High prevalence of Helicobacter pylori infection with dual resistance to metronidazole and clarithromycin in Hong Kong.
Metronidazole resistance is a common problem in most Asian countries, and clarithromycin has been widely used in Hong Kong. To determine the prevalence of Helicobacter pylori strains resistant to metronidazole and clarithromycin in Hong Kong and to assess the effect on eradication rates. Also to determine the genetic mutation in relation to phenotypic divergence in clarithromycin-resistant strains. H. pylori were cultured from gastric biopsies obtained from 87 patients during upper endoscopy. Minimal inhibitory concentrations of metronidazole and clarithromycin were determined by Etest and agar dilution methods. Mutations in clarithromycin-resistant strains were identified by polymerase chain reaction and restriction analysis. Random amplified polymorphic DNA fingerprinting was performed on clarithromycin-resistant and susceptible isolates. The prevalences of H. pylori strains resistant to metronidazole and clarithromycin were 49.4% and 10.8%, respectively, in Hong Kong. Dual resistance to metronidazole and clarithromycin were found in 7. 2% of patients. The agreement between E-test and agar dilution methods was determined by error-rate bound analysis as 95.4% for metronidazole and 100% for clarithromycin. Dual resistant strains reduced the eradication rate to 66.7%. Among clarithromycin-resistant strains tested, all were due to A2144G point mutation in 23S rRNA gene. Random amplified polymorphic DNA fingerprinting suggested various phenotypically mixed populations. The prevalence of metronidazole-resistant H. pylori strains remained static whilst the prevalence of clarithromycin-resistant strains was not rare in Hong Kong. An alarming 7.2% of patients were resistant to both the antimicrobials, which had a definite impact on treatment success. All cases of resistance to clarithromycin were due to A2144G mutation in 23S rRNA of H. pylori.


The relationship of toxin and antitoxin injection site to tetanus development in the rat.
The pattern of development of symptoms was studied following injection of 3 MLD (minimum lethal dose) of tetanus toxin in each of the following sites in the rat: vein, muscle, endoneurium, epineurium, spinal cord, subarachnoid space, and subdural space. Similar observations were made when 3 MPD (minimum protective dose) of antitoxin were injected into each of the above sites a few minutes after the intramuscular injection of toxin. Local tetanus followed intramuscular, endoneurial, and epineurial injection of the toxin; blood-borne tetanus also appeared in the latter instance. Tetanus dolorosus followed intraspinal injection of toxin. Both dorsal tetanus and blood-borne tetanus developed after subdural administration of toxin. Blood-borne tetanus, alone, appeared following intravenous and subarachnoid injection of toxin. In no case did injection of antitoxin at the various sites listed above prevent local tetanus from developing after intramuscular injection of toxin. Of the various sites injected with antitoxin, the intramuscular, intraspinal, and intravenous were the most effective. It is suggested that the endoneurial tissue spaces serve as a conduit for tetanus toxin from the muscle to the CNS. The perilemma of the peripheral nerve trunk may act as a selectively permeable membrane which permits tetanus toxin to pass from the epineurium to the endoneurium. Outward diffusion of toxin from the endoneurial spaces is apparently markedly reduced. The antitoxin probably is prevented from permeating this barrier in either direction. The importance of absorption of tetanus toxin by the lymphatic and blood circulation is discussed.


[Type A behaviour and life events as risk factors for cerebral infarct].
The role of psychosocial factors in cerebral infarct has been little studied and is therefore still undefined. OBJECTIVE and methods. To evaluate the effect of a pattern of behaviour which predisposes to stress, and of life events, on the occurrence of cerebral infarct, we studied a group and control involving 88 patients with cerebral infarcts diagnosed clinically and on imaging studies, and a control group of 99 persons paired for age and sex who lived in our health district. To evaluate the behaviour pattern we used Jenkins abbreviated questionnaire and for life events the Holmes and Rahe questionnaire. The type A behaviour pattern had a highly statistically significant association with cerebral infarct, which was not associated with the effects of other variables. This relation was the greater the lower the age of the person. It was not seen after the age of 75 years. The behaviour pattern was not related to arterial hypertension or with the aetiopathological mechanisms of the patients. In relation to the life events questionnaire, the number of events was significantly associated in the group of patients, but not with the total score of the questionnaire. However, the latter was significantly related to hypertensive patients and persons with a type A behaviour pattern. The commonest life events in both groups were related to the death or health problems of family members, the previous illnesses of the person and to financial and work problems. The type A behaviour pattern is individually associated with cerebral infarct, whilst stressful life events were involved in the cerebral infarcts of hypertensive and type A behaviour patients.


A Population Pharmacokinetic Modelling Approach to Unravel the Complex Pharmacokinetics of Vincristine in Children.
Vincristine, a chemotherapeutic agent that extensively binds to β-tubulin, is commonly dosed at 1.4-2.0 mg/m2 capped at 2 mg. For infants, doses vary from 0.025-0.05 mg/kg or 50-80% of the mg/m2 dose. However, evidence for lower doses in infants compared to older children is lacking. This study was conducted to unravel the complex pharmacokinetics of vincristine, including the effects of age, to assist optimal dosing in this population. 206 patients (0.04-33.9 years; 25 patients < 1 years), receiving vincristine, with 1297 plasma concentrations were included. Semi-mechanistic population pharmacokinetic analyses were performed using non-linear mixed effects modelling. A three-compartment model, with one saturable compartment resembling saturable binding to β-tubulin and thus, saturable distribution, best described vincristine pharmacokinetics. Body weight and age were covariates significantly influencing the maximal binding capacity to β-tubulin, which increased with increasing body weight and decreased with increasing age. Vincristine clearance (CL) was estimated as 30.6 L/h (95% confidence interval (CI) 27.6-33.0), intercompartmental CL (Q) as 63.2 L/h (95%CI 57.2-70.1), volume of distribution of the central compartment as 5.39 L (95%CI 4.23-6.46) and of the peripheral compartment as 400 L (95%CI 357-463) (all parameters correspond to a patient of 70 kg). The maximal binding capacity was 0.525 mg (95%CI 0.479-0.602) (for an 18 year old patient of 70 kg), with a high association rate constant, fixed at 1300 /h and a dissociation constant of 11.5 /h. A decrease of vincristine β-tubulin binding capacity with increasing age suggests that young children tolerate higher doses of vincristine.


[Current diagnosis and therapy of non-occlusive mesenteric ischemia].
Non-occlusive mesenteric ischemia (NOMI) is a life threatening disease. Therapy and prognosis depend upon the length of time elapsed between primary clinical manifestation and the time of definitive diagnosis and treatment. NOMI was diagnosed by intraarterial selective angiography in four patients. After a bolus administration of 20 g Alprostadil (Prostavasin) into the superior mesenteric artery, intraarterial perfusion was continued with 60 microg Alprostadil/day via the catheter for three days. The mesenteric ischemia resolved in all patients. One patient recovered completely. Three patients recovered from mesenteric ischemia, but died subsequently due to complications of their primary diseases. When NOMI without perforation or necrosis of the bowel wall is suspected clinically, immediate intraarterial angiography is the diagnostic method of choice. If NOMI is confirmed, the appropriate treatment is the intraarterial application of potent vasodilators for several days. The diagnostic work-up in suspected NOMI and the impact of different radiological examinations are explained. The literature is reviewed.


Edentulism and shortened dental arch in Brazilian elderly from the National Survey of Oral Health 2003.
To describe the distribution of edentulism and estimate the prevalence of functional dentition and shortened dental arch among elderly population. A population-based epidemiological study was carried out with a sample of 5,349 respondents aged 65 to 74 years obtained from the 2002 and 2003 Brazilian Ministry of Health/Division of Oral Health survey database. The following variables were studied: gender; macroregion of residence; missing teeth; percentage that met the World Health Organization goal for oral health in the age group 65 to 74 years (50% having at least 20 natural teeth); presence of shortened dental arch; number of posterior occluding pairs of teeth. The Chi-square test assessed the association between categorical variables. The Kruskal-Wallis and Mann-Whitney tests were used to assess differences of mean between number of posterior occluding pairs teeth, macro-region and gender. The elderly population had an average of 5.49 teeth (SD: 7.93) with a median of 0. The proportion of completely edentulous respondents was 54.7%. Complete edentulism was 18.2% in the upper arch and 1.9% in the lower arch. The World Health Organization goal was achieved in 10% of all respondents studied. However, only 2.7% had acceptable masticatory function and aesthetics (having at least shortened dental arch) and a mean number of posterior occluding pairs of 6.94 (SD=2.97). There were significant differences of the percentage of respondents that met the World Health Organization goal and presence of shortened dental arch between men and women. There were differences in shortened dental arch between macroregions. The Brazilian epidemiological oral health survey showed high rate of edentulism and low rate of shortened dental arch in the elderly population studied, thus suggesting significant functional and aesthetic impairment in all Brazilian macroregions especially among women.


Monthlong Intubated Patient with Life-Threatening COVID-19 and Cerebral Microbleeds Suffers Only Mild Cognitive Sequelae at 8-Month Follow-up: A Case Report.
To elaborate on possible cognitive sequelae related to COVID-19, associated cerebrovascular injuries as well as the general consequences from intensive care. COVID-19 is known to have several, serious CNS-related consequences, but neuropsychological studies of severe COVID-19 are still rare. M., a 45-year-old man, who survived a severe COVID-19 disease course including Acute Respiratory Distress Syndrome (ARDS), cerebral microbleeds, and 35 days of mechanical ventilation, is described. We elaborate on M's recovery and rehabilitation process from onset to the 8-month follow-up. The cognitive functions were evaluated with a comprehensive screening battery at 4 weeks after extubation and at the 8-month follow-up. Following extubation, M. was delirious, reported visual hallucinations, and had severe sleeping difficulties. At about 3 months after COVID-19 onset, M. showed mild to moderate deficits on tests measuring processing speed, working memory, and attention. At assessments at 8 months, M. performed better, with results above average on tests measuring learning, memory, word fluency, and visuospatial functions. Minor deficits were still found regarding logical reasoning, attention, executive functioning, and processing speed. There were no lingering psychiatric symptoms. While M. had returned to a part-time job, he was not able to resume previous work-tasks. This case-study demonstrates possible cognitive deficits after severe COVID-19 and emphasizes the need of a neuropsychological follow-up, with tests sensitive to minor deficits. The main findings of this report provide some support that the long-term prognosis for cognition in severe COVID-19 may be hopeful.


