[Clinical application and optimization of HEAD-US quantitative ultrasound assessment scale for hemophilic arthropathy].
Objective: To assess the feasibility of HEAD-US scale in the clinical application of hemophilic arthropathy (HA) and propose an optimized ultrasound scoring system. Methods: From July 2015 to August 2017, 1 035 joints ultrasonographic examinations were performed in 91 patients. Melchiorre, HEAD-US (Hemophilic Early Arthropathy Detection with UltraSound) and HEAD-US-C (HEAD-US in China) scale scores were used respectively to analyze the results. The correlations between three ultrasound scales and Hemophilia Joint Health Scores (HJHS) were evaluated. The sensitivity differences of the above Ultrasonic scoring systems in evaluation of HA were compared. Results: All the 91 patients were male, with median age of 16 (4-55) years old, including 86 cases of hemophilia A and 5 cases hemophilia B. The median (P25, P75) of Melchiorre, HEAD-US and HEAD-US-C scores of 1 035 joints were 2(0,6), 1(0,5) and 2(0,6), respectively, and the correlation coefficients compared with HJHS was 0.747, 0.762 and 0.765 respectively, with statistical significance (P<0.001). The positive rates of Melchiorre, HEAD-US-C and HEAD-US scale score were 63.0% (95%CI 59.7%-65.9%), 59.5% (95%CI 56.5%-62.4%) and 56.6% (95%CI 53.6%-59.6%) respectively, and the difference was statistically significant (P<0.001). Even for 336 cases of asymptomatic joints, the positive rates of Melchiorre, HEAD-US-C and HEAD-US scale score were 25.0% (95%CI 20.6%-29.6%), 17.0% (95%CI 12.6%-21.1%) and 11.9% (95%CI 8.4%-15.7%) respectively, and the difference was statistically significant (P<0.001). There were significant changes (P<0.05) in the ultrasonographic score of HA before and after onset of hemorrhage in 107 joints of 40 patients. The difference in variation amplitude of HEAD-US-C scores and HEAD-US scores before and after joint bleeding was statistically significant (P<0.001). Conclusion: Compared with Melchiorre, there were similar good correlations between HEAD-US, HEAD-US-C and HJHS. HEAD-US ultrasound scoring system is quick, convenient and simple to use. The optimized HEAD-US-C scale score is more sensitive than HEAD-US, especially for patients with HA who have subclinical state, which make up for insufficiency of sensitivity in HEAD-US scoring system.


Fish oil prevents rodent anxious states comorbid with diabetes: A putative involvement of nitric oxide modulation.
There is an urgent need to understand the pathophysiological mechanisms related to anxiety associated with diabetes, seeking more effective alternative treatments to treat it. For that, the effect of a preventive and prolonged treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, was tested in streptozotocin-diabetic (DBT) rats submitted to the anxiety tests. Additionally, an immunohistochemistry for neuronal NO synthase (nNOS) was performed in brain areas related to anxiety, such as lateral amygdala (AMY), hippocampus (HIP) and dorsolateral periaqueductal gray (dlPAG). Lastly, the effect of NO precursor L-arginine (L-Arg) or nNOS inhibitor 7-nitroindazole (7-NI) was tested in DBT animals treated with vehicle (VEH) or FO. Our data demonstrated that vehicle-treated DBT animals exhibited a more pronounced anxiogenic-like response and also presented high nNOS levels in the AMY, HIP and rostral dlPAG, what were both significantly prevented by FO treatment. This treatment was able to prevent the impairment in locomotor activity besides improving the high glycemic levels in DBT rats. Interestingly, while injection of 7-NI or L-Arg in VEH-treated DBT animals induced an anxiogenic-like and anxiolytic-like effect, respectively; the previous treatment with both L-Arg and 7-NI in FO-DBT animals abolished the anxiolytic-like effect induced by FO treatment. Altogether, our data support the hypothesis that a dysregulation in the NO production in brain areas as AMY, HIP and dlPAG may contribute to the mechanisms that link anxiety and diabetes, and the prevention of nNOS brain expression changes induced by a prolonged treatment with FO may be an important mechanism related to its anxiolytic-like effect.


ECM-incorporated hydrogels cross-linked via native chemical ligation to engineer stem cell microenvironments.
Limiting the precise study of the biochemical impact of whole molecule extracellular matrix (ECM) proteins on stem cell differentiation is the lack of 3D in vitro models that can accommodate many different types of ECM. Here we sought to generate such a system while maintaining consistent mechanical properties and supporting stem cell survival. To this end, we used native chemical ligation to cross-link poly(ethylene glycol) macromonomers under mild conditions while entrapping ECM proteins (termed ECM composites) and stem cells. Sufficiently low concentrations of ECM were used to maintain constant storage moduli and pore size. Viability of stem cells in composites was maintained over multiple weeks. ECM of composites encompassed stem cells and directed the formation of distinct structures dependent on ECM type. Thus, we introduce a powerful approach to study the biochemical impact of multiple ECM proteins (either alone or in combination) on stem cell behavior.


Circulating microRNA-194 regulates human melanoma cells via PI3K/AKT/FoxO3a and p53/p21 signaling pathway.
In the present study, we analyzed the role of microRNA-194 circulating regulated human melanoma cell growth. We found that microRNA-194 expression was markedly suppressed in human melanoma patients, compared with negative control group. Next, disease-free survival (DFS) and overall survival (OS) of high expression in human melanoma patients was higher than those of low expression in human melanoma patients. MicroRNA-194 overexpression inhibited cell proliferation, induced apoptosis, increased caspase-3/-9 activities and promoted Bax/Bcl-2 of human melanoma cells. Furthermore, microRNA-194 overexpression also suppressed PI3K/AKT/FoxO3a signaling pathway and induced p53/p21 signaling pathway. PI3K inhibitor, suppressed PI3K, phosphorylation-AKT, FoxO3a protein expression and increased the effects of microRNA-194 overexpression on cell growth, apoptosis, caspase-3/-9 activities and Bax/Bcl-2 protein expression of human melanoma cells through the induction of p53/p21 signaling pathway. Taken together, these data indicate that circulating microRNA-194 regulated human melanoma cells via PI3K/AKT/FoxO3a and p53/p21 signaling pathway.


Cytochemical and developmental changes in microbodies (glyoxysomes) and related organelles of castor bean endosperm.
Structural changes in endosperm cells of germinating castor beans were examined and complemented with a cytochemical analysis of staining with diaminobenzidine (DAB). Deposition of oxidized DAB occurred only in microbodies due to the presence of catalase, and in cell walls associated with peroxidase activity. Seedling development paralleled the disappearance of spherosomes (lipid bodies) and matrix of aleurone grains in endosperm cells. 6 to 7 days after germination, a cross-section through the endosperm contained cells in all stages of development and senescence beginning at the seed coat and progressing inward to the cotyledons. Part of this aging process involved vacuole formation by fusion of aleurone grain membranes. This coincided with an increase in microbodies (glyoxsomes), mitochondria, plastids with an elaborate tubular network, and the formation of a new protein body referred to as a dilated cisterna, which is structurally and biochemically distinct from microbodies although both apparently develop from rough endoplasmic reticulum (ER). In vacuolate cells microbodies are the most numerous organelle and are intimately associated with spherosomes and dilated cisternae. This phenomenon is discussed in relation to the biochemical activities of these organelles. Turnover of microbodies involves sequestration into autophagic vacuoles as intact organelles which still retain catalase activity. Crystalloids present in microbodies develop by condensation of matrix protein and are the principal site of catalase formerly in the matrix.


Quantitative proteomics reveals that distant recurrence-associated protein R-Ras and Transgelin predict post-surgical survival in patients with Stage III colorectal cancer.
Surgical resection supplemented with adjuvant chemotherapy is the current preferred treatment for Stage III colorectal cancer (CRC). However, as many as 48% of patients who undergo curative resection eventually suffer from incurable distant recurrence. To investigate the molecular mechanisms involved in Stage III CRC post-surgical distant recurrence, we identified a total of 146 differentially expressed proteins (DEPs) associated with distant recurrence in Stage III CRC using TMT-based quantitative mass spectrometry. Among these DEPs, the altered expressions of R-Ras and Transgelin were then validated in 192 individual specimens using immunohistochemistry (IHC). Furthermore, Kaplan-Meier analysis revealed that the levels of R-Ras and Transgelin were significantly associated with 5-year overall survival (OS) and disease-free survival (DFS), and multivariate Cox-regression analyses revealed that R-Ras and Transgelin were independent prognostic factors for OS and DFS, respectively. In conclusion, this study identified potential biochemical players involved in distant recurrence and indicates that R-Ras and Transgelin are potential post-surgical prognostic biomarkers for Stage III CRC. This proteomics data have been submitted to Proteome Xchange under accession number PXD002903.


Gender as an underestimated factor in mental health of medical students.
In Germany, currently two out of three medical students are female. Several studies corroborate that medical students show a significantly higher prevalence of stress-related mental disorders than the population in general. We aimed to evaluate, if gender has an influence on the distribution of mental stress parameters and learning style among male and female medical students. We investigated a total of 758 students of the medical faculty at the University of Erlangen-Nuernberg, Germany, using standardized and validated psychological questionnaires on depressive symptoms (BDI-II), burnout (BOSS-II) and quality of life (SF-12). In addition, we screened the students for their learning styles according to Kolb. Out of 723 participants who declared their gender, 57.8% were female and 37.6% were male. Female students showed significantly higher values for depressiveness as well as for emotional and cognitive burnout, whereas the mental quality of life was significantly lower. A considerably higher percentage of male students with a converging or an accommodating learning style were found in comparison to their female fellows. We postulate that an adaptation of the medical curriculum content to the investigated factors may contribute to a higher mental stability and less stress-related symptoms in medical students.


Natural antioxidants in the treatment and prevention of diabetic nephropathy; a potential approach that warrants clinical trials.
Diabetic nephropathy is the major cause of end-stage renal disease and effective and new therapeutic approaches are needed in diabetic nephropathy and chronic kidney diseases. Oxidative stress and inflammatory process are important factors contributing to kidney damage by increasing production of oxidants. KEAP1/Nrf2/ARE pathway regulates the transcription of many antioxidant genes and modulation of the pathway up regulates antioxidants. NFB controls the expression of genes involved in the inflammatory response. Natural substances have antioxidant and anti-inflammatory activities and have an impact on NFB and KEAP1/Nrf2/ARE pathways. The preclinical studies explored the effectiveness of whole herbs, plants or seeds and their active ingredients in established diabetic nephropathy. They ameliorate oxidative stress induced kidney damage, enhance antioxidant system, and decrease inflammatory process and fibrosis; most likely by activating KEAP1/Nrf2/ARE pathway and by deactivating NFB pathway. Whole natural products contain balanced antioxidants that might work synergistically to induce beneficial therapeutic outcome. In this context, more clinical studies involving whole plants or herbal products or mixtures of different herbs and plants and their active ingredients might change our strategies for the management of diabetic nephropathy. The natural products might be useful as preventive interventions and studies are required in this field.


