Perspectives on Acute Hepatitis A Control in Korea.
Until 1995, the incidence of symptomatic acute hepatitis A was minimal and there were no cases of national outbreak in Korea. However, there was a nationwide outbreak of hepatitis A that peaked in 2009. In 2019, a total of 10,083 cases of acute hepatitis A were reported for seven months of the year according to the Korea Center for Disease Control and Prevention. This may be attributed to the proportion of susceptible subjects in the Korean population, as about 10 years have passed since herd immunity was induced by the epidemic occurring during the late 2000s. Recent studies have shown that the rate of seropositivity for anti-hepatitis A virus antibodies (anti-HAV) is the lowest in adults in their 20s and has not changed much over the past 10 years, and seropositivity of anti-HAV in adults in their 30s has continued to decline from 69.6% in 2005 to 32.4% in 2014. Most young adults who have not yet experienced hepatitis A and are not vaccinated are vulnerable to hepatitis A infection. This year's epidemic of hepatitis A is a predictable outcome for vulnerable populations. Therefore, effective acute hepatitis A control and prevention strategies are needed, particularly for those in their 20s and 30s.


Distribution of electromechanical delay in the heart: insights from a three-dimensional electromechanical model.
In the intact heart, the distribution of electromechanical delay (EMD), the time interval between local depolarization and myocyte shortening onset, depends on the loading conditions. The distribution of EMD throughout the heart remains, however, unknown because current experimental techniques are unable to evaluate three-dimensional cardiac electromechanical behavior. The goal of this study was to determine the three-dimensional EMD distributions in the intact ventricles for sinus rhythm (SR) and epicardial pacing (EP) by using a new, to our knowledge, electromechanical model of the rabbit ventricles that incorporates a biophysical representation of myofilament dynamics. Furthermore, we aimed to ascertain the mechanisms that underlie the specific three-dimensional EMD distributions. The results revealed that under both conditions, the three-dimensional EMD distribution is nonuniform. During SR, EMD is longer at the epicardium than at the endocardium, and is greater near the base than at the apex. After EP, the three-dimensional EMD distribution is markedly different; it also changes with the pacing rate. For both SR and EP, late-depolarized regions were characterized with significant myofiber prestretch caused by the contraction of the early-depolarized regions. This prestretch delays myofiber-shortening onset, and results in a longer EMD, giving rise to heterogeneous three-dimensional EMD distributions.


User needs: the key to changing library services and policies.
A user survey and a series of faculty interviews are discussed as methods that can be used by a public relations librarian to change library policies and services in the direction of patrons' needs.


Natural Compound Licochalcone B Induced Extrinsic and Intrinsic Apoptosis in Human Skin Melanoma (A375) and Squamous Cell Carcinoma (A431) Cells.
Licochalcone B (Lico B), which is normally isolated from the roots of Glycyrrhiza inflata (Chinese Licorice), generally classified into organic compounds including retrochalcones. Potential pharmacological properties of Lico B include anti-inflammatory, anti-bacterial, anti-oxidant, and anti-cancer activities. However, its biological effects on melanoma and squamous cell carcinoma (SCC) are unknown. Based on these known facts, this study investigated the role of Lico B in apoptosis, through the extrinsic and intrinsic pathways and additional regulation of specificity protein 1 in human skin cancer cell lines. Annexin V/7-aminoactinomycin D staining, western blot analysis, mitochondrial membrane potential assay, and an anchorage-independent cell transformation assay demonstrated that Lico B treatment of human melanoma and SCC cells significantly inhibited cell proliferation and induced apoptotic cell death. More specifically, Lico B induced apoptosis through the regulation of specificity protein 1 and apoptosis-related proteins including CCAAT/enhancer-binding protein homologous protein, death receptors, and poly (ADP-ribose) polymerase. These results indicate that Lico B has apoptotic effect on A375 and A431 skin cancer cells, suggesting the potential value of Lico B for the treatment of human melanoma and SCC. Copyright © 2017 John Wiley & Sons, Ltd.


Predictors of early treatment discontinuation in patients enrolled on Phase I oncology trials.
Patients who do not complete one cycle of therapy on Phase I trials for reasons other than dose limiting toxicity (DLT) are considered inevaluable for toxicity and must be replaced. Individual records from patients enrolled to NCI-sponsored Phase I trials activated between 2000 and 2010 were used. Early discontinuation was defined as the failure to begin cycle 2 for reasons other than a DLT during cycle 1. A multinomial logistic regression with a 3-level nominal outcome (early discontinuation, DLT during cycle 1, and continuation to cycl1e 2) was used with continuation to cycle 2 serving as the reference category. The final model was used to create two risk scores. An independent external cohort was used to validate these models. Data from 3079 patients on 127 Phase I trials were analyzed. ECOG performance status (1, ≥ 2, two-sided P = .0315 and P = .0007), creatinine clearance (<60 ml/min, P = .0455), alkaline phosphatase (>2.5xULN, P = .0026), AST (>ULN, P = .0076), hemoglobin (<10 g/dL, P < .0001), albumin (<3.5 g/dL, P < .0001), and platelets (<400x109/L, P = .0732) were predictors of early discontinuation. The c-index of the final model was 0.63. Knowledge of risk factors for early treatment discontinuation in conjunction with clinical judgment can help guide Phase I patient selection.


Amputation through the knee for the nonambulatory patient.
The first amputation through the knee to be done in the United States was performed 150 years ago. Since then, its advantages have been noted repeatedly, but widespread acceptance has never been attained. Amputation through the knee should be the procedure of choice for the poor risk, bedridden patient because it is simple, safe and swift. There is minimal postoperative pain, and the stump is sufficiently long to be a useful appendage.


Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD+) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.


Dynamics of BMP and Hes1/Hairy1 signaling in the dorsal neural tube underlies the transition from neural crest to definitive roof plate.
The dorsal midline region of the neural tube that results from closure of the neural folds is generally termed the roof plate (RP). However, this domain is highly dynamic and complex, and is first transiently inhabited by prospective neural crest (NC) cells that sequentially emigrate from the neuroepithelium. It only later becomes the definitive RP, the dorsal midline cells of the spinal cord. We previously showed that at the trunk level of the axis, prospective RP progenitors originate ventral to the premigratory NC and progressively reach the dorsal midline following NC emigration. However, the molecular mechanisms underlying the end of NC production and formation of the definitive RP remain virtually unknown. Based on distinctive cellular and molecular traits, we have defined an initial NC and a subsequent RP stage, allowing us to investigate the mechanisms responsible for the transition between the two phases. We demonstrate that in spite of the constant production of BMP4 in the dorsal tube at both stages, RP progenitors only transiently respond to the ligand and lose competence shortly before they arrive at their final location. In addition, exposure of dorsal tube cells at the NC stage to high levels of BMP signaling induces premature RP traits, such as Hes1/Hairy1, while concomitantly inhibiting NC production. Reciprocally, early inhibition of BMP signaling prevents Hairy1 mRNA expression at the RP stage altogether, suggesting that BMP is both necessary and sufficient for the development of this RP-specific trait. Furthermore, when Hes1/Hairy1 is misexpressed at the NC stage, it inhibits BMP signaling and downregulates BMPR1A/Alk3 mRNA expression, transcription of BMP targets such as Foxd3, cell-cycle progression, and NC emigration. Reciprocally, Foxd3 inhibits Hairy1, suggesting that repressive cross-interactions at the level of, and downstream from, BMP ensure the temporal separation between both lineages. Together, our data suggest that BMP signaling is important both for NC and RP formation. Given that these two structures develop sequentially, we speculate that the longer exposure of RP progenitors to BMP compared with that of premigratory NC cells may be translated into a higher signaling level in the former. This induces changes in responsiveness to BMP, most likely by downregulating the expression of Alk3 receptors and, consequently, of BMP-dependent downstream transcription factors, which exhibit spatial complementary expression patterns and mutually repress each other to generate alternative fates. This molecular dynamic is likely to account for the transition between the NC and definitive RP stages and thus be responsible for the segregation between central and peripheral lineages during neural development.


Surgical repair of deep melting ulcers with porcine small intestinal submucosa (SIS) graft in dogs and cats.
To evaluate the efficacy of using a porcine small intestinal submucosa (SIS) graft for the surgical repair of deep melting ulcers in dogs and cats. Two cats and five dogs presented with deep and large melting ulcers of the cornea. In each case, the necrotic and collagenolytic tissue of the cornea was removed by keratectomy. A SIS graft, 1 mm greater than the corneal defect, was rehydrated in sterile saline and sutured to the edges of the ulcer with a simple interrupted pattern of 9/0 polyglactin 910. A nictitating membrane flap was utilized in two cats and four dogs for 2 weeks. All cases were treated postoperatively with topical and systemic antibiotics, a systemic anti-inflammatory drug and topical atropine. All animals were re-evaluated 15 days, 4 weeks, 35-45 days, 2-3 months and 6 months postsurgery. At 15 days postsurgery, a superficial intense corneal neovascularization surrounded the SIS graft. No ocular discomfort was present and fluorescein staining was negative in all cases. At 4 weeks the SIS graft was thick and opaque in all cases, although in one cat the SIS graft had partially detached. Between 35 and 45 days, SIS graft integration was evident in all eyes, and corneal neovascularization had decreased progressively. All eyes healed without complications and retained corneal transparency. This occurred even in the presence of corneal perforation in two cases: one prior to and one during surgery. Results of our study suggest the SIS graft may be an effective alternative surgical treatment to the traditional conjunctival grafts commonly used to repair melting ulcers in dogs and cats. The advantages of using a SIS graft include good corneal transparency, preservation of corneal integrity and maintenance of vision.


[Prospects of molecular pharmacology in oncology].
The evaluation of the precise mechanism of action of a new anticancer agent is a crucial step for a better utilization of drugs in cancer therapy. The increased knowledge of the molecular alterations present in different tumors, combined with the identification of the intracellular targets of a drug is the initial step for the possible, future molecular-oriented chemotherapy. It is in fact possible now to know if and how a given drug is able to interact with DNA and if the DNA sequence is a key factor in determining such interaction. Drugs are available with high sequence specificity of DNA interaction and these results, combined with the knowledge of the DNA sequences important for the regulation of gene expression, can help in identifying possible intracellular targets of the drugs. The recent introduction of the microarray technology has changed our approach to the study of drug effects on gene expression. In a single experiment is possible to identify changes in gene expression of plenty of genes and to have information on the alterations in the expression of gene families. These studies, combined to the effects on proteins involved in cell cycle control and in the induction of apoptosis, allow a better understanding of the interaction between drugs and cellular control mechanisms.


