Dengue in Thailand and Cambodia: an assessment of the degree of underrecognized disease burden based on reported cases.
Disease incidence data are needed to guide decision-making for public health interventions. Although dengue is a reportable disease in Thailand and Cambodia, the degree that reported incidence underrecognizes true disease burden is unknown. We utilized dengue incidence calculated from laboratory-confirmed outpatient and inpatient cases in prospective cohort studies to estimate the magnitude of dengue underrecognition and to establish more accurate disease burden estimates for these countries. Cohort studies were conducted among children aged <15 years by members of a dengue field site consortium over at least 2 dengue seasons. Age-group specific multiplication factors (MFs) were computed by comparing data from three cohort studies to national surveillance data in the same province and year. In Thailand, 14,627 person-years of prospective cohort data were obtained in two provinces and 14,493 person-years from one province in Cambodia. Average annual incidence of laboratory-confirmed dengue was 23/1,000 and 25/1,000 in Thailand, and 41/1,000 in Cambodia. Calculated MFs in these provinces varied by age-group and year (range 0.4-29). Average age-group specific MFs were then applied to country-level reporting data and indicated that in Thailand a median 229,886 (range 210,612-331,236) dengue cases occurred annually during 2003-2007 and a median 111,178 (range 80,452-357,135) cases occurred in Cambodia in children <15 years of age. Average underrecognition of total and inpatient dengue cases was 8.7 and 2.6-fold in Thailand, and 9.1 and 1.4-fold in Cambodia, respectively. During the high-incidence year 2007, >95,000 children in Thailand and >58,000 children in Cambodia were estimated to be hospitalized due to dengue. Calculating MFs by comparing prospective cohort study data to locally-reported national surveillance data is one approach to more accurately assess disease burden. These data indicate that although dengue is regularly reported in many countries, national surveillance data significantly underrecognize the true burden of disease.


Temperature dependence and polarization of fluorescence from Photosystem I in the cyanobacterium Synechocystis sp. PCC 6803.
To determine the fluorescence properties of cyanobacterial Photosystem I (PS I) in relatively intact systems, fluorescence emission from 20 to 295 K and polarization at 77 K have been measured from phycobilisomes-less thylakoids of Synechocystis sp. PCC 6803 and a mutant strain lacking Photosystem II (PS II). At 295 K, the fluorescence maxima are 686 nm in the wild type from PS I and PS II and at 688 nm from PS I in the mutant. This emission is characteristic of bulk antenna chlorophylls (Chls). The 690-nm fluorescence component of PS I is temperature independent. For wild-type and mutant, 725-nm fluorescence increases by a factor of at least 40 from 295 to 20 K. We model this temperature dependence assuming a small number of Chls within PS I, emitting at 725 nm, with an energy level below that of the reaction center, P700. Their excitation transfer rate to P700 decreases with decreasing temperature increasing the yield of 725-nm fluorescence.Fluorescence excitation spectra of polarized emission from low-energy Chls were measured at 77 and 295 K on the mutant lacking PS II. At excitation wavelengths longer than 715 nm, 760-nm emission is highly polarized indicating either direct excitation of the emitting Chls with no participation in excitation transfer or total alignment of the chromophores. Fluorescence at 760 nm is unpolarized for excitation wavelengths shorter than 690 nm, inferring excitation transfer between Chls before 760-nm fluorescence occurs.Our measurements illustrate that: 1) a single group of low-energy Chls (F725) of the core-like PS I complex in cyanobacteria shows a strongly temperature-dependent fluorescence and, when directly excited, nearly complete fluorescence polarization, 2) these properties are not the result of detergent-induced artifacts as we are examining intact PS I within the thylakoid membrane of S. 6803, and 3) the activation energy for excitation transfer from F725 Chls to P700 is less than that of F735 Chls in green plants; F725 Chls may act as a sink to locate excitations near P700 in PS I.


Haves and have nots must find a better way: The case for open scientific hardware.
Many efforts are making science more open and accessible; they are mostly concentrated on issues that appear before and after experiments are performed: open access journals, open databases, and many other tools to increase reproducibility of science and access to information. However, these initiatives do not promote access to scientific equipment necessary for experiments. Mostly due to monetary constraints, equipment availability has always been uneven around the globe, affecting predominantly low-income countries and institutions. Here, a case is made for the use of free open source hardware in research and education, including countries and institutions where funds were never the biggest problem.


A two-qubit logic gate in silicon.
Quantum computation requires qubits that can be coupled in a scalable manner, together with universal and high-fidelity one- and two-qubit logic gates. Many physical realizations of qubits exist, including single photons, trapped ions, superconducting circuits, single defects or atoms in diamond and silicon, and semiconductor quantum dots, with single-qubit fidelities that exceed the stringent thresholds required for fault-tolerant quantum computing. Despite this, high-fidelity two-qubit gates in the solid state that can be manufactured using standard lithographic techniques have so far been limited to superconducting qubits, owing to the difficulties of coupling qubits and dephasing in semiconductor systems. Here we present a two-qubit logic gate, which uses single spins in isotopically enriched silicon and is realized by performing single- and two-qubit operations in a quantum dot system using the exchange interaction, as envisaged in the Loss-DiVincenzo proposal. We realize CNOT gates via controlled-phase operations combined with single-qubit operations. Direct gate-voltage control provides single-qubit addressability, together with a switchable exchange interaction that is used in the two-qubit controlled-phase gate. By independently reading out both qubits, we measure clear anticorrelations in the two-spin probabilities of the CNOT gate.


Detection and quantitation of N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine adducts in DNA using online column-switching liquid chromatography tandem mass spectrometry.
The heterocyclic aromatic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is formed by the grilled cooking of certain foods such as meats, poultry and fish. PhIP has been shown to induce tumours in the colon, prostate and mammary glands of rats and is regarded as a potential human dietary carcinogen. PhIP is metabolically activated via cytochrome P450 mediated oxidation to an N-hydroxylamino-PhIP intermediate that is subsequently converted to an ester by N-acetyltransferases or sulfotransferases and undergoes heterolytic cleavage to produce a PhIP-nitrenium ion, which reacts with DNA to form the N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP-C8-dG) adduct. Thus far, the detection and quantification of PhIP-DNA adducts has relied to a large extent on (32)P-postlabelling methodologies. In order to expand the array of available techniques for the detection and improved quantification of PhIP-C8-dG adducts in DNA we have developed an online column-switching liquid chromatography (LC)-electrospray ionization (ESI)-tandem mass spectrometry (MS/MS) selected reaction monitoring (SRM) method incorporating an isotopically [(13)C(10)]-labelled PhIP-C8-dG internal standard for the analysis of DNA enzymatically hydrolysed to 2'-deoxynucleosides. A dose-dependent increase was observed for PhIP-C8-dG adducts when salmon testis DNA was reacted with N-acetoxy-PhIP. Analysis of DNA samples isolated from colon tissue of mice treated by oral gavage daily for 5 days with 50 mg/kg body weight of PhIP resulted in the detection of an average level of 14.8+/-3.7 PhIP-C8-dG adducts per 10(6) 2'-deoxynucleosides. The method required 50 microg of hydrolysed animal DNA on column and the limit of detection for PhIP-C8-dG was 2.5 fmol (1.5 PhIP-C8-dG adducts per 10(8) 2'-deoxynucleosides). In summary, the LC-ESI-MS/MS SRM method provides for the rapid automation of the sample clean up and a reduction in matrix components that would otherwise interfere with the mass spectrometric analysis, with sufficient sensitivity and precision to analyse DNA adducts in animals exposed to PhIP.