Association between seropositivity to Chlamydia pneumoniae and acute ischaemic stroke.
Recent studies suggest an association between Chlamydia pneumoniae infection with atherosclerosis, including cerebrovascular disease. We investigated the prevalence of Chlamydial seropositivity in patients with acute ischaemic stroke syndrome compared with age- and sex-matched control subjects. Specific antibodies (IgA) to C. pneumoniae were measured by microimmunofluorescence in both the clinical group (n=91) and the control group (n=112). Forty patients (43.9%) and 34 controls (30.3%) had positive IgA titres (P < 0.05). The pooled data from this and previous series yielded 45% of seropositivity in cerebrovascular patients vs. 19% in control subjects (P < 0.001). In conclusion, we suggest an association between chronic infection by C. pneumoniae and acute ischaemic stroke.


Is There a Disadvantage to Early Physical Therapy After Multiligament Surgery for Knee Dislocation? A Pilot Randomized Clinical Trial.
Multiligament knee injuries, though rare, can be profoundly disabling. Surgeons disagree about when to initiate rehabilitation after surgical reconstruction due to the conflicting priorities of postoperative stability and motion. (1) Does early or late initiation of physical therapy after multiligament knee surgery result in fewer postoperative manipulations? (2) Does early versus late physical therapy compromise stability postoperatively? (3) Does early initiation of physical therapy result in improved patient-reported outcomes, as measured by the Multi-ligament Quality of Life (ML-QOL) score? Between 2011 and 2016, 36 adults undergoing multiligament repair or reconstruction were prospectively enrolled in a randomized controlled trial and randomized 1:1 to either early rehabilitation or late rehabilitation after surgery. Eligibility included those with an injury to the posterior cruciate ligament (PCL) and at least one other ligament, as well as the ability to participate in early rehabilitation. Patients who were obtunded or unable to adhere to the protocols for other reasons were excluded. Early rehabilitation consisted of initiating a standardized physical therapy protocol on postoperative day 1 involving removal of the extension splint for quadriceps activation and ROM exercises. Late rehabilitation consisted of full-time immobilization in an extension splint for 3 weeks. Following this 3-week period, both groups engaged in the same standardized physical therapy protocol. All surgical reconstructions were performed at a single center by one of two fellowship-trained sports orthopaedic surgeons, and all involved allograft Achilles tendon PCL reconstruction. When possible, hamstring autograft was used for ACL and medial collateral ligament reconstructions, whereas lateral collateral ligament and posterolateral reconstruction was performed primarily with allograft. The primary outcome was the number of patients undergoing manipulation during the first 6 months. Additional outcomes added after trial registration were patient-reported quality of life scores (ML-QOL) at 1 year and an objective assessment of laxity through a physical examination and stress radiographs at 1 year. One patient from each group was not assessed for laxity or ROM at 1 year, and one patient from each group did not complete the ML-QOL questionnaires. No patient crossover was observed. With the numbers available, there was no difference in the use of knee manipulation during the first 6 months between the rehabilitation groups: 1 of 18 patients in the early group and 4 of 18 patients in the late group (p = 0.34). Similarly, there were no differences in knee ROM, stability, or patient-reported quality of life (ML-QOL) between the groups at 1 year. With the numbers available in this study, we were unable to demonstrate a difference between early and late knee rehabilitation with regard to knee stiffness, laxity, or patient-reported quality of life outcomes. The results of this small, randomized pilot study suggest a potential role for early rehabilitation after multiligament reconstruction for knee dislocation, which should be further explored in larger multi-institutional studies. Level II, therapeutic study.


The role of drug profiles as similarity metrics: applications to repurposing, adverse effects detection and drug-drug interactions.
Explosion of the availability of big data sources along with the development in computational methods provides a useful framework to study drugs' actions, such as interactions with pharmacological targets and off-targets. Databases related to protein interactions, adverse effects and genomic profiles are available to be used for the construction of computational models. In this article, we focus on the description of biological profiles for drugs that can be used as a system to compare similarity and create methods to predict and analyze drugs' actions. We highlight profiles constructed with different biological data, such as target-protein interactions, gene expression measurements, adverse effects and disease profiles. We focus on the discovery of new targets or pathways for drugs already in the pharmaceutical market, also called drug repurposing, in the interaction with off-targets responsible for adverse reactions and in drug-drug interaction analysis. The current and future applications, strengths and challenges facing all these methods are also discussed. Biological profiles or signatures are an important source of data generation to deeply analyze biological actions with important implications in drug-related studies.


Pituitary-adrenocortical responses to persistent noxious stimuli in the awake rat: endogenous corticosterone does not reduce nociception in the formalin test.
Although glucocorticoids inhibit inflammation and are used to treat painful inflammatory rheumatic diseases, the contribution, if any, of endogenous pituitary-adrenocortical activity to the control of pain remains unclear. We report that injection of dilute formalin into the hindpaw not only evokes inflammation and pain-related behavior, but it also increases ACTH and corticosterone to a greater extent than restraint and saline injection alone. This difference was particularly robust during the final periods of pain-related behavior in the formalin test, when the ACTH and corticosterone (B) levels in the restraint/saline control group had returned to normal. These results indicate that formalin-evoked increases in ACTH and B reflect nociceptive input, rather than the stress associated with handling. To test the hypothesis that the formalin-induced increase in corticosterone reduces pain and inflammation, we next evaluated the effect of adrenalectomy (to prevent activation of glucocorticoid receptors) or high-dose dexamethasone (to saturate glucocorticoid receptors) on nociceptive processing in the formalin test. Neither adrenalectomy nor dexamethasone changed behavioral or cardiovascular nociceptive responses. Furthermore, the increases in blood pressure and heart rate produced by formalin may not be mediated by adrenomedullary catecholamine release. In addition, we conclude that the nociceptive component of the formalin stimulus is sufficient to activate the pituitary-adrenocortical system in the awake rat, but that the resulting release of corticosterone does not feed back and reduce nociceptive processing.


Kinetics of oxytetracycline reaction with a hydrous manganese oxide.
Tetracycline antibiotics comprise a class of broad spectrum antimicrobial agents finding application in human therapy, animal husbandry, aquaculture, and fruit crop production. To better understand the processes affecting these antibiotics in soils and sediments, the kinetics of oxytetracycline transformation by a hydrous manganese oxide (MnO2) were investigated as a function of reactant concentration, pH, and temperature. Oxytetracycline was rapidly degraded by MnO2. Initial reaction rates exhibited pronounced pH-dependence, increasing as pH decreased. Reaction of oxytetracycline with MnO2 was accompanied by generation of Mn(II) ions, suggesting oxidative transformation of the antibiotic. At pH 5.6, apparent reaction orders for oxytetracycline and MnO2 were 0.7 and 0.8. Reaction order with respect to H+ was 0.6 between pH 4 and 9. Initial reaction rates increased by a factor of approximately 2.4 for 10 degrees C temperature increases; the apparent activation energy (60 kJ x mol(-1)) was consistent with a surface-controlled reaction. Reactivity of tetracycline antibiotics toward MnO2 increased in the following order: rolitetracyline oxytetracycline < or =tetracycline approximately meclocycline < chlortetracycline. The initial rate of chlortetracycline degradation by MnO2 was substantially larger than that of the other tetracycline antibiotics investigated. MnO2 reactivity toward oxytetracycline decreased with time; a retarded rate equation was used to describe oxytetracycline reaction with MnO2 under declining rate conditions. This study indicates that natural manganese oxides in soils and sediments are likely to promote appreciable degradation of tetracycline antibiotics, and that reaction rates are strongly dependent on reaction time scale and solution conditions.


Water-Soluble Organic Nanoparticles with Programable Intermolecular Charge Transfer for NIR-II Photothermal Anti-Bacterial Therapy.
Extensive recent efforts have been put on the design of high-performance organic near-infrared (NIR) photothermal agents (PTAs), especially over NIR-II bio-window (1000-1350 nm). So far, the development is mainly limited by the rarity of molecules with good NIR-II response. Here, we report organic nanoparticles of intermolecular charge-transfer complexes (CTCs) with easily programmable optical absorption. By employing different common donor and acceptor molecules to form CTC nanoparticles (CT NPs), absorption peaks of CT NPs can be controllably tuned from the NIR-I to NIR-II region. Notably, CT NPs formed with perylene and TCNQ have a considerably red-shifted absorption peak at 1040 nm and achieves a good photothermal conversion efficiency of 42 % under 1064 nm excitation. These nanoparticles were used for antibacterial application with effective activity towards both Gram-negative and Gram-positive bacteria. This work opens a new avenue into the development of efficient PTAs.


Theta particles: a structure found in hamster sarcoma virus.
Hamster sarcoma virus (HaSV), a ribonucleic acid tumor virus, pelleted from tissue culture fluid manifests type C morphology by electron microscopy. However, if virus is first concentrated by polyethylene glycol or ammonium sulfate followed by density gradient banding, the virus shows a dramatically atypical barred core structure, termed "theta particles." This structure suggests a condensation of the ribonucleoprotein into a flat disc. Atypical particles are found with HaSV and not in similarly treated feline leukemia virus or Rauscher-murine leukemia virus. Differences in the composition of HaSV as compared with these other viruses may be responsible for the production of such particles.