Increased risk of serious pneumococcal disease in patients with atopic conditions other than asthma.
We reported an increased risk of serious pneumococcal disease (SPD) among patients with asthma. It is not known whether this is true for patients with other atopic conditions. To determine the relationship between atopic conditions other than asthma and SPD. The study subjects were residents of Rochester, Minn, who developed SPD between 1964 and 1983 and their 2 sex-matched and age-matched controls. We used a population-based computer-linked medical diagnosis system to identify all individuals with potential SPD. All records were reviewed by using explicit predetermined criteria for SPD. All individuals with atopic conditions were identified by the physician diagnoses including atopic dermatitis or eczema, allergic rhinitis, and hay fever documented in medical records. The associations between these atopic conditions and SPD were assessed by using conditional logistic regression. A total of 3941 records were reviewed, and we identified 174 SPD cases. Of these 174 cases, 50.6% were male, and 94.3% were Caucasian. Twenty-six (14.9%) of the SPD cases and 29 (8.3%) of the controls had atopy. Atopic conditions other than asthma were associated with an increased risk of SPD (odds ratio, 2.13; 95% CI, 1.04-4.35; P = .04) after adjusting for smoking status, previous high-risk conditions for SPD, educational status, and ethnicity. Like asthma, other atopic conditions, particularly atopic dermatitis, are associated with an increased risk of SPD. There may be a common immunogenetic mechanism underlying increased risk of SPD among individuals with either asthma or other atopic conditions. Our study findings need to be studied further.


Murine norovirus infection of macrophages induces intrinsic apoptosis as the major form of programmed cell death.
Human norovirus is the leading cause of acute gastroenteritis worldwide, however despite the significance of this pathogen, we have a limited understanding of how noroviruses cause disease, and modulate the innate immune response. Programmed cell death (PCD) is an important part of the innate response to invading pathogens, but little is known about how specific PCD pathways contribute to norovirus replication. Here, we reveal that murine norovirus (MNV) virus-induced PCD in macrophages correlates with the release of infectious virus. We subsequently show, genetically and chemically, that MNV-induced cell death and viral replication occurs independent of the activity of inflammatory mediators. Further analysis revealed that MNV infection promotes the cleavage of apoptotic caspase-3 and PARP. Correspondingly, pan-caspase inhibition, or BAX and BAK deficiency, perturbed viral replication rates and delayed virus release and cell death. These results provide new insights into how MNV harnesses cell death to increase viral burden.


Evaluating team-based, lecture-based, and hybrid learning methods for neurology clerkship in China: a method-comparison study.
Neurology is complex, abstract, and difficult for students to learn. However, a good learning method for neurology clerkship training is required to help students quickly develop strong clinical thinking as well as problem-solving skills. Both the traditional lecture-based learning (LBL) and the relatively new team-based learning (TBL) methods have inherent strengths and weaknesses when applied to neurology clerkship education. However, the strengths of each method may complement the weaknesses of the other. Combining TBL with LBL may produce better learning outcomes than TBL or LBL alone. We propose a hybrid method (TBL + LBL) and designed an experiment to compare the learning outcomes with those of pure LBL and pure TBL. One hundred twenty-seven fourth-year medical students attended a two-week neurology clerkship program organized by the Department of Neurology, Sun Yat-Sen Memorial Hospital. All of the students were from Grade 2007, Department of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-Sen University. These students were assigned to one of three groups randomly: Group A (TBL + LBL, with 41 students), Group B (LBL, with 43 students), and Group C (TBL, with 43 students). The learning outcomes were evaluated by a questionnaire and two tests covering basic knowledge of neurology and clinical practice. The practice test scores of Group A were similar to those of Group B, but significantly higher than those of Group C. The theoretical test scores and the total scores of Group A were significantly higher than those of Groups B and C. In addition, 100% of the students in Group A were satisfied with the combination of TBL + LBL. Our results support our proposal that the combination of TBL + LBL is acceptable to students and produces better learning outcomes than either method alone in neurology clerkships. In addition, the proposed hybrid method may also be suited for other medical clerkships that require students to absorb a large amount of abstract and complex course materials in a short period, such as pediatrics and internal medicine clerkships.


Multiplex qPCR Assay for Direct Detection and Quantification of Colletotrichum truncatum, Corynespora cassiicola, and Sclerotinia sclerotiorum in Soybean Seeds.
Precise diagnosis of plant diseases is one of the most effective tools to minimize yield losses. Colletotrichum truncatum, Corynespora cassiicola, and Sclerotinia sclerotiorum are common soilborne pathogens that affect soybeans all over the world. We developed a multiplex quantitative real-time polymerase chain reaction (qPCR) assay to simultaneously detect and quantify the three pathogens in soybean seeds and to survey their occurrence in the main soybean production areas in Brazil. Species-specific primers and probes for C. truncatum and C. cassiicola were designed based on GAPDH and TEF1 genes, respectively, to be combined with qPCR detection of S. sclerotiorum previously reported. The multiplex qPCR assay was successful in the simultaneous detection of C. truncatum, C. cassiicola, and S. sclerotiorum, along with a host internal control. The four pathogens were detected and quantified in artificially and naturally infested soybean seeds, even in the lowest incidence level tested of 0.0625% or 1 infected seed out of 1,599 healthy ones. From 81 seed samples tested, C. truncatum was the most frequently detected pathogen and with higher incidence levels (0.25 to 0.125%), followed by S. sclerotiorum and C. cassiicola, both with lower incidence levels (0.125 to 0.0625%). Together, the results evidenced the high sensitivity of the multiplex qPCR assay, indicating its usefulness for a quick and reliable diagnosis of soybean diseases in seeds.


Apparent diffusive motion of centrin foci in living cells: implications for diffusion-based motion in centriole duplication.
The degree to which diffusion contributes to positioning cellular structures is an open question. Here we investigate the question of whether diffusive motion of centrin granules would allow them to interact with the mother centriole. The role of centrin granules in centriole duplication remains unclear, but some proposed functions of these granules, for example, in providing pre-assembled centriole subunits, or by acting as unstable 'pre-centrioles' that need to be captured by the mother centriole (La Terra et al 2005 J. Cell Biol. 168 713-22), require the centrin foci to reach the mother. To test whether diffusive motion could permit such interactions in the necessary time scale, we measured the motion of centrin-containing foci in living human U2OS cells. We found that these centrin foci display apparently diffusive undirected motion. Using the apparent diffusion constant obtained from these measurements, we calculated the time scale required for diffusion to capture by the mother centrioles and found that it would greatly exceed the time available in the cell cycle. We conclude that mechanisms invoking centrin foci capture by the mother, whether as a pre-centriole or as a source of components to support later assembly, would require a form of directed motility of centrin foci that has not yet been observed.


Typhoid hepatitis with immunoglobulins and complement deposits in bile canaliculi.
Documented typhoid fever in a 26-year-old patient was complicated by acute hepatitis with unusually profound jaundice. Liver biopsy revealed focal cell necrosis, mononuclear cell infiltration. Kupffer cell proliferation, and mild cholestasis. Immunofluorescent studies of the liver biopsy revealed deposits of IgG, IgA, IgM, and C3 in the bile canaliculi, suggesting a role for damage by immune complexes in typhoid hepatitis.


Retrospective analysis of basal cell carcinoma.
Basal cell carcinomas (BCCs) are the most prevalent cancer type among white-skinned populations worldwide. To analyze the gender and age-related incidence of basal cell carcinoma (BCC) histopathologic subtypes, to classify BCCs according to their anatomical location, invasion depth, and size, and to determine the relationship between BCC subtypes and margin of surgical excision. All BCCs analysed in our center between 2005 and 2010 were studied retrospectively. The samples, which were totally excised, were included on the basis of histopathological diagnosis of BCC, and confirmed by two pathologists. Patient data included sex, age at diagnosis, tumor location, histological subtypes, invasion depth, and size. We recorded 197 BCCs obtained from 181 white patients (80 females, 101 males). The mean age among males was 64.11, and 59.33 among females. Of the cases, 45.17% were nodular, 22.33% were mixed, and 15.22 were infiltrative type. 91.84% of the cases were located on the head and neck, 3.04% were on the limbs, and 1.52 % were on the trunk. In 32 cases, the margin of surgical excision was positive (17.7%): nodular 12%, infiltrative 43.3%, mixed 20.6%, micronodular 10%, and superfacial multicentric 5.5%. Of these total 32 cases, 34.4% were located on the eyes region, 28.1% were found on the nose, and 15.6% were on the ears. Invasion depth of tumors varied from 0.5 to 22.125 mm. The results of our study exhibit differences in anatomical distribution, sex and mean age, invasion depth, and size of BCC subtypes. The recurrence rate for incompletely excised tumors varies according to the location and type of the tumor. Infiltrative tumors are more likely to recur and have positive margin of surgical excision. The highest positive margin of surgical excision is in infiltrative BCC. Tumors at difficult-to-treat sites and large and/or deeply invasive tumors are more liable to recur.


Human endothelial cells augment early CD40 ligand expression in activated CD4+ T cells through LFA-3-mediated stabilization of mRNA.
Human endothelial cells (EC) augment CD40 ligand (CD40L) expression on PHA-activated CD4+ T cells at early times (e.g., 4-6 h). Fixed EC, devoid of mRNA, are comparable to living EC in their capacity to augment early CD40L expression on CD4+ T cells. Fixed EC increase T cell mRNA expression of both IL-2 and CD40L compared with PHA alone at 6 h. EC are unable to increase the rate of transcription of CD40L compared with PHA alone as measured with a promoter-reporter gene, although they do increase transcription of an IL-2 promoter-reporter gene. Fixed EC prolong the half-life of CD40L mRNA >2-fold. Inclusion of anti-human LFA-3 (CD58) mAb or pretreatment of EC with an LFA-3 antisense oligonucleotide blocks EC-induced increases in CD40L expression, whereas mAb to ICAM-1 or pretreatment with ICAM-1 antisense oligonucleotide does not. Moreover, mAb to LFA-3 reverses the capacity of EC to prolong the half-life of CD40L mRNA, whereas mAb to ICAM-1, even in combination with mAb to ICAM-2, does not. We conclude that EC use LFA-3 to increase early CD40L protein expression on newly activated CD4+ T cells by stabilizing CD40L mRNA.


