optimal reproduction as a consequence of higher adult mortality.


Calcaneal bone mineral density in young adults prescribed selective serotonin reuptake inhibitors.
Several previous studies have reported both an association between selective serotonin reuptake inhibitors (SSRI) and decreased bone mineral density and increased fractures, but no previous studies have specifically evaluated bone health in young adults who have a history of SSRI use. The purpose was to characterize the effect SSRI use in early adulthood on bone mineral density. A cross-sectional study was conducted on subjects who voluntarily responded to recruitment methods for the study. Young adults aged 18 to 25 years who were currently or had previously taken an SSRI for a minimum of 3 consecutive months were included in the study. A subject interview was conducted on each patient to collect background information. Each subject's calcaneal bone mineral density was then measured with an ultrasonometer. Complete data were collected on 51 subjects. The median duration of SSRI use was 24 ± 54 months. A significant negative correlation was observed between SSRI duration and calcaneal ultrasound T-score (r = -0.53, P < 0.001) which was unchanged in depressed subjects. Subjects on continuous SSRIs for >24 months had a significantly lower median T-score (0.30 ± 0.93) than subjects taking SSRIs for ≤ 24 months (0.90 ± 0.81; P = 0.0010). In this young relatively healthy population who were following most of the recommendations to improve bone health, a significant negative correlation was observed between the duration of SSRI use and bone mineral density. Subjects who were on SSRIs for longer than 24 months had a significantly lower T-score. Further large scale longitudinal studies are needed in this younger population to determine the effects of chronic SSRI use on bone health.


The 19-27 amino acid segment of gp51 adopts an amphiphilic structure and plays a key role in the fusion events induced by bovine leukemia virus.
Previous results indicate that the external glycoprotein gp51 of bovine leukemia virus plays an important role in the process of cell fusion induced by bovine leukemia virus (Bruck, C., Mathot, S., Portetelle, D., Berte, C., Franssen, J. D., Herion, P., and Burny, A. (1982) Virology 122, 342-352; Vonèche, V., Portetelle., D., Kettmann, R., Willems, L., Limbach, K., Paoletti, E., Ruysschaert, J. M., Burny, A., and Brasseur, R. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 3810-3814) and suggest that a region encompassing residues 23 and 25 of gp51 is involved in this process (Portetelle, D., Couez, D., Bruck, C., Kettmann, R., Mammerickx, M., Van der Maaten, M., Brasseur, R., and Burny, A. (1989) Virology 169, 27-33; Mamoun, R., Morisson, M., Rebeyrotte, N., Busetta, B., Couez, D., Kettmann, R., Hospital, M., and Guillemain, B. (1990) J. Virol. 64, 4180-4188). X-ray diffraction studies performed on envelope glycoproteins of influenza virus indicate that the NH2-terminal part of the external glycoprotein lies very close to the fusion peptide. The same overall structure seems to exist in human immunodeficiency virus as suggested by site-directed mutagenesis followed by syncytia induction assays. Our theoretical studies indicate that a segment expanding between residues 19 and 27 of gp51 probably adopts an amphipathic beta-strand structure. We hypothesize that the amphipathic 19-27 structure of gp51 plays an important role in the process of membrane fusion by interacting with the fusion peptide or with another region of gp30. Mutational analysis disrupting the amphipathy of the 19-27 region strongly altered the fusogenic capacity of the gp51-gp30 complex.


Impact of baseline tumor burden on overall survival in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the SELECT global phase 3 trial.
Radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) is an aggressive form of thyroid cancer. Lenvatinib is a multikinase inhibitor approved for treatment of RAI-R DTC. The impact of tumor response and tumor burden on overall survival (OS) after lenvatinib treatment in patients with RAI-R DTC was assessed. Data from patients treated with lenvatinib (N = 261) in SELECT were retrospectively analyzed. Patients were divided into lenvatinib responder or nonresponder subgroups and into low (≤40 mm) or high (>40 mm) tumor burden subgroups based on baseline sums of diameters of target lesions using Response Evaluation Criteria in Solid Tumors, version 1.1 (cutoff values were determined by receiver-operating characteristic analyses). Associations of tumor response and tumor burden with OS were assessed. Median OS was prolonged in lenvatinib responders versus nonresponders (52.2 vs 19.0 months; hazard ratio [HR], 0.32; 95% CI, 0.23-0.46). Patients with a lower tumor burden who received lenvatinib had prolonged OS versus those with a higher tumor burden (median OS, not reached vs 29.1 months, respectively; HR, 0.42; 95% CI, 0.28-0.63). Baseline tumor burden was associated with OS by multivariate analysis (HR, 0.56; 95% CI, 0.35-0.89; P = .0138). Patients with a lower tumor burden receiving lenvatinib had prolonged OS compared with those with a higher tumor burden receiving lenvatinib. Baseline tumor burden may be a prognostic factor for OS in patients with RAI-R DTC treated with lenvatinib.


2,2-dimethyl cyclopentanones by acid catalyzed ring expansion of isopropenylcyclobutanols. A short synthesis of (+/-)-alpha-cuparenone and (+/-)-herbertene.
2,2-dimethyl cyclopentanones are readily prepared by acid catalyzed ring expansion of isopropenylcyclobutanols; the method allows ready access to the family of sesquiterpenes cuparanes and herbertanes, as demonstrated by the synthesis of (+/-)-alpha-cuparenone and the direct precursor of (+/-)-herbertene.


Bridging of partially negative atoms by hydrogen bonds from main-chain NH groups in proteins: The crown motif.
The backbone NH groups of proteins can form N1N3-bridges to δ-ve or anionic acceptor atoms when the tripeptide in which they occur orients them appropriately, as in the RL and LR nest motifs, which have dihedral angles 1,2-αR αL and 1,2-αL αR , respectively. We searched a protein database for structures with backbone N1N3-bridging to anionic atoms of the polypeptide chain and found that RL and LR nests together accounted for 92% of examples found (88% RL nests, 4% LR nests). Almost all the remaining 8% of N1N3-bridges were found within a third tripeptide motif which has not been described previously. We term this a "crown," because of the disposition of the tripeptide CO groups relative to the three NH groups and the acceptor oxygen anion, and the crown together with its bridged anion we term a "crown bridge." At position 2 of these structures the dihedral angles have a tight αR distribution, but at position 1 they have a wider distribution, with ϕ and ψ values generally being lower than those at position 1. Over half of crown bridges involve the backbone CO group three residues N-terminal to the tripeptide, the remainder being to other main-chain or side-chain carbonyl groups. As with nests, bridging of crowns to oxygen atoms within ligands was observed, as was bridging to the sulfur atom of an iron-sulfur cluster. This latter property may be of significance for protein evolution.


Detection of cardiac right-to-left shunts by contrast-enhanced harmonic carotid duplex sonography.
Paradoxical embolization by cardiac right-to-left shunts (RLS) is increasingly recognized as an important factor for embolic stroke. Contrast-enhanced transcranial Doppler sonography (ce-TCDS) is an established diagnostic tool for RLS detection but is frequently limited because of an inadequate temporal acoustic bone window. The purpose of this study was to determine whether extracranial sonography (ECS) using harmonic frequencies improves detection of RLS. Extracranial color duplex sonography using harmonic frequencies enables visualization of even single ultrasound contrast agent microbubbles because of oscillation. Patients with stroke and positive RLS findings on transesophageal echocardiography underwent a simultaneous extracranial and transcranial sonographic examination of the proximal common carotid artery (CCA) and middle cerebral artery (MCA) on the same side. A Valsalva strain was performed for 10 seconds after intravenous bolus injection of a galactose-based nontranspulmonary contrast agent. The B-mode frame sequences of the transverse plane of the CCA obtained by harmonic ECS and the ce-TCDS recordings of high-intensity transient signals from the MCA were analyzed offline. In all patients with RLS, the shunts could be identified by harmonic ECS. A close correlation could be seen between the count of visualized microbubbles in the CCA and the number of high-intensity transient signals detected on ce-TCDS in the ipsilateral MCA. The results of this study indicate that contrast-enhanced ultrasound harmonic imaging of the CCA using a Valsalva strain might be an optional screening tool for detection of cardiac RLS in patients with insufficient acoustic bone windows.