Patients with subclinical hypothyroidism before 20 weeks of pregnancy have a higher risk of miscarriage: A systematic review and meta-analysis.
To evaluate the relationship between subclinical hypothyroidism (SCH) and the risk of miscarriage before 20 weeks of pregnancy. Literature databases were searched, including the PubMed, Web of Science, Embase and Cochrane databases, from January 1, 1980, to December 31, 2015. The following search terms were used: subclinical hypothyroidism, hypothyroidism, thyroid dysfunction, thyroid hypofunction, subclinical thyroid disease, thyroid dysfunction, pregnancy loss, abortion and miscarriage. Studies comparing the prevalence of miscarriage in pregnant women with SCH with those who were euthyroid were selected. From the studies matched, the relative risk (RR) and corresponding 95% confidence interval (95% CI) were calculated to yield outcomes. All the statistical analyses were performed using Review Manager (Revman) Version 5.3 and Stata Version 12.0 software. The publication bias of the studies was assessed by forest plot and Begg's test, while the stability of the results was evaluated by sensitivity analysis. Nine articles satisfying the inclusion criteria were analysed. Compared to euthyroid pregnant women, patients with non-treated SCH had a higher prevalence of miscarriage (RR = 1.90, 95% CI1.59-2.27, P<0.01). Additionally, SCH patients in the international diagnostic criteria group were more likely to suffer miscarriages than those in the ATA diagnostic criteria group (χ2 = 11.493, P<0.01). Moreover, there was no difference between patients with treated SCH and euthyroid women (RR = 1.14, 95% CI0.82-1.58, P = 0.43). Compared to isolated SCH women, the miscarriage risk of SCH patients with thyroid autoimmunity (TAI) was obviously higher (RR = 2.47, 95% CI1.77-3.45, P<0.01), and isolated SCH patients also had a higher prevalence of miscarriages than euthyroid women (RR = 1.45, 95% CI1.07-1.96, P = 0.02).A heterogeneity test, forest plot and Begg's test suggested that there was no significant heterogeneity or publication bias among the included articles, while the result of sensitivity analysis showed that our study exhibited high stability. SCH is a risk factor for miscarriage in women before 20 weeks of pregnancy, and early treatments can reduce the miscarriage rate. Regardless of the diagnostic criteria used, the miscarriage rate increased as long as a pregnant woman was confirmed to have SCH. The results show that the omission diagnostic rate may increase when the ATA diagnostic criteria are used. In addition, SCH patients with TAI have a higher prevalence of miscarriage, while isolated SCH patients also have a higher miscarriage rate than euthyroid women. Thus, we recommend early treatments to avoid adverse pregnancy outcomes and complications.


Recent updates on the bioactive compounds of the marine-derived genus Aspergillus.
The genus Aspergillus is widely distributed in terrestrial and marine environments. In the marine environment, several Aspergillus species have proved their potential to produce a plethora of secondary metabolites including polyketides, sterols, fatty acids, peptides, alkaloids, terpenoids and miscellaneous compounds, displaying a variety of pharmacological activities such as antimicrobial, cytotoxicity, anti-inflammatory and antioxidant activity. From the beginning of 2015 until December 2020, about 361 secondary metabolites were identified from different marine Aspergillus species. In our review, we highlight secondary metabolites from various marine-derived Aspergillus species reported between January 2015 and December 2020 along with their biological potential and structural aspects whenever applicable.


Introductory lecture: basic quantities in model biomembranes.
One of the many aspects of membrane biophysics dealt with in this Faraday Discussion regards the material moduli that describe energies at a supramolecular level. This introductory lecture first critically reviews differences in reported numerical values of the bending modulus K(C), which is a central property for the biologically important flexibility of membranes. It is speculated that there may be a reason that the shape analysis method tends to give larger values of K(C) than the micromechanical manipulation method or the more recent X-ray method that agree very well with each other. Another theme of membrane biophysics is the use of simulations to provide exquisite detail of structures and processes. This lecture critically reviews the application of atomic level simulations to the quantitative structure of simple single component lipid bilayers and diagnostics are introduced to evaluate simulations. Another theme of this Faraday Discussion was lateral heterogeneity in biomembranes with many different lipids. Coarse grained simulations and analytical theories promise to synergistically enhance experimental studies when their interaction parameters are tuned to agree with experimental data, such as the slopes of experimental tie lines in ternary phase diagrams. Finally, attention is called to contributions that add relevant biological molecules to bilayers and to contributions that study the exciting shape changes and different non-bilayer structures with different lipids.


Differences in patient ratings of medical home domains among adults with diabetes: comparisons across primary care sites.
There is growing and sustained recognition that Patient-Centered Medical Homes (PCMHs) represent a viable approach to dealing with the fragmentation of care faced by many individuals, including those living with diabetes. The National Committee for Quality Assurance (NCQA) has spearheaded a program that recognizes medical practices that adopt key elements of the PCMH. Even though practices can achieve the same level of recognition, it is unclear whether all PCMHs deliver care in the same manner and how these differences can be associated with patient ratings of their experience with care. This study uses a mixed-methods approach to explore differences in care delivery across 4 NCQA level 3 recognized PCMHs located in a southern state. Furthermore, the study examines the association between each clinic and patient ratings of key PCMH domains. The qualitative component of the study included in-depth interviews with medical directors at each site in order to determine how the PCMH at each clinic was operationalized. In addition, 1300 adult patients with diabetes were surveyed about their experiences with their PCMH. Bivariate and ordinal logistical analyses were conducted to determine how PCMH experiences varied across the 4 clinics. The in-depth interviews revealed that one clinic (clinic 1) had a stronger primary care orientation relative to the other locations. Furthermore, patients at these clinics were more likely to provide higher ratings of care across all PCMH domains. This study demonstrates that not all PCMH clinics are alike and that these differences can possibly affect patient perceptions of their care.


[Experimental investigation of efficacy and safety of different methods of endoscopic hemostasis].
Treatment of ulcerative gastroduodenal bleedings remains one of the most pressing problems in urgent surgery. Available methods of endoscopic hemostasis are not fully eligible to safety requirements, effectiveness and reliability. In this connection persist high levels of general and postoperative mortality in our country and around the world. The aim of this study is to identify the advantages and disadvantages of endoscopic radiofrequency effects in comparison with standard techniques of hemostasis, used in the treatment of ulcer bleeding in the world practice.


Preventing emergence of drug resistant tuberculosis in Myanmar's transitioning health system.
Multidrug-resistant tuberculosis (MDR-TB) is a particular threat to the populations of resource-limited countries. Although inadequate treatment of TB has been identified as a major underlying cause of drug resistance, essential information to inform changes in health service delivery and policy is missing. We investigate factors that may be driving the emergence of MDR-TB in Myanmar, a country where investment and health system reforms are ongoing to address the unexplained, high occurrence of MDR-TB. We conducted a multi-centre, retrospective case-control study in 10 townships across Yangon. Cases were 202 GeneXpert-confirmed MDR-TB patients with a history of prior first-line treatment for TB. Controls were 404 previously untreated smear-microscopy confirmed TB patients who had no evidence of resistance to anti-TB drugs. Information on patient and health service factors was collected through face-to-face patient interviews and hospital record reviews. Multivariable logistic regression analysis indicated that the following TB patient groups are at higher risk of developing MDR-TB after initial TB treatment: those who have diabetes (aOR 2.10; 95% CI 1.17-3.76), those who missed taking drugs during the initial treatment more than once weekly (aOR 2.35; 95% CI 1.18-4.65) and those with a higher socioeconomic (aOR 1.99; 95% CI 1.09-3.63) or educational status (aOR 1.78; 95% CI1.01-3.13). Coinciding with a surge in funding to improve health in Myanmar, this study identifies practices of patients and healthcare organizations that can be addressed, and high-risk TB patient groups that can be prioritized for treatment support. Specifically, the study shows that TB patients who experience frequent, short interruptions in treatment and those with diabetes may require enhanced treatment support and monitoring by health services in order to prevent further generation of drug resistance.


Serum immunoglobulin (IgG, IgM, IgA) and IgG subclass concentrations in healthy children: a study using nephelometric technique.
Immunoglobulin (Ig) G, IgM, IgA and IgG subclass (IgG1, IgG2, IgG3, IgG4) concentrations were determined in more than 500 healthy Turkish children using nephelometric technique. These parameters were thought to be highly varied for different ethnic groups because of environmental and genetic factors. Methodology used in previous studies has been reported to affect age-related normal values. Serum IgG, IgM, IgA and IgG1, IgG2, IgG3, IgG4 levels were measured in 510, 491, 486, 542, 511, 515, and 545 healthy children, respectively. According to their age, the patients were divided into 14 groups. In contrast to most of the previous studies, age-related normal values for IgG4 levels were also obtained. In conclusion, it has been suggested that our study as an example for Caucasians using nephelometric technique will supply useful information about age-related normal serum immunoglobulin and IgG subclass concentrations.


[Ultrastructure of small-cell lung cancer].
The research was concerned with electron microscopic analysis of 34 lung tumors histologically identified as small cell lung cancer. It was shown that ultrastructural studies can reliably identify histologic pattern of small cell lung cancer. In most cases, this type of cancer was represented by one of the following histologic patterns: epidermoid, glandular or neuroendocrine, the latter being predominant. An ultrastructural classification of small cell lung cancer is not advisable until a clinico-morphological analysis has been carried out.