Accelerated search for biomolecular network models to interpret high-throughput experimental data.
The functions of human cells are carried out by biomolecular networks, which include proteins, genes, and regulatory sites within DNA that encode and control protein expression. Models of biomolecular network structure and dynamics can be inferred from high-throughput measurements of gene and protein expression. We build on our previously developed fuzzy logic method for bridging quantitative and qualitative biological data to address the challenges of noisy, low resolution high-throughput measurements, i.e., from gene expression microarrays. We employ an evolutionary search algorithm to accelerate the search for hypothetical fuzzy biomolecular network models consistent with a biological data set. We also develop a method to estimate the probability of a potential network model fitting a set of data by chance. The resulting metric provides an estimate of both model quality and dataset quality, identifying data that are too noisy to identify meaningful correlations between the measured variables. Optimal parameters for the evolutionary search were identified based on artificial data, and the algorithm showed scalable and consistent performance for as many as 150 variables. The method was tested on previously published human cell cycle gene expression microarray data sets. The evolutionary search method was found to converge to the results of exhaustive search. The randomized evolutionary search was able to converge on a set of similar best-fitting network models on different training data sets after 30 generations running 30 models per generation. Consistent results were found regardless of which of the published data sets were used to train or verify the quantitative predictions of the best-fitting models for cell cycle gene dynamics. Our results demonstrate the capability of scalable evolutionary search for fuzzy network models to address the problem of inferring models based on complex, noisy biomolecular data sets. This approach yields multiple alternative models that are consistent with the data, yielding a constrained set of hypotheses that can be used to optimally design subsequent experiments.


[Registration of changes in the nucleoide conformation based on the analysis of the time dependence of viscosity].
The sensitivity of the method of anomalous time dependence of viscosity to changes in the conformation of DNA-protein complexes (such as nucleoide) by the action of (1) nalidixic acid on cells and (2) one- and two-charged ions Na+, Cl-, Cu2+, Ca2+, Mg2+, Zn2+, SO4(2-) on Escherichia coli cells has been studied. The data obtained suggest that the method anomalous time dependence of viscosity is highly sensitive to the conformation of high-molecular DNA-protein complexes. It was shown that the method anomalous time dependence of viscosity can be used to register cell sensitivity to changes in the concentration of one- and two-charged ions in suspension.


Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.
To retrospectively analyze the clinical symptoms, laboratory findings, and outcomes in patients with microscopic polyangiitis (MPA) who were enrolled in various clinical trials conducted by the French Vasculitis Study Group. A cohort of 85 patients meeting the Chapel Hill criteria for MPA participated in the study. Seventy-one of them were included in prospective therapeutic trials. Eighty-one diagnoses were biopsy proven. In the other patients, diagnosis was based on clinical findings. Forty-seven men and 38 women, with a mean +/- SD age of 56.8 +/- 14.6 years, met the criteria for MPA. Their main clinical symptoms were renal manifestations (78.8%), weight loss (72.9%), skin involvement (62.4%), fever (55.3%), mononeuritis multiplex (57.6%), arthralgias (50.6%), myalgias (48.2%), hypertension (34.1%), lung involvement (24.7%; alveolar hemorrhage 11.8%), and cardiac failure (17.6%). The mean +/- SD serum creatinine level before treatment was 2.59 +/- 2.96 mg/dl; 47 patients had renal insufficiency (serum creatinine > 1.36 mg/dl). Eight patients underwent dialysis at the time of diagnosis, and long-term dialysis was necessary for 10 patients. Antineutrophil cytoplasmic antibodies (ANCA) were present in 38 of 51 patients (74.5%), of whom 33 had a perinuclear staining pattern (pANCA) and 5 had a cytoplasmic pattern. Antibodies to proteinase 3 were present in 4 patients and antibodies to myeloperoxidase were detected in 31, as determined by enzyme-linked immunosorbent assay. Of the 30 patients who underwent renal and celiac angiography, 4 had microaneurysms. Of the 29 patients (34.1%) who had relapses, 8 died during or after the relapse. During followup, 28 of the 85 patients (32.9%) died. The mean +/- SD duration of followup of the group was 69.9 +/- 60.6 months. Deaths were less frequent when patients had been treated with steroids and immunosuppressive drugs (13 patients [24.1%]) than with steroids alone (15 patients [48.4%]) (P < 0.01). The 5-year survival rate was 74%. This study demonstrated that MPA is a multisystemic disease in which renal symptoms are frequent, but the disease is also associated with general symptoms, arthritis, mononeuritis multiplex, and other manifestations that are also seen in various vasculitides. The rarity of abnormal angiogram findings and the high frequency of pANCA are characteristic of MPA. In most cases, the outcome is comparable with those of other systemic vasculitides, but relapses are frequent.


Biochemical strategies to anticoagulation: a comparative overview.
Hypercoagulability is widely associated with sepsis, inflammation, diabetes, cancers, aging, and many pathological conditions, resulting in life-threatening disseminated intravascular coagulation (DIC), venous thrombosis, thromboembolism, cardiovascular complications, or even deadly multiple organ failure. Relieving coagulation dysfunction is not only a task for research scientists but also a challenge for physicians. The development of effective anticoagulants is under way with the basic understanding of the pathophysiology of hypercoagulable state. In this overview, various anticoagulants will be discussed according to the proposed inhibitory target-sites along the extrinsic pathway that is believed to play an integral role in homeostasis. Anticoagulants generally fall into two broad categories as natural or pharmacological ones. Antithrombin (AT), activated protein C (APC), and tissue factor pathway inhibitor (TFPI) mainly constitute the natural anticoagulant system apart from the recently reported physiological components such as lipoproteins, sphingosine, thrombomodulin (TM) or cellular Marcks protein. Pharmacological anticoagulants include warfarin, FVIIa inhibitors, FXa inhibitors, and thrombin inhibition by its direct inhibitors or heparins. In addition, a group of novel compounds inhibiting TF-dependent FVII activation result in anticoagulation; such upstream downregulation in the extrinsic pathway awaits further research to establish their in vivo benefits. The molecular genetic approaches such as developing soluble TF, FVII and thrombin mutants provide unique downregulation. Anticoagulation also extends its significance to anti-inflammation, making broad impacts on the improvement of human health.


Atlantic walrus signal latitudinal differences in the long-term decline of sea ice-derived carbon to benthic fauna in the Canadian Arctic.
Climate change is altering the biogeochemical and physical characteristics of the Arctic marine environment, which impacts sea ice algal and phytoplankton bloom dynamics and the vertical transport of these carbon sources to benthic communities. Little is known about whether the contribution of sea ice-derived carbon to benthic fauna and nitrogen cycling has changed over multiple decades in concert with receding sea ice. We combined compound-specific stable isotope analysis of amino acids with highly branched isoprenoid diatom lipid biomarkers using archived (1982-2016) tissue of benthivorous Atlantic walrus to examine temporal trends of sea ice-derived carbon, nitrogen isotope baseline and trophic position of Atlantic walrus at high- and mid-latitudes in the Canadian Arctic. Associated with an 18% sea ice decline in the mid-Arctic, sea ice-derived carbon contribution to Atlantic walrus decreased by 75% suggesting a strong decoupling of sea ice-benthic habitats. By contrast, a nearly exclusive amount of sea ice-derived carbon was maintained in high-Arctic Atlantic walrus (98% in 1996 and 89% in 2006) despite a similar percentage in sea ice reduction. Nitrogen isotope baseline or the trophic position of Atlantic walrus did not change over time at either location. These findings indicate latitudinal differences in the restructuring of carbon energy sources used by Atlantic walrus and their benthic prey, and in turn a change in Arctic marine ecosystem functioning between sea ice-pelagic-benthic habitats.


Hereditary chronic pancreatitis: implications for surgical treatment and follow-up.
Hereditary pancreatitis is an uncommon cause of chronic pancreatitis in Western society. It should be suspected when chronic pancreatitis presents in young adults. The diagnosis is made when chronic pancreatitis is present in several members of the same family who are determined not to have other risk factors for chronic pancreatitis. Molecular research focusing on mutations in the trypsinogen gene has uncovered the genetic defects associated with hereditary pancreatitis, and this knowledge has suggested the possible pathophysiologic mechanism of this disease. Because patients with hereditary pancreatitis develop their disease early in life they are very likely to require treatment for complications. As in patients with chronic pancreatitis of other etiologies those with hereditary pancreatitis should be treated medically for acute exacerbations. When complications occur or when the disease causes intractable pain surgery is recommended. Surgical therapy is tailored to the patient's pancreatic anatomy based on endoscopic retrograde cholangiopancreatography or CT scan. The two patients described in this report underwent successful longitudinal pancreaticojejunostomy (Puestow procedure) with good results. Finally it has been shown that patients with hereditary pancreatitis are at increased risk for developing pancreatic adenocarcinoma. Although not widely used pancreatic cancer screening programs have been suggested for surveillance of these patients.


Rapid identification of nonessential genes of herpes simplex virus type 1 by Tn5 mutagenesis.
The large genome of herpes simplex virus type of (HSV-1) encodes at least 80 polypeptides, the majority of which have no recognized function. A subgroup of these gene products appears to be nonessential for virus replication in cell culture, but contributes to the complex life cycle of the virus in the host. To identify such functions, a simple insertional mutagenesis method has been used for selective inactivation of individual HSV-1 genes. The bacterial transposon Tn5 was allowed to insert randomly into cloned restriction fragments representing the entire short unique (US) region of the HSV-1 genome. Of the 12 open reading frames that were mutagenized with Tn5, mutant derivatives of US2, US4, and US5 were recombined into the virus. These three genes proved to be nonessential for HSV-1 replication in Vero (African Green monkey kidney) cells and the US4 gene appeared to be involved in viral pathogenesis in the central nervous system of mice. This rapid mutagenesis procedure should prove useful in exploring the entire HSV-1 genome as well as the genomes of other complex animal viruses.