Evaluation of bis-alkylamidoxime O-alkylsulfonates as orally available antimalarials.
The main threat to controlling malaria is the emerging multidrug resistance of Plasmodium sp. parasites. Bis-alkylamidines were developed as a potential new chemotherapy that targets plasmodial phospholipid metabolism. Unfortunately, these compounds are not orally available. To solve this absorption issue, we investigated a prodrug strategy based on sulfonate derivatives of alkylamidoximes. A total of 25 sulfonates were synthesized as prodrug candidates of one bis-N-alkylamidine and of six N-substituted bis-C-alkylamidines. Their antimalarial activities were evaluated in vitro against P. falciparum and in vivo against P. vinckei in mice to define structure-activity relationships. Small alkyl substituents on the sulfonate group of both C-alkyl- and N-alkylamidines led to the best oral antimalarial activities; alkylsulfonate derivatives are chemically transformed into the corresponding alkylamidines.


Postural instability after lumbar spinal surgery: are there any predictive factors? A case control study.
The surgical spinal degenerative pathology mainly concerns the herniated intervertebral disks. Surgery is indicated when the pain becomes chronic and intense, and when motor signs appear. The results are positive in about 90% of cases, leading to the solution of the problem. However, an estimated percentage of 4% to 20% reported residual pain and postural instability after the surgical treatment of discectomy. We have examined a sample of patients, retrospectively registered, undergoing surgical treatment for degenerative lumbar disease. Some of them developed postural instability. They were subjected to cycles of postural gymnastics. Postural gymnastics has proved to be a tool capable of solving unstable post-surgical posture. It included an exercise of breathing, one or two of muscular distension, one of muscular reinforcement, and one of postural correction. We used an evaluation form we created in agreement with the physiatrist for postural exercises that was based on some basic parameters such as muscle and respiratory function. At each cycle, a score was attributed to the performance of muscular and respiratory exercise to evaluate the function and therefore the degree of instability (1-3 = mild, 4-7 = medium, 8-10 = severe). Results were satisfactory, with return to normal posture. The improvement of postural instability has been demonstrated both by the score of the evaluation forms that have highlighted the transition from a state of severe intensity to one of normality and by a clinical aspect, concerning the static and dynamic posture. The postural instability has a multifactorial genesis, and different mechanisms are involved: the vertebral bone structures and the pelvis, the paraspinal muscular structures, and the nerve structures. These structures are altered after surgery due to predisposing factors, and for the action of conditions acquired as obesity.


Respiratory motion management for external radiotherapy treatment.
We present the update of the recommendations of the French society of oncological radiotherapy on respiratory motion management for external radiotherapy treatment. Since twenty years and the report 62 of ICRU, motion management during the course of radiotherapy treatment has become an increasingly significant concern, particularly with the development of hypofractionated treatments under stereotactic conditions, using reduced safety margins. This article related orders of motion amplitudes for different organs as well as the definition of the margins in radiotherapy. An updated review of the various movement management strategies is presented as well as main technological solutions enabling them to be implemented: when acquiring anatomical data, during planning and when carrying out treatment. Finally, the management of these moving targets, such as it can be carried out in radiotherapy departments, will be detailed for a few concrete examples of localizations (abdominal, thoracic and hepatic).


Now wash your hands? A survey of hospital handwashing facilities.
We studied the adequacy of handwashing facilities on elderly-care wards in seven UK hospitals. We found 10.9% of sinks were inaccessible, 12% of sinks did not have any cleansing agent, 93.2% of ward sinks and 79% of treatment room sinks had no antiseptic agent. We conclude that in our survey, handwashing facilities were inadequate and have suggested a standard checklist for hospital sinks.


Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation.
AMP-activated protein kinase (AMPK) is a metabolic sensor involved in intracellular energy metabolism through the control of several homeostatic mechanisms, which include autophagy and protein degradation. Recently, we reported that AMPK activation by resveratrol promotes autophagy-dependent degradation of the amyloid-β (Aβ) peptides, the core components of the cerebral senile plaques in Alzheimer's disease. To identify more potent enhancers of Aβ degradation, we screened a library of synthetic small molecules selected for their structural similarities with resveratrol. Here, we report the identification of a series of structurally related molecules, the RSVA series, which inhibited Aβ accumulation in cell lines nearly 40 times more potently than did resveratrol. Two of these molecules, RSVA314 and RSVA405, were further characterized and were found to facilitate CaMKKβ-dependent activation of AMPK, to inhibit mTOR (mammalian target of rapamycin), and to promote autophagy to increase Aβ degradation by the lysosomal system (apparent EC(50) ∼ 1 μM). This work identifies the RSVA compounds as promising lead molecules for the development of a new class of AMPK activating drugs controlling mTOR signaling, autophagy, and Aβ clearance.


Dental abnormalities in children preparing for pediatric bone marrow transplantation.
The purpose of our study was to describe the types and frequencies of altered dental development in pediatric patients preparing for bone marrow transplantation (BMT). Retrospective review of the medical records and panoramic radiographs of all patients who underwent BMT at St Jude Children's Research Hospital between 1990 and 2000 for whom pre-BMT dental examination and panoramic radiography records were available. All patients were treated on institutional protocols. We recorded patient demographics and radiographic evidence of microdontia, hypodontia, taurodontia, root stunting, caries, enamel pearls, and pulpal calcifications. The 259 patients identified (150 male and 109 female) had a median age of 12.82 years (range, 3.18-25.93 years) at the time of BMT. In total, 203 were Caucasian, 38 were African-American, and 18 were of other races. In all, 150 (57.9%) had abnormal dentition. The most common dental abnormalities were caries (n=84), pulpal calcifications (n = 34), and dental extractions (n = 33). Developmental abnormalities occurred less frequently: taurodontia (n = 8), hypodontia (n = 10), microdontia (n = 11), and root stunting (n = 11). Dental abnormalities are prevalent in children undergoing BMT. Pre-transplant oral hygiene and dental examination should be standard care in order to minimize potential sites of infection.


Outcomes Following Revision Stapes Surgery in Children: A Single-Surgeon, Single-Center 15-Year Experience.
To review a single surgeon experience with revision pediatric stapes surgery for congenital stapes fixation (CSF) and tympanosclerosis (TS). Secondly, to determine whether hearing outcomes following revision surgery may be predicted by a thorough work-up aimed at assessing whether an extruded or malpositioned prosthesis is likely to be encountered intraoperatively. Tertiary referral center. Retrospective chart review. Fifteen patients having revision surgery for fixation of the stapes footplate over a 15-year period. Hearing results based on pre- and post-revision pure-tone average air-bone gap (PTA-ABG) and speech recognition threshold testing (SRT). Overall, the mean improvement of PTA-ABG following revision surgery was 11.9 dB (standard deviation [SD] 15.2) while SRTs improved by a mean of 12.3 (SD 19.9). Outcomes were significantly better in patients who reported a history of trauma following their initial surgery, when there was otoscopic evidence of an extruding or extruded prosthesis and/or a pre-revision CT (where performed) suggested an extruded or malpositioned prosthesis. No patients had a significant postoperative sensorineural hearing loss. Revision stapes surgery in children is a safe procedure in experienced hands which nonetheless should only be contemplated in patients in whom preoperative work-up suggests an extruded or malpositioned prosthesis is likely to be encountered intraoperatively.