Tissue Distribution, Growth Dilution, and Species-Specific Bioaccumulation of Organic Ultraviolet Absorbents in Wildlife Freshwater Fish in the Pearl River Catchment, China.
Tissue distributions and body-size dependent and species-specific bioaccumulation of 12 organic ultraviolet absorbents (UVAs) were investigated in 9 species of wildlife freshwater fish from the Pearl River catchment, South China. The concentrations of the 12 UVAs were from 109 to 2320 ng/g lipid weight in the fish tissue samples. The UVAs 2-hydroxy-4-methoxybenzophenone (BP-3), octocrylene (OCR), UV531, and 5 benzotriazole UV stabilizers (UVP, UV329, UV234, UV328, and UV327) were detected in more than half of the fish tissue samples. The UVA UV531 showed an obvious potential for bioaccumulation in the wild freshwater fish, with an estimated bioaccumulation factor (log BAF) and a biota-sediment accumulation factor (BSAF) of 4.54 ± 0.55 and 4.88 ± 6.78, respectively. Generally, liver (989 ± 464 ng/g lipid wt) contained the highest level of UVAs, followed in decreasing order by belly fat (599 ± 318 ng/g lipid wt), swimming bladder (494 ± 282 ng/g lipid wt), dorsal muscle (470 ± 240 ng/g lipid wt), and egg (442 ± 238 ng/g lipid wt). The bioaccumulation of UVAs in the freshwater wild fish was species specific and compound dependent. Bottom-dwelling detritus-ingesting omnivorous fish contained obviously higher UVA concentrations, suggesting that detritus/sediment ingestion is a significant pathway for exposure of the wild freshwater fish to the UVAs. The UVAs UV531 and BP-3 demonstrated a potential for growth dilution. Metabolism might play a significant role in elimination of the UVAs in the fish tissues, with the highest rate of metabolism in the liver. The UVAs did not demonstrate obvious trophic magnification in the freshwater ecosystem of the Pearl River catchment. More research is warranted to elucidate maternal transfer of the UVAs. Environ Toxicol Chem 2020;39:343-351. © 2019 SETAC.


Metabolite-Enzyme Coevolution: From Single Enzymes to Metabolic Pathways and Networks.
How individual enzymes evolved is relatively well understood. However, individual enzymes rarely confer a physiological advantage on their own. Judging by its current state, the emergence of metabolism seemingly demanded the simultaneous emergence of many enzymes. Indeed, how multicomponent interlocked systems, like metabolic pathways, evolved is largely an open question. This complexity can be unlocked if we assume that survival of the fittest applies not only to genes and enzymes but also to the metabolites they produce. This review develops our current knowledge of enzyme evolution into a wider hypothesis of pathway and network evolution. We describe the current models for pathway evolution and offer an integrative metabolite-enzyme coevolution hypothesis. Our hypothesis addresses the origins of new metabolites and of new enzymes and the order of their recruitment. We aim to not only survey established knowledge but also present open questions and potential ways of addressing them.


Enhancement of human immunodeficiency virus type 1 infection by cationic liposomes: the role of CD4, serum and liposome-cell interactions.
We have reported previously the enhancement of the infectivity of human immunodeficiency virus type 1 (HIV-1) by liposomes composed of the cationic lipid N-[2,3-(dioleyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA). To determine the mechanism by which this process occurs, we have investigated the role of CD4, serum concentration and liposome-cell interactions in the DOTMA-mediated stimulation of HIV-1 infection of A3.01 cells. Serum alone significantly inhibited the binding and infectivity of HIV-1, but DOTMA-mediated enhancement of infectivity was more pronounced in the presence of serum than in its absence. HIV-1 binding to cells was increased in the presence of DOTMA liposomes, DEAE-dextran and polybrene, all of which also enhanced infectivity to a similar extent at comparable concentrations. Fluorescence dequenching measurements indicated that DOTMA liposomes fused with HIV-1, but not with cell membranes, in the presence of serum. The enhancing effect of DOTMA liposomes on HIV-1 infectivity was CD4-dependent, and appeared to involve virus-liposome fusion and liposome binding to the cell surface. DOTMA liposomes did not mediate infection of the CD4-K562 and Raji cell lines.


Insights into persistence mechanisms of a zoonotic virus in bat colonies using a multispecies metapopulation model.
Rabies is a worldwide zoonosis resulting from Lyssavirus infection. In Europe, Eptesicus serotinus is the most frequently reported bat species infected with Lyssavirus, and thus considered to be the reservoir of European bat Lyssavirus type 1 (EBLV-1). To date, the role of other bat species in EBLV-1 epidemiology and persistence remains unknown. Here, we built an EBLV-1-transmission model based on local observations of a three-cave and four-bat species (Myotis capaccinii, Myotis myotis, Miniopterus schreibersii, Rhinolophus ferrumequinum) system in the Balearic Islands, for which a 1995-2011 serological dataset indicated the continuous presence of EBLV-1. Eptesicus serotinus was never observed in the system during the 16-year follow-up and therefore was not included in the model. We used the model to explore virus persistence mechanisms and to assess the importance of each bat species in the transmission dynamics. We found that EBLV-1 could not be sustained if transmission between M. schreibersii and other bat species was eliminated, suggesting that this species serves as a regional reservoir. Global sensitivity analysis using Sobol's method revealed that following the rate of autumn-winter infectious contacts, M. schreibersii's incubation- and immune-period durations, but not the infectious period length, were the most relevant factors driving virus persistence.


Mule bite to the male genitalia with complete penile and anterior urethra amputation: unusual case and review of the literature.
Animal bite is rare with few cases reported in the literature. The morbidity of animal bites is directly related to the severity of the initial wound. Most victims are boys, and dog bites are the most common injury. Infectious complications are unusual, since treatment is sought early (Wein 2007). Thus, urologists are not usually familiar with management and principles for treating this condition. The authors report the case of a 38-year-old male with a severe mule bite injury to the genitalia causing complete penile and anterior urethra amputation and scrotal wound with no involvement of its contents. To our knowledge, no such case had ever been reported in the medical literature. This kind of emergencies is challenging for urologists.


Sensitivity of vergence responses of 5- to 10-week-old human infants.
Infants have been shown to make vergence eye movements by 1 month of age to stimulation with prisms or targets moving in depth. However, little is currently understood about the threshold sensitivity of the maturing visual system to such stimulation. In this study, 5- to 10-week-old human infants and adults viewed a target moving in depth as a triangle wave of three amplitudes (1.0, 0.5, and 0.25 meter angles). Their horizontal eye position and the refractive state of both eyes were measured simultaneously. The vergence responses of the infants and adults varied at the same frequency as the stimulus at the three tested modulation amplitudes. For a typical infant of this age, the smallest amplitude is equivalent to an interocular change of approximately 2° of retinal disparity, from nearest to farthest points. The infants' accommodation responses only modulated reliably to the largest stimulus, while adults responded to all three amplitudes. Although the accommodative system appears relatively insensitive, the sensitivity of the vergence responses suggests that subtle cues are available to drive vergence in the second month after birth.


Enhancement of X-ray detection by single-walled carbon nanotube enriched flexible polymer composite.
Although organic-based direct conversion X-ray detectors have been developed, their photocurrent generation efficiency has been limited by recombination of excitons due to the intrinsically poor electrical properties of organic materials. In this report, we fabricated a polymer-based flexible X-ray detector and enhanced the X-ray detection sensitivity using a single-walled carbon nanotube (SWNT) enriched polymer composite. When this SWNT enriched polymer composite was used as the active layer of an X-ray detector, it efficiently separated charges at the interface between the SWNTs and polymer, preventing recombination of X-ray-induced excitons. This increased the photocurrent generation efficiency, as measured from current-voltage characteristics. Therefore, X-ray-induced photocurrent and X-ray detection sensitivity were enhanced as the concentration of SWNTs in the composite was increased. However, this benefit was counterbalanced by the slow and unstable time-dependent response at high SWNT concentrations, arising from reduced Schottky barrier heights between the active layer and electrodes. At high SWNT concentration, the dark current also increased due to the reduced Schottky barrier height, leading to decrease the signal-to-noise ratio (SNR) of the device. Experimental results indicated that 0.005 wt.% SWNT in the composite was the optimum composition for practical X-ray detector operation because it showed enhanced performance in both sensitivity and SNR. In mechanical flexibility tests, the device exhibited a stable response up to a bending radius of 0.5 cm, and the device had no noticeable change in diode current after 1,000 bending cycles. 8.67.Sc.


Hydroxy-selenomethionine: A novel organic selenium source that improves antioxidant status and selenium concentrations in milk and plasma of mid-lactation dairy cows.
This study aimed to evaluate the effect of hydroxy-selenomethionine (HMSeBA), a novel organic selenium (Se) source, on milk performance, antioxidative status, and Se concentrations in the milk and plasma of mid-lactation dairy cows compared with that of sodium selenite (SS). Fifty mid-lactation dairy cows with similar days in milk, milk yield, and parity received the same basal diet containing 0.06 mg of Se/kg of DM. They were assigned to 1 of 5 treatments according to a randomized complete block design: negative control (without Se supplementation), SS supplementation (0.3 mg of Se/kg of DM; SS-0.3) or HMSeBA supplementation (0.1, 0.3, or 0.5 mg of Se/kg of DM: SO-0.1, SO-0.3, and SO-0.5, respectively). The experiment lasted for 10 wk, including a pretrial period of 2 wk. The results indicated that neither Se supplementation nor Se source affected dry matter intake, milk yield, milk composition, or blood biochemical parameters, except for milk fat percentage. Simultaneously, milk fat percentage and milk fat yield increased linearly as the quantity of HMSeBA supplementation was increased. Production of 4% FCM and ECM was elevated linearly as dietary HMSeBA increased. The SO-0.3 group showed higher serum activity of glutathione peroxidase, total antioxidant capacity, and superoxide dismutase than the SS-0.3 group, but malondialdehyde content was not affected by Se source. Furthermore, HMSeBA supplementation linearly increased the activities of serum glutathione peroxidase and superoxide dismutase, but decreased malondialdehyde content. Compared with the SS-0.3 group, the SO-0.3 group showed augmented concentrations of total Se in milk and plasma, and total Se milk-to-plasma concentration ratio. In addition, increasing doses of HMSeBA linearly increased the concentrations of total Se in the milk and plasma. This study demonstrates that HMSeBA improves antioxidant status and increases milk and plasma Se concentrations more effectively than SS, indicating that HMSeBA could replace SS as an effective organic Se source for lactating dairy cows.


Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3.
Celecoxib is a COX-2 inhibitor that reduces the risk of colon cancer. However, the basis for its cancer chemopreventive activity is not fully understood. In this study, we defined a mechanism of celecoxib action based on degradation of cellular FLICE-inhibitory protein (c-FLIP), a major regulator of the death receptor pathway of apoptosis. c-FLIP protein levels are regulated by ubiquitination and proteasome-mediated degradation. We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition of glycogen synthase kinase-3 (GSK3), itself a candidate therapeutic target of interest in colon cancer. Celecoxib increased the levels of phosphorylated GSK3, including the α and β forms, even in cell lines, where phosphorylated Akt levels were not increased. Phosphoinositide 3-kinase inhibitors abrogated Akt phosphorylation as expected but had no effect on celecoxib-induced GSK3 phosphorylation. In contrast, protein kinase C (PKC) inhibitors abolished celecoxib-induced GSK3 phosphorylation, implying that celecoxib influenced GSK3 phosphorylation through a mechanism that relied upon PKC and not Akt. GSK3 blockade either by siRNA or kinase inhibitors was sufficient to attenuate c-FLIP levels. Combining celecoxib with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis. Proteasome inhibitor MG132 reversed the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover as expected. Our findings reveal a novel mechanism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK3, which celecoxib acts at an upstream level to control independently of Akt.