Promotion of direct angiogenesis in vitro and in vivo by Puerariae flos extract via activation of MEK/ERK-, PI3K/Akt/eNOS-, and Src/FAK-dependent pathways.
Puerariae flos has been used for oriental herbal medicine; however, its angiogenic effect has not been elucidated. We found that the extract from Puerariae flos (PFE) increased in vitro angiogenic events, such as endothelial cell proliferation, migration, and tube formation, as well as in vivo neovascularization. These events were followed by the activation of multiple signal modulators, such as extracellular signal-regulated kinase (ERK), Akt, endothelial nitric oxide synthase (eNOS), nitric oxide production, p38, Src, and focal adhesion kinase (FAK), without increasing vascular endothelial growth factor (VEGF) expression. Inhibition of ERK, Akt, and eNOS suppressed PFE-induced angiogenic events, and inhibition of p38 and Src activities blocked PFE-induced endothelial cell migration. PFE did not affect the expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 and transendothelial permeability, which are involved in the adverse effects of the well-known angiogenic inducer VEGF. These results suggest that PFE directly stimulates angiogenesis through the activation of MEK/ERK-, phosphatidylinositol 3-kinase/Akt/eNOS-, and Src/FAK-dependent pathways, without altering VEGF expression, vascular inflammation, and permeability in vitro and in vivo and may be used as a therapeutic agent for ischemic disease and tissue regeneration.


Interference of antibody production to hepatitis B surface antigen in a combination hepatitis A/hepatitis B vaccine.
A randomized trial comparing 3 manufacturing consistency lots of a combination hepatitis A/hepatitis B vaccine to each other and to hepatitis A vaccine and hepatitis B vaccine given separately and concurrently was done to evaluate safety, tolerability, and immunogenicity. Healthy volunteers >/=11 years of age were divided into 4 groups. Each of 3 groups received a separate consistency lot of the combination vaccine, and 1 group received separate but concurrent injections of hepatitis A and hepatitis B vaccines. Injections were given at weeks 0 and 24. The combination vaccine was generally well tolerated. The hepatitis A portion of the combination vaccine produced clinically acceptable high seropositivity rates 4 and 52 weeks after the first injection. The hepatitis B portion of the vaccine did not produce clinically acceptable seropositivity rates 4 weeks after the second injection. Lack of antibody production may be attributed, at least in part, to immunologic interference.


Monoclonal antibodies to infectious pancreatic necrosis virus: analysis of viral epitopes and comparison of different isolates.
A panel of five monoclonal antibodies (MAbs) produced against the West Buxton isolate of infectious pancreatic necrosis virus was used to investigate viral antigens and to compare different aquatic birnavirus isolates antigenically. Reciprocal blocking ELISA and neutralization assays indicated that these MAbs identified four, and possibly five, structurally and/or functionally different epitopes on the virion. Western immunoblot analysis demonstrated that one epitope was present on VP2, the large (51,000 mol. wt., 51K) capsid protein, and another epitope was located on the two smallest structural proteins, VP3 (32K) and VP4 (30K). Three MAbs did not react with any of the solubilized viral proteins; the epitopes recognized by these MAbs may have been altered when the virion was solubilized with SDS. Comparison of reactivity patterns of the five MAbs with various aquatic birnaviruses in ELISA and neutralization tests demonstrated that 14 isolates tested from four serotypes represented a minimum of nine antigenically distinct viruses; i.e., distinct patterns of reactivity were shown among several viruses within the same serotype. Two MAbs identified different epitopes that were highly conserved among, and largely restricted to, members of the West Buxton (U.S.A.) serotype, whereas two other MAbs recognized an epitope(s) present only on some members of this serotype. The other MAb defined an epitope that was more widely distributed among the aquatic birnaviruses and found on all representatives tested from two serotypes.


The pseudorabies virus UL11 protein is a virion component involved in secondary envelopment in the cytoplasm.
Homologs of the small tegument protein encoded by the UL11 gene of herpes simplex virus type 1 are conserved throughout all herpesvirus subfamilies. However, their function during viral replication has not yet been conclusively shown. Using a monospecific antiserum and an appropriate viral deletion and rescue mutant, we identified and functionally characterized the UL11 protein of the alphaherpesvirus pseudorabies virus (PrV). PrV UL11 encodes a protein with an apparent molecular mass of 10 to 13 kDa that is primarily detected at cytoplasmic membranes during viral replication. In the absence of the UL11 protein, viral titers were decreased approximately 10-fold and plaque sizes were reduced by 60% compared to wild-type virus. Intranuclear capsid maturation and nuclear egress resulting in translocation of DNA-containing capsids into the cytoplasm were not detectably affected. However, in the absence of the UL11 protein, intracytoplasmic membranes were distorted. Moreover, in PrV-DeltaUL11-infected cells, capsids accumulated in the cytoplasm and were often found associated with tegument in aggregated structures such as had previously been demonstrated in cells infected with a PrV triple-mutant virus lacking glycoproteins E, I, and M (A. R. Brack, J. M. Dijkstra, H. Granzow, B. G. Klupp, and T. C. Mettenleiter, J. Virol. 73:5364-5372, 1999). Thus, the PrV UL11 protein, like glycoproteins E, I, and M, appears to be involved in secondary envelopment.


Deep Brain Stimulation of the Nucleus Accumbens Core Affects Trait Impulsivity in a Baseline-Dependent Manner.
Deep brain stimulation (DBS) of the nucleus accumbens (NA) is explored as a treatment for refractory psychiatric disorders, such as obsessive-compulsive disorder (OCD), depressive disorder (MDD), and substance use disorder (SUD). A common feature of some of these disorders is pathological impulsivity. Here, the effects of NAcore DBS on impulsive choice and impulsive action, two distinct forms of impulsive behavior, were investigated in translational animal tasks, the delayed reward task (DRT) and five-choice serial reaction time task (5-CSRTT), respectively. In both tasks, the effects of NAcore DBS were negatively correlated with baseline impulsive behavior, with more pronounced effects in the 5-CSRTT. To further examine the effects of DBS on trait impulsive action, rats were screened for high (HI) and low (LI) impulsive responding in the 5-CSRTT. NAcore DBS decreased impulsive, premature responding in HI rats under conventional conditions. However, upon challenged conditions to increase impulsive responding, NAcore DBS did not alter impulsivity. These results strongly suggest a baseline-dependent effect of DBS on impulsivity, which is in line with clinical observations.


Attenuation by reactive oxygen species of glucocorticoid suppression on proopiomelanocortin gene expression in pituitary corticotroph cells.
Up-regulation of hypothalamo-pituitary-adrenal axis is maintained during acute inflammation and/or infection, in the face of sustained elevation of plasma glucocorticoid hormone. Inflammatory stress is usually associated with high plasma cytokine levels and increased generation of reactive oxygen species (ROS) as well. In this study, we examined the effect of ROS on the negative feedback regulation of glucocorticoid in hypothalamo-pituitary-adrenal axis using AtT20 corticotroph cells in vitro. When the cells were treated with H2O2, glucocorticoid suppression on the proopiomelanocortin gene promoter activity was attenuated in a dose-dependent manner. H2O2 also inhibited the ligand-stimulated nuclear translocation of glucocorticoid receptor. The released glucocorticoid suppression by H2O2 was not observed when the cells were cotreated with antioxidants. Together, these results suggest that increased ROS generation in the oxidative redox state attenuates the glucocorticoid negative feedback system, at least in part, by interfering with the nuclear translocation of glucocorticoid receptor and eliminating the repression on proopiomelanocortin gene expression.


The interface between United Kingdom, Irish and Australasian college qualifications.
Colleges in different parts of the world fulfil an important role in setting standards and ensuring a high calibre of postgraduate dental education and training. They have evolved to fulfil the requirements of the particular circumstances prevailing in each country. With the changes that are taking place throughout the world and the increasing demands for high quality general and specialist dental care, all of the colleges are modifying their structures and examination formats. In many ways these changes are bringing the colleges more in line with each other. In view of this, there is a need for better communication and closer collaboration between the colleges. In the United Kingdom and Ireland proposals for shorter, more structured training programmes and for more specialist dental care to be provided outside hospitals, together with the influence of European Community law, have resulted in major changes. Among the effects of these changes are a restructuring of training programmes, the development and recognition of new specialties and the reconfiguration of college qualifications.


Reduction in protein tyrosine phosphorylation during differentiation of human leukemia cell line K-562.
Human chronic myelogenous leukemia cell line K-562 expresses the bcr/c-abl fusion protein which is an active protein tyrosine kinase. Multiple tyrosine-phosphorylated proteins were detected in K-562 cells by immunoblotting with a high-affinity anti-phosphotyrosine antibody. When K-562 cells were induced with hemin to progress through the erythroid differentiation pathway, reduction in the levels of these tyrosine-phosphorylated proteins was observed. This reduction in tyrosine-phosphorylated proteins was not found in another chronic myelogenous leukemia cell line which could not be induced to differentiate by hemin. This and other observations established that the reduction in protein tyrosine phosphorylation is a specific differentiation response. The bcr/c-abl protein synthesis was reduced in hemin-treated K-562 cells. Thus, erythroid differentiation of K-562 cells reduces the level of the bcr/c-abl tyrosine kinase and the phosphotyrosine content of its substrate proteins.


Incidence and pattern of cardiovascular disease in a Nigerian teaching hospital.
Epidemiological data on cardiovascular disorders are generally lacking in the developing nations. The aim of this study was to assess the five years' incidence and pattern of cardiovascular disease in a Nigerian Teaching Hospital. The records of patients diagnosed as having various cardiovascular disorders between 1997 and 2001 were scrutinized. Data such as age, sex, diagnosis, length of hospitalization and status at discharge (dead or alive) were obtained. A total number of 1104 patients were recorded. Heart failure (35%) followed by hypertension (32%) was found to be the most prevalent.