Studies on citrate-phosphate-dextrose (CPD) blood supplemented with adenine.
The effect of varying adenine concentrations in citrate-phosphate-dextrose (CPD) blood was studied in an attempt to optimize the storage conditions for human erythrocytes with regard to posttransfusion viability and oxygen release function. The maintenance of diphosphoglycerate (DPG) was impaired by adenine supplementation; this effect was closely related to the adenine concentration. A 0.25 mM adenine concentration in CPD blood improved the adenosine triphosphate (ATP) levels and the posttransfusion viability markedly, without appreciably impairing the DPG maintenance. The results suggest that CPD solution supplemented with adenine to give a 0.25 mM concentration in the blood is a better preservative for human erythrocytes than the commonly used acid-citrate-dextrose (ACD), CPD, and ACD-adenine solutions with regard to posttransfusion viability and oxygen release function. Adenine addition to this low concentration is not expected to cause renal damage even after massive transfusion.


High-grade neuroendocrine carcinomas of the gallbladder and bile duct: Report of four cases with pathological correlation.
The extrahepatic biliary system is one of the unusual locations of extrapulmonary neuroendocrine carcinoma. To our knowledge, there has been no report describing the imaging findings of this rare malignancy of the biliary tree. We report 3 large-cell neuroendocrine carcinomas and a small-cell carcinoma arising from the biliary system. Biliary tumors showing on computed tomography an aggressive invasion to the liver or extensive lymph node involvement should raise the suspicion of their being high-grade neuroendocrine tumors.


Carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in European hamsters.
Laboratory-bred European hamsters received intragastric administrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) once weekly for 20 weeks. The animals showed mainly squamous cell papillomas and carcinomas of the fore-stomach. The tumour incidence was higher in males (80%) than in females (30%). The average tumour latency was comparatively short (25 weeks).


Stress fracture of the finger in a bowler.
A 28-year-old semiprofessional bowler was seen initially with pain in the right ring finger that was aggravated by bowling and relieved by rest. He had localized tenderness of the middle phalanx; x-ray films revealed a stress fracture. The fracture healed with restriction of activity and he was able to gradually resume bowling. Although rare, stress fracture should be considered in the differential diagnosis of finger pain in a patient with a history of overuse.


Improved long-term suppression of HIV-1 replication with a triple-class multidrug regimen compared with standard of care antiretroviral therapy.
The treatment of HIV-1-infected patients with triple-drug combination therapy results in profound suppression of viral replication. In most therapy-naive patients plasma HIV-1-RNA levels (pVL) drop below the lower limit of quantification (LLQ) of currently used assays. In a large percentage of such patients, more sensitive assays provide evidence of residual viral replication. The question is whether more potent therapy can further suppress this residual replication. Thirty control patients who, using very strict criteria, had not experienced virological failure during 3 years of standard therapy, were compared with 10 patients treated with a five-drug regimen, consisting of three different classes of antiretroviral drugs (alternative multidrug regimen). A modified ultrasensitive assay with an LLQ of 5 copies/ml was used to re-test plasma obtained at week 48 and at three timepoints at and around week 144. At weeks 48 and 144 pVL could be quantified significantly more frequently in control patients than in patients using the alternative multidrug regimen (week 48: 42 versus 0% with quantifiable pVL, P = 0.017; week 144: 60 versus 14% with at least one quantifiable pVL, P = 0.036, respectively). A low baseline CD4T cell count was predictive of quantifiable pVL in control patients, but not in alternative multidrug patients. This proof-of-principle study demonstrates that the use of an alternative multidrug regimen results in stronger long-term suppression of pVL compared with clinically successful treatment with standard therapy.


Redox chemistry of complexes of nickel(II) with some biologically important peptides in the presence of reduced oxygen species: an ESR study.
The reactions between some Ni(II) oligopeptides (Gly-His-Lys, (Gly)4, Asp-Ala-His-Lys, Gly-Gly-His, beta Ala-His, and serum albumin) and reduced oxygen species have been characterized by spin-trapping experiments using DMPO and Me2SO. Most of the peptides possessed superoxide dismutase- and catalase-like activities leading to the formation of either oxene [NiO]2+ or, in the case of beta Ala-His, hydroxyl radicals. Both these species may affect DNA integrity through distinct mechanisms.


The influence of intravenous anaesthetic agents on primarily increased intracranial pressure.
In the choice of anaesthetics and techniques the danger of a possible progressive increase of intracranial pressure (ICP) should be considered. Therefore the influence of intravenous anaesthetic agents on mean arterial pressure, ICP, and cerebral perfusion pressure (CPP) in patients with primarily increased ICP was observed under standard conditions for 20-40 minutes. Etomidate, thiopentone, propanidid, and ketamine showed remarkable effects on ICP, even in patients with disturbed cerebro-vascular reactivity. Etomidate and thiopentone cause a fall of ICP by 26%. Because of its stabilizing effects on circulation etomidate does not induce a reduction of CPP, whereas thiopentone will do so because of its depressing effect on blood pressure. Propanidid appears to be a less suitable agent when there is raised ICP, because it induces fluctuations of ICP and blood pressure up to the third minute after injection. According to our results, monoanaesthesia with ketamine cannot be recommended when there is increased ICP because it causes a prolonged increase in ICP, and reduction of blood pressure and CPP.


Exogenous O6-methylguanine inhibits adduct removal and sensitizes human cells to killing by the chemical carcinogen N-methyl-N'-nitro-N-nitrosoguanidine.
We partially depleted the O6-methylguanine-DNA methyltransferase activity in four O6-methylguanine (O6-mGua) repair-proficient (Mer+) human cell strains with exogenous O6-mGua (2 mM for 3 h, a non-toxic regimen) and then challenged them with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MT-partially depleted HT29 cells removed O6-mGua from DNA at about half the rate of control cells, while removal of 3-methyladenine was unaffected. In spite of partial depletion of MT, however, cell killing by MNNG in a colony-forming assay with HT29, A549, A498 or KD cells was not greatly affected. (This is in contrast to the dramatic potentiation of CNU cytotoxicity observed previously.) In an attempt to sensitize Mer+ strains to killing by MNNG, we treated cells with O6-mGua following MNNG exposure (0.4 mM for 4 days), in addition to the pre-MNNG treatment of 2 mM O6-mGua for 3 h. This sensitized KD and HT29 cells 2-fold to killing by MNNG, based on the dose at 10% survival, but did not sensitive Mer- A1336. However, post-treatment alone was as effective as combined pre- and post-treatment in sensitizing KD cells to killing. Thus, when the O6-mGua post-treatment was begun, greater than 50% of O6-mGua was already removed from cell DNA. Our findings may be accounted for by at least two schemes, one in which nonlethal O6-mGua are removed from DNA rapidly, while potentially lethal O6-mGua are repaired later. The other scheme proposes that exogenous O6-mGua increases the lethality of a non-O6-mGua lesion by reducing its repair both in Mer+ and Mer- cells. Both schemes are consistent with the hypothesis that O6-mGua may be a lethal DNA lesion in human cells.


Symmetric lipophilic polyamines exhibiting antitumor activity.
Unsymmetric lipophilic polyamine derivatives are considered as potential antitumor agents. Here, a series of novel symmetric lipophilic polyamines (LPAs) based on norspermine and triethylenetetramine (TETA) backbones bearing alkyl substituents with different lengths (from decyl to octadecyl) at C(1) atom of glycerol were synthesized. Performed screening of the cytotoxicity of novel compounds on the panel of tumor cell lines (MCF-7, KB-3-1, B16) and non-malignant fibroblasts hFF3 in vitro revealed a correlation between the length of the aliphatic moieties in LPAs and their toxic effects - LPAs with the shortest decyl substituent were found to exhibit the highest cytotoxicity. Furthermore, norspermine-based LPAs displayed somewhat more pronounced cytotoxicity compared with their TETA-based counterparts. Further mechanistic studies demonstrated that hit LPAs containing the norspermine backbone and tetradecyl or decyl substituents efficiently induced apoptosis in KB-3-1 cells. Moreover, decyl-bearing LPA inhibited motility and enhanced adhesiveness of murine B16 melanoma cells in vitro, showing promising antimetastatic potential. Thus, developed novel symmetric norspermine-based LPAs can be considered as promising anticancer chemotherapeutic candidates.