Produce-associated foodborne disease outbreaks, USA, 1998-2013.
The US Food Safety Modernization Act (FSMA) gives food safety regulators increased authority to require implementation of safety measures to reduce the contamination of produce. To evaluate the future impact of FSMA on food safety, a better understanding is needed regarding outbreaks attributed to the consumption of raw produce. Data reported to the US Centers for Disease Control and Prevention's Foodborne Disease Outbreak Surveillance System during 1998-2013 were analysed. During 1998-2013, there were 972 raw produce outbreaks reported resulting in 34 674 outbreak-associated illnesses, 2315 hospitalisations, and 72 deaths. Overall, the total number of foodborne outbreaks reported decreased by 38% during the study period and the number of raw produce outbreaks decreased 19% during the same period; however, the percentage of outbreaks attributed to raw produce among outbreaks with a food reported increased from 8% during 1998-2001 to 16% during 2010-2013. Raw produce outbreaks were most commonly attributed to vegetable row crops (38% of outbreaks), fruits (35%) and seeded vegetables (11%). The most common aetiologic agents identified were norovirus (54% of outbreaks), Salmonella enterica (21%) and Shiga toxin-producing Escherichia coli (10%). Food-handling errors were reported in 39% of outbreaks. The proportion of all foodborne outbreaks attributable to raw produce has been increasing. Evaluation of safety measures to address the contamination on farms, during processing and food preparation, should take into account the trends occurring before FSMA implementation.


[Prevention, control and vaccine development of African swine fever: challenges and countermeasures].
African swine fever (ASF) is a hemorrhagic and devastating infectious disease of pigs caused by African swine fever virus (ASFV), with mortality up to 100%. The first ASF outbreak occurred in China in August 2018, followed by 69 cases of ASF in 18 provinces in more than three months, causing a heavy burden to the pig industry. Based on the global epidemic situation of ASF and the experience of prevention and control in other countries, the ASF control and eradication situation in China is extremely complex and serious. The availability of effective and safe ASF vaccines is an urgent requirement to reinforce control and eradication strategies. Therefore, this article starts with the latest findings of ASFV, summarizes the progress in prevention and control strategies and vaccine approaches for ASFV. We also discuss the challenges of preventing and controlling ASF, focusing on current vaccine strategies, the gaps, future research directions, and key scientific issues in commercial applications. We hope to provide basic information for the development of vaccines and prevention control strategies against this disease in China.


Limitations of CNNs for Approximating the Ideal Observer Despite Quantity of Training Data or Depth of Network.
The performance of a convolutional neural network (CNN) on an image texture detection task as a function of linear image processing and the number of training images is investigated. Performance is quantified by the area under (AUC) the receiver operating characteristic (ROC) curve. The Ideal Observer (IO) maximizes AUC but depends on high-dimensional image likelihoods. In many cases, the CNN performance can approximate the IO performance. This work demonstrates counterexamples where a full-rank linear transform degrades the CNN performance below the IO in the limit of large quantities of training data and network layers. A subsequent linear transform changes the images' correlation structure, improves the AUC, and again demonstrates the CNN dependence on linear processing. Compression strictly decreases or maintains the IO detection performance while compression can increase the CNN performance especially for small quantities of training data. Results indicate an optimal compression ratio for the CNN based on task difficulty, compression method, and number of training images.


Post-partum antibody-dependent cell-mediated immunity in the rat following perinatal exposure to iodine-131.
A study was recently completed which indicated the first generation of adult rats that had been exposed perinatally to iodine-131 possessed peripheral blood lymphoid-cells capable of expressing cytotoxicity towards cultured small bowel adenocarcinoma target cells, i.e., active antitumor cell-mediated immunity (CMI). The results gathered during the current investigation suggest that such animals similarly express anti-tumor antibody-dependent cell-mediated immunity (ADCC). The animal model employed consisted of Fisher F344 inbred rats exposed to iodine-131 (sodium) during their 16th to 18th day of gestation, and at an interval of two months post-partum when the offsprings had matured into adults, they and their mothers were evaluated for the presence of serum components capable of expressing ADCC activities toward X-ray induced small bowel adenocarcinoma target cells. Significant ADCC activities were found to be expressed by the offspring while no analogous immunological responses could be detected in the serum of the mothers. This lack of maternal ADCC activity suggests the existence of a biological block developing during pregnancy resulting in the mother being immunological nonresponsive to carcinogenic insults. One serum component present in the offspring identified as being responsible for initiating ADCC was an immunoglobulin of the IgG class as based upon its physical characteristics: solubility, molecular weight, and reactivity with anti-immunoglobulins, pepsin, and protein A. The interpretation of these findings is that perinatal exposure to radioiodine results in the development of cells having foreign-like properties in the offspring which are recognized by the animal's immune system, thus resulting in detectable antitumor CMI and ADCC immune responses.


Simultaneous Nasal Septal Schneiderian Papilloma and Respiratory Epithelial Adenomatoid Hamartoma.
Schneiderian papilloma is typically found on the lateral nasal wall, but, in rare cases, can be located at the mucosa of the nasal septum. Respiratory epithelial adenomatoid hamartoma (REAH) is rare, non-neoplastic lesion characterized by an abnormal proliferation of glandular part of the respiratory nasal mucosa. We present a case of a 42-year-old man with five-year history of bilateral nasal obstruction, rhinorrhea, epistaxis, and hyposmia. On endoscopic examination, we found lobulated, yellowish-pink soft tissue masses on both sides of the nasal septum. The results of histopathological analyses showed the characteristics of Schneiderian papilloma in the lesion excised from the right and REAH in the lesion excised from the left side of the nasal cavity. To our knowledge, cases of simultaneous presentation of Schneiderian papilloma and REAH on opposite sides of the nasal septum have not been published so far. An appropriate cooperation of rhinologist and pathologist allows for a correct diagnosis of these rare and unusual lesions.


Periareolar Approach in Oncoplastic Breast Conservative Surgery.
Breast cancer represents the most frequent cancer in female population. Nowadays breast conservative surgery (BCS) is an accepted option for breast malignancies, and its indications has been extended thanks to the advent of oncoplastic surgery, reducing both mastectomy and re-excision rate, avoiding at the same time breast deformities. From January 2008 to November 2011, 84 women underwent BCS with periareolar approach for oncoplastic volume replacement. We divided patients into four groups analyzing breast size and resection volume (Group 1: small-moderate sized breast with resection <20%; Group 2: small-moderate sized breast with resection >20%; Group 3: big sized breast with resection <20%; Group 4: big sized breast with resection >20%). We evaluated patients' satisfaction regarding final esthetic outcome using the specific module "Satisfaction with outcome" of the Breast-Q questionnaire 1 year after surgery. The mean age was 52.1 years, and the mean follow-up was 11.2 months. During the follow-up, 12 patients have been lost. We obtained high satisfaction mean value with Breast-Q questionnaire in each group: 75.8 in group 1, 63.4 in group 2, 81.1 in group 3, 69.7 in group 4. Periareolar approach as oncoplastic volume replacement technique is useful in correction of breast deformity after BCS: it is a versatile technique that can be easily adapted for any breast tumor location and for wide glandular resection.


TGF-beta1 and VEGF after fresh frozen bone allograft insertion in oral-maxillo-facial surgery.
Bone regeneration technique using allografts is widely used in oral surgery to repair alveolar defects and to increase alveolar volume for endosseous implant insertions. Bone allografts promote the reabsorption and neo-synthesis of bone tissue, which are regulated by numerous cytokines, proteins and growth factors. In this study, six patients with insufficient alveolar volume for endosseous implant insertions, were treated with bone regeneration technique using Fresh Frozen Bone (FFB) allografts collected from the femoral head or the hip. Samples of bone graft collected during graft insertion surgery and biopsies collected six months later during implantology were fixed, decalcified and analyzed histomorphologically and morphometrically by haematoxylin-eosin staining. In addition, TGF-beta1 and VEGF were analyzed by immunohistochemistry. The histological analysis of FFBs showed wide areas of calcified bone organized in osteons intermingled with areas of non-calcified matrix containing osteoblasts. However, the regenerated alveolar bone, collected six months after the graft insertion surgery, showed wide areas of non-calcified matrix. TGF-beta1 and VEGF were less expressed in FFB than in regenerated alveolar bone.


Excellent superiority and specificity of COBAS TaqMan HCV assay in an early viral kinetic change during pegylated interferon alpha-2b plus ribavirin treatment.
An early virological response (EVR) after the start of interferon (IFN) treatment for chronic hepatitis C leads to a successful virological outcome. To analyze an association between sustained virological response (SVR) and EVR by comparing TaqMan with Amplicor assays in HCV genotype 1-infected patients treated with pegylated (PEG)-IFN alpha-2b plus ribavirin (RBV). We retrospectively analyzed a total of 80 HCV genotype 1 patients (39 SVR and 41 non-SVR patients), who received an enough dosage and a complete 48-week treatment of PEG-IFN alpha-2b plus RBV. Serum HCV RNA levels were measured by both TaqMan and Amplicor assays for each patients at Weeks 2, 4, 8 and 12 after the start of the antiviral treatment. Of the 80 patients with undetectable HCV RNA by Amplicor, 17 (21.3%) patients were positive for HCV RNA by TaqMan at Weeks 12. The quantification results showed that no significant difference in the decline of HCV RNA level between TaqMan and Amplicor 10-fold method assays within the initial 12 weeks of the treatment was found. However, the qualitative analysis showed significant differences of the positive predictive rates for SVR were found between TaqMan (100% at weeks 4 and 100% at weeks 8) and Amplicor (80.0% and 69.6%, respectively). The COBAS TaqMan HCV assay is very useful for monitoring HCV viremia during antiviral treatment to predict a SVR in HCV genotype 1 patients.