Influence of 2-(18F) fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography on recurrent ovarian cancer diagnosis and on selection of patients for secondary cytoreductive surgery.
The objective of this prospective study was to compare the sensitivities and the specificities of combined 2-(F) fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT), abdominal/transvaginal ultrasound (US), and CT for diagnosing recurrent ovarian cancer (OC) and to evaluate the influence of PET/CT on referral of patients with solitary recurrence to secondary cytoreductive surgery. From April 2005 to November 2007, 60 patients were consecutively included to PET/CT 68 times. The inclusion criteria were remission of 3 months or longer and recurrent OC suspected from physical examination, US, or increasing cancer antigen 125 (CA125) level (>50 U/mL or >15% above baseline level). Recurrent OC was diagnosed 58 times in 52 patients. The sensitivities of US, CT, and PET/CT for diagnosing recurrence were 66% (P = 0.003), 81% (P = 0.0001), and 97% (P < 0.0001), respectively. The specificity of US, CT, and PET/CT for diagnosing recurrence was 90%. Positron emission tomography/CT diagnosed recurrence in 19 (66%) of 29 patients without recurrence according to US and in 10 (50%) of 20 patients without recurrence after CT. Multiple recurrent tumors were found using PET/CT in 27 (69%) of 39 patients with solitary tumors on US and in 8 (42%) of 19 patients with solitary tumors on CT. We conclude that the diagnostic value of PET/CT for detecting recurrent OC was higher than those of US and CT and that PET/CT more accurately identified patients with solitary recurrence. However, prospective clinical trials are needed to specify the characteristics of patients most likely to undergo complete secondary surgery and to further clarify the role of PET/CT in selecting patients for secondary surgery.


Complex polysaccharide inclusions in skeletal muscle adjacent to sarcomas in two dogs.
Inclusions of periodic acid-Schiff-positive, amylase resistant material were found within skeletal muscle fibers adjacent to an osteosarcoma in the proximal femur of an 8-year-old intact female Cocker Spaniel dog (dog No. 1) and adjacent to a synovial cell sarcoma of the stifle joint in a 7-year-old spayed female Bouvier des Flandres dog (dog No. 2). Inclusions were pale blue-gray with hematoxylin and eosin stain and formed irregular inclusions, replacing up to approximately 80% of the fiber diameter. Inclusions from dog No. 2 were of non-membrane-bound granular to filamentous material that occasionally formed discrete, elongate electron-dense masses. The features of these inclusions were similar to those of materials previously described as complex polysaccharide, polyglucosan bodies, amylopectin, and Lafora bodies. Evidence for a generalized metabolic disorder was not found in these two dogs, suggesting that storage of complex polysaccharide can occur as a relatively nonspecific response to metabolic alterations in skeletal muscle in a variety of conditions.


The U.K. Prospective Diabetes Study. A review.
The objective of the U.K. Prospective Diabetes Study (UKPDS), initiated in 1977, was set up to determine whether improved blood glucose control in people with type 2 diabetes will prevent the complications of diabetes. The UKPDS was also designed to determine whether there are differences between conventional policy (diet therapy) and three different regimens of intensive treatment policy, based on sulfonylurea, metformin, or insulin. Interim efficacy analyses revealed that the intensive policies with sulfonylurea, insulin, and metformin were equally effective in reducing fasting plasma glucose concentrations. However, glucose and HbA1c measurements steadily increased with time, reflecting ongoing deterioration of beta-cell function. Cardiovascular disease was the major cause of complications, and the risk factors included raised LDL cholesterol concentrations, low HDL cholesterol concentrations, elevated blood pressure, elevated HbA1c concentrations, and smoking. A final study report was issued in September 1998, when the median duration of therapy was 11 years.


Use of sodium deoxycholate to extract cell wall components of virulent Mycobacterium bovis.
Mycobacterium bovis ATCC No. 19210 was grown on Middlebrook 7H-10 medium with pyruvate. Cells were harvested, and extracts were prepared, using 2% sodium deoxycholate (DOC) and 0.003M EDTA (in 0.1M Tris-HCl, 0.15M NaCl with 0.02% sodium azide [pH 8.4]). Phenylmethylsulfonyl fluoride was added, and the cells were extracted for 48 hours at 4 C. Cells were removed by centrifugation at 10,000 X g for 30 minutes. The supernatant was filter sterilized and separated into 2 fractions (peak A and peak B) by size-exclusion chromatography. The nonfractionated DOC extract and DOC peak A elicited delayed-type hypersensitivity responses at each of the protein concentrations tested (0.5, 1.5, and 4.5 micrograms) in M bovis-sensitized guinea pigs; responses were not detected, using DOC peak B. Significant differences were detected for each of the antigens when enzyme-linked immunosorbent assay values were compared, using sera from cattle before and 10 months after they were exposed to M bovis (P less than 0.01).


Wnt3a signaling induces murine dental follicle cells to differentiate into cementoblastic/osteoblastic cells via an osterix-dependent pathway.
Dental follicle cells, putative progenitor cells for cementoblasts, osteoblasts and periodontal ligament cells, interplay with Hertwig's epithelial root sheath (HERS) cells during tooth root formation, in which HERS is considered to have an inductive role in initiating cementogenesis by epithelial-mesenchymal interaction. However, the specific mechanisms controlling the cementoblast/osteoblast differentiation of dental follicle cells are not fully understood. Canonical Wnt signaling has been implicated in increased bone formation by controlling mesenchymal stem cell or osteoblastic cell functions. This study examined the possible expression of canonical Wnt ligand in HERS and the role of Wnt signaling during the cementoblast/osteoblast differentiation of dental follicle cells. The expression of Wnt3a, a representative canonical Wnt ligand, in HERS was assessed by immunohistochemistry. The differentiation and function of immortalized murine dental follicle cells were evaluated by measuring alkaline phosphatase (ALP, Alpl) activity and osteogenic gene expression. We identified the expression of Wnt3a in HERS during mouse tooth root development by immunohistochemistry as well as in cultured human epithelial rest cells of Malassez by real-time polymerase chain reaction, while no expression of Wnt3a was detected in cultured dental mesenchymal cells. Exposure of immortalized murine dental follicle cells to Wnt3a-induced ALP activity as well as expression of the Alpl gene. Pretreatment of cells with Dickkopf-1, a potent canonical Wnt antagonist, markedly attenuated the effect of Wnt3a on ALP expression. Furthermore, Wnt3a induced transcriptional activity of runt-related transcription factor 2 (Runx2) and expression of osterix at gene and/or protein levels. Treatment with osterix-small interfering RNA significantly inhibited Wnt3a-induced ALP expression at gene and protein levels. These findings suggest that HERS has a potential role in stimulating cementoblast/osteoblast differentiation of dental follicle cells via the Wnt/β-catenin signaling pathway.


Diagnostic accuracy of the RBANS in mild cognitive impairment: limitations on assessing milder impairments.
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has demonstrated adequate sensitivity in detecting cognitive impairment in a number of neuropsychiatric conditions, including Alzheimer's disease. However, its ability to detect milder cognitive deficits in the elderly has not been examined. The current study examined the clinical utility of the RBANS by comparing two groups: Patients with Mild Cognitive Impairment (MCI; n = 72) and cognitively intact peers (n = 71). Significant differences were observed on the RBANS Total score, 3 of the 5 Indexes, and 6 of the 12 subtests, with individuals with MCI performing worse than the comparison participants. Specificity was very good, but sensitivity ranged from poor to moderate. Areas under the receiver operating characteristic curves for the RBANS Immediate and Delayed Memory Indexes and the Total Scale score were adequate. Although significant differences were observed between groups and the areas under the curves were adequate, the lower sensitivity values of the RBANS suggests that caution should be used when diagnosing conditions such as MCI.


Antiretroviral exposure and comorbidities in an aging HIV-infected population: The challenge of geriatric patients.
As HIV-infected adults on successful antiretroviral therapy (ART) are expected to have close to normal lifespans, they will increasingly develop age-related comorbidities. The objective of this cross-sectional study was to compare in the French Dat'AIDS cohort, the HIV geriatric population, aged 75 years and over, to the elderly one, aged from 50 to 74 years. As of Dec 2015, 16,436 subjects (43.8% of the French Dat'AIDS cohort) were aged from 50 to 74 (elderly group) and 572 subjects (1.5%) were aged 75 and over (geriatric group). Durations of HIV infection and of ART were slightly but significantly different, median at 19 and 18 years, and 15 and 16 years in the elderly and geriatric group, respectively. The geriatric group was more frequently at CDC stage C and had a lower nadir CD4. This group had been more exposed to first generation protease inhibitors and thymidine analogues. Despite similar virologic suppression, type of ART at the last visit significantly differed between the 2 groups: triple ART in 74% versus 68.2%, ART ≥ 4 drugs in 4.7% versus 2.7%; dual therapy in 11.6% versus 16.4% in the elderly group and the geriatric group, respectively. In the geriatric group all co-morbidities were significantly more frequent, except dyslipidemia, 4.3% of the elderly group had ≥4 co-morbidities versus18.4% in the geriatric group. Despite more co-morbidities and more advanced HIV infection the geriatric population achieve similar high rate of virologic suppression than the elderly population. A multidisciplinary approach should be developed to face the incoming challenge of aging HIV population.


Sparse Deconvolution and Causality Analysis of Inflammatory Markers During Cardiac Surgery.
Major bodily trauma such as cardiac surgery elicits (in response to tissue injury and other exogenous surgical factors) a whole-body inflammation response during which specialized signaling proteins called cytokines are synthesized and invoke multiple defense mechanisms. Many proinflammatory and anti-inflammatory cytokines such as interleukins (IL) and tumor necrosis factor (TNF) are produced to initiate bodily repair. Due to the adverse health consequences, including mortality, of a maladaptive cytokine response, understanding their complex dynamics using system-theoretic modeling and analysis may pave the way for controlling the inflammatory response which may eventually improve medical outcomes for patients. To this end, we use clinical data from ten patients undergoing coronary arterial bypass graft surgery to study the response of four cytokines (IL6, IL8, IL10, TNFα) and the neuroendocrine hormone cortisol. We perform deconvolution to obtain the secretory pulses underlying their pulsatile production and analyze causal interactions, mathematically uncovering some interactive relationships found in previous experimental studies.Clinical relevance- This work is a first step towards a mechanistic inference of the inflammatory response to surgery that could eventually help control the inflammatory response and could inform medical interventions to improve patient outcomes.


Ocular manifestations of the antiphospholipid syndrome.
Antiphospholipid syndrome (APS) is an autoimmune disease characterised by a heterogenous group of antibodies directed against negatively charged phospholipids including antiphospholipid antibodies (aPL), anticardiolipin antibodies (aCL) and β-2 glycoprotein I (aβ-2-GP1). The major features of this disorder include arterial and venous thrombosis and recurrent fetal loss. The vasculature of the eye is frequently involved and may be the presenting manifestation. A diagnosis of APS should be considered in a young patients without traditional thromboembolic risk factors presenting with ocular vaso-occlusive disease. Management of these patients involves a team-approach with a haematologist/oncologist or rheumatologist to manage the coagulation status of these patients to prevent further systemic vascular occlusions.