Ultrafine Co1-xS nanoparticles embedded in a nitrogen-doped porous carbon hollow nanosphere composite as an anode for superb sodium-ion batteries and lithium-ion batteries.
Cobalt sulfides are attractive as intriguing candidates for anodes in SIBs and LIBs owing to their unique chemical and physical properties. In this study, a precursor of Co1-xS with a uniform and hollow nanospherical architecture is obtained with a high yield via a mild solvothermal method in the presence of 2-methylimidazole at first. Then, Co1-xS, Co1-xS/C (ultrafine Co1-xS nanoparticles embedded in the shells of the nitrogen-doped porous carbon hollow nanosphere), and Co1-xS@C (Co1-xS nanoparticles entirely covered by an external amorphous carbon layer) were selectively fabricated via direct calcination or PPy coating & calcination of the obtained precursor. Co1-xS/C shows best electrochemical performance than the other two materials as anodes for sodium-ion batteries (SIBs). Besides the excellent rate performance, a high reversible discharge capacity of 320 mA g-1 can be retained after 130 cycles at 1 A g-1. The impressive performance may be attributed to the unique structure, higher conductivity, and more active sites of Co1-xS/C. In addition, 559 mA h g-1 was maintained after 100 cycles at 500 mA g-1 when the Co1-xS/C composite was applied as an anode in lithium-ion batteries (LIBs). The high reversible capacity, excellent cycle stability combined with the facile synthesis procedure render Co1-xS/C a prospective anode material for rechargeable batteries.


Corrosion of base metal alloys in vitro.
Corrosion of base metal alloys was studied by placing the alloys in artificial saliva for 2 months and then determining the concentration of metal ions in the saliva. The distribution of the attack on the surface was examined. The results indicated that the amount of metal ions in the artificial saliva could be related to the Cr content of the alloy. When the Cr content exceeded 16% very little corrosion was observed. The corrosive attack was located at Cr depleted areas, grain boundaries. The Cr depletion probably resulted from coring during solidification.


The immunosuppressive effect of Mycoplasma meleagridis on nonreplicating antigens.
The humoral responses of Mycoplasma meleagridis-free and -infected turkeys were compared following primary and secondary antigenic stimulation with inactivated Salmonella pullorum or dinitrophenyl-bovine gamma globulin. The mycoplasma-infected groups had significantly lower antibody responses to both antigens. The suppression was more evident in the secondary response. The results suggest that the immune response in turkeys infected with M. meleagridis is similar to that of bursectomized chickens: the ability of chickens to synthesize immunoglobulin G is affected more readily than the ability to synthesize IgM.


A histological and immunohistochemical study of the humoral immune system of the lungs in young Thoroughbred horses.
Lungs were obtained from 16 Thoroughbred horses, aged 1 day to 2 years, which had died or been humanely killed for reasons unrelated to disease of the lower respiratory tract. The lungs were then subjected to a histological and immunohistochemical examination of the humoral immune system. At birth there was no evidence of organized lymphoid tissue, and lymphocytes and plasma cells were virtually absent in all tissue compartments in the first week of life. However, by 12 weeks, foals exhibited well developed bronchus- and bronchiole-associated lymphoid tissue, but this had regressed progressively at 1 and 2 years of age. Plasma cells were present in large numbers in the walls of bronchi and bronchioles in foals aged 8 to 12 weeks. IgA-producing plasma cells were common in the lower respiratory tract of these young horses, in addition to IgG- and IgM-producing plasma cells.


Purification and characterization of the alkaline phosphatase from Echinococcus granulosus cyst membranes.
The purification to homogeneity and the characterization of Echinococcus granulosus alkaline phosphatase (AP; EC 18.104.22.168) from hydatid cyst membranes are described. After n-butanol extraction, the parasite enzyme was sequentially purified by affinity chromatography on concanavalin A-sepharose followed by gel filtration. The purified protein (210 kDa) had a tetrameric structure composed of 4 56-kDa subunits. Its isoelectric point (4.8) and its kinetic parameters were determined (Km = 0.24 +/- 0.05 mmol/L; Vm = 173 +/- 21 nmol/min/mg protein for p-nitrophenylphosphate). The parasite enzyme differed from the host liver enzyme in its thermal stability, optimum reaction temperature, optimum pH, and catalytic parameters, but not in its apparent molecular weight. Furthermore, sera from patients infected with E. granulosus recognized the parasite AP on immunoblots, whereas uninfected controls were negative. These results as well as the role of this enzyme in the host-parasite relationship emphasize its potential importance as a diagnostic and prognostic antigen in the monitoring of hydatid infection.


The prognosis of elderly subjects with oesophageal varices.
Discharge survival following variceal bleeding was similar in 27 elderly subjects, aged 65-93 years, and 125 younger subjects, aged under 65 (63% versus 70%, p greater than 0.05). Of 39 elderly subjects with varices which were not bleeding on admission, 82% were discharged alive but subsequent mortality was higher and long-term survival was similar (median 1 year) on life-table analysis. The overall long-term survival in the 66 elderly subjects was far worse than in the comparable group of 269 subjects under 65 (p less than 0.001). However, the excess deaths were from causes unrelated to hepatic failure or bleeding (e.g. stroke). Considering only deaths from hepatic failure or bleeding, long-term survival in the elderly and young was similar (p greater than 0.5). We conclude that elderly subjects with varices should be managed as actively as younger subjects since the majority are discharged alive and prolonged survival is common (25% at 3 years).


Digital nerve conduction velocity for evaluation of peripheral nerve impairments in vibration syndrome.
In order to evaluate peripheral nerve impairments in vibration syndrome, sensory nerve conduction velocity (SCV) in the digital segment of the median nerve was measured by applying electrical stimulation to the wrist and recording from two pairs of electrodes attached to the middle finger. Fractionated SCVs were also measured in the palm-to-finger, wrist-to-palm, and elbow-to-wrist segments of the median nerve. Subjects were 65 patients with vibration syndrome and 48 healthy controls of similar age. SCVs in the digital nerve segment were significantly slower in the patients than in the controls. Significant slowing was also found in the wrist-to-palm segment. SCVs in the palm-to-finger and elbow-to-wrist segments did not differ between the two groups. Slowed SCVs were most frequently encountered in the digital segment (38% of the patients). The slowing in the wrist-to-palm segment was found in 20% of the patients. Present findings indicate that the digital segment is most frequently affected in vibration-induced neuropathy, and measurement of SCVs in the digital segment would serve to evaluate the peripheral neuropathy in vibration syndrome.


Porin activity of Anaplasma phagocytophilum outer membrane fraction and purified P44.
Anaplasma phagocytophilum, an obligatory intracellular bacterium that causes human granulocytic anaplasmosis, has significantly less coding capacity for biosynthesis and central intermediary metabolism than do free-living bacteria. Thus, A. phagocytophilum needs to usurp and acquire various compounds from its host. Here we demonstrate that the isolated outer membrane of A. phagocytophilum has porin activity, as measured by a liposome swelling assay. The activity allows the diffusion of L-glutamine, the monosaccharides arabinose and glucose, the disaccharide sucrose, and even the tetrasaccharide stachyose, and this diffusion could be inhibited with an anti-P44 monoclonal antibody. P44s are the most abundant outer membrane proteins and neutralizing targets of A. phagocytophilum. The P44 protein demonstrates characteristics consistent with porins of gram-negative bacteria, including detergent solubility, heat modifiability, a predicted structure of amphipathic and antiparallel beta-strands, an abundance of polar residues, and a C-terminal phenylalanine. We purified native P44s under two different nondenaturing conditions. When reconstituted into proteoliposomes, both purified P44s exhibited porin activity. P44s are encoded by approximately 100 p44 paralogs and go through extensive antigenic variation. The 16-transmembrane-domain beta-strands consist of conserved P44 N- and C-terminal regions. By looping out the hypervariable region, the porin structure is conserved among diverse P44 proteins yet enables antigenic variation for immunoevasion. The tricarboxylic acid (TCA) cycle of A. phagocytophilum is incomplete and requires the exogenous acquisition of L-glutamine or L-glutamate for function. Efficient diffusion of L-glutamine across the outer membrane suggests that the porin feeds the Anaplasma TCA cycle and that the relatively large pore size provides Anaplasma with the necessary metabolic intermediates from the host cytoplasm.


Risk factors for human immunodeficiency virus (HIV) infections in homosexual men.
To clarify risk factors for infection with the human immunodeficiency virus (HIV) we selected at random 785 homosexual men who had participated in studies of hepatitis B in San Francisco in 1978-80 for a follow-up study of the acquired immunodeficiency syndrome. Although most had not been contacted in over five years, 492 (63 per cent) were located and enrolled. The 240 (67 per cent) who had developed antibodies to HIV, as measured by an enzyme-linked immunosorbent assay (ELISA), were compared with 119 who had remained seronegative. In multivariate analyses, receptive anal intercourse with ejaculation by nonsteady sexual partners, many sexual partners per month, and other indicators of high levels of sexual activity were highly associated with seroconversions. None of the sexual practices that we studied appeared to offer protection against HIV infection.


Value of Microperimetry in Detecting Early Retinal Toxicity of Hydroxychloroquine in Children with Juvenile Systemic Lupus Erythematosus.
To evaluate retinal sensitivity in children who are on hydroxychloroquine (HCQ) for systemic lupus erythematosus using microperimetry and compare the results with those of the Humphrey visual field (HVF) 10-2 and spectral-domain optical coherence tomography (SD-OCT). A case-control cross-sectional study including 19 patients (less than 18 years old) on HCQ for at least 5 years. Controls were 21 normal children. Participants underwent a complete ophthalmic examination, then were investigated using HVF 10-2, SD-OCT, and microperimetry. Ocular examination revealed no abnormalities. The overall mean microperimetry sensitivity of the patients (15.75 dB) was not significantly different from that of the controls (16.35 dB). The HVF 10-2 showed a significant difference in the mean deviation of the patients. Conclusions and Message: Microperimetry was not more revealing than HVF 10-2 and SD-OCT. Larger studies are required to compare the diagnostic accuracy of screening modalities of retinal toxicity in children on HCQ.


Predicting hypoxaemia during flights in children with cystic fibrosis.
We have previously suggested that it is possible to predict oxygen desaturation during flight in children with cystic fibrosis and chronic lung disease by non-invasive measurement of oxygen saturation following inhalation of 15% oxygen--the pre-flight hypoxic challenge. This study reports on the results of measurements over 5 years. The study comprised a pre-flight hypoxic challenge measuring oxygen saturation by finger tip pulse oximetry (SpO(2)) during tidal breathing of 15% oxygen in nitrogen and spirometric testing 1 month before the flight followed by SpO(2) measurements during intercontinental flights to and from holidays abroad with children in wake and sleep states. Pre-flight tests were completed on 87 children with cystic fibrosis. Desaturation of <90% occurred in 10 children at some stage during the flight, three of whom received supplementary oxygen. Using a cut off SpO(2) of 90%, the pre-flight hypoxic challenge correctly predicted desaturation in only two of these children. The sensitivity and specificity of the pre-flight hypoxic challenge were 20% and 99%, respectively, compared with 70% and 96% for spirometric tests (using a cut off for forced expiratory volume in 1 second (FEV(1)) of <50% predicted). Overall, pre-flight spirometric tests were a better predictor of desaturation during flight with the area under the Receiver Operating Characteristic (ROC) curve of 0.89 compared with 0.73 for the hypoxic challenge test. In this group of subjects pre-flight spirometric testing was a better predictor of desaturation during flight than the pre-flight hypoxic challenge.