The role of behavioral inhibition and behavioral approach systems in the associations between mood and alcohol consequences in college: a longitudinal multilevel analysis.
The behavioral inhibition system (BIS) and behavioral approach system (BAS) are thought to influence sensitivity to reinforcement and punishment, making them useful for predicting mood-related drinking outcomes. This study provided the first examination of BIS and BAS as moderators of longitudinal within-person associations between mood and alcohol-related consequences in college student drinkers. Participants (N = 637) at two public U.S. universities completed up to 14 online surveys over the first three years of college assessing past-month general positive and negative moods, as well as past-month alcohol use and consequences. BIS and BAS were assessed at baseline. Using multilevel regression, we found that BIS and BAS moderated the within-person associations between negative mood and alcohol consequences. For students high on BIS only, high on BAS only, or high on both BIS and BAS, within-person increases in negative mood were associated with greater alcohol consequences in the first year of college. However, these negative mood-alcohol consequence associations diminished over time for students high on BIS and low on BAS, but remained strong for students high on both BIS and BAS. Within-person associations between positive mood and alcohol consequences changed from slightly positive to slightly negative over time, but were not moderated by BIS or BAS. Findings suggest that BIS and BAS impact the within-person association between general changes in negative mood and negative alcohol consequences, working jointly to maintain this relationship over time.


Pharmacophore modeling, molecular docking, and molecular dynamics simulation approaches for identifying new lead compounds for inhibiting aldose reductase 2.
Aldose reductase 2 (ALR2), which catalyzes the reduction of glucose to sorbitol using NADP as a cofactor, has been implicated in the etiology of secondary complications of diabetes. A pharmacophore model, Hypo1, was built based on 26 compounds with known ALR2-inhibiting activity values. Hypo1 contains important chemical features required for an ALR2 inhibitor, and demonstrates good predictive ability by having a high correlation coefficient (0.95) as well as the highest cost difference (128.44) and the lowest RMS deviation (1.02) among the ten pharmacophore models examined. Hypo1 was further validated by Fisher's randomization method (95%), test set (r = 0.91), and the decoy set shows the goodness of fit (0.70). Furthermore, during virtual screening, Hypo1 was used as a 3D query to screen the NCI database, and the hit leads were sorted by applying Lipinski's rule of five and ADME properties. The best-fitting leads were subjected to docking to identify a suitable orientation at the ALR2 active site. The molecule that showed the strongest interactions with the critical amino acids was used in molecular dynamics simulations to calculate its binding affinity to the candidate molecules. Thus, Hypo1 describes the key structure-activity relationship along with the estimated activities of ALR2 inhibitors. The hit molecules were searched against PubChem to find similar molecules with new scaffolds. Finally, four molecules were found to satisfy all of the chemical features and the geometric constraints of Hypo1, as well as to show good dock scores, PLPs and PMFs. Thus, we believe that Hypo1 facilitates the selection of novel scaffolds for ALR2, allowing new classes of ALR2 inhibitors to be designed.


CT follow-up of microprolactinomas during bromocriptine-induced pregnancy.
In the last few years complete or partial regression of prolactinomas has been demonstrated in nonpregnant women treated by bromocriptine. Thus bromocriptine therapy appears as an attractive alternative to surgery for management of infertility related to hyperprolactinemia. However, numerous reports emphasized the possibility of an excessive growth of the pituitary adenoma with visual field defects during the last 3 months of pregnancy. To avoid these complications, the authors followed with serial CT scans the growth of microprolactinoma at the 5th or 6th month of pregnancy. Among six pregnant women, one patient presented a marked upward extension of the adenoma. Bromocriptine was then reintroduced and the effectiveness in reducing tumor growth was proved by CT scan at the 7th month. Regarding low risk of using intravenous iodinated contrast medium in pregnant women and of fetal radiation damage, the authors emphasize the value of CT in the follow-up of bromocriptine-induced pregnancies.


Sedative and cardiovascular effects of midazolam and diazepam alone or combined with clonidine in patients undergoing hemodynamic studies for suspected coronary artery disease.
Sedation during coronary angiography has been rarely studied, and it is important to know which drug is the best to sedate these patients. To evaluate the quality of sedation and the effects of midazolam and diazepam alone or combined with clonidine on the heart rate (HR) and blood pressure (BP) of patients with suspected coronary artery disease. This is a controlled, randomized, double-blind, prospective clinical study of 160 patients divided into five groups of 32 patients each, according to the drug used: group C (clonidine 0.5 microg/kg); group M (midazolam 40 microg/kg); group MC (combination of midazolam 40 microg/kg and clonidine 0.5 microg/kg); group D (diazepam 40 microg/kg); and group DC (combination of diazepam 40 microg/kg and clonidine 0.5 microg/kg). Sedation was evaluated based on the Ramsay scale and on the use of meperidine 0.04 mg.kg-1. Invasive BP monitoring, HR and the sedation score were analyzed every five minutes at four different time points. Patients who received midazolam presented higher sedation scores as well as HR and BP variation (p < 0.05). Those who received diazepam or clonidine had lower sedation scores, which were more satisfactory for the performance of the procedure, and presented a lower BP and HR variation (p > 0.05). Midazolam was associated with a greater sedative and cardiovascular effect, whereas for diazepam these effects were less intense. Clonidine and diazepam had similar effects on BP, HR and sedation.


The American College of Surgeons Response to the COVID-19 Pandemic (Part I): Cancer Care, COVID-19 Registry, Surgeon Wellness.
From the onset of the COVID-19 global pandemic of 2020, the American College of Surgeons has been a leader in disseminating reliable information on the nature of the crisis and assuring quality of surgical care during the enforced lockdown of inpatient and outpatient care.


Duration perception for visual stimuli is impaired in dyslexia but deficits in visual processing may not be the culprits.
Dyslexics underperform controls in estimating and comparing time intervals defined by visual stimuli. Accuracy in vision-based duration perception requires efficient processing of visual events because these will define the onset and offset of time intervals. Since dyslexics have difficulties processing dimensions of visual stimuli like luminance contrasts and motion, we do not know the extent to which these visual deficits are responsible for their difficulties in judging time intervals. To address this gap, we asked adults with dyslexia and matched controls to perform an interval comparison task involving five different types of visual stimuli with different levels of challenge regarding luminance contrasts and motion. If the expected disadvantage of dyslexics in visual duration perception increased for stimuli requiring increased luminance or motion processing, this would indicate that visual processing plays a role. Results showed poorer time discrimination in dyslexics, but this disadvantage did not change according to stimulus type. Complementary analyses of oculomotor behavior during the task suggested that the poorer timing performance of dyslexics may relate instead to attention and/or engagement with the task. Our findings strengthen the evidence in favor of visual duration perception deficits in dyslexia, but not the hypothesis that these result from purely visual problems.


Special Issue Editorial: Isolation and Analysis of Characteristic Compounds from Herbal and Plant Extracts.
Herbal and plant extracts exhibit various types of properties and activities that have been applied in the medicinal field to treat diseases and achieve better health [...].


Lisdexamfetamine for the treatment of acute methamphetamine withdrawal: A pilot feasibility and safety trial.
There is no effective treatment for methamphetamine withdrawal. This study aimed to determine the feasibility and safety of a tapering dose of lisdexamfetamine for the treatment of acute methamphetamine (MA) withdrawal. Open-label, single-arm pilot study, in an inpatient drug and alcohol withdrawal unit assessing a tapering dose of oral lisdexamfetamine dimesylate commencing at 250 mg once daily, reducing by 50 mg per day to 50 mg on Day 5. Measures were assessed daily (days 0-7) with 21-day telephone follow-up. Feasibility was measured by the time taken to enrol the sample. Safety was the number of adverse events (AEs) by system organ class. Retention was the proportion to complete treatment. Other measures included the Treatment Satisfaction Questionnaire for Medication (TSQM), the Amphetamine Withdrawal Questionnaire and craving (Visual Analogue Scale). Ten adults seeking inpatient treatment for MA withdrawal (9 male, median age 37.1 years [IQR 31.7-41.9]), diagnosed with MA use disorder were recruited. The trial was open for 126 days; enroling one participant every 12.6 days. Eight of ten participants completed treatment (Day 5). Two participants left treatment early. There were no treatment-related serious adverse events (SAEs). Forty-seven AEs were recorded, 17 (36%) of which were potentially causally related, all graded as mild severity. Acceptability of the study drug by TSQM was rated at 100% at treatment completion. Withdrawal severity and craving reduced through the admission. A tapering dose regimen of lisdexamfetamine was safe and feasible for the treatment of acute methamphetamine withdrawal in an inpatient setting.


Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups.
Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).


An exploration of reported mortality from cutaneous squamous cell carcinoma using death certification and cancer registry data.
Cutaneous squamous cell carcinoma (cSCC) is increasing in incidence but mortality rates are low. Identifying high-risk tumours is important when rationalizing clinical review for patients with cSCC. To assess the accuracy of death certification in cases of reported fatal cSCC and to identify risk factors for fatal cSCC. A retrospective, observational study of cases of fatal cSCC over 11 years (1993-2004) in Leeds, identified in cancer registry and death certification data. Fifty-eight patients were recorded by the registry as having fatal cSCC in this period. Review of case notes and pathology specimens, where available (34 cases), confirmed that 21/34 patients had died of cSCC. Five were on the ear and none on the lip. Four patients had been treated for leukaemia or lymphoma and one was a renal transplant recipient. On pathology review five patients proved to have had malignant adnexal tumours rather than cSCC, and one a melanoma. In addition, three patients had disease of the ear canal or vulva. A proportion of deaths were falsely attributed to cSCC as a result of inaccurate histological diagnosis. Some fatalities were related to tumours in sites known to be at higher risk, and a significant proportion was postulated to be related to immunosuppression. In those cases attributed to cSCC in which this could be assessed, the majority were American Joint Committee on Cancer stage 2 and only 24% were in high-risk sites.


Role of microbes in bioaccumulation of heavy metals in municipal solid waste: Impacts on plant and human being.
The presence of heavy metals in municipal solid waste (MSW) is considered as prevalent global pollutants that cause serious risks to the environment and living organisms. Due to industrial and anthropogenic activities, the accumulation of heavy metals in the environmental matrices is increasing alarmingly. MSW causes several adverse environmental impacts, including greenhouse gas (GHG) emissions, river plastic accumulation, and other environmental pollution. Indigenous microorganisms (Pseudomonas, Flavobacterium, Bacillus, Nitrosomonas, etc.) with the help of new pathways and metabolic channels can offer the potential approaches for the treatment of pollutants. Microorganisms, that exhibit the ability of bioaccumulation and sequestration of metal ions in their intracellular spaces, can be utilized further for the cellular processes like enzyme signaling, catalysis, stabilizing charges on biomolecules, etc. Microbiological techniques for the treatment and remediation of heavy metals provide a new prospects for MSW management. This review provides the key insights on profiling of heavy metals in MSW, tolerance of microorganisms, and application of indigenous microorganisms in bioremediation. The literatures revealed that indigenous microbes can be exploited as potential agents for bioremediation.


Soft Palate Subacute Necrotising Sialadenitis: A Case Report.
Subacute Necrotising Sialadenitis (SANS) is a self-limiting, inflammatory disorder of minor salivary glands of unknown etiology. Minor salivary glands over soft and hard palate are most commonly affected. SANS shares considerable clinical features with necrotizing sialometaplasia, which is also the commonest differential diagnosis. We present an intriguing case of soft palate SANS in a 55 year old lady.


How Common Is Thoracic Outlet Syndrome?
The incidence of neurogenic thoracic outlet syndrome is completely unknown, and has been wildly overestimated in the past. Based on a prospectively maintained database at our academic Thoracic Outlet Center, we estimate the yearly incidence of neurogenic and venous thoracic outlet syndrome to be approximately 3 and 1 per 100,000 population, respectively. The ratio of neurogenic to venous thoracic outlet syndrome seems to be approximately 80:20 based on presentation, and 75:25 based on operative correction. These data will help to understand the impact of these disorders, and perhaps help to guide resource management.


The BSCM score: a guideline for surgical decision-making for brainstem cavernous malformations.
Microsurgical resection of brainstem cavernous malformations (BSCMs) can be performed today with acceptable morbidity and mortality. However, in this highly eloquent location, the indication for surgery remains challenging. We aimed to elaborate a score system that may help clinicians with their choice of treatment in patients with BSCMs in this study. A single-center series of 88 consecutive BSCMs patients with 272 follow-up visits were included in this study. Univariable and multivariable generalized estimating equations (GEE) were constructed to identify the association of variables with treatment decisions. A score scale assigned points for variables that significantly contributed to surgical decision-making. Surgical treatment was recommended in 37 instances, while conservative treatment was proposed in 235 instances. The mean follow-up duration was 50.4 months, and the mean age at decision-making was 45.9 years. The mean BSCMs size was 14.3 ml. In the multivariable GEE model, patient age, lesion size, hemorrhagic event(s), mRS, and axial location were identified as significant factors for determining treatment options. With this proposed score scale (grades 0-XII), non-surgery was the first option at grades 0-III. The crossover point between surgery and non-surgery recommendations lay between grades V and VI while surgical treatment was found in favor at grades VII-X. In conclusion, the proposed BSCM operating score is a clinician-friendly tool, which may help neurosurgeons decide on the treatment for patients with BSCMs.


Inhibition of bacterial pathogens by lactobacilli.
Lactobacilli produce many antimicrobial substances including organic acids, hydrogen peroxide and bacteriocins. Antagonistic activity of lactobacilli is an important factor in the protection of the vagina of fertile women against infection by certain pathogens. In the present study, we investigated 17 strains of lactobacilli, including 11 strains of vaginal origin. The aim was to investigate in more detail the antibacterial activity of lactobacilli and to attempt to assess substances responsible for inhibition. The investigated lactobacilli inhibited some strains of Escherichia coli, Serratia marcescens, Shigella boydii, Listeria monocytogenes, Listeria ivanovii, Listeria innocua and Staphylococcus aureus. We have provided evidence that inhibition is due mainly to organic acids and to a lesser extent, to bacteriocins.


Efficacy of Eltrombopag with Immunosuppressive Therapy Versus Immunosuppressive Therapy Alone on Severe Aplastic Anaemia: A Systematic Review and Meta-analysis.
Severe aplastic anaemia (SAA) is a syndrome of bone marrow failure caused by T cell-mediated destruction of haematopoietic stem cells and progenitor cells. Whether patients with SAA should be treated with eltrombopag (EPAG) and immunosuppressive therapy (IST) or IST alone remains debatable. Therefore, we conducted this meta-analysis to compare the efficacy of eltrombopag + IST with that of IST alone in patients with SAA and to assess the difference in the efficacy of eltrombopag in adults and children. We performed this meta-analysis by retrieving studies that met the inclusion and exclusion criteria from PubMed, EMBASE, and the Cochrane Library up to 1 January 2023. We used a random-effects model to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for primary and secondary outcomes. I2 statistics were used to evaluate the heterogeneity of the included studies. Six studies involving a total of 699 patients were included. In terms of the primary outcomes, our pooled results indicated that patients treated with EPAG + IST had a higher 6-month overall response rate (OR = 2.25; 95% CI, 1.60-3.16; p < 0.00001), a higher 6-month complete response rate (OR = 2.61; 95% CI, 1.82-3.74; p < 0.00001), and a lower 6-month nonresponse rate (OR = 0.32; 95% CI, 0.19-0.52; p < 0.00001). However, there was no significant difference in the rate of 6-month partial response (OR = 0.94; 95% CI, 0.49-1.81; p = 0.85). This meta-analysis indicated that patients treated with additional eltrombopag for IST may have a higher rate of haematological response.