Direct in vivo cellular reprogramming involves transition through discrete, non-pluripotent steps.
Cells can change identity during normal development, in response to tissue damage or defined artificial treatments, or during disease processes such as cancer. Strikingly, not only the reprogramming of tissue cells to an embryonic stem cell-like state, but also the direct conversion from one cell type to another have been described. Direct cell type conversion could represent an alternative strategy for cellular therapies. However, little is known about the actual cellular steps undertaken by a cell as it changes its identity and their possible consequences for the organism. Using an in vivo single-cell system of natural direct reprogramming, in which a C. elegans rectal cell transforms into a motoneuron, we present an in-depth analysis of the cellular transformations involved. We found that the reprogrammed cell transits through intermediate states during direct in vivo reprogramming. We identified and characterised a mutant in the conserved COE transcription factor UNC-3 in which this cellular transformation is blocked. We determined that complete erasure of initial identity first takes place, followed by stepwise, unc-3-dependent, redifferentiation into a motoneuron. Furthermore, unlike in vitro induced reprogramming, reversion to a dedifferentiated identity does not lead to an increase in cellular potential in a natural, in vivo context. Our findings suggest that direct cell type conversion occurs via successive steps, and that dedifferentiation can occur in the absence of cell division. Furthermore, our results suggest that mechanisms are in place in vivo to restrict cell potential during reprogramming, a finding with important implications for regenerative medicine.


Impact of family history of cancer on colorectal cancer screening: a propensity score-matched analysis from the Health Information National Trends Survey (HINTS).
Early detection of colon cancer leads to better survival outcomes. This can be achieved through colorectal cancer (CRC) screening. People with a family history of cancer (FHC) have increased risk of developing CRC. Increasing screening in this group will reduce CRC mortality. This study evaluated CRC screening in people with FHC. The study used data from the Health Information National Trends Survey (HINTS) 5, cycle 3. This is an annual cross-sectional survey with a nationally representative sample of American adults. The objective was to study the association between FHC and performing CRC screening. Propensity score matching was used to create a matched population with variables that constituted beliefs in cancer from the survey. Replication procedure, which is based on repeated sampling and allows for accurate computation of standard errors, was used for calculating statistical tests. Multivariable models were fitted in the matched population to assess the association between FHC and performing CRC screening. People with FHC were 14% (OR = 1.14; 95% CI: 0.81-1.60) more likely to perform CRC screening than those without FHC, even though not statistically significant. Age in years (OR = 1.14; 95% CI: 1.12-5.27) had increased likelihood of performing CRC screening, while other races such as American Indians/Alaskan Natives (except African Americans) compared to Caucasians (OR = 0.49; 95% CI: 0.29-0.84) had significantly decreased likelihood of performing CRC screening. FHC was not significantly associated with having a colorectal cancer screening test. Public health advocacy should be directed towards increasing awareness of CRC screening among people with FHC.


Evidence for PTZ-like cues as a function of time following treatment with chlordiazepoxide: implications for understanding tolerance and withdrawal.
The present study used a two-lever, drug-discrimination procedure to train rats to discriminate between the cues associated with 5 mg/kg of the anxiolytic, chlordiazepoxide (CDP) and 15 mg/kg of the anxiogenic, pentylenetetrazol (PTZ), to investigate the relationship between withdrawal and acute tolerance. Training doses of the two drugs were chosen so that rats responded about equally on both levers when tested on saline (SAL). Following acquisition of the discrimination, rats were injected with 10 mg/kg CDP and tested for lever choice at various intervals from 6 h to 192 h. These tests revealed that cues associated with CDP withdrawal lasted approximately three times longer than the cues associated with the drug's primary effects. At the shortest retest interval (6 h) after treatment with 10 mg/kg CDP, rats responded primarily on the CDP lever, followed by a shift to predominant responding on the PTZ lever at the 16 h and 24 h intervals before returning to predrug, baseline levels at the longer intervals (48-192 h). In order to investigate the relationship between tolerance and withdrawal to the cue properties of CDP, CDP dose-response curves were determined 24 h following treatment with SAL or 10 mg/kg CDP. Acute tolerance, as defined by a rightward, parallel shift in the dose-response function, was observed in the rats pretreated with CDP. Furthermore, it was evident that the baseline shift associated with CDP withdrawal, rather than a weaker drug cue, accounted for acute tolerance. The results from this study are relevant to evaluating the role positive and negative reinforcement play in motivating compulsive drug use.


[Risk factors of complications (bleedings) in duodenal ulcer disease].
The role of ulceration risk factors in the development of duodenal ulcer complications was under examination. The leading role of risk factors for the development of complications in case of an infection of the stomach mucous coat with virulent VacA-positive strains of Helicobacter pylori belonging to the s1/s2 subtype and characterized by a high amount of mixed genotypes of the VacA gene (64%)--was established. The proved growth of immunological inflammation markers and depression of the humoral immunity part was discovered.


AI-based digital image dietary assessment methods compared to humans and ground truth: a systematic review.
Human error estimating food intake is a major source of bias in nutrition research. Artificial intelligence (AI) methods may reduce bias, but the overall accuracy of AI estimates is unknown. This study was a systematic review of peer-reviewed journal articles comparing fully automated AI-based (e.g. deep learning) methods of dietary assessment from digital images to human assessors and ground truth (e.g. doubly labelled water). Literature was searched through May 2023 in four electronic databases plus reference mining. Eligible articles reported AI estimated volume, energy, or nutrients. Independent investigators screened articles and extracted data. Potential sources of bias were documented in absence of an applicable risk of bias assessment tool. Database and hand searches identified 14,059 unique publications; fifty-two papers (studies) published from 2010 to 2023 were retained. For food detection and classification, 79% of papers used a convolutional neural network. Common ground truth sources were calculation using nutrient tables (51%) and weighed food (27%). Included papers varied widely in food image databases and results reported, so meta-analytic synthesis could not be conducted. Relative errors were extracted or calculated from 69% of papers. Average overall relative errors (AI vs. ground truth) ranged from 0.10% to 38.3% for calories and 0.09% to 33% for volume, suggesting similar performance. Ranges of relative error were lower when images had single/simple foods. Relative errors for volume and calorie estimations suggest that AI methods align with - and have the potential to exceed - accuracy of human estimations. However, variability in food image databases and results reported prevented meta-analytic synthesis. The field can advance by testing AI architectures on a limited number of large-scale food image and nutrition databases that the field determines to be adequate for training and testing and by reporting accuracy of at least absolute and relative error for volume or calorie estimations.


Improving FoRe: A New Inlet Design for Filtering Samples through Individual Microarray Spots.
In this publication we present an improvement to our previously introduced vertical flow microarray, the FoRe array, which capitalizes on the fusion of immunofiltration and densely packed micron test sites. Filtering samples through individual microarray spots allows us to rapidly analyze dilute samples with high-throughput and high signal-to-noise. Unlike other flowthrough microarrays, in the FoRe design samples are injected into micron channels and sequentially exposed to different targets. This arrangement makes it possible to increase the sensitivity of the microarray by simply increasing the sample volume or to rapidly reconcentrate samples after preprocessing steps dilute the analyte. Here we present a new inlet system which allows us to increase the analyzed sample volume without compromising the micron spot size and dense layout. We combined this with a model assay to demonstrate that the device is sensitive to the amount of antigen, and as a result, sample volume directly correlates to sensitivity. We introduced a simple technique for analysis of blood, which previously clogged the nanometer-sized pores, requiring only microliter volumes expected from an infant heel prick. A drop of blood is mixed with buffer to separate the plasma before reconcentrating the sample on the microarray spot. We demonstrated the success of this procedure by spiking TNF-α into blood and achieved a limit of detection of 18 pM. Compared to traditional protein microarrays, the FoRe array is still inexpensive, customizable, and simple to use, and thanks to these improvements has a broad range of applications from small animal studies to environmental monitoring.


Clay-polymer nanocomposites: Progress and challenges for use in sustainable water treatment.
Contaminant removal from water involves various technologies among which adsorption is considered to be simple, effective, economical, and sustainable. In recent years, nanocomposites prepared by combining clay minerals and polymers have emerged as a novel technology for cleaning contaminated water. Here, we provide an overview of various types of clay-polymer nanocomposites focusing on their synthesis processes, characteristics, and possible applications in water treatment. By evaluating various mechanisms and factors involved in the decontamination processes, we demonstrate that the nanocomposites can overcome the limitations of individual polymer and clay components such as poor specificity, pH dependence, particle size sensitivity, and low water wettability. We also discuss different regeneration and wastewater treatment options (e.g., membrane, coagulant, and barrier/columns) using clay-polymer nanocomposites. Finally, we provide an economic analysis of the use of these adsorbents and suggest future research directions.


Internal carotid artery aneurysm mimicking normal-tension glaucoma.
Differentiating glaucomatous from nonglaucomatous optic disc cupping remains challenging. We present a case of a 48-year-old woman with an internal carotid aneurysm of approximately 3.5 mm × 6.5 mm that mimicked normal-tension glaucoma. The patient had a 2-year history of low vision acuity in her left eye and frontal oppressive headache. Owing to the carotid aneurysm, she developed an asymmetric vertical cup-to-disc ratio above 0.2, and marked inferotemporal neuronal rim loss and pallor of the residual rim were noted in the left disc. She also developed a visual field defect with an arcuate scotoma in the left eye. The patient was referred to a neurosurgeon and underwent endovascular aneurysm occlusion. This case highlights the diagnostic importance of recognizing that many neurological defects remain underdiagnosed.