Polyphyletic origin of pyrrolizidine alkaloids within the Asteraceae. Evidence from differential tissue expression of homospermidine synthase.
The evolution of pathways within plant secondary metabolism has been studied by using the pyrrolizidine alkaloids (PAs) as a model system. PAs are constitutively produced by plants as a defense against herbivores. The occurrence of PAs is restricted to certain unrelated families within the angiosperms. Homospermidine synthase (HSS), the first specific enzyme in the biosynthesis of the necine base moiety of PAs, was originally recruited from deoxyhypusine synthase, an enzyme involved in the posttranslational activation of the eukaryotic initiation factor 5A. Recently, this gene recruitment has been shown to have occurred several times independently within the angiosperms and even twice within the Asteraceae. Here, we demonstrate that, within these two PA-producing tribes of the Asteraceae, namely Senecioneae and Eupatorieae, HSS is expressed differently despite catalyzing the same step in PA biosynthesis. Within Eupatorium cannabinum, HSS is expressed uniformly in all cells of the root cortex parenchyma, but not within the endodermis and exodermis. Within Senecio vernalis, HSS expression has been previously identified in groups of specialized cells of the endodermis and the adjacent root cortex parenchyma. This expression pattern was confirmed for Senecio jacobaea as well. Furthermore, the expression of HSS in E. cannabinum is dependent on the development of the plant, suggesting a close linkage to plant growth.


Age-related changes of sulcal imprints on the endocranium in the Japanese macaque (Macaca fuscata).
The degree of expression of sulcal patterns on endocasts of nonhuman primates has been shown to depend primarily on species (brain size) and age of the individual. It has been suggested that brain details on endocasts are reproduced better in juvenile than adult primates. Here, we investigated age-related changes in the imprint of the major sulci on the endocranium of Japanese macaques (Macaca fuscata) from the juvenile period to adulthood. Using CT scans of 25 (12 males, 13 females) cranial specimens from macaques, we generated virtual endocasts to assess imprints of the seven main sulci on the endocranial surface. Expression of each sulcal imprint was evaluated by imprint score method. The degree of expression of sulcal imprints differed between sulci. Arcuate, superior temporal, and principal sulci were well defined, whereas lunate and intraparietal sulci were poorly represented. Sulcal imprints showed significant age-related changes in Japanese macaques from juvenile to elderly. Sulcal imprints showed a slight decrease in degree of expression from the juvenile period (2-4 years) to adolescence (4-6 years), and then remained unchanged until mid-adulthood (15-16 years). The degree of expression of the sulcal imprints significantly decreased from mid-adulthood to old age (>20 years). The degree of expression of the sulcal imprints (relief forms) in inner table bone surface (endocranium) reveals significant age-related decreases in adults. The great decrease starts at around 20 years of age. The endocranial volume showed a significant age-related increase, and thus, it is suggested that the endocranial surface in macaques may be resorbed with advancing age.


[Results of A-scan echography in diseases of the orbit].
Standard A-scan sonography was performed in 191 patients with orbital mass lesions. In 36 cases tissue differentiation was not possible; in a further 11 patients the orbital lesion was not detected by ultrasonography. However, it provided an accurate histological diagnosis preoperatively in 87% of the remaining 144 patients.


The globalization of naval provisioning: ancient DNA and stable isotope analyses of stored cod from the wreck of the Mary Rose, AD 1545.
A comparison of ancient DNA (single-nucleotide polymorphisms) and carbon and nitrogen stable isotope evidence suggests that stored cod provisions recovered from the wreck of the Tudor warship Mary Rose, which sank in the Solent, southern England, in 1545, had been caught in northern and transatlantic waters such as the northern North Sea and the fishing grounds of Iceland and Newfoundland. This discovery, underpinned by control data from archaeological samples of cod bones from potential source regions, illuminates the role of naval provisioning in the early development of extensive sea fisheries, with their long-term economic and ecological impacts.


Epigenetic regulation of vitamin D deficiency.
Tweetable abstract Epigenetic insights into vitamin D deficiency, a global health concern, are described here. This editorial illuminates the role of epigenetic mechanisms in understanding the molecular basis of vitamin D deficiency, shedding light on precision medicine.


Use of 13C nuclear magnetic resonance to assess fossil fuel biodegradation: fate of [1-13C]acenaphthene in creosote polycyclic aromatic compound mixtures degraded by bacteria.
[1-13C]acenaphthene, a tracer compound with a nuclear magnetic resonance (NMR)-active nucleus at the C-1 position, has been employed in conjunction with a standard broad-band-decoupled 13C-NMR spectroscopy technique to study the biodegradation of acenaphthene by various bacterial cultures degrading aromatic hydrocarbons of creosote. Site-specific labeling at the benzylic position of acenaphthene allows 13C-NMR detection of chemical changes due to initial oxidations catalyzed by bacterial enzymes of aromatic hydrocarbon catabolism. Biodegradation of [1-13C]acenaphthene in the presence of naphthalene or creosote polycyclic aromatic compounds (PACs) was examined with an undefined mixed bacterial culture (established by enrichment on creosote PACs) and with isolates of individual naphthalene- and phenanthrene-degrading strains from this culture. From 13C-NMR spectra of extractable materials obtained in time course biodegradation experiments under optimized conditions, a number of signals were assigned to accumulated products such as 1-acenaphthenol, 1-acenaphthenone, acenaphthene-1,2-diol and naphthalene 1,8-dicarboxylic acid, formed by benzylic oxidation of acenaphthene and subsequent reactions. Limited degradation of acenaphthene could be attributed to its oxidation by naphthalene 1,2-dioxygenase or related dioxygenases, indicative of certain limitations of the undefined mixed culture with respect to acenaphthene catabolism. Coinoculation of the mixed culture with cells of acenaphthene-grown strain Pseudomonas sp. strain A2279 mitigated the accumulation of partial transformation products and resulted in more complete degradation of acenaphthene. This study demonstrates the value of the stable isotope labeling approach and its ability to reveal incomplete mineralization even when as little as 2 to 3% of the substrate is incompletely oxidized, yielding products of partial transformation. The approach outlined may prove useful in assessing bioremediation performance.


The treatment of acute diarrhea in the third millennium: a pediatrician's perspective.
Diarrheal diseases continue to be a major cause of morbidity and mortality worldwide. Although new, potentially useful drugs such as acetorphan are appearing at the horizon, the cornerstone of treatment remains a proper oral rehydration (ORT). Yet, the rates at which ORT is used are still disappointingly low. Despite dramatic progresses in the understanding of the pathophysiology of diarrhea, the list of available drugs is indeed short. Recently however, several new options have appeared that may bear a great potential in the near future. The first is a potential improvement of ORS. It was recently shown that the addition of a resistant starch to oral rehydration solution reduces fecal fluid loss and shortens the duration of diarrhea in patients with cholera. Starches that are resistant to hydrolysis by amylase in fact generate in the colon short-chain fatty acids, which are known to enhance sodium absorption. The second development in treating diarrheal disease is acetorphan (racecadotril). This enkephalinase inhibitor has in fact been shown to be effective in reducing by almost half the stool output of 135 young children with acute diarrhea. Finally, probiotics. In the last few years, they have attracted a great deal of renewed interest, particularly focusing on their effects in treating and preventing diarrheal diseases. Lactobacillus GG proved effective in several clinical trials, mostly randomized and placebo-controlled, in the prevention and/or treatment of acute diarrheal disease in children. We have recently shown (6) the safety and efficacy in its administration in the ORS, especially in Rotavirus-induced diarrheas, in a large multicenter, randomized, double blind and placebo-controlled study conducted on behalf of the ESPGHAN Working Group on Acute Diarrhea.


A review of the reliability and validity of Likert-type scales for people with intellectual disability.
Likert-type scales are increasingly being used among people with intellectual disability (ID). These scales offer an efficient method for capturing a wide range of variance in self-reported attitudes and behaviours. This review is an attempt to evaluate the reliability and validity of Likert-type scales in people with ID. Fifty-one studies reporting response rates, response bias, reliability and validity of Likert-type scales among adolescents and adults with ID were reviewed. Low response rates were found among adolescents and adults with moderate to profound ID, when pictorial representations of response alternatives were not employed, and for Likert-type scales with self-descriptive statements. Response bias was evident, particularly among adolescents and adults with moderate to profound ID. Likert-type scales have better reliability and validity among adolescents and adults with borderline IQ or mild ID. Pretests and clarifying questions increase reliability and validity. Likert-type scales should include pictorial representations of response alternatives, a single set of one or two word response descriptors, clarifying questions, and pretests, and are best used with adolescents and adults with borderline IQ to mild ID.


Large Anisotropy Barrier in a Tetranuclear Single-Molecule Magnet Featuring Low-Coordinate Cobalt Centers.
The tetranuclear cobalt cluster compound [Co4(μ-NPtBu3)4][B(C6F5)4] (tBu = tert-butyl) was synthesized by chemical oxidation of Co4(NPtBu3)4 with [FeCp2][B(C6F5)4] and magnetically characterized to study the effect of electronic communication between low-coordinate metal centers on slow magnetic relaxation in a transition metal cluster. The dc magnetic susceptibility data reveal that the complex exhibits a well-isolated S = 9/2 ground state, which persists even to 300 K and is attributed to the existence of direct metal-metal orbital overlap. The ac magnetic susceptibility data further reveals that the complex exhibits slow magnetic relaxation in the absence of an applied field, and that the relaxation dynamics can be fit with a combination of Orbach, quantum tunneling, and Raman relaxation processes. The effective spin reversal barrier for this molecule is 87 cm-1, the largest reported to date for a transition metal cluster, and arises due to the presence of a large easy-axis magnetic anisotropy. The complex additionally exhibits waist-restricted magnetic hysteresis and magnetic blocking below 3.6 K. Taken together, these results indicate that coupling of low-coordinate metal centers is a promising strategy to enhance magnetic anisotropy and slow magnetic relaxation in transition metal cluster compounds.