Mechanistic studies of intracellular delivery of proteins by cell-penetrating peptides in cyanobacteria.
The plasma membrane plays an essential role in selective permeability, compartmentalization, osmotic balance, and cellular uptake. The characteristics and functions of cyanobacterial membranes have been extensively investigated in recent years. Cell-penetrating peptides (CPPs) are special nanocarriers that can overcome the plasma membrane barrier and enter cells directly, either alone or with associated cargoes. However, the cellular entry mechanisms of CPPs in cyanobacteria have not been studied. In the present study, we determine CPP-mediated transduction efficiency and internalization mechanisms in cyanobacteria using a combination of biological and biophysical methods. We demonstrate that both Synechocystis sp. PCC 6803 and Synechococcus elongatus PCC 7942 strains of cyanobacteria possess red autofluorescence. Green fluorescent protein (GFP), either alone or noncovalently associated with a CPP comprised of nine arginine residues (R9/GFP complexes), entered cyanobacteria. The ATP-depleting inhibitor of classical endocytosis, N-ethylmaleimide (NEM), could block the spontaneous internalization of GFP, but not the transduction of R9/GFP complexes. Three specific inhibitors of macropinocytosis, cytochalasin D (CytD), 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), and wortmannin, reduced the efficiency of R9/GFP complex transduction, indicating that entry of R9/GFP complexes involves macropinocytosis. Both the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and membrane leakage analyses confirmed that R9/GFP complexes were not toxic to the cyanobacteria, nor were the endocytic and macropinocytic inhibitors used in these studies. In summary, we have demonstrated that cyanobacteria use classical endocytosis and macropinocytosis to internalize exogenous GFP and CPP/GFP proteins, respectively. Moreover, the CPP-mediated delivery system is not toxic to cyanobacteria, and can be used to investigate biological processes at the cellular level in this species. These results suggest that both endocytic and macropinocytic pathways can be used for efficient internalization of regular protein and CPP-mediated protein delivery in cyanobacteria, respectively.


Identification of a packaged cellular mRNA in virions of rous sarcoma virus.
A novel messenger activity has been identified by in vitro translation of the 70S virion RNAs of a variety of avian leukosis and avian sarcoma viruses. When the 70S virion RNA complex was heat dissociated and the polyadenylated RNA was fractionated on neutral sucrose gradients, a polypeptide of 34,000 daltons (34K) was observed in the translation products of 18S polyadenylic acid-containing virion RNA. Aside from the p60(src)-related subgenomic messenger activities, this was the only prominent messenger activity that sedimented at <20S. It was determined that the 34K protein was not virally coded because (i) messenger activity for the 34K protein was not generated by mild alkaline hydrolysis of 35S genomic RNA, (ii) the 34K proteins synthesized in response to different virion RNAs had identical tryptic peptide maps, and (iii) the tryptic peptide map of the 34K protein coded for by virion RNA was identical to that of a major in vitro translation product of 34,000 daltons made from 18S uninfected chick cell polyadenylated RNA. The 18S RNA was shown to be contained within virion particles, rather than part of a cellular structure copurifying with virus preparations, by demonstrating the presence of 34K messenger activity in virion cores made from detergent-disrupted virus. This cellular mRNA, however, was not observed in the virion RNAs of Rous-associated virus types 0 and 2 avian leukosis viruses and therefore is not packaged by all avian retroviruses. Since no other cellular message has been detected by this assay, it seems likely that the 34K mRNA found in 70S virion RNA is the result of selective packaging of an abundant host cell mRNA by certain avian retroviruses.


Nitrogen reduction and functionalization by a multimetallic uranium nitride complex.
Molecular nitrogen (N2) is cheap and widely available, but its unreactive nature is a challenge when attempting to functionalize it under mild conditions with other widely available substrates (such as carbon monoxide, CO) to produce value-added compounds. Biological N2 fixation can do this, but the industrial Haber-Bosch process for ammonia production operates under harsh conditions (450 degrees Celsius and 300 bar), even though both processes are thought to involve multimetallic catalytic sites. And although molecular complexes capable of binding and even reducing N2 under mild conditions are known, with co-operativity between metal centres considered crucial for the N2 reduction step, the multimetallic species involved are usually not well defined, and further transformation of N2-binding complexes to achieve N-H or N-C bond formation is rare. Haber noted, before an iron-based catalyst was adopted for the industrial Haber-Bosch process, that uranium and uranium nitride materials are very effective heterogeneous catalysts for ammonia production from N2. However, few examples of uranium complexes binding N2 are known, and soluble uranium complexes capable of transforming N2 into ammonia or organonitrogen compounds have not yet been identified. Here we report the four-electron reduction of N2 under ambient conditions by a fully characterized complex with two Uiii ions and three K+ centres held together by a nitride group and a flexible metalloligand framework. The addition of H2 and/or protons, or CO to the resulting complex results in the complete cleavage of N2 with concomitant N2 functionalization through N-H or N-C bond-forming reactions. These observations establish that a molecular uranium complex can promote the stoichiometric transformation of N2 into NH3 or cyanate, and that a flexible, electron-rich, multimetallic, nitride-bridged core unit is a promising starting point for the design of molecular complexes capable of cleaving and functionalizing N2 under mild conditions.


Correlation of in vitro bromodeoxyuridine labeling index and DNA aneuploidy with survival or recurrence in brain-tumor patients.
There are no previous reports correlating the in vitro bromodeoxyuridine (BUdR) labeling index (LI) with the clinical outcome in patients with brain tumors. The reliability of the LI as a predictor of patient survival or recurrence was examined in this study of 66 human brain tumors (19 gliomas, 18 meningiomas, and 29 others). Anti-BUdR staining was performed on surgically extirpated tumor tissue that had been treated with BUdR as previously described. Correlation of the BUdR LI with patient survival or tumor recurrence rate was carried out by the method of Kaplan and Meier. Deoxyribonucleic acid (DNA) aneuploidy was estimated in 52 cases. The results of this study indicate that BUdR LI values correlated well with the clinical course of patients with brain tumor. In comparison with patients with higher LI's, there was both a significantly higher survival rate for tumors other than meningiomas and a higher recurrence-free rate for meningiomas in patients with LI's of less than 4% and 1%, respectively. Although there was a tendency for patients without tumor aneuploidy to show better survival data than the others, no statistical difference was observed. These results suggest that the in vitro BUdR labeling method is reliable for prediction of a patient's prognosis, whereas prognosis on the basis of DNA aneuploidy alone is uncertain.


Influences of Sociosexuality and Commitment on Online Sexual Activities: The Mediating Effect of Perceptions of Infidelity.
The perceived infidelity of online sexual activity (OSA) has been noted as an important factor contributing to individual differences in OSA among people in romantic relationships. We proposed that two major factors related to infidelity-sociosexuality (willingness to engage in uncommitted sexual relationships) and commitment-might be associated with engaging in OSA via the perceived infidelity of OSA among individuals in romantic relationships. OSAs were classified as viewing sexually explicit material, seeking sexual partners, cybersex, and flirting. Participants were 313 heterosexuals in romantic relationships who completed measures of OSA experience, sociosexuality, commitment, and perceptions of infidelity. The results showed that more unrestricted sociosexuality and less commitment were associated with more frequent engagement in OSAs. Moreover, perceptions of infidelity mediated these associations of sociosexuality and commitment with OSA. These findings suggest that perceived infidelity is important for understanding the mechanism underlying people's engagement in OSA.


Expression of leukocyte adherence-related glycoproteins during differentiation of HL-60 promyelocytic leukemia cells.
We used the HL-60 human promyelocytic leukemia cell line to analyze the surface expression of a family of adherence-related leukocyte surface antigens during myeloid differentiation. These antigens are composed of discrete alpha subunits, designated alpha L, alpha M, and alpha X, that are each noncovalently associated with a common beta subunit. Monoclonal antibodies directed against the individual subunits served as markers in both indirect immunofluorescence studies and immunoprecipitations from HL-60 cells differentiated preferentially towards mature granulocytes (DMSO, retinoic acid) or monocyte/macrophages (PMA, vitamin D3). In undifferentiated HL-60 cells, the alpha L and alpha X subunits were constitutively expressed, whereas the alpha M subunit was not. Differentiation of HL-60 cells along the granulocytic pathway with DMSO resulted in a marked increase in alpha M and minimal increases in alpha L and alpha X. The phenotypic expression of these antigens on DMSO-treated HL-60 cells closely resembled that on normal circulating PMN. Differentiation along the monocyte/macrophage pathway when using PMA or vitamin D3 resulted in major increases in alpha L and alpha X expression, as well as alpha M. These changes resulted in a surface phenotype characteristic of that present on human monocyte-derived macrophages. Triggering of undifferentiated HL-60 cells with PMA caused no increase in subunit expression, whereas stimulation of DMSO-differentiated HL-60 cells with PMA produced more than a 1.5-fold enhancement of both the alpha M and alpha X subunits, and stimulation of human PMN with PMA increased the surface expression of alpha M more than fourfold and alpha X subunit twofold. Stimulation with PMA produced no change in expression of the alpha L subunit in any of the three cell populations. These results indicate that the alpha subunits of this glycoprotein family can be selectively regulated during in vitro differentiation of a human promyelocytic leukemia cell line. Second, DMSO-differentiated HL-60 cells and human PMN possessed an intracellular pool of alpha M and alpha X, but not alpha L, that could be translocated to the surface. Thus, despite structural and functional relationships among the alpha subunits in this glycoprotein family, they undergo disparate surface expression and intracellular regulation during differentiation.


Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy.
Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O2•-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054-67. ©2017 AACR.