Factors associated with genitourinary medicine clinic attendance and sexually transmitted infection diagnosis among central and east European migrants in London.
There has been a large influx of central and east European (CEE) migrants to the U.K. following the expansion of the European Union. This paper examines factors associated with genitourinary medicine (GUM) clinic attendance and sexually transmitted infection (STI) diagnosis among CEE migrants in London. A survey of sexual behaviour was conducted among CEE migrants attending two central London GUM clinics (n=299) and community venues in London (n=2276). Routinely collected clinic data were also analysed. CEE migrants made up 2.9% of male and 7.0% of female attendees at the clinics. Half the women attending sessions for female sex workers were from CEE countries, and paying for sex was widely reported by men. Women were more likely than men to have attended a GUM clinic in the U.K. (7.6% vs. 4.5%, p=0.002). GUM survey respondents were more likely than community survey respondents to report one or more new sexual partners in the past year (women 67.9% vs. 28.3%, p < 0.001; men 75.6% vs. 45.1%, p < 0.001) and homosexual partnership(s) in the past 5 years (men 54.3% vs. 1.8%, p < 0.001), but were less likely to report assortative heterosexual mixing (women 25.9% vs. 74.2%, p < 0.001; men 56.5% vs. 76.3%, p < 0.001). CEE patients make up a notable minority of patients attending two central London GUM clinics. Higher numbers of sexual partners, homosexual partnerships and sexual mixing with people from outside the country of origin are associated with GUM clinic attendance. Heterosexual CEE men report behaviours associated with HIV/STI acquisition but appear to be underutilising GUM services.


Feedback of audit results can improve clinical teaching (but may also impair it).
The objective of this study was to determine whether formal, written feedback to teachers would improve the quality of teaching. Twenty-seven units that were teaching clinical skills in teaching hospitals (TH), district general hospitals (DGH) and GP surgeries were used as the setting. One hundred and eighty-eight students in Audit Phase 1 (1997) and 175 students in Audit Phase 2 (1998) completed a questionnaire regarding time utilization during teaching sessions, tutor characteristics and course attributes. Feedback of results from the Audit Phase 1 questionnaire to each individual unit was combined with anonymized results of the other units. TH units (which had scored poorly in the first questionnaire) significantly improved the quality of their teaching. This was seen in increases in (1) the degree of prior preparation, (2) the number of sessions that adhered to the guidelines provided in the study guide, (3) time spent with patients and (4) the interest shown in the students. By contrast, the DGH units and GP units (which had scored well in the first questionnaire), scored poorly in the second questionnaire for prior preparation (GP units) and educational value (DGH units). It is concluded that feedback can improve the quality of student teaching. However, when presented as a contrast with other poorly performing units, feedback may induce complacency.


Horner's syndrome revisited: with an update of the central pathway.
A brief summary is presented of the life of Johann Friedrich Horner, the eminent Swiss ophthalmologist, renowned for describing the effects of paralysis of the human cervical sympathetic nerves. His early education, the quality of his professional training, and the influence of his mentors, notably Carl Ludwig and Albrecht von Graefe, contributed to his discovery of the syndrome. The full text of Horner's original work (translated by J. F. Fulton, 1929a, Arch. Surg. 18:2025-2039) is cited. The history of clinical and experimental work carried out on the autonomic nervous system prior to Horner's discovery is reviewed, including the studies of Pourfour du Petit (cited in Fulton, 1929a and Singer and Underwood, 1962, Clarendon); Hare, 1838, Lond. Med. Gaz. 23:16-18; Bernard (cited by Singer and Underwood); Budge (1853, Acad. de Sci., p.377-378); Mitchell et al. (1864, Lippincott). Hare and Mitchell et al. came close to making the discovery but were apparently hindered by their inability to interpret the signs they elicited in their patients. The experiments of Claude Bernard gave succinct accounts of the effects of damage to the cervical sympathetic nerves in animals, although there appears to be no evidence that he made similar observations in humans. Horner was the first to give a detailed, scientifically supported account and accurately interpret the signs of cervical sympathetic nerve damage in a human subject. The anatomy of the pathway is reviewed and the detailed structure of its central part updated. Evidence from computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon-emission computerized tomography (SPECT) studies have confirmed that reciprocally connected centers in the insular cortex, central nucleus of amygdala, hypothalamus, mesencephalic and pontine tegmentum, nucleus of tractus solitarius, and the ventrolateral medulla form the central pathway. The nucleus of tractus solitarius is probably the main reflex center for the sympathetic system, whereas the ventrolateral medulla serves as the pathway through which the central neurons influence the preganglionic neurons of the thoracolumbar outflow. Emotional and sensory inputs from the frontal and somatosensory cortices provide the inputs needed by the insula to drive the sympathetic nervous system to produce appropriate responses.


Targeting ischemic penumbra: part I - from pathophysiology to therapeutic strategy.
Penumbra is the viable tissue around the irreversibly damaged ischemic core. The purpose of acute stroke treatment is to salvage penumbral tissue and to improve brain function. However, the majority of acute stroke patients who have treatable penumbra are left untreated. Therefore, developing an effective non-recanalizational therapeutics, such as neuroprotective agents, has significant clinical applications. Part I of this serial review on "targeting penumbra" puts special emphases on penumbral pathophysiology and the development of therapeutic strategies. Bioenergetic intervention by massive metabolic suppression and direct energy delivery would be a promising future direction. An effective drug delivery system for this purpose should be able to penetrate BBB and achieve high local tissue drug levels while non-ischemic region being largely unaffected. Selective drug delivery to ischemic stroke penumbra is feasible and deserves intensive research.


Pediatric neurological complications of 2009 pandemic influenza A (H1N1).
To analyze the spectrum of neurological manifestations in children hospitalized with pandemic influenza A H1N1 virus of 2009 (pH1N1). Retrospective case series of children hospitalized from May 1, 2009, through November 30, 2009. Tertiary-care children's hospital in Colorado. All hospitalized patients with pH1N1 with neurological consult or diagnosis, lumbar puncture, electroencephalogram, or neuroimaging were selected as suspected cases. These were systematically reviewed and selected for final analysis if confirmed by pre-established definitions as a neurological complication. Of 307 children with pH1N1, 59 were selected as having suspected cases of neurological complications. Twenty-three children were confirmed to have a neurological complication. Of these 23, 15 (65%) required intensive care monitoring. The median length of stay was 4 days. Seventeen (74%) had a preexisting neurological diagnosis. The most common manifestation was seizure with underlying neurological disease (in 62% of cases) followed by encephalopathy with or without neuroimaging changes (in 26% of cases). Results from a lumbar puncture showed elevated protein levels in 3 of 6 patients but no significant pleocytosis. Seven of the 9 electroencephalograms showed diffuse slowing, and findings from magnetic resonance imaging were abnormal in 5 of 6 children. Deaths occurred in 13% of patients, and short-term disability in 22%. Children infected with pH1N1 presented with a wide spectrum of neurological manifestations, which occurred primarily in individuals with preexisting neurological conditions. These individuals had a severe disease course, evidenced by need for intensive care services and relatively high rates of mortality or neurological disability. Children with underlying neurological conditions should be particularly targeted for influenza prevention and aggressive supportive treatment at the onset of influenzalike symptoms.


Comparison of Magnetic Resonance Analysis of Myocardial Scarring With Biomarker Release Following S-T Elevation Myocardial Infarction.
Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) is commonly assumed to represent myocardial fibrosis; however, comparative human histological data are limited, and there is no consensus on the most accurate method for LGE quantitation. We evaluated the relationship between CMR assessment of regional fibrosis and infarct size assessment using serial biomarkers after ST elevation acute myocardial infarction (STEMI). Ninety-three patients treated for STEMI (59±10 years, 86% male) underwent CMR 6 months after infarction. Infarct size was quantified by CMR-LGE using manual and range of semi-automated thresholds (range: 2-10 standard deviations [SD]) above reference myocardium and the full width-half maximum (FWHM) technique, and compared with the rise in serum biomarkers. The agreement between CMR and biomarker in the identification of large infarcts based on peak troponin (TnI) levels was also analysed. Quantification methods had a strong influence on the infarct size assessment with CMR-LGE. Significant correlations were observed between LGE and biomarkers across all of the signal intensity thresholds. Whilst there was a wide variation with respect to the estimation of total LGE size (from 6.8±7.7 to 32.1±11.3 grams), the variation in the correlation with peak troponin level was much smaller (r-values ranging from 0.670 to 0.876). There was good agreement between CMR-LGE and biomarker assessment of infarct size; the best agreement between CMR-LGE and large infarction using a threshold of 8SD for peak TnI>50ng/mL (Cohen's kappa (κ)=0.722), and a threshold of 4SD for peak TnI >95ng/mL (κ=0.761). The correlation between CMR-LGE quantification of infarct size and biomarker release following STEMI at a range of semi-automated thresholds was consistently strong, with good agreement between measures across a range of thresholds.


Cohort trends in incidence of cervical cancer in Denmark in relation to gonorrheal infection.
In England & Wales and in Scotland an association has been found between the cohort pattern in mortality for cervical cancer and gonorrheal infection, used as indicator of sexually transmitted diseases in general. An equivalent association could not be found in the United States. In Denmark a peak in gonorrheal infection was observed towards the end of World War II. The maximum level attained in Denmark was higher than reported from the other countries; in Copenhagen the attack rate was 3.3 times the rate for the rest of Denmark. Incidence data on cervical cancer in Denmark are available from 1943 to 1977. The 1918-27 birth cohort is assumed to be the one most heavily affected by the gonorrhea epidemic during the war. Incidence data accumulated over a broad age span show no general excess risk of cervical cancer for women born 1918-27, but the incidence is increased for this cohort 15-20 years after the gonorrheal infection. The cervical cancer rates are higher for women in Copenhagen than for all Danish women, but the excess risks for the affected cohorts are less systematic here. The limited size of the population in Copenhagen, migrations, and an intensive screening are possible explanations for the divergence between the results for all of Denmark and for Copenhagen. The study indicates an association in Denmark between sexually transmitted diseases and cervical cancer, and the study shows the importance of taking the risk-modifying effect of screening into account in studies of etiology for cervical cancer.


[Apoptosis in myocardial ischemia and reperfusion].
Apoptosis initiated in cells of tissues maintaining homeostasis under the influence of growth factors and hormones has been recently described during the early stage of myocardial infarction in the reperfusion zone of the cardiac muscle. Although it has been proved that apoptosis of cardiomyocytes plays one of the key roles in progression of the reperfusion syndrome, molecular and cellular mechanisms of this phenomenon are not yet resolved. Prospects are discussed of a new trend in preventive treatment of ischemic and reperfusion-related affection of the myocardium relying upon blocking of apoptosis of cardiomyocytes.