A quantitative co-localization analysis of large unspliced tenascin-C(L) and laminin-5/gamma2-chain in basement membranes of oral squamous cell carcinoma by confocal laser scanning microscopy.
A structural interaction of the oncofetal large tenascin-C splice variants (Tn-C(L)) and the gamma2-chain of laminin-5 (Ln-5/gamma2) was recently demonstrated in oral squamous cell carcinoma (OSCC). In situ different patterns of co-localization and co-deposition of both proteins could be detected. Especially the co-localization in re-established basement membrane (BM) structures seemed to be biologically meaningful within the process of tumour progression. The amount of Tn-C(L) incorporated in reorganized OSCC BM structures at the tumour margins was investigated by a laser scanning microscopy-based quantitative co-localization analysis. In the BM of normal oral mucosa no Tn-C(L) could be detected. In dysplastic and neoplastic oral mucosa a distinct co-localization of Tn-C(L) and Ln-5/gamma2 in the BM region could be observed. The extent of Tn-C(L) arrangement into reorganized BM structures correlated with malignancy grade. The results suggest at first, a modulation of carcinomatous BM structures by the inclusion of oncofetal matrix proteins during tumour progression and secondly, the BM incorporation of the adhesion-modulating molecule Tn-C(L) as a pre-invasive structural phenomenon in OSCC.


Palladium carbene complexes as persistent radicals.
A series of palladium(ii) radical carbene complexes, [PC˙(sp2)P]PdI, [PC˙(sp2)P]PdBr, and [PC˙(sp2)P]PdCl (PC(sp3)H2P = bis[2-(di-iso-propylphosphino)-phenyl]methane), is described. Compound [PC˙(sp2)P]PdI dimerizes to {[PC(sp2)P]PdI}2 in the solid state, akin to the formation of Gomberg's dimer. While the bromo and the iodo derivatives could be obtained from the oxidation of [PC(sp2)P]Pd(PMe3) by the respective dihalogens, a halogen transfer reaction from CH2Cl2 was used for the formation of [PC˙(sp2)P]PdCl. The halogen transfer from CH2X2 (X = Cl, Br, I) could be used to obtain all three radical carbene palladium complexes and also allowed the isolation of [PC(CH2)P]Pd(PMe3), which is the result of methylene group transfer from CH2X2. Compound [PC(CH2)P]Pd(PMe3) was independently synthesized from [PC(CH3)HP]PdCl2, which contains a supporting ligand analogous to that of the radical carbene complexes but has one of the hydrogen atoms replaced by a methyl group. All three carbene radical species abstract a hydrogen from 9,10-dihydroanthracene or n Bu3SnH.


Identification of a T-cell epitope on the circumsporozoite protein of Plasmodium vivax.
A series of overlapping peptides, representing sequences in the vicinity of region II on the Plasmodium vivax circumsporozoite protein, was synthesized. One of the peptides (PV-23), a 20-mer containing the 6 C-terminal amino acids of region II, was found to evoke an in vitro T-cell proliferative response in spleen cells from C3Hf (H-2km2) mice immunized with the peptide. These results demonstrate that PV-23 contains a T-cell epitope. To our knowledge, this is the first report of a T-cell epitope on the circumsporozoite protein of P. vivax.


The association of high sensitivity C-reactive protein and incident Alzheimer disease in patients 60 years and older: The HUNT study, Norway.
With ageing, long-standing inflammation can be destructive, contributing to development of several disorders, among these Alzheimer's disease (AD). C-reactive protein (CRP) is a relatively stable peripheral inflammatory marker, but in previous studies the association between highly sensitive CRP (hsCRP) and AD have shown inconsistent results. This study examines the association between AD and hsCRP in blood samples taken up to 15 years prior to the diagnoses of 52 persons with AD amongst a total of 2150 persons ≥60 years of age. Data from Norway's Nord-Trøndelag Health Study (HUNT 2) and the Health and Memory Study (HMS) were linked. The participants had an average age of 73 years, and diagnosed with AD up to 15 years [mean 8.0 (±3.9)] following hsCRP measurement. Logistic regression models showed an adverse association between hsCRP and AD in participants aged 60-70.5 (odds ratio: 2.37, 95% CI: 1.01-5.58). Conversely, in participants aged 70.6-94, there was an inverse association between hsCRP and AD (odds ratio: 0.39, 95% CI: 0.19-0.84). When applying multivariate models the findings were significant in individuals diagnosed 0.4-7 years after the hsCRP was measured; and attenuated when AD was diagnosed more than seven years following hsCRP measurement. Our study is in line with previous studies indicating a shift in the association between hsCRP and AD by age: in adults (60-70.5 years) there is an adverse association, while in seniors (>70.6 years) there is an inverse association. If our findings can be replicated, a focus on why a more active peripheral immune response may have a protective role in individuals ≥70 years should be further examined.


Double k-Grid Method for Solving the Bethe-Salpeter Equation via Lanczos Approaches.
Convergence with respect to the size of the k-points sampling grid of the Brillouin zone is the main bottleneck in the calculation of optical spectra of periodic crystals via the Bethe-Salpeter equation (BSE). We tackle this challenge by proposing a double grid approach to k-sampling compatible with the effective Lanczos-based Haydock iterative solution. Our method relies on a coarse k-grid that drives the computational cost, while a dense k-grid is responsible for capturing excitonic effects, albeit in an approximated way. Importantly, the fine k-grid requires minimal extra computation due to the simplicity of our approach, which also makes the latter straightforward to implement. We performed tests on bulk Si, bulk GaAs and monolayer MoS2, all of which produced spectra in good agreement with data reported elsewhere. This framework has the potential of enabling the calculation of optical spectra in semiconducting systems where the efficiency of the Haydock scheme alone is not enough to achieve a computationally tractable solution of the BSE, e.g., large-scale systems with very stringent k-sampling requirements for achieving convergence.


Influence of ultrasound induced cavitation on magnetic resonance imaging contrast in the rat liver in the presence of macromolecular contrast agent.
Local drug delivery by ultrasound (US)-induced cavitation is a promising strategy for increasing the drug concentration at the target location and for decreasing the systemic toxicity effects. The presence of microbubbles during sonication at the targeted location improves the likelihood for cavitation that can be exploited to increase the capillary permeability. The objective of this work was to evaluate the magnetic resonance imaging (MRI) contrast changes in hepatic tissue in vivo, induced by US-triggered cavitation and destruction of microbubbles (Sonovue), in the presence of a coinjected blood pool MRI contrast agent (Vistarem) used as a reporter macromolecule. The potential tissue damage induced by microbubbles destruction was also evaluated by histology. The change in the hepatic distribution of the macromolecular MRI contrast agent associated with cavitation was monitored at 1.5 T with a look-locker fast inversion recovery sequence to map the longitudinal relaxation rates, before and during 1 hour after intravenous administration of Vistarem and Sonovue. In 1 group of rats (n = 5), these microbubbles were immediately destroyed with a clinical echograph, using a high mechanical index (MI = 1.5) at low frequency (2 MHz). The control group (n = 7) received identical injections without application of US. The parametric relaxation rate images were computed, and the changes in time were analyzed to account for the potential effect of microbubble destruction by US on the permeability of the hepatic vessels. The animals were killed 1 day after the experiment for routine histology of the liver. For both groups of animals, after an initial increase, a transient decay of the longitudinal relaxation rate was observed, followed by a constant plateau after 20 minutes. The analysis of the mean relaxation rates in the liver showed significant (P < 0.01) higher values for the group with destruction of microbubbles as compared with the control group. The US-triggered cavitation and destruction of microbubble with the proposed protocol suggests an increased concentration of Vistarem of a factor 2 in the hepatic tissue. No tissue damage was observed at the microscopic analysis. The absence of tissue alterations indicates that the destruction of this US contrast agent could be safe in vivo under an appropriate choice of the sonication parameters. This approach opens new perspectives for translation toward clinical applications of local drug delivery. Ultrasound-mediated microbubble destruction may help in increasing the local concentration of a drug currently limited by the endothelial barrier. In addition, it may help in reducing the systemic toxicity to normal cells in standard chemotherapies, because the enhanced capillary permeability effect can be spatially adjusted by selecting the sonicated region.


The effect of preoperative quadriceps exercise on functional outcome after total knee arthroplasty.
To compare the level of pain scores, range of motion, quadriceps strength and quality of life after TKA patients between preoperative quadriceps exercise group and usual care group. A randomized controlled trial study. From January 2011-January 2012, 60 patients undergoing primary TKA were included. The patients were randomized into two groups with the use of blocking letter in 30 patients for each. The patients assigned to the preoperative quadriceps exercise group were asked to participate in three weeks home quadriceps strengthening exercise program until their TKA. The patients assigned to the usual care group were asked to continue their normal activities until their TKA. Preoperative data were collected within three weeks prior to the TKA. Should be 4 data collection included visual analog scale (VAS), quadriceps strength, knee range of motion and Modified WOMAC score. Both groups were evaluated four times: three weeks before surgery, 1 month, 3 months and 6 months after surgery. 60 patients was divided into 2 groups, the preoperative quadriceps exercise group and the usual care group. Most patients were female, older than 60 years, primary school educated, housekeeper occupation. Body mass index, duration of knee pain, Paracetamal and NSAIDs use were not statistically significant different. The quadriceps exercise group had statistically significant decreased pain in the postoperative 3 months (p = 0.003). The quadriceps exercise group had statistically significant decreased mean Modified WOMAC score in the postoperative 1, 3 months (p < or = 0.001, 0.001) and quadriceps strength better than the usual care group during the follow-up in the postoperative 3 months. Preoperative quadriceps exercise at least three weeks prior total knee replacement result in short-term benefit such as decreased pain, improved quadriceps strength and improved quality of life after elective TKA.


On the compatibility criteria for protein encapsulation inside mesoporous materials.
The properties of the enzyme pepsin, relevant to its incorporation inside the channels of mesoporous silica materials in the preparation of bioinorganic hybrids, are highlighted by molecular dynamics simulations of aqueous solutions of the protein under conditions optimal for encapsulation in SBA-15. The protein size, shape, flexibility and surface properties are calculated with the aim of deriving general accessibility/compatibility criteria favouring encapsulation inside mesoporous systems.