Percutaneous biopsy of lesions in the cavernous sinus region through the foramen ovale: diagnostic accuracy and limits in 50 patients.
The cavernous sinus and surrounding regions-specifically the Meckel cave, posterior sector of the cavernous sinus itself, and the upper part of the petroclival region-are the location of a large variety of lesions that require individual consideration regarding treatment strategy. These regions may be reached for biopsy by a percutaneous needle inserted through the foramen ovale. The aim of this retrospective study was to evaluate the diagnostic accuracy of percutaneous biopsy in a consecutive series of 50 patients referred for surgery between 1991 and 2010. Seven biopsies (14%) were unproductive and 43 (86%) were productive, among which 28 lesions subsequently underwent histopathological examination during a second (open) surgery. To evaluate the diagnostic accuracy of the procedure, results from surgery were compared with those from the biopsy. Sensitivity of the percutaneous biopsy was 0.83 (95% CI 0.52-0.98), specificity was 1 (95% CI 0.79-1), and κ coefficient was 0.81. Because of its valuable diagnostic accuracy, percutaneous biopsy of the cavernous sinus and surrounding regions should be performed in patients with parasellar masses when neuroimaging does not provide sufficient information of a histopathological nature. This procedure would enable patients to obtain the most appropriate therapy, such as resective surgery, corticosteroids, chemotherapy, radiotherapy, or radiosurgery.


Discrimination between psychogenic and organic erectile dysfunction.
The aim of this study was to develop a screening test based on the Leiden Impotence Questionnaire (LIQ) in order to assist in the difficult process of differentiating between psychogenic and organic erectile dysfunction (ED). The main sample consisted of 176 patients with ED, which was classified according to the results of the urological and psychiatric assessment as either organic, in 109 (62%) patients, or psychogenic, in 67 (38%) patients. A logistic regression model including six general items from the LIQ correctly identified psychogenic ED in 62% of the cases, and organic ED in 86%, with an overall correct classification rate of 76%. Adding information regarding sexual intercourse and the relationship in patients who had a partner and were having sexual intercourse the correct classification rates were: psychogenic 77%, organic 94%, and overall 87%. Discrimination between psychogenic and organic ED is improved when more information concerning sexual activity can be assessed.


N-Acetylcysteine (NAC) for the Prevention of Liver Failure in Heat Injury-Mediated Ischemic Hepatitis.
Exertional Heat Illness with associated ischemic hepatitis (IH) is a common occurrence among military trainees; however, few specific therapies exist if unresponsive to appropriate supportive measures. A 27-year-old basic combat trainee presented with altered mental status, renal insufficiency, rhabdomyolysis, and a core temp of 107.9 °F after collapsing during a run, leading to the diagnosis of heat stroke. While the patient's azotemia and creatinine kinase levels rapidly improved with aggressive intravenous hydration, transaminases continued to increase to nearly 155 times the upper limit of normal. Further laboratory evaluation revealed coagulopathy and thrombocytopenia suggestive of acute liver failure (ALF). On hospital day three, the patient was started on N-acetylcysteine (NAC). Evaluation for infectious and autoimmune etiologies of ALF was unremarkable; thus, the patient's symptomatology was attributed to IH resulting from heat stroke. Liver function normalized on NAC. Heat Injury is common among US Army recruits and results in thousands of hospitalizations in recent years. IH is characterized by diffuse hepatocyte necrosis following an episode of hemodynamic instability, and is an established sequela of Heat Injury. The mortality of IH among critically ill patients has been estimated to be as high as 60%, with those demonstrating coagulopathy especially at risk. NAC is shown to improve the transplant-free survival rate in non-acetaminophen related ALF, consistent with its proposed mechanisms of improving hepatic blood flow and conjugating toxic metabolites. NAC therapy should be considered early in the course of heat injury-mediated IH to reduce reperfusion injury, improving transplant free outcomes.


An association between recurrent otitis media in infancy and later hyperactivity.
An association between the frequency of otitis media in early childhood and later hyperactivity is reported in this study. The subjects were 67 children referred to a child development clinic for evaluation of school failure. Ranging from 6 to 13 years old, all the children demonstrated specific school learning problems, and 27 were also considered hyperactive by two or more raters. Sixteen of the hyperactive children were treated with central nervous system stimulant medication. In retrospect, there was positive correlation between an increasing number of otitis media infections in early childhood and the presence and severity of hyperactive behavior. Ninety-four percent of children medicated for hyperactivity had three or more otitis infections, and 69 percent had greater than 10 infections. In comparison, 50 percent of non-hyperactive school-failure patients had three or more infections and 20 percent had greater than 10 infections. Twenty-two of 28 children (79%) known to have more than 10 infections experienced recurrent otitis before 1 year of age.


Plastic accumulation in the Mediterranean sea.
Concentrations of floating plastic were measured throughout the Mediterranean Sea to assess whether this basin can be regarded as a great accumulation region of plastic debris. We found that the average density of plastic (1 item per 4 m2), as well as its frequency of occurrence (100% of the sites sampled), are comparable to the accumulation zones described for the five subtropical ocean gyres. Plastic debris in the Mediterranean surface waters was dominated by millimeter-sized fragments, but showed a higher proportion of large plastic objects than that present in oceanic gyres, reflecting the closer connection with pollution sources. The accumulation of floating plastic in the Mediterranean Sea (between 1,000 and 3,000 tons) is likely related to the high human pressure together with the hydrodynamics of this semi-enclosed basin, with outflow mainly occurring through a deep water layer. Given the biological richness and concentration of economic activities in the Mediterranean Sea, the affects of plastic pollution on marine and human life are expected to be particularly frequent in this plastic accumulation region.


Diversity-function relationships changed in a long-term restoration experiment.
The central tenet of biodiversity-ecosystem function (BEF) theory, that species richness increases function, could motivate restoration practitioners to incorporate a greater number of species into their projects. But it is not yet clear how well BEF theory predicts outcomes of restoration, because it has been developed through tests involving short-run and tightly controlled (e.g., weeded) experiments. Thus, we resampled our 1997 BEF experiment in a restored salt marsh to test for long-term effects of species richness (plantings with 1, 3, and 6 species per 2 x 2 m plot), with multiple ecosystem functions as response variables. Over 11 years, 1- and 6-species assemblages converged on intermediate richness (mean = 3.9 species/ 0.25-m2 plot), and composition changed nonrandomly throughout the site. While three species became rare, the two most productive species became co-dominant. The two dominants controlled and increased shoot biomass, which appeared to decrease species richness. Diversity-function relationships became less positive over 11 years and differed significantly with (a) the species-richness metric (planted vs. measured), and (b) the indicator of function (shoot biomass, height, and canopy layering). The loss of positive relationships between species richness and function in our restored site began soon after we stopped weeding and continued with increasing dominance by productive species. Where species-rich plantings are unlikely to ensure long-term restoration of functions, as in our salt marsh, we recommend dual efforts to establish (1) dominant species that provide high levels of target functions, and (2) subordinate species, which might provide additional functions under current or future conditions.


Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular β-glucosidase 2, and other glycosidases.
Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible male contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve ring-closing metathesis and Sharpless asymmetric dihydroxylation and for the four-membered analogues Sharpless epoxidation, epoxide ring-opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6) was moderately active against rat-derived ceramide-specific glucosyltransferase, and four of the other eight-membered analogues were weakly active against rat-derived β-glucosidase 2. Among the four-membered analogues, ((2R,3S,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25) displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat-derived enzyme. ((2S,4S)-3-Hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (27) was found to be a selective inhibitor of β-glucosidase 2, with potency similar to NB-DNJ. Additional glycosidase assays were performed to identify potential other therapeutic applications. The eight-membered iminosugars exhibited specificity for almond-derived β-glucosidase, and the 1-nonylazetidine 25 inhibited α-glucosidase (Saccharomyces cerevisiae) with an IC(50) of 600 nM and β-glucosidase (almond) with an IC(50) of 20 μM. Only N-nonyl derivatives were active, emphasizing the importance of a long lipophilic side chain for inhibitory activity of the analogues studied.