Trust, commitment, love and sex: HIV, monogamy, and gay men.
Research on gay men's relationships has neglected monogamy. Instead, it has tended to (a) emphasize HIV risk and relationship agreements between partners regarding sex and condom use with outside partners or (b) focus on nonmonogamous relationships as emblematic of relationship innovation. On the basis of qualitative interviews with 36 gay Australian men who favored a monogamous relationship as ideal, this article explores the meaning and practice of monogamy and its association with HIV risk. The authors present themes that include men's use of condoms in monogamous relationships, expectations of fidelity, and understandings of trust and security as the basis to meaningful and satisfying relationships.


Virus-induced diabetes mellitus. XX. Polyendocrinopathy and autoimmunity.
Mice infected with reovirus type 1 developed transient diabetes and a runting syndrome. The diabetes was characterized by hyperglycemia, abnormal glucose tolerance tests, and hypoinsulinemia. Inflammatory cells and viral antigens were found in the islets of Langerhans, and virus particles were seen in alpha, beta, and delta cells. The runting syndrome consisted of retarded growth, oily hair, alopecia, and steatorrhea. Inflammatory cells and viral antigens were found in the anterior, but not posterior pituitary. Electron microscopy revealed virus particles in growth hormone (GH)-producing cells and radioimmunoassay showed that the concentration of GH in the blood was decreased. Examination of sera from infected mice revealed autoantibodies that, by immunofluorescence, reacted with cytoplasmic antigens in the islets of Langerhans, anterior pituitary, and gastric mucosa of uninfected mice. Absorption studies and enzyme-linked immunosorbent assays designed to identify the reactive antigens showed that some of the autoantibodies were directed against insulin and others against GH. Reovirus type 3, in contrast to reovirus type 1, did not induce autoantibodies to GH. By use of recombinant viruses, the segment of the reovirus genome responsible for the induction of autoantibodies to GH was identified. Virus containing the S1 gene segment from reovirus type 1, which codes for the sigma 1 polypeptide (i.e., hemagglutinin), infected cells in the anterior pituitary and induced autoantibodies to GH, whereas virus containing the S1 gene segment from reovirus type 3 failed to infect cells in the anterior pituitary and did not induce autoantibodies to GH. We conclude that reovirus type 1 infection can lead to polyendocrinopathy and autoimmunity and that the S1 gene segment is required for the induction of autoantibodies to GH.


Bioactivities of the Popular Edible Brown Seaweed Sargassum fusiforme: A Review.
Sargassum fusiforme has a wide range of active constituents (such as polysaccharides, sterols, polyphenols, terpenes, amino acids, trace elements, etc.) and is an economically important brown algae with a long history. In recent years, S. fusiforme has been intensively studied and has attracted wide attention in the fields of agriculture, environment, medicine, and functional food. In this review, we reviewed the current research status of S. fusiforme at home and abroad over the past decade by searching Web of science, Google Scholar, and other databases, and structurally analyzed the active components of S. fusiforme, and on this basis, we focused on summarizing the cutting-edge research and scientific issues on the role of various active substances in S. fusiforme in exerting antioxidant, anti-inflammatory, antitumor, antidiabetic, immunomodulatory, antiviral antibacterial, and anticoagulant effects. The mechanisms by which different substances exert active effects were further summarized by exploring different experimental models and are shown visually. It provides a reference to promote further development and comprehensive utilization of S. fusiforme resources.


Autoradiographic visualization and characterization of [3H]ouabain binding to the Na+,K+-ATPase of rat brain and pineal.
Ouabain binds to the catalytic subunit of Na+,K+-ATPase and specific [3H]ouabain binding can be used as a measure of the number of active enzyme molecules present in a given tissue. Specific [3H]ouabain binding can be demonstrated in frozen, cryostat sections from rat brain and pineal and these sites have the characteristics of Na+,K+-ATPase. Incubations carried out in the absence of ATP or the presence of excess unlabeled ouabain reduces specific binding by greater than or equal to 98%. The addition of K+ or omission of Mg2+ also result in a decrease in specific binding. Strophanthidin, digoxin and digoxigenin displace [3H]ouabain binding with IC50 values of 0.73, 0.48 and 1.4 microM, respectively. Scatchard analyses of specific [3H]ouabain binding in brain sections shows a single class of non-interacting binding sites with an apparent affinity (Kd) of 339 nM and a maximal binding capacity (Bmax) of 34.9 pmol/mg protein. [3H]Ouabain binding is unevenly distributed throughout the brain with the olfactory nuclei, superior colliculus, dentate gyrus, pontine nuclei and pineal gland having a relatively high density of binding sites. The outer layers (1-3) of the cerebral cortex show more labeling than the inner layers (4-6) and most other brain areas have intermediate levels of [3H]ouabain binding sites, whereas white matter has virtually no specific binding. Computer-assisted densitometry was used to measure changes in specific [3H]ouabain binding after kainic acid injection into the caudate nucleus. An initial increase in [3H]ouabain binding was observed at 1 and 24 h after lesioning and a decrease in [3H]ouabain binding was evident by 9 days after lesioning.(ABSTRACT TRUNCATED AT 250 WORDS)


[Ultrasonic biometry for foetal weight determination (author's transl)].
A new formula has been derived from computer-aided analysis for predictive calculation of foetal weight. Biparietal diameter and mean thorax diameter were the parameters for measurement, while the truncus was additionally included for another method by which even higher demands could be met. Weight determination proper was based on a practicable vanishing point diagram (nomogram). -- A critical appraisal is made of the methods previously used for weight forecasting on the basis of ultrasonic biometry. The authors' own approach is described in great detail and for convenient check-up by means of mathematical tables and graphs. It is claimed to give better results, particularly in marginal areas of foetal development, such as hypertrophy and/or macrosomia in concomitance with diabetes mellitus or retardation. -- Data published by other authors were recalculated, with the view to producing hard evidence to the superiority of the new formula.


Ki-67 Proliferative Activity in the Tumor Margins as a Robust Prognosis Factor in Glioblastoma Patients.
The infiltrative margin of glioblastomas (GBM) contains proliferative tumor cells difficult to estimate radiologically as they are included in the hyperintense signal of T2 sequences and they remain in the cavity margin after tumor resection. The amount of these cells could determine overall survival (OS) of these patients. From October 2007 to January 2010, patients whose MRI were suggestive of newly diagnosed, resectable high-grade glioma were operated using fluorescence-guided surgery (FGS). Separate samples were selectively taken from nonfluorescent white matter areas just adjacent to the border of the pale fluorescence and staining was made for Ki-67. OS was analyzed with Kaplan-Meier and Cox regression. Multivariate analysis included the following prognosis variables: age, extent of resection (EOR), O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and performance status index. Sample included 65 patients, comprising 37 men and 28 women, with a median Karnofsky Performance Score (KPS) of 80 (40-100) and mean age of 60 (34-78) years. Mean preoperative tumor volume was 35.8 mL. EOR was 100% in 52 patients (80%), with the lower EOR being 88%. For Ki-67, 39 patients had <5% and 26 had ≥5%. OS was 26.8 months (95% confidence interval [CI]: 18.9-28.2) for the Ki-67 low group versus 15.8 months (95% CI: 7.7-18.2) for the Ki-67 high group (p = 0.002). Proliferative activity in the normal-looking brain around the resection cavity measured with Ki-67 immunostaining is an important independent prognostic factor for GBM cases with complete resection of enhancing tumor. When complete resection is not reached, this factor is not relevant for prognosis.


Metabolic regulation of APOBEC-1 complementation factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes.
APOBEC-1 Complementation Factor (ACF) is an RNA-binding protein that interacts with apoB mRNA to support RNA editing. ACF traffics between the cytoplasm and nucleus. It is retained in the nucleus in response to elevated serum insulin levels where it supports enhanced apoB mRNA editing. In this report we tested whether ACF may have the ability to regulate nuclear export of apoB mRNA to the sites of translation in the cytoplasm. Using mouse models of obesity-induced insulin resistance and primary hepatocyte cultures we demonstrated that both nuclear retention of ACF and apoB mRNA editing were reduced in the livers of hyperinsulinemic obese mice relative to lean controls. Coincident with an increase in the recovery of ACF in the cytoplasm was an increase in the proportion of total cellular apoB mRNA recovered in cytoplasmic extracts. Cytoplasmic ACF from both lean controls and obese mouse livers was enriched in endosomal fractions associated with apoB mRNA translation and ApoB lipoprotein assembly. Inhibition of ACF export to the cytoplasm resulted in nuclear retention of apoB mRNA and reduced both intracellular and secreted ApoB protein in primary hepatocytes. The importance of ACF for modulating ApoB was supported by the finding that RNAi knockdown of ACF reduced ApoB secretion. An additional discovery from this study was the finding that leptin is a suppressor ACF expression. Dyslipidemia is a common pathology associated with insulin resistance that is in part due to the loss of insulin controlled secretion of lipid in ApoB-containing very low density lipoproteins. The data from animal models suggested that loss of insulin regulated ACF trafficking and leptin regulated ACF expression may make an early contribution to the overall pathology associated with very low density lipoprotein secretion from the liver in obese individuals.


Adriamycin-mediated introduction of a limited number of single-strand breaks into supercoiled DNA.
It was reported previously that Adriamycin converts form I covalently closed circular, supercoiled bacteriophage PM2 DNA to the relaxed circular form II DNA; no form III linear DNA was produced as a result of the extracellular action of Adriamycin in the presence of NADH-dehydrogenase. When form II DNA, produced by the action of Adriamycin, was treated with the BAL 31 nuclease, a single sharp DNA band after agarose gel electrophoresis indicated the presence of only full-length linear form III DNA. As one of its activities, the BAL 31 nuclease introduces a single-strand break in the complementary strand opposite a preexisting single-strand break. When form II DNA, produced by the action of gamma irradiation, was reacted with the BAL enzyme, the resulting linear DNA molecules exhibited a broad range of molecular weights, indicating the presence of many single-strand breaks in the substrate form II DNA. When the Adriamycin-produced form II DNA was treated with restriction endonucleases that cleave PM2 DNA at a single site, either with or without pretreatment with the BAL enzyme, the formation of only full-length linear DNA was observed. Thus, the drug is capable of introducing one or only a very limited number of single-strand breaks into supercoiled DNA; furthermore, these breaks are introduced at random sites along the DNA molecules.