Identification of Reactive Hypoglycemia with Different Basic BMI and Its Causes by Prolonged Oral Glucose Tolerance Test.
To identify the population susceptible to reactive hypoglycemia and explain the possible reasons for their susceptibility. Ninety-four patients were divided into normal weight, overweight and obese groups before a 75-gram prolonged oral glucose tolerance test (POGTT). The incidence of reactive hypoglycemia (blood glucose ≤3.1 mmol/L or 55 mg/dL at points of 0-4 hours) was compared among three groups, and blood glucose and insulin levels were monitored simultaneously from 0 - 4 hours to assess the level of insulin resistance and insulin sensitivity. Furthermore, the degree of insulin resistance among three groups and within each subgroup (whether hypoglycemia events occurred) was compared. Among the three groups, the incidence of hypoglycemia was significantly different at 3 (P=0.033) and 4 hours (P=0.020). At 4 hours, the incidence of reactive hypoglycemia in the obese group was approximately 3 times that in the normal weight group. The insulin level in obese group at 4 hours was nearly 4 times higher than that in normal group, and the same result also exists in the same subgroup of different groups. In addition, the hypoglycemia subgroup of obese group had higher insulin level than non-hypoglycemia (P=0.000). The homeostasis model assessment of insulin resistance index increased with increasing BMI among the three groups (P=0.000), while the Matsuda index decreased (P=0.000). The comparison of the homeostasis model assessment of insulin resistance index between subgroups in each group showed that the P values were 0.021, 0.038 and 0.085, successively, and the P values for the Matsuda index were 0.019, 0.013 and 0.119, respectively. Obese people has higher rate of reactive hypoglycemia than other groups in POGTT, in which insulin resistance may play an important role. But patients who are evaluated for reactive hypoglycemia need to be observed for at least 3 or 4 hours.


Clinical predictors of bloodstream infections and mortality in hospitalized Malawian children.
In sub-Saharan Africa, bloodstream infections (BSI) are a major cause of pediatric mortality. Because of limited resources and facilities in these developing countries, treatment often must be based solely on clinical observations and patient history and includes the use of broad spectrum antimicrobials, a factor in the emergence of antibiotic resistance. During July 28 through August 18, 1998 we analyzed clinical, epidemiologic and microbiologic data from a cohort of 225 hospitalized children in Malawi, Africa, to determine clinical indices associated with the presence/absence of BSI and/or mortality for use in settings with minimal microbiologic laboratory and intensive care facilities. BSI (n = 35 children) were associated with malnutrition, chronic cough, lethargy by history, lethargy on examination and oral thrush; 92% of children without these symptoms were BSI-negative. Mortality (21 of 173 children with known mortality status) was associated with malnutrition, lethargy on examination, prior receipt of antimalarials and acute decreased feeding. Of those with > or =2 of these indices 69% died; of those with <2 of the indices 94% survived. Infection with human immunodeficiency virus was not significantly related to either BSI or mortality status. Malnutrition, but not HIV, was strongly related to both BSI and mortality. Assessment of these BSI and mortality indices at hospital admission provides rapid, cost-free indication of which children are most/least in need of empiric antimicrobial therapy or intensive observation, thereby maximizing appropriate use of antimicrobials and limited facilities while minimizing inappropriate antimicrobial usage.


The Efficacy of Istradefylline for Treating Mild Wearing-Off in Parkinson Disease.
The adenosine A2A antagonist istradefylline has been used to treat Parkinson disease (PD) with symptoms of wearing-off since 2013 in Japan. Previous randomized controlled trials of istradefylline compared with placebo included PD patients experiencing an average daily OFF time of more than 2 hours. The purpose of this study is to assess the efficacy of 20 mg/d istradefylline in PD subjects experiencing an average daily OFF time of 3 hours or less. Fifteen patients were enrolled into this retrospective study. They received 20 mg/d istradefylline for 12 weeks. Changes in the Unified Parkinson's Disease Rating Scale part III scores in the ON state (ON-UPDRS-III) scores and daily OFF time were assessed at baseline and after 4, 8, and 12 weeks of administration of istradefylline. At baseline, all subjects had shorter daily OFF times, lower doses of L-DOPA and higher ON-UPDRS-III scores than those in previous randomized controlled trials. Twelve weeks of istradefylline significantly reduced ON-UPDRS-III scores (P < 0.001, Wilcoxon signed rank test). Eleven patients (73%) showed more than 50% reductions in ON-UPDRS-III scores. Improvement of ON-UPDRS-III was significantly correlated with baseline ON-UPDRS-III, and the mean ON-UPDRS-III score at end point was 12.1. Our result suggests that 20 mg/d istradefylline significantly improved motor functions in PD patients with mild wearing-off.


Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival.
The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information regarding cancer occurrence and trends in the U.S. This year's report features a special section on cancer survival. Information concerning cancer cases was obtained from the NCI, CDC, and NAACCR and information concerning recorded cancer deaths was obtained from the CDC. The authors evaluated trends in age-adjusted cancer incidence and death rates by regression models and described and compared survival rates over time and across racial/ethnic populations. Incidence rates for all cancers combined decreased from 1991 through 2001, but stabilized from 1995 through 2001 when adjusted for delay in reporting. The incidence rates for female lung cancer decreased (although not statistically significant for delay adjusted) and mortality leveled off for the first time after increasing for many decades. Colorectal cancer incidence rates also decreased. Death rates decreased for all cancers combined (1.1% per year since 1993) and for many of the top 15 cancers occurring in men and women. The 5-year relative survival rates improved for all cancers combined and for most, but not all, cancers over 2 diagnostic periods (1975-1979 and 1995-2000). However, cancer-specific survival rates were lower and the risk of dying from cancer, once diagnosed, was higher in most minority populations compared with the white population. The relative risk of death from all cancers combined in each racial and ethnic population compared with non-Hispanic white men and women ranged from 1.16 in Hispanic white men to 1.69 in American Indian/Alaska Native men, with the exception of Asian/Pacific Islander women, whose risk of 1.01 was similar to that of non-Hispanic white women. The continued measurable declines for overall cancer death rates and for many of the top 15 cancers, along with improved survival rates, reflect progress in the prevention, early detection, and treatment of cancer. However, racial and ethnic disparities in survival and the risk of death from cancer, and geographic variation in stage distributions suggest that not all segments of the U.S. population have benefited equally from such advances.


Absence of latent Epstein-Barr virus in thymic epithelial tumors as demonstrated by Epstein-Barr-encoded RNA(EBER) in situ hybridization.
Several studies have established that Epstein-Barr virus (EBV) is associated with lympho-proliferative disorders such as Burkitt's lymphoma and Hodgkin's disease. EBV is also present in undifferentiated nasopharyngeal carcinomas and in tumors of similar morphology (lymphoepithelioma-like carcinomas) arising in a variety of organs, predominantly in stomach, salivary gland and thymus. As reports of EBV-positive thymic epithelial tumors (TET) have been divergent and as different methods have been used to detect EBV, the aim of this study was to investigate the possible role of EBV in TET of Danish patients. Archival material of 157 cases of TET (105 thymomas and 52 thymic carcinomas, including 4 lymphoepithelioma-like thymic carcinomas (LELTC)) was analyzed for EBV by applying a sensitive and specific method for detecting latently EBV-infected cells (in situ hybridization for EBV-encoded RNA (EBER)). All investigated cases were EBER negative. EBV does not seem to be implicated in the pathogenesis of TET. However, a review of the literature showed that 28% of LELTC were EBER ISH positive. As they occurred in young people (mean 18 years), at an age when the patients were susceptible to infection by EBV, it is suggested that EBV merely acts as an innocent bystander.


MR spectroscopy and diffusion imaging in people with human immunodeficiency virus: Relationships to clinical and immunologic findings.
People with human immunodeficiency virus (HIV; PWH) present a complex array of immunologic and medical disorders that impact brain structure and metabolism, complicating the interpretation of neuroimaging. This pilot study of well-characterized multi-morbid PWH examined how medical and immunologic factors predicted brain characteristics on proton MR spectroscopy (1H-MRS) and diffusion-weighted imaging (DWI). Eighteen individuals on combination antiretroviral therapy (cART), with mean age of 56 years, underwent medical history review, neuroimaging, and on the day of imaging, blood draw for assay of 20 plasma cytokines and flow cytometric characterization of peripheral blood mononuclear cell subsets. Predictors of n-acetyl aspartate, choline, myoinositol, glutamate/glutamine, fractional anisotropy and mean diffusivity were identified through bivariate correlation; those significant at p < .1000 were advanced to multivariate analysis, with models created for each neuroimaging outcome. Monocyte subsets and diverse cytokines accounted for 16 of 25 (64%) variables predicting 1H-MRS spectra in frontal gray and white matter and basal ganglia; monocyte subsets did not predict any DWI characteristic. In contrast, age, presence of hypertension, and duration of HIV infection accounted for 13 of 25 (52%) variables predicting diffusion characteristics in the corpus callosum, thalamic radiations, and basal ganglia but only 3 of 25 (12%) predictors of 1H-MRS features. 1H-MRS neurometabolites were most often predicted by immunologic factors sensitive to temporal variation, whereas DWI metrics were more often related to longer-term disease state. In multi-morbid cART-era populations, selection and interpretation of neuroimaging modalities should account for complex temporal and pathogenetic influences of immunologic abnormality, disease state, and aging.


The influence of early-phase remodeling events on the biomechanical properties of engineered vascular tissues.
During the last decade, the use of ex vivo-derived materials designed as implant scaffolds has increased significantly. This is particularly so in the area of regenerative medicine, or tissue engineering, where the natural chemical and biomechanical properties have been shown to be advantageous. By focusing on detailed events that occur during early-phase remodeling processes, our objective was to detail progressive changes in graft biomechanics to further our understanding of these processes. A perfusion bioreactor system and acellular human umbilical veins were used as a model three-dimensional vascular scaffold on which human myofibroblasts were seeded and cultured under static or defined pulsatile conditions. Cell function in relation to graft mechanical properties was assessed. Cells doubled in density from approximately 1 × 10(6) to 2 ± 0.4 × 10(6) cells/cm ringlet, whereas static cultures remained unchanged. The material's compressive stiffness and ultimate tensile strength remained unchanged in both static and dynamic systems. However the Young's modulus values increased significantly in the physiologic range, whereas in the failure range, a significant reduction (66%) was shown under dynamic conditions. As pulse and flow conditions are modulated, complex mechanical changes are occurring that modify the elastic modulus differentially in both physiologic and failure ranges. Mechanical properties play an important role in graft patency, and a dynamic relationship between structure and function occurs during graft remodeling. These investigations have shown that as cells migrate into this ex vivo scaffold model, significant variation in material elasticity occurs that may have important implications in our understanding of early-stage vascular remodeling events.