Tualang honey promotes apoptotic cell death induced by tamoxifen in breast cancer cell lines.
Tualang honey (TH) is rich in flavonoids and phenolic acids and has significant anticancer activity against breast cancer cells comparable to the effect of tamoxifen (TAM), in vitro. The current study evaluated the effects of TH when used in combination with TAM on MCF-7 and MDA-MB-231 cells. We observed that TH promoted the anticancer activity of TAM in both the estrogen receptor-(ER-)responsive and ER-nonresponsive human breast cancer cell lines. Flow cytometric analyses indicated accelerated apoptosis especially in MDA-MB-231 cells and with the involvement of caspase-3/7, -8 and -9 activation as shown by fluorescence microscopy. Depolarization of the mitochondrial membrane was also increased in both cell lines when TH was used in combination with TAM compared to TAM treatment alone. TH may therefore be a potential adjuvant to be used with TAM for reducing the dose of TAM, hence, reducing TAM-induced adverse effects.


RNA/MBNL1-containing foci in myoblast nuclei from patients affected by myotonic dystrophy type 2: an immunocytochemical study.
Myotonic dystrophy type 2 (DM2) is a dominantly inherited autosomal disease with multi-systemic clinical features and it is caused by expansion of a CCTG tetranucleotide repeat in the first intron of the zinc finger protein 9 (ZNF9) gene in 3q21.The expanded-CCUG-containing transcripts are retained in the cell nucleus and accumulate in the form of focal aggregates which specifically sequester the muscleblind-like 1 (MBNL1) protein, a RNA binding factor involved in the regulation of alternative splicing. The structural organization and composition of the foci are still incompletely known. In this study, the nuclear foci occurring in cultured myoblasts from DM2 patients were characterised at fluorescence and transmission electron microscopy by using a panel of antibodies recognizing transcription and processing factors of pre-mRNAs. MBNL1 proved to co-locate in the nuclear foci with snRNPs and hnRNPs, whereas no co-location was observed with RNA polymerase II, the non-RNP splicing factor SC35, the cleavage factor CStF and the PML protein. At electron microscopy the MBNL1-containing nuclear foci appeared as roundish domains showing a rather homogeneous structure and proved to contain snRNPs and hnRNPs. The sequestration of splicing factors involved in early phases of pre-mRNA processing supports the hypothesis of a general alteration in the maturation of several mRNAs, which could lead to the multiple pathological dysfunctions observed in dystrophic patients.


Pattern of carbon dioxide stimulated breathing in patients with chronic airway obstruction.
The pattern of stimulated breathing during carbon dioxide inhalation was studied in a group of 21 patients with severe irreversible airways obstruction (mean FEV1 = 0.9 litre, mean FEV1/FVC% = 50%). Carbon dioxide rebreathing experiments were performed, the ventilatory response being defined in terms of total ventilation (V) and CO2 sensitivity (S). Breathing pattern was defined by the changes in tidal volume (delta VT) and respiratory frequency (delta f) and the maximum VT achieved (VTmax). Contrary to some previous studied no significant relationship could be demonstrated between the severity of airway obstruction (FEV1/FVC%, Raw) and the ventilatory response to rebreathing (V, S, delta VT, delta f, VTmax). However, measurements of dynamic lung volume (FEV1, FVC, IC) were found to be significantly correlated with the breathing pattern variables (delta VT, delta f, VTmax). Resting PaO2 and PaCO2 were significantly correlated with delta VT but not delta f. Results indicate that the degree of airway obstruction does not dictate the ventilatory or breathing pattern response to carbon dioxide induced hyperpnoea. In contrast it is the restriction of dynamic lung volume, by limiting the VT response, that appears to determine the ventilatory and breathing pattern response in patients with severe airway obstruction.


The very real dangers of executive coaching.
A personal coach to help your most promising executives reach their potential--sounds good, doesn't it? But, according to Steven Berglas, executive coaches can make a bad situation worse. Because of their backgrounds and biases, they ignore psychological problems they don't understand. Companies need to consider psychotherapeutic intervention when the symptoms plaguing an executive are stubborn or severe. Executives with issues that require more than coaching come in many shapes and sizes. Consider Rob Bernstein, an executive vice president of sales at an automotive parts distributor. According to the CEO, Bernstein had just the right touch with clients but caused personnel problems inside the company. The last straw came when Bernstein publicly humiliated a mail clerk who had interrupted a meeting to ask someone to sign for a package. At that point, the CEO assigned Tom Davis to coach Bernstein. Davis, a former corporate lawyer, worked with Bernstein for four years. But Davis only exacerbated the problem by teaching Bernstein techniques for "handling" employees--methods that were condescending at best. While Bernstein appeared to be improving, he was in fact getting worse. Bernstein's real problems went undetected, and when his boss left the company, he was picked as the successor. Soon enough, Bernstein was again in trouble, suspected of embezzlement. This time, the CEO didn't call Davis; instead, he turned to the author, a trained psychotherapist, for help. Berglas soon realized that Bernstein had a serious narcissistic personality disorder and executive coaching could not help him. As that tale and others in the article teach us, executives to be coached should at the very least first receive a psychological evaluation. And company leaders should beware that executive coaches given free rein can end up wreaking personnel havoc.


Basic level category structure emerges gradually across human ventral visual cortex.
Objects can be simultaneously categorized at multiple levels of specificity ranging from very broad ("natural object") to very distinct ("Mr. Woof"), with a mid-level of generality (basic level: "dog") often providing the most cognitively useful distinction between categories. It is unknown, however, how this hierarchical representation is achieved in the brain. Using multivoxel pattern analyses, we examined how well each taxonomic level (superordinate, basic, and subordinate) of real-world object categories is represented across occipitotemporal cortex. We found that, although in early visual cortex objects are best represented at the subordinate level (an effect mostly driven by low-level feature overlap between objects in the same category), this advantage diminishes compared to the basic level as we move up the visual hierarchy, disappearing in object-selective regions of occipitotemporal cortex. This pattern stems from a combined increase in within-category similarity (category cohesion) and between-category dissimilarity (category distinctiveness) of neural activity patterns at the basic level, relative to both subordinate and superordinate levels, suggesting that successive visual areas may be optimizing basic level representations.


Acute onset incomitant image disparity modifies saccadic and vergence eye movements.
New-onset impairment of ocular motility will cause incomitant strabismus, i.e., a gaze-dependent ocular misalignment. This ocular misalignment will cause retinal disparity, that is, a deviation of the spatial position of an image on the retina of both eyes, which is a trigger for a vergence eye movement that results in ocular realignment. If the vergence movement fails, the eyes remain misaligned, resulting in double vision. Adaptive processes to such incomitant vergence stimuli are poorly understood. In this study, we have investigated the physiological oculomotor response of saccadic and vergence eye movements in healthy individuals after shifting gaze from a viewing position without image disparity into a field of view with increased image disparity, thus in conditions mimicking incomitance. Repetitive saccadic eye movements into a visual field with increased stimulus disparity lead to a rapid modification of the oculomotor response: (a) Saccades showed immediate disconjugacy (p < 0.001) resulting in decreased retinal image disparity at the end of a saccade. (b) Vergence kinetics improved over time (p < 0.001). This modified oculomotor response enables a more prompt restoration of ocular alignment in new-onset incomitance.


Phage selection of photoswitchable peptide ligands.
Photoswitchable ligands are powerful tools to control biological processes at high spatial and temporal resolution. Unfortunately, such ligands exist only for a limited number of proteins and their development by rational design is not trivial. We have developed an in vitro evolution strategy to generate light-activatable peptide ligands to targets of choice. In brief, random peptides were encoded by phage display, chemically cyclized with an azobenzene linker, exposed to UV light to switch the azobenzene into cis conformation, and panned against the model target streptavidin. Isolated peptides shared strong consensus sequences, indicating target-specific binding. Several peptides bound with high affinity when cyclized with the azobenzene linker, and their affinity could be modulated by UV light. The presented method is robust and can be applied for the in vitro evolution of photoswitchable ligands to virtually any target.