Dynamics of heart rate variability in patients with type 2 diabetes mellitus during spinal anaesthesia: prospective observational study.
Little is known about the changes in autonomic function during spinal anaesthesia in type 2 diabetic patients. The purpose of the study was to assess the influence of spinal anaesthesia on the heart rate variability in type 2 diabetic patients according to the glycated hemoglobin (HbA1c) level. Sixty-six patients who were scheduled for elective orthostatic lower limb surgery were assigned to three groups (n = 22, each) according to HbA1c; controlled diabetes mellitus (HbA1c < 7 %), uncontrolled diabetes mellitus (HbA1c > 7 %) and the control group. The heart rate variability was measured 10 min before (T0), and at10 min (T1), 20 min (T2) and 30 min (T3) after spinal anaesthesia. Before spinal anaesthesia, total, low-and high-frequency power were significantly lower in the uncontrolled diabetec group than in other group (p < 0.05). During spinal anaesthesia, total, low- and high-frequency powers were did not change in the uncontrolled diabetec group while the low-frequency power in the controlled diabetec group was significantly depressed (p < 0.05). The ratio of low-to high-frequency was comparable among the groups, while it was reduced at T1-2 than at T0 in all the groups. The blood pressures were higher in the uncontrolled diabetec group than in the other groups. Spinal anaesthesia had an influence on the cardiac autonomic modulation in controlled diabetec patients, but not in uncontrolled diabetec patients. There were no differences in all haemodynamic variables during an adequate level of spinal anaesthesia in controlled and uncontrolled type 2 DM. ClinicalTrials.gov NCT02137057.


A haemagglutinin in the tissue fluid of the Pacific oyster, Crassostrea gigas, with specificity for sialic acid residues in glycoproteins.
An agglutinin for human red cells has a specificity for sialic acid and a high affinity for bovine salivary glycoprotein. Digestion of the glycoprotein with Pronase or neuraminidas indicated that binding of sialic acid to receptors in the agglutinin is the first step in the mechanism of formation of a stable complex between ligand and receptor.


Multidetector computed tomography of the head in acute stroke: predictive value of different patterns of the dense artery sign revealed by maximum intensity projection reformations for location and extent of the infarcted area.
Maximum intensity projections reconstructions from 2.5 mm unenhanced multidetector computed tomography axial slices were obtained from 49 patients within the first 6 h of anterior-circulation cerebral strokes to identify different patterns of the dense artery sign and their prognostic implications for location and extent of the infarcted areas. The dense artery sign was found in 67.3% of cases. Increased density of the whole M1 segment with extension to M2 of the middle cerebral artery was associated with a wider extension of cerebral infarcts in comparison to M1 segment alone or distal M1 and M2. A dense sylvian branch of the middle cerebral artery pattern was associated with a more restricted extension of infarct territory. We found 62.5% of patients without a demonstrable dense artery to have a limited peripheral cortical or capsulonuclear lesion. In patients with a 7-10 points on the Alberta Stroke Early Programme Computed Tomography Score and a dense proximal MCA in the first hours of ictus the mean decrease in the score between baseline and follow-up was 5.09+/-1.92 points. In conclusion, maximum intensity projections from thin-slice images can be quickly obtained from standard computed tomography datasets using a multidetector scanner and are useful in identifying and correctly localizing the dense artery sign, with prognostic implications for the entity of cerebral damage.


Formaldehyde-induced fluorescence method for touch preparations from amelanotic melanoma tissues: a simple and rapid method for the demonstration of melanogenic activities of amelanotic melanoma cells.
Touch preparations from four amelanotic melanoma tissue samples were studied with the formaldehyde-induced fluorescence method. Fluorescent amelanotic melanoma cells could easily be detected under a fluorescence microscope. The fluorescence microscopic pictures obtained by the touch-fluorescence method were equally evaluated with those obtained by the classical fluorescence method. The method made it possible to demonstrate the melanogenic activity of amelanotic melanoma cells within 30 min. The routine application of this method to the diagnosis of amelanotic melanoma is suggested.


Aortocoronary bypass without extracorporeal circulation: why and when?
Thirty patients have been operated on since July 1986. The mean age was 55 years (range 32-68). Twenty-three simple and 7 double bypasses were performed. The internal mammary artery and 1 prosthetic conduit were used for the 29 left anterior descending (LAD) anastomoses and saphenous vein for the others [5 right coronary artery (RCA), 3 diagonal]. The use of an implantable Doppler probe for continuous monitoring during the 1st postoperative week confirmed patency and gave an estimated flow (mean: 79.23 ml/min, range 43.4). There were no deaths and no cases of infarction or ischaemia, but stress test performance improved. The main advantage of this rapid and safe technique was avoidance of morbidity of extracorporeal circulation (ECC) and limited operative myocardial ischaemia. Criteria of selection were unstable, permanent angina (14); unsuccessful PTCA (8) PTCA and failure (5 emergency cases), redo surgery (4); poor LV function (EF less than 20%) (3); fibrinolytic treatment or severe coagulopathy (2). The ideal patient has severe stenosis with or without retrograde filling of LAD with either RCA or circumflex (which require a lateral thoracotomy).


Design of N-cinnamyl sulfinamides as new sulfur-containing olefin ligands for asymmetric catalysis: achieving structural simplicity with a categorical linear framework.
The design and development of an extraordinarily interesting new class of chiral sulfur-olefin hybrid ligands with remarkable structural simplicity were described. These unique sulfinamide-olefin ligands have been proved to be highly effective ligands in rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids to α,β-unsaturated carbonyl compounds (up to 99% yield and 98% ee).


Erratum: efficacy of proton pump inhibitors for patients with duodenal ulcers: A pairwise and network meta-analysis of randomized controlled trials.
[This corrects the article DOI: 10.4103/1319-3767.199117.].


Thromboxane production in the blood of women increases after menopause whereas tumor necrosis factor is reduced in women compared with men.
Previously we have shown that incubation of heparinized blood with a low dose of lipopolysaccharides (5 ng/ml) resulted in a 60% higher generation of TxB2 in the blood of young men as compared with that of young women. In the present study, we investigated a group consisting of 38 healthy men and 38 healthy postmenopausal women aged 50-73 years with no drug use and no known chronic disease. In contrast to our earlier observation that young men produce more TxB2 than young women, no significant difference was observed between the men and women when all the participants above 50 years of age were included (5.7 +/- 0.6 ng/l for men versus 5.2 +/- 0.7 ng/l for women). However, a strong correlation was found with simple regression analysis when increasing TxB2 generation was compared with years after menopause (P < 0.0001). No such correlation was observed for increasing age of men and their TxB2 production. The LPS stimulation system of whole blood was also used to evaluate the production of tumor necrosis factor (TNF-alpha) in older people. Men were found to generate 60% more TNF-alpha than women, but no correlation was found between increasing age of women and TNF-alpha production as observed with TxB2. Risk factors such as SDS-cholesterol, fibrinogen and factor VII were the same in men and women, whereas total cholesterol was higher in women than in men (P < 0.05). Since TxA2 is known to be a mediator of atherosclerotic-induced lesions and TNF-alpha is a well-established indicator of inflammatory reactions, we propose that the reduced production of TxB2 and TNF-alpha in women in our model system may partially explain the lower incidence of atherosclerosis in women as compared with men, and the phenomenon of increased incidence of this disease after menopause.


Medication-related osteonecrosis of the jaw triggered by endodontic failure in oncologic patients.
To describe the association between endodontic treatment failure and medication-related osteonecrosis of the jaw (MRONJ) in a cohort of oncologic patients in therapy with antiresorptive and antiangiogenic drugs. Patients were selected as affected by MRONJ in absence of the common local risk factors (oral surgical procedures or ill-fitting dentures) but showing failure of previous endodontic treatment performed at least 6 months before the starting of antiresorptive/antiangiogenic therapies. Jaw lesions were all surgically treated and patients underwent a strict clinical and radiological follow-up. Among 18 patients, who developed 18 MRONJ, the only detectable local risk factor was the presence of teeth with failed endodontic treatment (more precisely, root canal underfilling in eight cases, root canal overfilling in two cases, root perforation in three cases, root fracture in five cases). All patients completely healed after surgical procedure and no recurrence was observed. Endodontic treatment failure should be considered a local risk factor for MRONJ development in oncologic patients. For such reason, it is mandatory to carefully evaluate them prior than the beginning of antiresorptive and antiangiogenic drugs administration.