Gas breakthrough and emission through unsaturated compacted clay in landfill final cover.
Determination of gas transport parameters in compacted clay plays a vital role for evaluating the effectiveness of soil barriers. The gas breakthrough pressure has been widely studied for saturated swelling clay buffer commonly used in high-level radioactive waste disposal facility where the generated gas pressure is very high (in the order of MPa). However, compacted clay in landfill cover is usually unsaturated and the generated landfill gas pressure is normally low (typically less than 10 kPa). Furthermore, effects of clay thickness and degree of saturation on gas breakthrough and emission rate in the context of unsaturated landfill cover has not been quantitatively investigated in previous studies. The feasibility of using unsaturated compacted clay as gas barrier in landfill covers is thus worthwhile to be explored over a wide range of landfill gas pressures under various degrees of saturation and clay thicknesses. In this study, to evaluate the effectiveness of unsaturated compacted clay to minimize gas emission, one-dimensional soil column tests were carried out on unsaturated compacted clay to determine gas breakthrough pressures at ultimate limit state (high pressure range) and gas emission rates at serviceability limit state (low pressure range). Various degrees of saturation and thicknesses of unsaturated clay sample were considered. Moreover, numerical simulations were carried out using a coupled gas-water flow finite element program (CODE-BRIGHT) to better understand the experimental results by extending the clay thickness and varying the degree of saturation to a broader range that is typical at different climate conditions. The results of experimental study and numerical simulation reveal that as the degree of saturation and thickness of clay increase, the gas breakthrough pressure increases but the gas emission rate decreases significantly. Under a gas pressure of 10 kPa (the upper bound limit of typical landfill gas pressure), a 0.6m or thicker compacted clay is able to prevent gas breakthrough at degree of saturation of 60% or above (in humid regions). Furthermore, to meet the limit of gas emission rate set by the Australian guideline, a 0.6m-thick clay layer may be sufficient even at low degree of saturation (i.e., 10% like in arid regions).


Sulindac inhibits activation of the NF-kappaB pathway.
Sulindac is a non-steroidal anti-inflammatory agent that is related both structurally and pharmacologically to indomethacin. In addition to its anti-inflammatory properties, sulindac has been demonstrated to have a role in the prevention of colon cancer. Both its growth inhibitory and anti-inflammatory properties are due at least in part to its ability to decrease prostaglandin synthesis by inhibiting the activity of cyclooxygenases. Recently, we demonstrated that both aspirin and sodium salicylate, but not indomethacin, inhibited the activity of an IkappaB kinase beta (IKKbeta) that is required to activate the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we show that sulindac and its metabolites sulindac sulfide and sulindac sulfone can also inhibit the NF-kappaB pathway in both colon cancer and other cell lines. Similar to our previous results with aspirin, this inhibition is due to sulindac-mediated decreases in IKKbeta kinase activity. Concentrations of sulindac that inhibit IKKbeta activity also reduce the proliferation of colon cancer cells. These results suggest that the growth inhibitory and anti-inflammatory properties of sulindac may be regulated in part by inhibition of kinases that regulate the NF-kappaB pathway.


Immobilization of ZnO-TiO2 Nanocomposite into Polyimidazolium Amphiphilic Chitosan Film, Targeting Improving Its Antimicrobial and Antibiofilm Applications.
This study presents a green protocol for the fabrication of a multifunctional smart nanobiocomposite (NBC) (ZnO-PIACSB-TiO2) for secure antimicrobial and antibiofilm applications. First, shrimp shells were upgraded to a polyimidazolium amphiphilic chitosan Schiff base (PIACSB) through a series of physicochemical processes. After that, the PIACSB was used as an encapsulating and coating agent to manufacture a hybrid NBC in situ by co-encapsulating ZnONPs and TiO2NPs. The physicochemical and visual characteristics of the new NBC were investigated by spectral, microscopic, electrical, and thermal methods. The antimicrobial indices revealed that the newly synthesized, PIACSB-coated TiO2-ZnO nanocomposite is an exciting antibiotic due to its amazing antimicrobial activity (MIC/MBC→0.34/0.68 μg/mL, 0.20/0.40 μg/mL, and 0.15/0.30 μg/mL working against S. aureus, E. coli, and P. aeruginosa, respectively) and antifungal capabilities. Additionally, ZnO-PIACSB-TiO2 is a potential fighter of bacterial biofilms, with the results being superior to those of the positive control (Cipro), which worked against S. aureus (only 8.7% ± 1.9 biofilm growth), E. coli (only 1.4% ± 1.1 biofilm growth), and P. aeruginosa (only 0.85% ± 1.3 biofilm growth). Meanwhile, the NBC exhibits excellent biocompatibility, as evidenced by its IC50 values against both L929 and HSF (135 and 143 µg/mL), which are significantly higher than those of the MIC doses (0.24-24.85 µg/mL) that work against all tested microbes, as well as the uncoated nanocomposite (IC50 = 19.36 ± 2.04 and 23.48 ± 1.56 µg/mL). These findings imply that the new PIACSB-coated nanocomposite film may offer promising multifunctional food packaging additives to address the customer demand for safe, eco-friendly food products with outstanding antimicrobial and antibiofilm capabilities.


Rh nanoparticles supported on ultrathin carbon nanosheets for high-performance oxygen reduction reaction and catalytic hydrogenation.
We reported a facile and scalable salt-templated approach to produce monodisperse Rh nanoparticles (NPs) on ultrathin carbon nanosheets with the assistance of calcination under inert gas. More importantly, in spite of the essentially poor ORR activity of Rh/C, the acquired Rh/C hybrid nanosheets display a comparable ORR activity to the optimal commercial Pt/C catalyst, which may be due to the extra-small size of Rh NPs and the 2D defect-rich amorphous carbon nanosheets that can facilitate the charge transfer and reactive surface exposure. Moreover, Rh/C nanosheets present the optimal current density and best durability with the minimum decline during the entire test, so that ∼93% activity after 20 000 s is achieved, indicating a good lifetime for ORR. In contrast, commercial Pt/C and commercial Rh/C exhibited worse durability, so that ∼74% and ∼85% activities after 20 000 s are maintained. What's more, in the model system of reduction of 4-nitrophenol (4-NP), the kinetic constant k for Rh/C nanosheets is 3.1 × 10-3, which is 4.5 times than that of the commercial Rh/C catalyst, revealing that our Rh/C hybrid nanosheets can be potentially applied in industrial catalytic hydrogenation. This work opens a novel and facile way for the rest of the precious metal NPs to be supported on ultrathin carbon nanosheets for heterogeneous catalysis.


In vivo restoration of full-thickness cartilage defects by poly(lactide-co-glycolide) sponges filled with fibrin gel, bone marrow mesenchymal stem cells and DNA complexes.
A composite construct comprising of bone marrow mesenchymal stem cells (BMSCs), plasmid DNA encoding transforming growth factor-beta1 (pDNA-TGF-beta1), fibrin gel and poly (lactide-co-glycolide) (PLGA) sponge was designed and employed to repair articular cartilage defects. To improve the gene transfection efficiency, a cationized chitosan derivative N,N,N-trimethyl chitosan chloride (TMC) was employed as the vector. The TMC/DNA complexes had a transfection efficiency of 9% to BMSCs and showed heterogeneous TGF-beta1 expression in a 10-day culture period in vitro. In vivo culture of the composite constructs was performed by implantation into full-thickness cartilage defects of New Zealand white rabbit joints, using the constructs absence of pDNA-TGF-beta1 or BMSCs as controls. Heterogeneous expression of TGF-beta1 in vivo was detected at 4 weeks, but its level was decreased in comparison with that of 2 weeks. After implantation for 12 weeks, the cartilage defects were successfully repaired by the composite constructs of the experimental group, and the neo-cartilage integrated well with its surrounding tissue and subchondral bone. Immunohistochemical and glycosaminoglycans (GAGs) staining confirmed the similar amount and distribution of collagen type II and GAGs in the regenerated cartilage as that of hyaline cartilage. The cartilage special genes expressed in the neo-tissue were closer to those of the normal cartilage. An overall score of 2.83 was obtained according to Wakitani's standard. By contrast, only part of the defects was repaired by the pDNA-TGF-beta1 absence constructs, and no cartilage repair but fibrous tissue was found for the BMSCs absence constructs. Therefore, combination of the PLGA sponge/fibrin gel scaffold with BMSCs and gene therapy is an effective method to restore cartilage defects and may have a great potential for practical applications in the near future.


[Systematics of osteodensitometric methods and acronyms].
The radiological diagnosis of osteoporosis is primarily based on osteodensitometry. The continuous development of new methods requires persistent analysis of its potential and limits. The knowledge of the differences of osteodensitometric methods is essential for understanding patient reports. The acronyms are internationally established, their correct usage is advocated.


Biomechanical Alterations during Sit-to-Stand Transfer Are Caused by a Synergy between Knee Osteoarthritis and Obesity.
Osteoarthritis is one of the major causes of immobility and its current prevalence in elderly (>60 years) is 18% in women and 9.6% in men. Patients with osteoarthritis display altered movement patterns to avoid pain and overcome movement limitations in activities of daily life, such as sit-to-stand transfers. Currently, there is a lack of evidence that distinguishes effects of knee osteoarthritis on sit-to-stand performance in patients with and without obesity. The purpose of this study was therefore to investigate differences in knee and hip kinetics during sit-to-stand movement between healthy controls and lean and obese knee osteoarthritis patients. Fifty-five subjects were included in this study, distributed over three groups: healthy controls (n=22), lean knee osteoarthritis (n=14), and obese knee OA patients (n=19). All subjects were instructed to perform sit-to-stand transfers at self-selected, comfortable speed. A three-dimensional movement analysis was performed to investigate compensatory mechanisms and knee and hip kinetics during sit-to-stand movement. No difference in sit-to-stand speed was found between lean knee OA patients and healthy controls. Obese knee osteoarthritis patients, however, have reduced hip and knee range of motion, which is associated with reduced peak hip and knee moments. Reduced vertical ground reaction force in terms of body weight and increased medial ground reaction forces indicates use of compensatory mechanisms to unload the affected knee in the obese knee osteoarthritis patients. We believe that an interplay between obesity and knee osteoarthritis leads to altered biomechanics during sit-to-stand movement, rather than knee osteoarthritis alone. From this perspective, obesity might be an important target to restore healthy sit-to-stand biomechanics in obese knee OA patients.