High prevalence of hepatitis G virus infection in multiply transfused children with thalassaemia.
We investigated the prevalence of hepatitis G virus (HGV) RNA in relation to the frequency of blood transfusions in thalassaemic children and in volunteer blood donors in Thailand. Furthermore, we studied the frequency of coinfection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) as well as a possible relationship to the alanine aminotransferase (ALT) status of the blood samples, taken at random from thalassaemic children who have received multiple blood transfusions and from volunteer blood donors. The results show detectable HGV-RNA in 32.6% of transfusion patients and in 5% of blood donors. The prevalence of HGV-RNA peaked between the 11th and 50th transfusion. The relationship between HGV infection and ALT status was not statistically relevant.


HIV and Sexuality Stigma Reduction Through Engagement in Online Forums: Results from the HealthMPowerment Intervention.
HIV and sexuality stigma impede HIV prevention and care efforts. HealthMpowerment.org (HMP) is an interactive mobile phone- and web-based HIV prevention and care intervention for young Black men who have sex with men (YBMSM; ages 18-30) in the United States. HMP included three forums where participants could share their experiences. In this study, we explored whether engaging in stigma-related discussions was associated with changes in YBMSM's stigma-related scores throughout the trial. YBMSM (ages 18-30; N = 238) participating in HMP completed surveys at baseline, and 3 and 6 month follow-ups that included a series of scales focused on HIV and sexuality (internalized homophobia; sexual prejudice) stigma. Sixty-two participants contributed to the forums (1497 posts). We coded instances where YBMSM's conversations were stigma related (915 posts, 61.1%), including discussions of anticipated (74/915, 8.1%), experienced (125/915, 13.7%), internalized (410/915, 44.8%), and/or challenged (639/915, 69.8%) stigma regarding sexuality and HIV. Using a mixed methods approach, we examined whether changes in YBMSM's stigma scores were associated with stigma-related discussions within the forum. We controlled for age, HIV status, income, and educational attainment in these multivariable models. YBMSM who discussed experiencing HIV stigma in the forums reported decreases in perceived HIV stigma over time (b = - 0.37, p ≤ 0.05). YBMSM whose forum posts indicated anticipated HIV stigma reported increases in HIV stigma over time (b = 0.46, p ≤ 0.01). Participants who challenged sexuality-related stigma in forums had lower internalized homophobia (b = - 0.68, p ≤ 0.01) at baseline. YBMSM whose discussions focused on experiencing sexuality-related stigma reported increases in internalized homophobia (b = 0.39, p ≤ 0.01) and sexual prejudice (b = 0.87, p ≤ 0.05) over time. Developing strategies to combat stigma remains a key priority. HMP created an online space where YBMSM could discuss HIV and sexuality stigma. Although a limited number of HMP participants authored the majority of these forum discussions, the discussions were associated with changes in the sample's stigma scores over time. Online interventions (e.g., social media, apps) should consider the inclusion of forums to address stigma and test the efficacy of forums to improve YBMSM's HIV prevention and care continuum outcomes.


Cannabis use is associated with reduced prevalence of progressive stages of alcoholic liver disease.
Abusive alcohol use has well-established health risks including causing liver disease (ALD) characterized by alcoholic steatosis (AS), steatohepatitis (AH), fibrosis, cirrhosis (AC) and hepatocellular carcinoma (HCC). Strikingly, a significant number of individuals who abuse alcohol also use Cannabis, which has seen increased legalization globally. While cannabis has demonstrated anti-inflammatory properties, its combined use with alcohol and the development of liver disease remain unclear. The aim of this study was to determine the effects of cannabis use on the incidence of liver disease in individuals who abuse alcohol. We analysed the 2014 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (NIS) discharge records of patients 18 years and older, who had a past or current history of abusive alcohol use (n = 319 514). Using the International Classification of Disease, Ninth Edition codes, we studied the four distinct phases of progressive ALD with respect to three cannabis exposure groups: non-cannabis users (90.39%), non-dependent cannabis users (8.26%) and dependent cannabis users (1.36%). We accounted for the complex survey sampling methodology and estimated the adjusted odds ratio (AOR) for developing AS, AH, AC and HCC with respect to cannabis use (SAS 9.4). Our study revealed that among alcohol users, individuals who additionally use cannabis (dependent and non-dependent cannabis use) showed significantly lower odds of developing AS, AH, AC and HCC (AOR: 0.55 [0.48-0.64], 0.57 [0.53-0.61], 0.45 [0.43-0.48] and 0.62 [0.51-0.76]). Furthermore, dependent users had significantly lower odds than non-dependent users for developing liver disease. Our findings suggest that cannabis use is associated with a reduced incidence of liver disease in alcoholics.


Proteomic analysis of rat laryngeal muscle following denervation.
Laryngeal muscle atrophy induced by nerve injury is a major factor contributing to the disabling symptoms associated with laryngeal paralysis. Alterations of global proteins in rat laryngeal muscle following denervation were, therefore, studied using proteomic techniques. Twenty-eight adult Sprague-Dawley rats were divided into normal control and denervated groups. The thyroarytenoid (TA) muscle was excised 60 days after right recurrent laryngeal nerve was resected. Protein separation and identification were preformed using 2-DE and MALDI-MS with database search. Forty-four proteins were found to have significant alteration in expression level after denervation. The majority of these proteins (57%), most of them associated with energy metabolism, cellular proliferation and differentiation, signal transduction and stress reaction, were decreased levels of expression in denervated TA muscle. The remaining 43% of the proteins, most of them involved with protein degradation, immunoreactivity, injury repair, contraction, and microtubular formation, were found to have increased levels of expression. The protein modification sites by phosphorylation were detected in 22% of the identified proteins that presented multiple-spot patterns on 2-D gel. Significant changes in protein expression in denervated laryngeal muscle may provide potential therapeutic strategies for the treatment of laryngeal paralysis.


Lever attacking and pressing as a function of conditioning and extinguishing a lever-press avoidance response in rats.
Six experimental rats were conditioned to press one of two available levers to avoid shock. The levers registered bites as well as presses. For four of these rats, shock was contingent on lever bites when a specified time period had elapsed after the previous shock. An extinction period, in which only periodic noncontingent shocks were presented, followed avoidance training. Six yoked-control rats received the same sequence of shocks as did the corresponding experimental rats in both the conditioning and extinction phases. All six experimental rats repeatedly bit the avoidance lever. Four bit it more than the nonavoidance lever during conditioning, and five bit it more during extinction. Five of the six experimental rats consistently bit the levers many more times during each session than did their respective control rats, suggesting that avoidance conditioning facilitated lever biting. Rates of lever biting and pressing by all of the experimental rats and by some of the control rats were highest immediately following shock throughout both phases. During later portions of the intervals following shock, characteristic effects of conditioning and extinction were observed. This finding suggests that extinction of avoidance behavior by unavoidable shock presentations can be demonstrated more readily when shock-elicited responding is extricated from the data.