Auxiliary variables for numerically solving nonlinear equations with softly broken symmetries.
General methods for solving simultaneous nonlinear equations work by generating a sequence of approximate solutions that successively improve a measure of the total error. However, if the total error function has a narrow curved valley, the available techniques tend to find the solution after a very large number of steps, if ever. The solver first converges rapidly to the valley, but once there it converges extremely slowly to the solution. In this paper we show that in the specific physically important case where these valleys are the result of a softly broken symmetry, the solution can often be found much more quickly by adding the generators of the softly broken symmetry as auxiliary variables. This makes the number of variables more than the equations and hence there will be a family of solutions, any one of which would be acceptable. We present a procedure for finding solutions in this case and apply it to several simple examples and an important problem in the physics of false vacuum decay. We also provide a Mathematica package that implements Powell's hybrid method with the generalization to allow more variables than equations.


Phonosurgery of vocal fold polyps, cysts and nodules is beneficial.
This study reports our experience with microscopic phonosurgery (PS) of benign lesions of the vocal folds. During the five-year period from 2003 to 2007, a total of 97 patients had PS for vocal fold polyps (n = 63), vocal fold cysts (n = 17), vocal fold nodules (n = 12) or vocal fold oedema (n = 5). Their average age was 41 years; 62% were women and 69% were smokers. Post-operative voice therapy was given to 45 patients. Post-operative clinical evaluation was available for data analysis in 89 patients (92%). Voice quality was assessed using the Multi-Dimensional Voice Program (MDVP), video-stroboscopy and self-reported assessment. The median follow-up time was 3.9 months. Post-operative voice quality was reported as unaffected in 85%, improved but moderately affected in 13%, and severely affected in one patient with a cyst and vocal fold sulcus. Unaffected voice quality was obtained in 91% of patients not receiving voice therapy and in 77% of patients receiving voice therapy. All lesions except one polyp in the anterior commissure were completely removed. MDVP was performed both pre- and post-operatively in 22% of patients. The effect was a significant improvement of jitter (p = 0.013), shimmer (p = 0.001) and Soft Phonation Index (p = 0.013). PS is a quick and effective treatment with uncommon and transient post-operative complications. Objective assessment of the voice pre- and post-operatively should be used consistently and applied in controlled studies evaluating the additional impact of pre- and post-operative voice therapy. not relevant. not relevant.


Mediation of cytotoxic effects of streptococcal M protein by nontype-specific antibody in human sera.
The cytotoxic moiety(ies) in highly purified streptococcal M protein has been shown to be distinct from the type-specific M determinant. This nontype-specific M-associated determinant(s) (NTSM) causes humoral and cellular immunotoxic responses in man. NTSM is common to M protein prepared from all streptococcal serotypes studied so far. In this study, immunoabsorbents prepared by entrapping purified M proteins in polyacrylamide gel were employed to identify, separate, and purify antibodies directed against NTSM as well as against the type-specific M (TSM) determinants. We found that anti-NTSM present in human blood mediated cytotoxic platelet and leukocyte reactions in the presence of "M proteins" prepared from groups A, C, and G streptococci. Human sera that produced cytotoxic reactions and fixed complement in the presence of highly purified M protein but that contained no antibody to the homologous TSM determinant were used as a source of anti-NTSM. Anti-NTSM was absorbed with and eluted from M protein-polyacrylamide particles and identified as IgG. Antibodies to NTSM were present in most normal human sera and some primate sera (rhesus monkey and baboons) but not in the sera of other common laboratory animals. Further absorption studies showed NTSM to be a component not only of extractable M protein but also of protoplast membranes and of cell walls of avirulent streptococci that lacked extractable TSM antigen. Preparation of antisera that can distinguish between the type-specific protective moiety and the closely associated immunotoxic components in purified M protein vaccines may help answer whether or not M-associated moieties play a role in pathogenesis of poststreptococcal diseases.


Modified Mechanical Percussion for Upper Urinary Tract Stone Fragments After Extracorporeal Shock Wave Lithotripsy: A Prospective Multicenter Randomized Controlled Trial.
To investigate the effectiveness of modified mechanical percussion for eliminating upper urinary tract stone fragments after extracorporeal shock wave lithotripsy. We assigned patients aged 18-60 years with upper urinary tract calculi to the modified mechanical percussion (trial) or observation (control) group. Kidney-ureter-bladder radiography and ultrasound were used for diagnostic evaluation. The primary outcome was the stone-expulsion rate (SER) at 6 hours. The first stone-expulsion time, the SER at 3, 12, and 24 hours, the stone-free rate, additional interventions, and adverse events (AEs) were recorded. A total of 120 patients underwent randomization: 60 for each group. The mean first stone-expulsion time in the trial and control groups was 6.75 and 13.58 hours, respectively (P = .001). The SERs at 3, 6, and 12 hours in the trial group were 51.8%, 75.4%, and 76.8%, respectively, which were higher than the control group (all P <.05). Among patients who expelled fragments within 6 hours, the stone-free rates were improved at 1 week (P = .002) and at 2 weeks (P = .000). Patients needed fewer additional interventions in the trial group (P = .035). AEs occurred in 42.9% (24 of 56) and 67.9% (38 of 56) of the patients in the trial and control groups, respectively (P = .008). Age, gender, stone size and location, and SER at 24 hours did not differ significantly among the groups. Modified mechanical percussion significantly improved SERs and accelerated stone passage after shock wave lithotripsy, resulting in a stone-free status with a lower risk of AEs and reduced need for additional interventions.


Bilateral Pedicle and Crossed Translaminar Screws in C2.
Multiple techniques exist for the fixation of C2, including axial pedicle screws and bilateral translaminar screws. We describe a novel method of incorporating both the translaminar and pedicle screws within C2 to improve fixation to the subaxial spine in patients requiring posterior cervical instrumentation for deformity correction or instability. We report three cases of patients with cervical spinal instability, who underwent cervical spine instrumentation for stabilization and/or deformity correction. Bilateral C2 pedicle screws were inserted, followed by bilateral crossed laminar screws. The instrumentation method successfully achieved fixation in all three patients. There were no immediate postoperative complications, and hardware positioning was satisfactory. Instrumenting C2 with translaminar and pedicle screws is technically feasible, and it may improve fixation to the subaxial spine in patients with poor bone quality or severe subaxial deformity, which require a stronger instrumentation construct.


[Sexual life after hysterectomy].
The evaluation of sexual life after hysterectomy is still controversial. The aim of the study was to analyse the impact of hysterectomy on frequency and quality of the woman's sexual life. The total of 539 women operated in II Department of Obstetrics and Gynecology in 1990-2000 were interviewed about symptoms as well as advantages and disadvantages after abdominal hysterectomy. Sexual desire after operation decreased. The rate of dyspareunia dropped. Frequency of sexual intercourse and orgasm decreased non-significantly. The percentage of women non reporting vaginal dryness decreased significantly from 18.5% to 37.3% after hysterectomy. Sexual activity overall improved after hysterectomy.


Ovarian stone. A case report.
To our knowledge, ovarian calcification and ossification involving the whole ovary with images that mimic stone formations have not been reported before. A 42-year-old woman presented with severe abdominal pain. Plain abdominal radiography showed a well-defined, calcified mass, 4 x 5 cm, located in the pelvis. Physical examination showed a right adnexal mass accompanied by severe pain and tenderness while lifting. Transvaginal ultrasound showed an ill-defined mass with acoustic comet tail. Computed tomography demonstrated a well-defined mass on the right adnexa, 4 x 5 cm, with an extensively calcified shell. Surgical exploration revealed an enlarged, ovoid, pale brown ovary, which looked exactly like an ovary made of stone. The pathologic findings were compatible with a benign chocolate cyst with extensive calcification and ossification. The pelvic pain resolved completely after the surgery. Though the cause of this unique case remains unknown, torsion with subsequent infarction of an ovarian endometrioma was suggested. Complete excision was the treatment of choice.


The Use of Mock Standardized/Simulated Patient Encounters in Facilitating Development of Clinical Competence in Medical Students.
Background Standardized patient (SP) encounters are used in medical school to mimic clinical practice by exposing students to possible clinical situations they may encounter in future practice. SP includes trained individuals who portray the roles of patients to help medical students practice recording medical histories, physical exam skills, communication skills, and typing a subjective, objective, assessment and plan (SOAP) note. The goal of SP is to prepare medical students adequately during their didactic years before beginning clerkships. SP encounters have become standard in medical school curriculums, but the option for a mock SP encounter has not. Methods In this study, a total of 34 participants completed an eight-question survey before a mock SP experience and after their graded SP encounters to assess the students' confidence levels and preparedness. Each question addressed a different aspect of the student's satisfaction and attitude regarding the SP encounters. The answers were measured on a Likert scale from 1 (not prepared) to 5 (very prepared). The central tendency (mean) was analyzed using a T-test with Welch's method. The standard deviation was analyzed using Bonett's test. A Cronbach's alpha was used to show the reliability of the survey used. Results The first four questions addressed the student's satisfaction with their mock SP experience. The mean student satisfaction with being able to ask questions to improve their knowledge and understanding improved, with a p-value of < 0.001. Student satisfaction with having the opportunity to record a patient's history improved, with a p-value of < 0.001. The overall satisfaction with having a chance to practice physical exam skills improved, with a p-value of < 0.001. Mean student satisfaction with practicing treatment and counseling of patients improved, with a p-value of <0.001. The final four questions addressed the students' attitudes regarding their experience. The mean confidence of students improved, with a p-value of <0.001. Students also reported an improved attitude towards the feedback they received, with a p-value of <0.001. The final two questions did not show a statistically significant difference in answers. Students rated the final two questions equally before and after the mock SP experience, with p-values > 0.05. These questions addressed whether mock SP encounters would be beneficial and asked if they wanted additional mock simulation opportunities built into the curriculum. Conclusions The students showed improved confidence, attitudes, and satisfaction surrounding standardized patient encounters. The results supported the hypothesis that there would be a difference between the responses before and after the SP encounter. The questionnaire showed that the students reported subjective changes in their competence following the encounter.