Mapping the synthesis of low nuclearity polyoxometalates from octamolybdates to Mn-Anderson clusters.
A comprehensive study of the isomer-independent synthesis of TRIS ((HOCH(2))(3)CNH(2)) Mn-Anderson compounds from Na(2)MoO(4)·2H(2)O, via the corresponding octamolybdate species, is presented. Three octamolybdate salts of [Mo(8)O(26)](4-) in the β-isomer form, with tetramethylammonium (TMA), tetraethylammonium (TEA) and tetrapropylammonium (TPA) as the counter cation, were synthesised from the sodium molybdate starting material. Fine white powdery products for the three compounds were obtained, which were fully characterised by elemental analysis, TGA, solution and solid state Raman, IR and ESI-MS, revealing a set ratio of Na and organic cations for each of the three compounds; (TMA)(2)Na(2)[Mo(8)O(26)] (1), (TEA)(3)Na(1)[Mo(8)O(26)] (2) and (TPA)(2)Na(2)[Mo(8)O(26)] (3), and the analyses also confirmed that the three compounds all consisted of the octamolybdate in the β-isomeric form. ESI-MS analyses of 1, 2 and 3 show similar fragmentation for these β-isomers compared to the previously reported study for the α-isomer ((TBA)(4)[α-Mo(8)O(26)]) (A) in the synthesis of ((TBA)(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)]) (B), and compounds 1, 2 and 3 were successfully used to synthesise equivalent TRIS Mn-Anderson compounds: (TMA)(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (4), (TEA)(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (5) and (TPA)(2)Na(1)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (6), as well as Na(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (7). This is the first example where symmetric organically-grafted Mn-Anderson compounds have been synthesised in DMF from anything but the {Mo(8)O(26)} α-isomer.


Urinary dysfunction in Duchenne muscular dystrophy.
In Duchenne muscular dystrophy (DMD), sphincter muscles tend to be clinically spared. However, urinary incontinence is occasionally reported, usually late in the course of the disease. We wished to determine the etiology of urinary dysfunction in patients with DMD. Seven boys with DMD and urinary dysfunction were examined by a neurologist and a urologist followed by urodynamic and electrophysiological assessment. Based on the results of these evaluations, patients were defined as having an upper motor neuron (UMN), lower motor neuron (LMN), or myopathic lesion. Five of the patients had UMN abnormalities consisting of either uninhibited contractions or bladder/sphincter dyssynergy. One patient had a LMN lesion with prolonged duration and high-amplitude motor units. No patient demonstrated myopathic motor units. Five boys had undergone spinal fusion for scoliosis. We conclude that urinary incontinence in DMD is most often due to UMN dysfunction and not due to a severe myopathy of the detrusor or external sphincter. The most likely causes of the UMN abnormalities are severe scoliosis or a complication of spinal fusion surgery.


Strong effect of climate on ectomycorrhizal fungal composition: evidence from range overlap between two mountains.
Separating the effects of environmental factors and spatial distance on microbial composition is difficult when these factors covary. We examined the composition of ectomycorrhizal (EM) fungi along elevation gradients on geographically distant mountains to clarify the effect of climate at the regional scale. Soil cores were collected from various forest types along an elevation gradient in southwestern Japan. Fungal species were identified by the internal transcribed spacer regions of the rDNA using direct sequencing. The occurrence of fungal species in this study was compared with a previous study conducted on a mountain separated by ∼550 km. In total, we recorded 454 EM fungi from 330 of 350 soil cores. Forty-seven fungal species (∼20% of the total excluding singletons) were shared between two mountains, mostly between similar forest types on both mountains. Variation partitioning in redundancy analysis revealed that climate explained the largest variance in EM fungal composition. The similarity of forest tree composition, which is usually determined by climatic conditions, was positively correlated with the similarity of the EM fungal composition. However, the lack of large host effects implied that communities of forest trees and EM fungi may be determined independently by climate. Our data provide important insights that host plants and mutualistic fungi may respond to climate change idiosyncratically, potentially altering carbon and nutrient cycles in relation to the plant-fungus associations.


Adherence and Risk Behaviour in Patients with HIV Infection Receiving Antiretroviral Therapy in Bangkok.
It could be postulated that due to lifestyle factors, patients with poor antiretroviral therapy (ART) adherence may also have risky sexual behaviour potentially leading to HIV transmission. There are limited data regarding unprotected sex risk and ART adherence in resource limited settings and our study set out to investigate these in an HIV clinic in Bangkok. Patients completed an anonymous questionnaire regarding their relationship details, ART adherence, sexual behaviour, alcohol and drug use and HIV transmission beliefs. Laboratory findings and medical history were also collected. Unprotected sex risk (USR) was defined as inconsistent condom use with a partner of negative or unknown HIV status. Five hundred and twelve patients completed the questionnaire. Fifty seven per cent of patients reported having taken ARV >95% of the time in the last month and 58% had been sexually active in the previous 30 days. Only 27 patients (5%) were classified as having USR in our cohort. Multivariate analysis showed USR was associated with female gender (OR 2.9, 95% CI 1.2-7.0, p0.02) but not with adherence, age, type or number of partners, recreational drug or alcohol use nor beliefs about HIV transmission whilst taking ART. Levels of USR in this resource limited setting were reassuringly low and not associated with poor ART adherence; as all USR patients had undetectable viral loads onward HIV transmission risk is likely to be low but not negligible. Nonetheless condom negotiation techniques, particularly in women, may be useful in this group.


The efficacy of third generation anti‑HER2 chimeric antigen receptor T cells in combination with PD1 blockade against malignant glioblastoma cells.
Without effective treatment, glioblastoma is one of the deadliest cancers worldwide. The aim of the present study was to explore whether combinational immunotherapy is effective for treating malignant glioblastoma in vitro. The therapeutic efficacy of third generation anti‑human epidermal growth factor receptor 2 (HER2) chimeric antigen receptor (CAR)‑T cells alone and in combination with PD1 blockade was investigated for the treatment of malignant glioblastoma cells in vitro. Anti‑HER2 CAR‑T cells were prepared by transducing activated primary human T cells with lentiviruses which expressed third generation anti‑HER2 CAR. The CAR‑positive cell ratio was detected using flow cytometry. The expression level of CAR was detected by western blot analysis. The binding of anti‑HER2 CAR‑T cells to HER2+ U251 glioblastoma cells was examined under a fluorescence microscope. The cytokine secretion of CAR‑T cells induced by target cells was analyzed via ELISA. The cytotoxicity of anti‑HER2 CAR‑T cells alone or in combination with anti‑programmed death‑1 (PD1) antibody against HER2+/PDL1+ U251 cells was examined using an LDH assay. The CAR‑positive cell ratio and expression level of CAR in prepared CAR‑T cells were both high enough. Anti‑HER2 CAR‑T cells could specifically bind to U251 cells. The IL‑2 and IFN‑γ secretion of CAR‑T cells increased after being co‑cultured with U251 cells, and further increased in the presence of anti‑PD1 antibody. Anti‑HER2 CAR‑T cells displayed a potent cytotoxicity against U251 cells. In addition, the presence of anti‑PD1 antibody further enhanced the efficacy of anti‑HER2 CAR‑T cells against U251 cells. The present results indicated that blocking PD1 immuno‑suppression can increase the activation of CAR‑T cells after they are activated by a targeting antigen. Third generation anti‑HER2 CAR‑T cells along with PD1 blockade have a great therapeutic potential for combatting malignant glioblastoma.


Tomographic Extraction of the Internuclear Separation Based on Two-Center Interference with Aligned Diatomic Molecules.
We experimentally investigate the two-dimensional photoelectron momentum spectra of aligned diatomic molecules in an intense laser field. Our results reveal a novel prominent valley structure in the molecular alignment dependence of the high-energy photoelectron spectra along the laser polarization. Resorting to the molecular strong-field approximation and a simple semiclassical analysis, we show that this valley structure stems from the destructive two-center interference of the laser-driven rescattered electrons in diatomic molecules. Based on this two-center interference with aligned diatomic molecules, we demonstrate for the first time a tomographic method to extract the molecular internuclear separation, providing a more straightforward approach of molecular imaging, in comparison with, e.g., laser-induced electron diffraction and fixed-angle broadband laser-driven electron scattering.


Inability of malaria vaccine to induce antibodies to a protective epitope within its sequence.
Saimiri monkeys immunized with a recombinant protein containing 20 copies of the nine amino acid repeat of the Plasmodium vivax circumsporozoite (CS) protein developed high concentrations of antibodies to the repeat sequence and to sporozoites, but were not protected against challenge. After intravenous injection of an immunoglobulin G3 monoclonal antibody (NVS3) against irradiated P. vivax sporozoites, four of six monkeys were protected against sporozoite-induced malaria, and the remaining two animals took significantly longer to become parasitemic. Epitope mapping demonstrated that NVS3 recognizes only four (AGDR) of the nine amino acids within the repeat region of the P. vivax CS protein. The monkeys immunized with (DRAADGQPAG)20 did not produce antibodies to the protective epitope AGDR. Thus, determination of the fine specificity of protective immune responses may be critical to the construction of successful subunit vaccines.


Different distribution of pentraxin 3 and C-reactive protein in coronary atherosclerotic plaques.
To understand the differences between histopathological characteristics related to PTX3 (pentraxin 3) and CRP (C-reactive protein) in coronary atherosclerotic plaques. To assess the localization of PTX3 and CRP in coronary plaque, immunohistochemistry was performed using 157 coronary artery specimens from 45 autopsied cases. Overall, immunoreactivity to CRP was more intense than that to PTX3 in lipid rich plaque; however, PTX3 was notably abundant in areas of intraplaque hemorrhage, in which CRP was quite sparse. On quantitative analysis, complicated plaques showed more immunopositive area of PTX3 than fibroatheroma, but with CRP, this trend disappeared. In addition, we examined the phenotype of macrophages in PTX3- and CRP-rich areas using CD163 staining (M2 macrophages). Consequently, these areas were differently characterized by the accumulation of macrophages with high and low magnitude of CD163 positivity, respectively. Next, we immunohistochemically investigated relationships among PTX3, CRP, histological components and clinical presentation in 73 coronary atherectomy specimens obtained from 35 and 38 patients with unstable (UAP) and stable angina pectoris (SAP), respectively. Both PTX3 and CRP were more intense in culprit plaques from patients with UAP than with SAP, and they significantly correlated with CD68 (pan macrophage)-positive areas; however, there was no correlation between PTX3 and CRP. Although PTX3 and CRP were more enhanced in unstable than in stable coronary plaques, their distribution distinctly differed, suggesting that they play distinct biological roles in unstable plaques.