Vibrio vulnificus outbreaks in Dutch eel farms since 1996: strain diversity and impact.
Vibrio vulnificus is a potentially zoonotic bacterial pathogen of fish, which can infect humans (causing necrotic fasciitis). We analysed 24 V. vulnificus isolates (from 23 severe eel disease outbreaks in 8 Dutch eel farms during 1996 to 2009, and 1 clinical strain from an eel farmer) for genetic correlation and zoonotic potential. Strains were typed using biotyping and molecular typing by high-throughput multilocus sequence typing (hiMLST) and REP-PCR (Diversilab®). We identified 19 strains of biotype 1 and 5 of biotype 2 (4 from eels, 1 from the eel farmer), that were subdivided into 8 MLST types (ST) according to the international standard method. This is the first report of V. vulnificus biotype 1 outbreaks in Dutch eel farms. Seven of the 8 STs, of unknown zoonotic potential, were newly identified and were deposited in the MLST database. The REP-PCR and the MLST were highly concordant, indicating that the REP-PCR is a useful alternative for MLST. The strains isolated from the farmer and his eels were ST 112, a known potential zoonotic strain. Antimicrobial resistance to cefoxitin was found in most of the V. vulnificus strains, and an increasing resistance to quinolones, trimethoprim + sulphonamide and tetracycline was found over time in strain ST 140. Virulence testing of isolates from diseased eels is recommended, and medical practitioners should be informed about the potential risk of zoonotic infections by V. vulnificus from eels for the prevention of infection especially among high-risk individuals. Additional use of molecular typing methods such as hiMLST and Diversilab® is recommended for epidemiological purposes during V. vulnificus outbreaks.


Treponema pallidum receptor binding proteins interact with fibronectin.
Analysis of plasma proteins avidly bound to T. pallidum surfaces revealed the ability of T. pallidum to acquire numerous host macromolecules. No acquisition was evident by the avirulent spirochete, T. phagedenis biotype Reiter. Western blotting technology using hyperimmune antifibronectin serum as a probe revealed the ability of virulent treponemes to avidly bind fibronectin from a complex medium such as plasma. The specificity of the tiplike adherence of motile T. pallidum to fibronectin-coated glass surfaces and to fibronectin on HEp-2 cells was reinforced by the observation that pretreatment of coverslips or cell monolayers with monospecific antiserum against fibronectin substantially reduced T. pallidum attachment. The stoichiometric binding of T. pallidum to fibronectin-coated coverslips and the inability of unlabeled or 35S-radiolabeled treponemes to interact with glass surfaces treated with other plasma proteins further established the specific nature of the interaction between virulent T. pallidum and fibronectin. The avid association between three outer envelope proteins of T. pallidum and fibronectin was also demonstrated. These treponemal surface proteins have been previously identified as putative receptor-binding proteins responsible for T. pallidum parasitism of host cells. The data suggest that surface fibronectin mediates tip-oriented attachment of T. pallidum to host cells via a receptor-ligand mechanism of recognition.


A model for multi-view ultrasonic array inspection of small two-dimensional defects.
The multi-view total focusing method (TFM) is an imaging algorithm for ultrasonic full matrix array data that exploits internal reflections and mode conversions in the inspected object to create multiple images, the views. Modelling the defect response in multi-view TFM is an essential first step in developing new detection and characterisation methods which exploit the information present in these views. This paper describes a ray-based forward model for small two-dimensional defects and compares its results against finite-element simulations and experimental data for the inspection of a side-drilled hole, a notch and a crack. A simpler version of this model, based on a single-frequency approximation, is derived and compared. A good agreement with the multi-frequency model and a speed-up of several orders of magnitude are achieved.


Benzobis(imidazolium)-cucurbit[8]uril complexes for binding and sensing aromatic compounds in aqueous solution.
The utilities of benzobis(imidazolium) salts (BBIs) as stable and fluorescent components of supramolecular assemblies involving the macrocyclic host, cucurbit[8]uril (CB[8]), are described. CB[8] has the unusual ability to bind tightly and selectively to two different guests in aqueous media, typically methyl viologen (MV) as the first guest, followed by an indole, naphthalene, or catechol-containing second guest. Based on similar size, shape, and charge, tetramethyl benzobis(imidazolium) (MBBI) was identified as a potential alternative to MV that would increase the repertoire of guests for cucurbit[8]uril. Isothermal titration calorimetry (ITC) studies showed that MBBI binds to CB[8] in a 1:1 ratio with an equilibrium association constant (K(a)) value of 5.7×10(5) M(-1), and that the resulting MBBI·CB[8] complex binds to a series of aromatic second guests with K(a) values ranging from 10(3) to 10(5) M(-1). These complexation phenomena were supported by mass spectrometry, which confirmed complex formation, and a series of NMR studies that showed the expected upfield perturbation of aromatic peaks and of the MBBI methyl peaks. Surprisingly, the binding behavior of MBBI is strikingly similar to that of MV, and yet MBBI offers a number of substantial advantages for many applications, including intrinsic fluorescence, high chemical stability, and broad synthetic tunability. Indeed, the intense fluorescence emission of the MBBI·CB[8] complex was quenched upon binding to the second guests, thus demonstrating the utility of MBBI as a component for optical sensing. Building on these favorable properties, the MBBI·CB[8] system was successfully applied to the sequence-selective recognition of peptides as well as the controlled disassembly of polymer aggregates in water. These results broaden the available guests for the cucurbit[n]uril family and demonstrate potentially new applications.


Computerized clinical decision support systems for primary preventive care: a decision-maker-researcher partnership systematic review of effects on process of care and patient outcomes.
Computerized clinical decision support systems (CCDSSs) are claimed to improve processes and outcomes of primary preventive care (PPC), but their effects, safety, and acceptance must be confirmed. We updated our previous systematic reviews of CCDSSs and integrated a knowledge translation approach in the process. The objective was to review randomized controlled trials (RCTs) assessing the effects of CCDSSs for PPC on process of care, patient outcomes, harms, and costs. We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews Database, Inspec, and other databases, as well as reference lists through January 2010. We contacted authors to confirm data or provide additional information. We included RCTs that assessed the effect of a CCDSS for PPC on process of care and patient outcomes compared to care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. We added 17 new RCTs to our 2005 review for a total of 41 studies. RCT quality improved over time. CCDSSs improved process of care in 25 of 40 (63%) RCTs. Cumulative scientifically strong evidence supports the effectiveness of CCDSSs for screening and management of dyslipidaemia in primary care. There is mixed evidence for effectiveness in screening for cancer and mental health conditions, multiple preventive care activities, vaccination, and other preventive care interventions. Fourteen (34%) trials assessed patient outcomes, and four (29%) reported improvements with the CCDSS. Most trials were not powered to evaluate patient-important outcomes. CCDSS costs and adverse events were reported in only six (15%) and two (5%) trials, respectively. Information on study duration was often missing, limiting our ability to assess sustainability of CCDSS effects. Evidence supports the effectiveness of CCDSSs for screening and treatment of dyslipidaemia in primary care with less consistent evidence for CCDSSs used in screening for cancer and mental health-related conditions, vaccinations, and other preventive care. CCDSS effects on patient outcomes, safety, costs of care, and provider satisfaction remain poorly supported.


Intervertebral disc herniation: prevalence and association with clinical diagnosis.
Low back pain is one of the common health problems encountered in life with intervertebral disc herniation being a common cause of its occurrence. Magnetic resonance imaging has emerged the gold standard for diagnosing a herniated disc. To assess the frequency and pattern of occurrence of disc herniation as well as evaluate the association of disc herniation on magnetic resonance imaging with clinical symptoms. A total of 120 adult patients who came for magnetic resonance imaging scan of the lumbosacral spine for a period of 1year in the department of Radiology University of Port-Harcourt Teaching Hospital. The end plates of 600 lumbar interspaces were graded for type, size and site of lumbar disc herniation. The age distribution of patients was from 18-80 years; mean age was 51.0.


Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association.
We undertook an epidemiological study to investigate whether measles, mumps, and rubella (MMR) vaccine may be causally associated with autism. Children with autism born since 1979 were identified from special needs/disability registers and special schools in eight North Thames health districts, UK. Information from clinical records was linked to immunisation data held on the child health computing system. We looked for evidence of a change in trend in incidence or age at diagnosis associated with the introduction of MMR vaccination to the UK in 1988. Clustering of onsets within defined postvaccination periods was investigated by the case-series method. We identified 498 cases of autism (261 of core autism, 166 of atypical autism, and 71 of Asperger's syndrome). In 293 cases the diagnosis could be confirmed by the criteria of the International Classification of Diseases, tenth revision (ICD10: 214 [82%] core autism, 52 [31%] atypical autism, 27 [38%] Asperger's syndrome). There was a steady increase in cases by year of birth with no sudden "step-up" or change in the trend line after the introduction of MMR vaccination. There was no difference in age at diagnosis between the cases vaccinated before or after 18 months of age and those never vaccinated. There was no temporal association between onset of autism within 1 or 2 years after vaccination with MMR (relative incidence compared with control period 0.94 [95% CI 0.60-1.47] and 1.09 [0.79-1.52]). Developmental regression was not clustered in the months after vaccination (relative incidence within 2 months and 4 months after MMR vaccination 0.92 [0.38-2.21] and 1.00 [0.52-1.95]). No significant temporal clustering for age at onset of parental concern was seen for cases of core autism or atypical autism with the exception of a single interval within 6 months of MMR vaccination. This appeared to be an artifact related to the difficulty of defining precisely the onset of symptoms in this disorder. Our analyses do not support a causal association between MMR vaccine and autism. If such an association occurs, it is so rare that it could not be identified in this large regional sample.


Reproduction and aging in marmosets and tamarins.
This chapter presents data on the relations between reproduction and aging in both captive and free-ranging marmosets and tamarins. The relationship is examined from two perspectives. First, the relation of age to physiological impairments in reproductive function is explored. Callitrichid females, in common with many other nonhuman primates, begin to display anovulation associated with follicular depletion at a point relatively close to the maximum life span. Unlike Old World primates, however, they continued to display significant steroidogenic activity in the ovary. There are age effects on some reproductive output variables, such as litter size and inter-birth interval, though the effects are often small. Like other mammals, male marmosets display a change in levels of androgens with age, although the magnitude of the decrease is not large and they actually mount an elevated response to GnRH challenge as they age. We also examined whether age affects either the establishment or maintenance of a breeding position, the factors most important in determining lifetime reproductive success. Infant mortality did increase with increasing parturitions, suggesting that there may have been aging or parturition effects on lactation. Generally, marmoset females were well past the age of sexual maturity at the beginning of the tenure and approaching 8-9 years at the end of it. Reproductive decline did not appear to be a gradual process, but a rather abrupt one, often causing the dismantling of the group. There are potentially interesting relations among maternal age, mass and declining reproductive performance, given the known importance of mass as a determinant of reproductive success in female callitrichids.


Statistical Optimization of Oral Vancomycin-Eudragit RS Nanoparticles Using Response Surface Methodology.
A Box-Behnken design with three replicates was used for preparation and evaluation of Eudragit vancomycin (VCM) nanoparticles prepared by double emulsion. The purpose of this work was to optimize VCM nanoparticles to improve the physicochemical properties. Nanoparticles were formed by using W1/O/W2 double-emulsion solvent evaporation method using Eudragit RS as a retardant material. Full factorial design was employed to study the effect of independent variables, RPM (X1), amount of emulsifier (X2), stirring rate (X3), volume of organic phase (X4) and volume of aqueous phase (X5), on the dependent variables as production yield, encapsulation efficiency and particle size. The optimum condition for VCM nanoparticles preparation was 1:2 drug to polymer ratio, 0.2 (%w/w) amount of emulsifier , 25 mL (volume of organic phase), 25 mL (volume of aqueous phase), 3 min (time of stirring) and 26000 RPM. RPM and emulsifier concentrations were the effective factors on the drug loading (R2 = 90.82). The highest entrapment efficiency was obtained when the ratio of drug to polymer was 1:3. Zeta (ζ) potential of the nanoparticles was fairly positive in molecular level. In vitro release study showed two phases: an initial burst for 0.5 h followed by a very slow release pattern during a period of 24 h. The release of VCM was influenced by the drug to polymer ratio and particle size and was found to be diffusion controlled. The best-fit release kinetic was achieved with Peppas model. In conclusion, the VCM nanoparticle preparations showed optimize formulation, which can be useful for oral administrations.


Can "realist" randomised controlled trials be genuinely realist?
In this paper, we respond to a paper by Jamal and colleagues published in Trials in October 2015 and take an opportunity to continue the much-needed debate about what applied scientific realism is. The paper by Jamal et al. is useful because it exposes the challenges of combining a realist evaluation approach (as developed by Pawson and Tilley) with the randomised controlled trial (RCT) design.We identified three fundamental differences that are related to paradigmatic differences in the treatment of causation between post-positivist and realist logic: (1) the construct of mechanism, (2) the relation between mediators and moderators on one hand and mechanisms and contexts on the other hand, and (3) the variable-oriented approach to analysis of causation versus the configurational approach.We show how Jamal et al. consider mechanisms as observable, external treatments and how their approach reduces complex causal processes to variables. We argue that their proposed RCT design cannot provide a truly realist understanding. Not only does the proposed realist RCT design not deal with the RCT's inherent inability to "unpack" complex interventions, it also does not enable the identification of the dynamic interplay among the intervention, actors, context, mechanisms and outcomes, which is at the core of realist research. As a result, the proposed realist RCT design is not, as we understand it, genuinely realist in nature.


Paleopathological features of the cervical spine in the early middle ages: natural history of degenerative diseases.
Trauma and degenerative joint disease are the most common pathological conditions observed in archaeological skeletal remains. We describe the prevalence of different types of cervical bone diseases observed in the early Middle Ages (6th to 8th centuries AD). Human skeletons were excavated from Germanic row graves in southwestern Germany. One hundred ninety-six cervical spines thus obtained were examined for bone disease. The degenerative changes were classified into Grades 1 (marginal osteophytes), 2 (uneven joint surfaces), and 3 (osseous ankylosis). Cervical spinal canal stenosis was defined as anteroposterior diameters of <11 mm and intervertebral foraminal stenosis as <3.0 mm in the smallest diameter. Of the skeletons, 27.5% demonstrated degenerative changes of the cervical spine. The mean age of the skeletons at the time of death was 33.4 years, compared with 43.7 years for those with degenerative disease. Degenerative changes of the vertebral bodies (usually Grades 1 and 2) were most common in the C5-C6 (12.4%, P < 0.05) and C6-C7 (15.3%, P < 0.05) segments. The medial (6.1%) and lateral (0.6%) atlantoaxial joints were rarely involved in degenerative disease. The facet joints from C3-C4 to C6-C7 demonstrated degenerative changes (usually Grades 1 and 2) in 8.0 to 11.8% of cases. The C2-C3 facet joints were significantly involved in degenerative disease in 19.7% of cases (P < 0.05), one-fourth of which demonstrated osseous ankylosis. We observed cervical spinal canal stenosis in 5 skeletons (2.6%) and osseous intervertebral foraminal stenoses in 12 (6.1%). Isolated cases of other pathological processes, i.e., spondylitis ankylopoietica, occipitalization of the atlas and axis, and an odontoid fracture with pseudoarthrosis, were also recorded. In the early Middle Ages, the prevalence of degenerative cervical spine disease was the same as that observed today. The C2-C3 facet joints demonstrated high rates of degenerative disease.