Transcriptional regulation of early-response genes during polyomavirus infection.
Infection of quiescent BALB/c 3T3 cells with polyomavirus leads to the biphasic accumulation of RNA from several early-response genes. The steady-state levels of RNA of c-fos, c-myc, and c-jun were detected at 0 to 1 and 12 to 30 h after infection but not at 6 h postinfection. Infections with mutant viruses suggest that in the context of a virus infection with other tumor (T) antigens present, large T and middle T antigens are dispensable for the effect and small t antigen is important for the regulation, perhaps in conjunction with large T or middle T antigens. These results are in agreement with those of Zullo et al. (Proc. Natl. Acad. Sci. USA 84:1210-1214). We have further found that this regulation occurs in NIH 3T3 cells and primary mouse embryo fibroblasts. DNA synthesis is not required for this effect. Half-lives of c-fos, c-myc, and c-jun were similarly short at both early and late times after infection, as determined by dactinomycin chase. The regulation of expression occurs at the transcriptional level. Nuclear run-on experiments showed increased rates of transcription both early and late after infection. Also, the polyomavirus early region can transactivate the c-fos promoter in transient transfection assays.


[Drug-induced hepatotoxicity in children. Where we are and where we are going].
Childhood is characterized by continuous growth and development during which the organs and systems gradually mature. Because drug pharmacokinetics and pharmacodynamics in children differ from those in adults, pediatric patients are highly susceptible to adverse drug reactions. Surprisingly, very few studies have been designed to study the efficacy and safety of drugs in this population and consequently dosage regimens are based on the assumption that children are small adults. We present a detailed review of these controversial aspects and propose the establishment of a multicenter, multidisciplinary network to monitor drug-induced liver disease in children. This project represents the integration of an epidemiological approach into routine clinical care. A protocol agreed by consensus for the collection of data on cases of hepatotoxicity with uniform and internationally accepted criteria for causality assessment and the classification of drug-induced liver injuries is proposed.


A differentially amplified Hall effect displacement sensor for positioning control of a long-range flexure stage.
This paper presents a novel positioning feedback sensor using a pair of Hall effect elements on a long-range flexure stage. The proposed Hall effect positioning feedback sensor eliminates error and uncertainty by measuring the center of the flexure stage, where a machine tool or measurement probes would take place in the industrial application. A pair of Hall effect elements were amplified in a differential configuration as the cylindrical permanent magnet enclosed in the center of the shuttle in the flexure stage that moves back and forth, generating a uniform gradient magnetic flux intensity. Nonlinear magnetic flux characteristics of a single Hall effect element were eliminated, and high-quality sensor sensitivity was achieved by differential amplification of the two Hall effect elements. The magnetic field analysis to characterize the linearity of the proposed displacement sensor was simulated using the finite element method to prove that the non-linearity of a single hall effect element may be mitigated by employing the differential amplification technique. The flexure stage was additively manufactured into a monolithic structure, and the permanent magnet was fitted into the shuttle of the flexure stage. Each Hall effect element was placed on either side of the magnet at a certain distance on the axis of shuttle movement. The proposed sensor was characterized by performing dynamic system identification of the flexure stage: open-loop response and closed-loop response. The Laser Displacement Sensor (LDS) with the 10 nm resolution was used for baseline comparison and datum line with respect to the proposed sensor. The proposed sensor responses agreed well with LDS in various dynamic inputs. The sensor response was analyzed with two differential amplification signal processing techniques. The maximum sensitivity of the two signal processing techniques was determined to be 16.55 mV/μm, and the resolution was observed as 2.5 μm. In sum, the differentially amplified Hall effect displacement sensor achieved positioning feedback with high sensitivity and linearity and minimized the sensor placement error while maintaining low cost and simple configuration.


The relationship of oxygen transport and cardiac index for the prevention of sickle cell crises.
The formation of deoxyhemoglobin S (deoxy-Hb S) polymers is the key triggering event for the complex pathophysiologic manifestations of sickle cell anemia (SCA). This polymer formation is associated with a marked right-shifted oxyhemoglobin dissociation curve (decreased affinity, increased P50), which results in a decrease in arterial oxygen saturation (SaO2. There is a delay period ("delay time") from the formation of deoxy-Hb S to polymerization that is markedly sensitive (to the power of 30-40) to the concentration and solubility changes of deoxy-Hb S. Deoxy-Hb S polymer formation leads to sickle cell vaso-occlusion, a unique characteristic of SCA. This theoretical study, which views SCA as a disease of oxygen transport, provides a novel framework to suggest that a small to modest increase in cardiac index (by decreasing the P50 and thus increasing the SaO2) could change the distribution of the delay times (sec) such that the balance between occlusion and opening of microcirculatory vessels is shifted favoring the opening of these vessels, therefore disfavoring vaso-occlusion. Our approach integrates a mathematical model of oxygen transport in SCA with: (1) the expression relating the solubility of deoxy-Hb S to SaO2, and (2) the kinetic expression relating the delay time to the solubility of deoxy-Hb S.


Repair of iridodialysis using 8-0 polypropylene.
Investigate the effectiveness of repair of iridodialysis with 8-0 polypropylene. We present four cases of traumatic iridodialysis that were repaired by 8-0 polypropylene suture. Better iris reposition and stability were achieved with 8-0 polypropylene suture despite wide degree traumatic iridodialysis in all patients. In this study, we used 8-0 polypropylene suture, which is thicker, cheaper, and more durable than 10-0 sutures. We suggest that usage of 8-0 polypropylene sutures may provide better iris repositioning.


Putative enhancer sites in the bovine genome are enriched with variants affecting complex traits.
Enhancers are non-coding DNA sequences, which when they are bound by specific proteins increase the level of gene transcription. Enhancers activate unique gene expression patterns within cells of different types or under different conditions. Enhancers are key contributors to gene regulation, and causative variants that affect quantitative traits in humans and mice have been located in enhancer regions. However, in the bovine genome, enhancers as well as other regulatory elements are not yet well defined. In this paper, we sought to improve the annotation of bovine enhancer regions by using publicly available mammalian enhancer information. To test if the identified putative bovine enhancer regions are enriched with functional variants that affect milk production traits, we performed genome-wide association studies using imputed whole-genome sequence data followed by meta-analysis and enrichment analysis. We produced a library of candidate bovine enhancer regions by using publicly available bovine ChIP-Seq enhancer data in combination with enhancer data that were identified based on sequence homology with human and mouse enhancer databases. We found that imputed whole-genome sequence variants associated with milk production traits in 16,581 dairy cattle were enriched with enhancer regions that were marked by bovine-liver H3K4me3 and H3K27ac histone modifications from both permutation tests and gene set enrichment analysis. Enhancer regions that were identified based on sequence homology with human and mouse enhancer regions were not as strongly enriched with trait-associated sequence variants as the bovine ChIP-Seq candidate enhancer regions. The bovine ChIP-Seq enriched enhancer regions were located near genes and quantitative trait loci that are associated with pregnancy, growth, disease resistance, meat quality and quantity, and milk quality and quantity traits in dairy and beef cattle. Our results suggest that sequence variants within enhancer regions that are located in bovine non-coding genomic regions contribute to the variation in complex traits. The level of enrichment was higher in bovine-specific enhancer regions that were identified by detecting histone modifications H3K4me3 and H3K27ac in bovine liver tissues than in enhancer regions identified by sequence homology with human and mouse data. These results highlight the need to use bovine-specific experimental data for the identification of enhancer regions.


Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN.
Neurotropic adeno-associated virus (AAV) serotypes such as AAV9 have been demonstrated to transduce spinal alpha motor neurons when administered intravenously (i.v.) at high doses. This observation led to the recent successful application of i.v. AAV9 delivery to treat infants with spinal muscular atrophy, an inherited deficiency of the survival of motor neuron (SMN) protein characterized by selective death of lower motor neurons. To evaluate the efficiency of motor neuron transduction with an AAV9 variant (AAVhu68) using this approach, three juvenile nonhuman primates (NHPs; aged 14 months) and three piglets (aged 7-30 days) were treated with an i.v. injection of an AAVhu68 vector carrying a human SMN transgene at a dose similar to that employed in the spinal muscular atrophy clinical trial. Administration of 2 × 1014 genome copies per kilogram of body weight resulted in widespread transduction of spinal motor neurons in both species. However, severe toxicity occurred in both NHPs and piglets. All three NHPs exhibited marked transaminase elevations. In two NHPs, the transaminase elevations resolved without clinical sequelae, while one NHP developed acute liver failure and shock and was euthanized 4 days after vector injection. Degeneration of dorsal root ganglia sensory neurons was also observed, although NHPs exhibited no clinically apparent sensory deficits. There was no correlation between clinical findings and T-cell responses to the vector capsid or transgene product in NHPs. Piglets demonstrated no evidence of hepatic toxicity, but within 14 days of vector injection, all three animals exhibited proprioceptive deficits and ataxia, which profoundly impaired ambulation and necessitated euthanasia. These clinical findings correlated with more severe dorsal root ganglia sensory neuron lesions than those observed in NHPs. The liver and sensory neuron findings appear to be a direct consequence of AAV transduction independent of an immune response to the capsid or transgene product. The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of i.v. delivery of AAV vectors at high doses, irrespective of the capsid serotype or transgene. Preclinical and clinical studies involving high systemic doses of AAV vectors should include careful monitoring for similar toxicities.


Decapeptide agonists of human C5a: the relationship between conformation and spasmogenic and platelet aggregatory activities.
A series of decapeptide analogues corresponding to the C-terminal region of human C5a anaphylatoxin (C5a65-74) was synthesized with residue substitutions to restrict conformational flexibility in the C-terminus. These conformationally constrained peptides behaved as agonists of C5a in spasmogenic assays (smooth muscle contraction in human fetal artery, guinea pig ileum, and guinea pig lung parenchyma) as well as guinea pig platelet aggregation. There were significant correlations in the potencies of these peptides between the various assays. A structure-function analysis led to the identification of a preferred backbone conformation that correlated with the expression of these biological responses. These backbone structural motifs were consistent with a helix-like conformation for residues 65-69, an elongated structure for residues 70-71, and a beta-turn of either type II or type V for residues (71)72-74. The most potent of these agonists expressed almost 5% of the potency of natural C5a.


Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents.
Culture-based blood-brain barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility of in vitro barrier properties and permeability remain as major challenges. Here, we report that self-assembling multicellular BBB spheroids display reproducible BBB features and functions. The spheroid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the surface, acting as a barrier that regulates transport of molecules. The spheroid surface exhibits high expression of tight junction proteins, VEGF-dependent permeability, efflux pump activity and receptor-mediated transcytosis of angiopep-2. In contrast, the transwell co-culture system displays comparatively low levels of BBB regulatory proteins, and is unable to discriminate between the transport of angiopep-2 and a control peptide. Finally, we have utilized the BBB spheroids to screen and identify BBB-penetrant cell-penetrating peptides (CPPs). This robust in vitro BBB model could serve as a valuable next-generation platform for expediting the development of CNS therapeutics.