Nuclear compartmentalization of DNA repair.
The continuous threats on genome integrity by endogenous and exogenous sources have rendered cells competent to overcome these challenges by activating DNA repair pathways. A complex network of proteins and their modifications participate in orchestrated signaling cascades, which are induced in response to DNA damage and may determine the choice of repair pathway. In this review, we summarize recent findings in the field of DNA Double Strand Break repair with regard to the positioning of the break in the highly compartmentalized nucleus. We aim to highlight the importance of chromatin state along with the nuclear position of the DNA lesions on the choice of DNA repair pathway and maintenance of genome integrity.


Radical-Polar Crossover Catalysis with a d0 Metal Enabled by a Redox-Active Ligand.
Radical-polar crossover mechanisms are invoked in numerous late transition metal and photocatalyzed reactions. To the best of our knowledge, reductive radical-polar crossover mechanisms are not invoked for group 3 early transition metals due to their propensity to exist in high oxidation states. Through use of a redox-active (tris)amido ligand we have accessed this mechanism for use with early transition metals. This mechanism is showcased through enabling product formation for a wide variety of elimination products from α-halo substituted benzylic bromides. The mechanism of this new type of reactivity with Sc is explored, and Hammett analysis reveals an anionic intermediate. The wide functional group tolerance of this reaction is also demonstrated.


COVID-19 Antibody Tests: A Valuable Public Health Tool with Limited Relevance to Individuals.
Antibody tests for detecting past infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have many uses for public health decision making, but demand has largely come from individual consumers. This review focuses on the individual relevance of antibody tests: their accuracy in detecting prior infection, what past SARS-CoV-2 infection can currently infer about future immunity or possible medical sequelae, and the potential future importance of antibody tests for vaccine selection and medical screening. Given uncertainty about the antibody tests (quality, accuracy level, positive predictive value) and what those tests might indicate immunologically (durability of antibodies and necessity for protection from reinfection), seropositive test results should not be used to inform individual decision making, and antibody testing should remain a tool of public health at this time.


Integration single-cell and bulk RNA-sequencing data to reveal senescence gene expression profiles in heart failure.
Heart failure (HF) represents one of healthcare's biggest challenges. Although rarely noticed, aging is a crucial risk factor for cardiovascular disease. Our study aims to reveal aging's role in HF by integrating single-cell RNA-sequencing (scRNA-seq) and bulk RNA-sequencing databases. We collected HF heart sample data from the Gene Expression Omnibus database and senescence gene data from CellAge. The FindCluster () package was used for cell cluster analysis. Differentially expressed genes (DEG) were identified operating the FindMarkers function. Cell activity score calculation was performed using the AUCell package. UpSetR plotted the intersection between DEGs of active cell types, bulk data DEGs, and genes associated with aging. Using the DGIdb database gene-drug interaction data, we search for potential targeted therapeutics based on common senescence genes. The scRNA-seq data revealed myocardial heterogeneity in HF tissues. A series of crucial common senescence genes were found. The senescence gene expression profile hints at an intriguing connection between monocytes and HF. After analyzing the DEGs in the bulk dataset, the DEGs in scRNA-seq, the DEGs in each active cell type, and senescence genes, we identified ten genes as common senescence genes present in HF. Correlation analysis of transcriptomics, proteomics, and ceRNA was performed to provide ideas for future studies individually. Moreover, we discovered that common senescence genes and potential therapeutic drugs interact among different cell types. Further research is needed on the expression pattern of senescence genes and molecular regulation in HF. In summary, we identified the functional significance of the senescence gene in HF using integrated data. It is possible that this more profound understanding of how senescence contributes to the development of HF will aid in unraveling the mechanisms that promote the disease and provide hints for developing therapeutics.


Advances in lipase-catalyzed esterification reactions.
Lipase-catalyzed esterification reactions are among the most significant chemical and biochemical processes of industrial relevance. Lipases catalyze hydrolysis as well as esterification reactions. Enzyme-catalyzed esterification has acquired increasing attention in many applications, due to the significance of the derived products. More specifically, the lipase-catalyzed esterification reactions attracted research interest during the past decade, due to an increased use of organic esters in biotechnology and the chemical industry. Lipases, as hydrolyzing agents are active in environments, which contain a minimum of two distinct phases, where all reactants are partitioned between these phases, although their distribution is not fixed and changes as the reaction proceeds. The kinetics of the lipase-catalyzed reactions is governed by a number of factors. This article presents a thorough and descriptive evaluation of the applied trends and perspectives concerning the enzymatic esterification, mainly for biofuel production; an emphasis is given on essential factors, which affect the lipase-catalyzed esterification reaction. Moreover, the art of using bacterial and/or fungal strains for whole cell biocatalysis purposes, as well as carrying out catalysis by various forms of purified lipases from bacterial and fungal sources is also reviewed.


Antibacterial, antifungal, antidiabetic, and antioxidant activities potential of Coleus aromaticus synthesized titanium dioxide nanoparticles.
The nanoparticles based drug delivery and treatment related research has been increased significantly in the recent years. Hence, the antibacterial, antifungal, and antioxidant activity potential of pre synthesized and characterized Titanium dioxide nanoparticles (TiO2 NPs) were investigated in this study through respective standard protocols. Interestingly, the obtained results revealed that TiO2 NPs have concentration dependent antibacterial activity against bacterial pathogens such as E. coli, P.mirabilis, V. cholerae, P. aeruginosa, S. typhimurium, and S. aureus at 100 μg mL-1 concentration. Furthermore, these TiO2 NPs showed remarkable antifungal activity against aspergillosis causing fungal pathogens such as A. niger, A. fumigatus, A. nidulans, and A. flavus at 100 μg mL-1 concentration. α-glucosidase. This TiO2 NPs also effectively inhibit the α-amylase (17%) and α-Glucosidase (37%) enzyme activity at 100 μg mL-1 dosage. The DPPH assay revealed that TiO2 NPs effectively scavenge DPPH free radicals by up to 89% at 100 μg mL-1 concentration, which was comparable to butylated hydroxytoluene (96%). These results suggest that the plant-based TiO2 NPs have remarkable in-vitro antibacterial, antifungal, and antioxidant activity. These may be considered for additional in-vitro and in-vivo experiments to assess their potential biomedical applications.


Ionising radiation and mutation induction at mouse minisatellite loci. The story of the two generations.
The analysis of the effects of ionising radiation on germline mutations is limited by the number of offspring that need to be analysed following exposure to a dose, which is relevant to risk assessment in humans. We have developed a new experimental approach using hypervariable mouse expanded simple tandem repeat (ESTR) loci (minisatellites) which are both highly sensitive to ionising radiation and which permit changes in mutation rates to be detected in relatively small samples. Here, we review the progress made in validating the model, and the unexpected features it has revealed, including a novel form of radiation-induced genetic instability that can be transmitted from one generation to the next.


Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG.
Hosts infected with low doses of mycobacteria develop T helper cell type 1 (Th1) immunity, but at relatively higher doses, a switch to Th2 immunity occurs. Prostaglandin E2 (PGE2) is a proposed mediator of the Th1-to-Th2 shift of immune responses, and mycobacterial products induce PGE2-releasing macrophages (PGE2-MØ) in the mouse spleen in a dose-dependent manner. Splenic PGE2-M Ø from Balb/c mice, given 0.01 or 1 mg heat-killed (HK) Mycobacterium bovis bacillus Calmette-Guerin (BCG) intraperitoneally (i.p.), were characterized by the ex vivo release of PGE2 (>10 ng/10(6) cells), cytokine production, and expression of PGG/H synthase (PGHS)-1, PGHS-2, cytosolic PGE synthase (PGES), and microsomal PGES-1. At Day 14 after the treatment, mice treated with 1 mg, but not 0.01 mg, BCG had increased levels of PGHS-2+ PGE2-MØ, total serum immunoglobulin E (IgE), and serum IgG1 antibodies (Th2 responses) against heat shock protein 65 and purified protein derivative. Cultures of spleen cells isolated from these mice expressed interleukin (IL)-4 and IL-10 in recall responses. Treatment of mice receiving 1 mg BCG with NS-398 (a PGHS-2 inhibitor, 10 mg/kg i.p., daily) resulted in enhanced interferon-gamma (IFN-gamma) production with reduced IL-4 and IL-10 production in recall responses. This treatment also resulted in decreased total serum IgE levels. Treatment of C57Bl/6 mice with HK-BCG (0.5 mg dose) also induced a mixture of Th1 and Th2 responses, although IFN-gamma production was markedly increased, and IL-4 was decreased compared with Balb/c mice. Thus, our results indicate that by 14 days following treatment of mice with high doses of HK-BCG, splenic PGE2-MØ formation is associated with a PGHS-2-dependent shift from Th1-to-Th2 immune responses.


Psychosocial adjustment following burns: An integrative literature review.
Burn care innovations have vastly reduced mortality rates and improved prognoses, fostering the need for multi-disciplinary input in holistic recovery. Consequently psychological and social considerations post-burn are included in National Burn Care Standards and have featured increasingly in burns literature. To identify the key findings of the rapidly expanding literature base for psychosocial adjustment post-burn, highlighting the most important knowledge and future directions for both practice and research. MEDLINE, CINAHL, EMBASE, PsycINFO, BNI, HMIC databases were searched from January 2003 to September 2013 using search terms regarding psychosocial adjustment post-burn. After exclusions 24 papers underwent critical appraisal. Studies were categorised by the element of adjustment that they examined; psychopathology, quality of life, return to work, interpersonal, post-traumatic growth. Strengths, weaknesses, and significant findings within each category were presented. Although psychopathology and quality of life were well-researched compared to other categories, all would benefit from methodological improvements such as sample size or dropout rates. Coping strategies, premorbid psychopathology, and personality consistently featured as predictors of adjustment, although research should now move from identifying predictors, to clarifying the concept and parameters of psychosocial adjustment while developing and evaluating interventions to improve outcomes.


Risk of vertebral and non-vertebral fractures in patients with sarcoidosis: a population-based cohort.
In this retrospective cohort study using the Clinical Practice Research Datalink (CPRD), patients with sarcoidosis have an increased risk of clinical vertebral fractures and when on recent treatment with oral glucocorticoids, also an increased risk of any fractures and osteoporotic fractures. Sarcoidosis is a chronic inflammatory disease, in which fragility fractures have been reported despite normal BMD. The aim of this study was to assess whether patients with sarcoidosis have an increased risk of clinical fractures compared to the general population. A retrospective cohort study was conducted using the CPRD. All patients with a CPRD code for sarcoidosis between January 1987 and September 2012 were included. Cox proportional hazards models were used to derive adjusted relative risks (RRs) of fractures in all sarcoidosis patients compared to matched controls, and within the sarcoidosis group according to use and dose of systemic glucocorticoids. Five thousand seven hundred twenty-two sarcoidosis patients (mean age 48.0 years, 51 % females, mean follow-up 6.7 years) were identified. Compared to 28,704 matched controls, the risk of any fracture was not different in patients with sarcoidosis. However, the risk of clinical vertebral fractures was significantly increased (adj RR 1.77; 95 % CI 1.06-2.96) and the risk of non-vertebral fractures was decreased although marginally significant (adj RR 0.87; 95 % CI 0.77-0.99). Compared to sarcoidosis patients not taking glucocorticoids, recent use of systemic glucocorticoids was associated with an increased risk of any fracture (adj RR 1.50; 95 % CI 1.20-1.89) and of an osteoporotic fracture (adj RR 1.47; 95 % CI 1.07-2.02). Patients with sarcoidosis have an increased risk of clinical vertebral fractures, and when using glucocorticoid therapy, an increased risk of any fractures and osteoporotic fractures. In contrast, the risk of non-vertebral fractures maybe decreased. Further investigation is needed to understand the underlying mechanisms of these contrasting effects on fracture risk.


Anatomic direct repair of chronic distal biceps brachii tendon rupture without interposition graft.
Rupture of the biceps brachii insertion is relatively uncommon and may present late. Chronic ruptures pose a management dilemma, with higher reported complication rates when surgery is delayed, whilst conservatively treated injuries may do badly in active patients. Six consecutive male patients with delayed presentation of biceps rupture were treated operatively using a limited standard anterior approach, a secondary proximal "retrieval" incision, and EndoButton fixation. This modification of the well-described EndoButton technique for distal biceps reconstruction allows passage of the shortened tendon in maximal elbow flexion and a rehabilitation program without immobilization. The mean interval to repair was 79 days (range, 35-116 days). The mean age at presentation was 47.5 years. The injury mechanisms were unexpected loads on a flexed supinated forearm. Patients were assessed at a mean of 20.2 months. Range of motion was restored to 94% in flexion and 95% in prosupination compared with the uninjured limb. Supination endurance was reduced by 9 repetitions/min compared with the contralateral side (mean, 83.4 repetitions/min). Mayo Elbow Performance Scores were universally 100 and the mean Disabilities of Arm, Shoulder and Hand score was 4. Patient satisfaction was high, with visual analog scores of 92 to 100. No major complications occurred, and all repairs were intact at the final follow-up. Our outcomes are comparable to acute repair, with restoration of range of motion and function and few complications.


Thoracic electrical bioimpedance versus suprasternal Doppler in emergency care.
There are a number of cardiac output (CO) monitors that could potentially be used in the ED. Two of the most promising methods, thoracic electrical bioimpedance and suprasternal Doppler, have not been directly compared. The aim of this study was to investigate the feasibility of CO monitoring using suprasternal Doppler and bioimpedance in emergency care and compare haemodynamic data obtained from both monitors. Haemodynamic measurements were made on the same group of patients using bioimpedance (Niccomo, Medis, Germany) and suprasternal Doppler (USCOM, Sydney, Australia). Usable CO data were obtained in 97% of patients by suprasternal Doppler and 87% by bioimpedance. The median CO obtained by Doppler was 3.4 L/min lower than bioimpedance. The stroke volume median was lower by 51 mL in Doppler. These two methods of non-invasive cardiac monitoring are not interchangeable. The results suggest that the choice of non-invasive cardiac monitor is important, but the grounds on which to make this choice are not currently clear.


NMO-IgG Induce Interleukin-6 Release via Activation of the NF-κB Signaling Pathway in Astrocytes.
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) that frequently affects the optic nerve and spinal cord. Interleukin-6 (IL-6) is considered a key cytokine in the pathogenesis of NMOSD, and the level of IL-6 is significantly increased in the sera and cerebrospinal fluid (CSF) of patients with NMOSD. We have reported that the production of IL-6 depends on the JAK/STAT3 signaling pathway. However, it is not clear whether the NF-κB-dependent inflammatory response stimulated by neuromyelitis optica IgG (NMO-IgG) could also drive the production of IL-6 in astrocytes. In this study, we used an in vitro model of primary rat astrocytes stimulated by NMO-IgG to study the role of the NF-κB signaling pathway in mediating the release of IL-6. First, we confirmed that the level of IL-6 was significantly higher in the sera of NMOSD patients than that of healthy people by humoral fluid analysis and that NMO-IgG can significantly induce the release of IL-6 from astrocytes by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Then, Western blotting and immunocytochemistry showed that NMO-IgG can activate the intracellular NF-κB signaling pathway. Finally, it was found that S3633, an inhibitor of the NF-κB signaling pathway, can effectively inhibit the increase in IL-6 levels. These results prove that the production of IL-6 is partly mediated by the NF-κB signaling pathway, providing a potential effective strategy for targeted treatment of NMOSD.