Alterations in intramuscular water movement associated with mechanical changes in human skeletal muscle fibers: an evaluation using magnetic resonance diffusion-weighted imaging and B-mode ultrasonography.
Intramuscular water movement is expected to be affected by the mechanical changes of the muscle fibers. However, the effect of changes in fiber length (FL) and pennation angle (PA) on the water movement has not been sufficiently investigated in human skeletal muscles. To determine the relationship between intramuscular water movement and the mechanical changes in human muscle fibers. Axial magnetic resonance diffusion-weighted images of the right leg (eight men) were taken using a 1.5-Tesla device with the ankle joint maximally dorsiflexed and maximally plantar flexed. The apparent diffusion coefficient (ADC) values of both the dorsiflexors (the superficial and deep parts of the tibialis anterior) and the plantar flexors (medial gastrocnemius and soleus) were calculated along three orthogonal axes (S-I: superior-to-inferior, A-P: anterior-to-posterior, and R-L: right-to-left). FL and PA of both muscle groups were also calculated from longitudinal B-mode ultrasound images with the ankle joint maximally dorsiflexed and plantar flexed. There was a significant increase in the ADC in superficial (P < 0.05) and deep (P < 0.05) parts of the dorsiflexors in the S-I direction when the ankle was plantar flexed and in the A-P and R-L directions when the ankle was dorsiflexed (P < 0.05). The plantar flexors showed significantly elevated ADC in the S-I direction when the ankle was dorsiflexed (P < 0.05), and in the A-P and R-L directions when the ankle was plantar flexed (P < 0.05). The dorsiflexors also showed significantly increased PA and decreased FL values when the ankle was dorsiflexed (P < 0.05). The plantar flexors displayed similar morphological changes when the ankle was plantar flexed (P < 0.05). Water diffusion is affected by structural changes in the long axis of the muscle fibers, namely the changes in PA and FL.


Prevention and management of complications following tracheal resections-lessons learned at the Massachusetts General Hospital.
Tracheal surgery has developed and evolved over the last 50 years, becoming an integral part of the clinical practice of modern thoracic surgeons. Today, surgeons can safely and effectively operate on most patients suffering from post-intubation tracheal stenosis, tracheal tumors and other pathologies that result in an abnormal shape and function of the central airways. The Massachusetts General Hospital (MGH) in Boston witnessed first-hand the birth and growth of tracheal surgery under Dr. Hermes Grillo, becoming a reference center and accumulating one of the largest institutional experiences in the world. This vast experience of the management of patients with tracheal pathologies has allowed our group at MGH to refine the care of these patients, including their judicious preoperative evaluation, meticulous surgical treatment, and dedicated postoperative care. However, this experience has also provided valuable lessons on the potential complications that can arise after tracheal surgery. Here, we attempt to accumulate our institutional knowledge and experience to provide a summary of the key aspects to prevent complications following tracheal resections. Unfortunately, complications can occur despite strict adherence to the core principles of tracheal surgery, and therefore, we also highlight our institutional experience with the early recognition and management of the most common and dreaded complications.


Maturation of interdependence between extra-alveolar arteries and lung parenchyma in piglets.
Mechanical interdependence between intrapulmonary structures and parenchyma has not been studied previously in immature postnatal lungs. To study these interactions, lung elastic moduli were measured by pressure-volume and punch indentation studies in lobes excised from 3-day-old (n = 6), 1-month-old (n = 6), and 3-month-old (n = 7) piglets. After extra-alveolar arteries were filled with a radiopaque fluid silicone compound, transpulmonary pressure and arterial pressure were varied independently as the lobar vein was occluded. Arterial diameters and lengths were measured from radiographs. Behavior of 3-month-old lungs was consistent with previous studies of adult lungs, but results were unique in 3-day-old lungs. That is, during stepwise deflation of the immature lungs 1) intravascular pressures fell when arteries were occluded experimentally, 2) arteries increased their diameters when kept at a constant intravascular pressure, and 3) arterial lengths decreased by less than 3%. Behavior of 1-month-old lungs was intermediate. A previous continuum mechanics analysis of pressure-diameter behavior was modified to account for compression by alveolar pressure as vascular diameters increase. It was concluded that 1) radial and axial dimensions of extra-alveolar arteries are virtually independent of parenchymal expansion in newborn piglet lungs and 2) periarterial interstitial pressures increase as these lungs are inflated. Our interpretation of these findings is that a mechanical association of the arteries to the parenchyma occurs gradually with postnatal maturation.


Non-specific (entropic) forces as major determinants of the structure of mammalian chromosomes.
Four specific forces (H-bonds, van der Waals forces, hydrophobic and charge interactions) shape the structure of proteins, and many biologists assume they will determine the shape of all structures in the cell. However, as the mass and contour length of a human chromosome are ~7 orders of magnitude larger than those of a typical protein, additional forces can become significant. We review evidence that additional non-specific (entropic) forces are major determinants of chromosomal shape and position. They are sufficient to drive the segregation (de-mixing) of newly replicated DNA to the poles of bacterial cells, while an entropic centrifuge can both form human chromosomes into territories and position them appropriately in nuclei; more locally, a depletion attraction can loop bacterial and human genomes.


Which antifungal agent for onychomycosis? A pharmacoeconomic analysis.
The incidence of fungal nail infections is increasing and this is possibly because of several factors: better methods of detection, a growing population of immunocompromised patients who have a greater susceptibility to such infections, the increased use of immunosuppressive drugs, the increasing number of elderly people, worldwide travel, and the use of communal bathing facilities. Onychomycosis is a fungal infection of the fingernails and toenails that accounts for about 30% of all superficial fungal infections. It is characterised by nail discoloration, thickening and ultimately destruction of the nail plate. Management of this disease has improved significantly and treatment patterns have dramatically changed in recent years as a result of advances in new treatment options (e.g. oral antifungal agents) and changes in treatment regimens (e.g. pulse therapy). Also, newer drugs for onychomycosis have improved tolerability profiles compared with older agents. The overall costs of treating onychomycosis are substantial, and it has been estimated that direct cost for US Medicare patients with the disease is 43 million US dollars per year (year of costing not available). Pharmacoeconomic studies help in the decision-making process when selecting the most cost-effective antifungal agents to treat onychomycosis. To date there have been a number of national and international economic studies aimed at effectively assessing the efficacy and costs of the treatment options available to cure onychomycosis. The objectives of this paper are to (i) review the published findings regarding the epidemiology of onychomycosis; (ii) summarise the original pharmacoeconomic studies that describe the economic impact of the disease; and (iii) address the impact of the disease on patients' health-related quality of life.


Determination of the loudness dependence of auditory evoked potentials: single-electrode estimation versus dipole source analysis.
The loudness dependence of auditory evoked potentials (LDAEP) has been described as a measure of central serotonergic activity. Single-electrode estimation and dipole source analysis (DSA) are the most utilized methods for the estimation of LDAEP. To date, it is assumed that both methods are equally reliable. Nevertheless, according to our knowledge, the advantage of either method has not yet been shown directly. The aim of our study was to compare single-electrode estimation and dipole source analysis in the determination of the LDAEP. Tones of five different intensities were presented binaurally to 10 healthy volunteers. Amplitudes of N1/P2 and LDAEP were determined at the central electrode site referenced to average and to linked mastoids and with DSA in the left and the right hemispheres. Scores were normalized (z-scores), compared, and correlated. Contrary to our expectations, we found a significant difference between scores obtained with single-electrode estimation and with DSA. The difference may be caused by confounding activation of a frontal source in the single-electrode method. The single-electrode approach cannot be equated with DSA in the determination of the LDAEP. This should be considered when comparing the results of different LDAEP studies using only one of these methods.


The prognostic and predictive value of the lymphocyte to monocyte ratio in luminal-type breast cancer patients treated with CEF chemotherapy.
Several reports have suggested that peripheral blood-based parameters are associated with host immunity response, which is an essential component of the pathogenesis and progression of cancer. The purpose of the present study was to identify the prognostic significance of various peripheral blood-based biomarkers and to determine the optimal cut-off value suitable for luminal breast cancer patients. We found that lymphocyte-to-monocyte ratio (LMR) was significant prognostic predictors. And the patients with a CEF regimen and LMR ratio ≥ 5.2 gained a good prognosis. This study suggested that the LMR could be regarded as an independent prognostic factor in luminal breast cancer patients. The elevated LMR level also had enhanced 5-fluorouracil sensitivity in luminal breast cancer patients.