Latent TGF-β binding protein 2 and 4 have essential overlapping functions in microfibril development.
Microfibrils are exracellular matrix components necessary for elastic fiber assembly and for suspending lenses. We previously reported that latent TGF-β binding protein 2 (LTBP-2), a microfibril-associated protein, is required for forming stable microfibril bundles in ciliary zonules. However, it was not understood why Ltbp2 null mice only showed an eye-specific phenotype, whereas LTBP-2 is abundantly expressed in other tissues containing microfibrils in wild type mice. Here, we show that LTBP-4, another microfibril-associated protein, compensates for the loss of LTBP-2 in microfibril formation. Ltbp2/4S double knockout (DKO) mice showed increased lethality due to emphysema, which was much more severe than that found in Ltbp4S null mice. Elastic fibers in the lungs of Ltbp2/4S DKO mice were severely disorganized and fragmented. Cultured mouse embryonic fibroblasts (MEFs) from Ltbp2/4S DKO embryos developed reduced microfibril meshwork in serum-free conditions, whereas the microfibril formation was restored by the addition of either recombinant LTBP-2 or -4. Finally, ectopic expression of LTBP-4 in the whole body restored ciliary zonule microfibril bundles in the eyes of Ltbp2 null mice. These data suggest that LTBP-2 and -4 have critical overlapping functions in forming the robust structure of microfibrils in vitro and in vivo.


Stray light correction algorithm for multichannel hyperspectral spectrographs.
An algorithm is presented that corrects a multichannel fiber-coupled spectrograph for stray or scattered light within the system. The efficacy of the algorithm is evaluated based on a series of validation measurements of sources with different spectral distributions. This is the first application of a scattered-light correction algorithm to a multichannel hyperspectral spectrograph. The algorithm, based on characterization measurements using a tunable laser system, can be extended to correct for finite point-spread response in imaging systems.


SCE analysis in peripheral blood lymphocytes of a group of filling station attendants.
Petroleum derivatives constitute a complex mixture of chemicals which contain known genotoxicants. Thus, chronic occupational exposure to such derivatives may be considered to possess genotoxic risk. Service station attendants are workers exposed to petroleum derivatives and, as consequence, biomonitoring studies designed to evaluate the genetic risk are required. Here we present the data on sister chromatid exchange (SCE) frequencies, proliferation rate index (PRI) and cells with high frequency of SCE (HFC) from a group of 42 attendant workers. In addition, data from a group of 45 unexposed (controls) are presented. The results obtained indicate that there are no significant differences in SCE values between the exposed workers when compared to the non-exposed individuals. The only difference is found when smoking habit is considered, the smokers having significant increases in the SCE frequency. There is a slight increase in the HFC frequency of the occupationally exposed group but the difference did not attain statistical significance.


In vitro stabilization and in vivo improvement of ocular pharmacokinetics of the multi-therapeutic agent baicalin: Delineating the most suitable vesicular systems.
Baicalin is a multi-purpose flavonoid used in the treatment of different ocular diseases. Owing to its poor stability in basic pH and its poor solubility, a suitable carrier system is needed to enhance its ocular therapeutic potential. Therefore, the objective of this work was to prepare and contrast different baicalin vesicular systems; namely liposomes, penetration enhancer vesicles PEVs and transfersomes. Results revealed that baicalin vesicles exhibited suitable particle size and zeta potential, high entrapment efficiency and controlled release. Depending on the vesicular composition, selected formulations were able to resist physical changes of particle size, zeta potential, entrapment efficiency and in vitro release after storage for 3 months, while retarding the degradation of baicalin. Selected vesicular formulations displayed equivalent or superior antioxidant potential compared to baicalin solution, with absolute superiority over ascorbic acid reference, while demonstrating sterilization endurance and safety on ocular tissues. Pharmacokinetic studies revealed that transfersomes displayed the fastest onset of action, while liposomes displayed the highest extent of absorption as concluded from the Tmax, Cmax, and AUC0-∞ values with 4-5 folds increase in bioavailability compared to baicalin control solution. This delineates baicalin vesicular systems as a promising platform for treatment of ocular diseases such as inflammation, cataract and diabetic retinopathy.


[Effects of repeated treatment with electroconvulsive shock or imipramine on [3H]prazosin binding sites in the rat frontal cortex].
Two subtypes (alpha 1A and alpha 1B) of alpha 1-adrenoceptors have been defined on the basis of radioligand binding studies with 2-(2,6-dimethoxyphenoxyethyl)-1,4-benzodioxane (WB4101). In contrast, functional studies with blood vessels have proposed another subclassification, where the alpha 1-adrenoceptors can be classified into putative two (alpha 1H and alpha 1L) or three (alpha 1H, alpha 1L and alpha 1N) subtypes. The present study was performed to elucidate the effects of repeated treatment with electroconvulsive shock (ECS) or imipramine on the subtypes of alpha 1-adrenoceptors. The density of the alpha 1H binding sites (including alpha 1A and alpha 1B binding sites) in the frontal cortex was increased by repeated treatment with ECS but decreased by imipramine. These treatments did not change the density of alpha 1L binding sites. These results indicated that repeated treatment with ECS and imipramine had different effects on the alpha 1H binding sites in the rat frontal cortex. In addition, the effects of antipsychotic drugs, antidepressant drugs and calcium channel antagonists on [3H]prazosin binding were studied. The order of inhibition of [3H]prazosin binding was: antipsychotic drugs (1.4-4.2 nM) > antidepressant drugs (69-116 nM) > calcium channel antagonists. The calcium channel antagonists, verapamil (720 nM), diltiazem (4.3 microM) and nicardipine (75 microM) were weakly bound. These results suggested that the antimanic effects of calcium channel antagonists were not associated with inhibition of alpha 1-adrenoceptors.


Molecular Testing for Acute Respiratory Tract Infections: Clinical and Diagnostic Recommendations From the IDSA's Diagnostics Committee.
The clinical signs and symptoms of acute respiratory tract infections (RTIs) are not pathogen specific. Highly sensitive and specific nucleic acid amplification tests have become the diagnostic reference standard for viruses, and translation of bacterial assays from basic research to routine clinical practice represents an exciting advance in respiratory medicine. Most recently, molecular diagnostics have played an essential role in the global health response to the novel coronavirus pandemic. How best to use newer molecular tests for RTI in combination with clinical judgment and traditional methods can be bewildering given the plethora of available assays and rapidly evolving technologies. Here, we summarize the current state of the art with respect to the diagnosis of viral and bacterial RTIs, provide a practical framework for diagnostic decision making using selected patient-centered vignettes, and make recommendations for future studies to advance the field.


[Mineral and bone disturbances associated with chronic kidney disease].
In the course of chronic kidney disease (CKD) comes to the disturbances in mineral and bone metabolism and extra-skeletal calcification. In subsequent stages of CKD, these processes intensify, leading to a deterioration in the quality of life and disability. They are also a major cause of morbidity and mortality from cardiovascular causes in CKD. In 2005, the Organization of Kidney Disease: Improving Global Outcomes (KIDGO), proposed replacing the term Renal Osteodystrophy in mineral and bone complications CKD (chronic kidney disease mineral and bone related disorders; CKD-MBD) as the disorder is not confined to the skeleton. CKD-MBD is manifested by the presence of changes in laboratory tests (corrected serum calcium, organic phosphate, parathyroid hormone, concentrations of vitamin D derivatives), changes in bone (bone metabolism, bone mineralization and trabecular bone volume), the occurrence of calcifications in the soft tissues and the arterial vessels.


Suppression of T cell-mediated cutaneous basophil hypersensitivity by serum from guinea pigs immunized with mycobacterial adjuvant.
Guinea pigs immunized with protein antigens emulsified with complete Freund's adjuvant (CFA) and skin tested at 3-4 wk have classical tuberculin-type delayed hypersensitivity (DH) reactions with few basophils present. However, recipients of T cells from these animals have delayed responses containing large basophil infiltrates and thus resemble basophil-rich cutaneous basophil hypersensitivity (CBH) responses that are elicited in animals immunized without CFA. This suggests that animals immunized with CFA have T cells with basophil-recruiting capacity but that this activity is suppressed. Using a transfer system, we found that immune serum from donors immunized with CFA had the ability to suppress the basophil-recruiting capacity of immune T cells. When immune serum and peritoneal exudate cells from guinea pigs immunized with CFA were co-transferred intravenously to normal recipients, the cell-mediated transfer of basophil-rich responses was suppressed. The responsible serum factor was antigen nonspecific, had an approximately 70,000 mol wt, and acted preferentially on cells from donors that express basophil-poor DH responses. Thus, tuberculin-type delayed hypersensitivity and CBH might be mediated by a common T cell, but the resulting basophil component of the delayed response depends on the modulation of T cell recruitment of basophils by factors in CFA-immune serum.


Carmine Melino and the Institute of Hygiene.
Throughout his 94 years of life, Carmine Melino brilliantly pursued different professional paths, his life being a constant stimulus for students, colleagues, friends and the family. Following the early formative years of study, here, we briefly list his scientific achievements in Occupational Medicine and Hygiene as well as his broad literary interests. Carmine was an inspiration to his generation not only because of his professional achievements, but also for his warm personality, exemplary hard-playing life and unbounded enthusiasm. A polymath, post-enlightenment ethos flowed to all his friends and colleagues, creating an ambience where intellectual excellence was highly appreciated and avidly pursued.


[Systemic mastocytosis: significance of contemporary methods of imaging in diagnosis of this disease].
Mastocytosis is a rare disease characterized by increase in mast cell numbers. The most frequent organ identified as the site of increased numbers of mast cells is the skin. However, uncontrolled growth of mast cells may occur in many other organs and tissues; this disease is called systemic mastocytosis. Nowadays there are four categories of mast cell disease: 1) indolent mastocytosis, 2) mastocytosis with a hematologic disorder, 3) aggressive mastocytosis, and 4) mast cell leukemia. Although the diagnosis of systemic mastocytosis rests finally on identification of mast cells by histopathological examination of the involved tissues, radiological studies may suggest more decisive tests. In this paper the authors discuss usefulness of different methods of radiological imaging in the diagnostics of mastocytosis.