Phase I trial of daily oral Polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia.
To define the optimal dose of Polyphenon E for chronic daily administration and tolerability in patients with chronic lymphocytic leukemia (CLL). Previously untreated patients with asymptomatic Rai stage 0 to II CLL were eligible for participation. Polyphenon E with a standardized dose of epigallocatechin-3-gallate (EGCG) was administered using the standard phase I design with three to six patients per dose level (range, 400 to 2,000 mg by mouth twice a day). Trough plasma EGCG levels were measured 1 month after initiation of therapy. Response was classified using the National Cancer Institute (NCI) Working Group (WG) Criteria. Thirty-three eligible patients were accrued to dose levels 1 to 8. The maximum-tolerated dose was not reached. The most common adverse effects included transaminitis (33%, all grade 1), abdominal pain (30% grade 1, 0% grade 2, and 3% grade 3), and nausea (39% grade 1 and 9% grade 2). One patient experienced an NCI WG partial remission. Other signs of clinical activity were also observed, with 11 patients (33%) having a sustained > or = 20% reduction in absolute lymphocyte count (ALC) and 11 (92%) of 12 patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas during treatment. Trough plasma EGCG levels after 1 month of treatment ranged from 2.9 to 3,974 ng/mL (median, 40.4 ng/mL). Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase I trial. Declines in ALC and/or lymphadenopathy were observed in the majority of patients. A phase II trial to evaluate efficacy using 2,000 mg twice a day began in November 2007.


Rationally designed short polyisoprenol-linked PglB substrates for engineered polypeptide and protein N-glycosylation.
The lipid carrier specificity of the protein N-glycosylation enzyme C. jejuni PglB was tested using a logical, synthetic array of natural and unnatural C10, C20, C30, and C40 polyisoprenol sugar pyrophosphates, including those bearing repeating cis-prenyl units. Unusual, short, synthetically accessible C20 prenols (nerylnerol 1d and geranylnerol 1e) were shown to be effective lipid carriers for PglB sugar substrates. Kinetic analyses for PglB revealed clear K(M)-only modulation with lipid chain length, thereby implicating successful in vitro application at appropriate concentrations. This was confirmed by optimized, efficient in vitro synthesis allowing >90% of Asn-linked β-N-GlcNAc-ylated peptide and proteins. This reveals a simple, flexible biocatalytic method for glycoconjugate synthesis using PglB N-glycosylation machinery and varied chemically synthesized glycosylation donor precursors.


Colchicine inhibits heterotopic ossification: experimental study in rabbits.
Heterotopic ossification is a common complication of hip surgery and musculoskeletal or brain trauma. To confirm by in vivo study that colchicine inhibits osteoblast cell proliferation with marked decrease in tissue mineralization. Heterotopic ossification was induced in three groups of New Zealand white rabbits (females, 6 months old, weight 3-3.5 kg) by injecting 2 ml bone marrow drawn from the iliac crest into their right thigh muscle. To prevent heterotopic ossification, colchicine (0.25 mg/ day) was administered orally for 4 weeks to two groups of adult rabbits: group A (preload group)--1 week preceding bone marrow injection; group B--on day of injection; and group C--control group. After 4 weeks the rabbits were evaluated by radiographs and ultrasound for evidence of heterotopic ossification. At the end of the study histologic samples were taken from all the thighs. Imaging and histologic studies showed, with statistical significance, almost complete prevention of heterotopic ossification formation in group A (preload) and a marked decrease in group B, when compared with the controls where large new bone had formed at the injection site. These results indicated the inhibitory effects of colchicine on a bone-forming process in soft tissue such as heterotopic ossification. The role of colchicine in preventing heterotopic ossification in other bone-forming conditions, such as hip arthroplasty or pelvic trauma, and after brain trauma, remains to be evaluated in a clinical setting.


Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels.
Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors.


Anthocyanin-rich extracts inhibit multiple biomarkers of colon cancer in rats.
The aim of the present study was to investigate the chemoprotective activity of anthocyanin-rich extracts (AREs) from bilberry (Vaccinium myrtillus L.), chokeberry (Aronia meloncarpa E.), and grape (Vitis vinifera) by assessing multiple biomarkers of colon cancer in male rats treated with a colon carcinogen, azoxymethane. Fischer 344 male rats were fed the AIN-93 diet (control) or AIN-93 diet supplemented with AREs for 14 wk. Biomarkers that were evaluated included the number and multiplicity of colonic aberrant crypt foci (ACF), colonic cell proliferation, urinary levels of oxidative DNA damage, and expression of cyclooxygenase (COX) genes. To assess the bioavailability, levels of anthocyanins in serum, urine, and feces were evaluated. Total ACF were reduced (P<0.05) in bilberry, chokeberry, and grape diet groups compared with the control group. The number of large ACF was also reduced (P<0.05) in bilberry and chokeberry ARE-fed rats. Colonic cellular proliferation was decreased in rats fed bilberry ARE and chokeberry ARE diets. Rats fed bilberry and grape ARE diets had lower COX-2 mRNA expression of gene. High levels of fecal anthocyanins and increased fecal mass and fecal moisture occurred in ARE-fed rats. There was also a significant reduction (P<0.05) in fecal bile acids in ARE-fed rats. The levels of urinary 8-hydroxyguanosine were similar among rats fed different diets. These results support our previous in vitro studies suggesting a protective role of AREs in colon carcinogenesis and indicate multiple mechanisms of action.


Neural correlates and predictive power of trait resilience in an acutely traumatized sample: a pilot investigation.
Resilience refers to the ability to thrive despite adversity and is defined as a multidimensional phenomenon, spanning internal locus of control, sense of meaning, social problem-solving skills, and self-esteem. We aimed to investigate the predictive value of resilience for the development of posttraumatic stress disorder (PTSD) and to examine the neural correlates mediating the relationship between resilience and recovery from a traumatic event in acutely traumatized subjects. We hypothesized that resilience would mediate the relationship between childhood trauma and posttraumatic recovery. We conducted a prospective study with 70 acutely traumatized subjects with DSM-IV PTSD recruited at the emergency department, assessing PTSD symptom severity at 3 time points within the first 3 months posttrauma. Scores for childhood trauma as assessed with the Childhood Trauma Questionnaire and trait resilience as assessed with the Connor-Davidson Resilience Scale were used as predictors of symptom severity. A subsample of 12 subjects additionally underwent a functional 4 Tesla magnetic resonance imaging scan 2 to 4 months posttrauma. We employed the traumatic script-driven imagery paradigm to assess the correlations between trait resilience and blood oxygen level-dependent (BOLD) response. The study was conducted from 2003 to 2007. Resilience predicted PTSD symptom severity at 5 to 6 weeks (β = -0.326, P = .01) as well as at 3 months (β = -0.423, P = .003) posttrauma better than childhood trauma. Resilience essentially mediated the relationship between childhood trauma and posttraumatic adjustment. Resilience scores were positively correlated with BOLD signal strength in the right thalamus as well as the inferior and middle frontal gyri (Brodmann area 47). This pilot investigation revealed a significant relationship between resilience and emotion regulation areas during trauma recall in an acutely traumatized sample. Resilience was established as a significant predictor of PTSD symptom severity and mediated the influence of childhood trauma on posttraumatic adjustment.


Ultrafast cation intercalation in nanoporous nickel hexacyanoferrate.
Cation intercalation into nanoporous coordination polymers is utilized in, e.g., Li(+)/Na(+) secondary batteries, the decontamination of radioactive (137)Cs(+), and so on. Here, we observed an ultrafast intercalation of Na(+) and Rb(+) within 1500 ms in a thin film of nickel hexacyanoferrate, Na0.68Ni[Fe(CN)6]0.675.0H2O, in aqueous solutions. Quantitative analyses of the intercalation kinetics revealed that the high cation diffusion constant (D ∼ 10(-9) cm(2) s(-1)) is responsible for the intercalation.