Triple-X syndrome and premature ovarian failure.
Two patients with 47,XXX karyotypes and premature ovarian failure are described. Both presented with episodes of amenorrhea, elevated levels of circulating follicle-stimulating hormone and luteinizing hormone, and decreased estrogen concentrations. However, evidence of follicular activity existed in both cases. Why some women with 47,XXX karyotypes suffer from premature ovarian failure and why others have normal fertility and normal lengths of reproductive function is not known. Reports of immunologic disorders in patients with the triple-X syndrome and data showing that control of the lymphocyte may be related to the X chromosome point to a possible link between premature ovarian failure in 47,XXX women and immunologic abnormalities.


The Northern Marshall Islands Radiological Survey: data and dose assessments.
Fallout from atmospheric nuclear tests, especially from those conducted at the Pacific Proving Grounds between 1946 and 1958, contaminated areas of the Northern Marshall Islands. A radiological survey at some Northern Marshall Islands was conducted from September through November 1978 to evaluate the extent of residual radioactive contamination. The atolls included in the Northern Marshall Islands Radiological Survey (NMIRS) were Likiep, Ailuk, Utirik, Wotho, Ujelang, Taka, Rongelap, Rongerik, Bikar, Ailinginae, and Mejit and Jemo Islands. The original test sites, Bikini and Enewetak Atolls, were also visited on the survey. An aerial survey was conducted to determine the external gamma exposure rate. Terrestrial (soil, food crops, animals, and native vegetation), cistern and well water samples, and marine (sediment, seawater, fish and clams) samples were collected to evaluate radionuclide concentrations in the atoll environment. Samples were processed and analyzed for 137Cs, 90Sr, 239+240Pu and 241Am. The dose from the ingestion pathway was calculated using the radionuclide concentration data and a diet model for local food, marine, and water consumption. The ingestion pathway contributes 70% to 90% of the estimated dose. Approximately 95% of the dose is from 137Cs. 90Sr is the second most significant radionuclide via ingestion. External gamma exposure from 137Cs accounts for about 10% to 30% of the dose. 239+240Pu and 241Am are the major contributors to dose via the inhalation pathway; however, inhalation accounts for only about 1% of the total estimated dose, based on surface soil levels and resuspension studies. All doses are computed for concentrations decay corrected to 1996. The maximum annual effective dose from manmade radionuclides at these atolls ranges from .02 mSv y(-1) to 2.1 mSv y(-1). The background dose in the Marshall Islands is estimated to be 2.4 mSv y(-1). The combined dose from both background and bomb related radionuclides ranges from slightly over 2.4 mSv y(-1) to 4.5 mSv y(-1). The 50-y integral dose ranges from 0.5 to 65 mSv.


A project plan for construction and cabling of picture archiving and communication system network.
To determine a network solution to meet the network requirements of the heavy data flow, load balance, and potential network storms from expansion of picture archiving and communication system (PACS) application. Intel Netstructure 480T Giga Switch was used as the main switch and connected to each building by fiber channel at 1 Giga speed to archive 100 MB/s to each port. At the same time, the in-dependence of the original network construction was physically kept. The layer 3 and 4 switchers were used as load balance to reduce the heavy load of the network, and all the cabling for PACS used the super CAT5 along with the Intel NetStructure 1520 to prepare for potential network storms. An advanced intranet was set up to fully meet the high standard requirement of the PACS. The foundation for upgrading the whole network system to 1 Giga application was built to achieve sharing and transmission of images, information, and patient data within the hospital. The base was established for the standardized management of the hospital. Good planning is the first step in setting up PACS, and the equipment forms the necessary platform to run PACS and all kinds of hospital information system (HIS). The networking construction is the foundation of e-hospital.


Maternal immunization to Gov system alloantigens on human platelets.
Immunization to platelet alloantigens can occur during pregnancy or after the transfusion of blood components. Platelet alloantibodies can cause neonatal alloimmune thrombocytopenia and posttransfusion purpura. Transfusion-induced alloimmunization to a novel platelet alloantigen system, Gov, expressed on the 175-kDa glycosyl phosphatidylinositol-anchored platelet glycoprotein, CD109, was previously described. This report describes three unrelated patients who were alloimmunized to Gov(a) or Gov(b) during pregnancy. Platelets were typed by using radioimmunoprecipitation for HPA-1a, -3a, -5a, -5b, Gov(a), and Gov(b) and by polymerase chain reaction-restriction fragment length polymorphism for HPA-1a, -1b, -3a, and -3b. Maternal sera were screened for platelet antibodies by using radioimmunoprecipitation and the antigen capture assay. Patients 1 and 2 were investigated after the diagnosis of neonatal alloimmune thrombocytopenia in their children, and alloantibodies specific for Gov(b) and Gov(a), respectively, were detected in maternal serum. Serum from patient 3, who had mild idiopathic thrombocytopenia purpura with no detectable autoantibody, was found to contain alloantibodies to Gov(b) and to HPA-5b, presumably as a result of immunization during pregnancy. Platelet typings confirmed that the patients were at risk for alloimmunization to the respective antigen. This report of three cases of maternal alloimmunization to antigens in the Gov system indicates that immunization can occur via placental transfer of antigen and that Gov system alloantibodies may be associated with neonatal alloimmune thrombocytopenia.


Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant.
Psychiatric illness is common in HIV-infected patients and underlines the importance for screening not only for cognitive impairment but also for co-morbid mental disease. The rationale for combining immunomodulatory neurokinin- 1 receptor (NK1-R) antagonists with combined antiretroviral therapy (cART) is based on multimodal pharmacologic mechanisms. The NK1-R antagonist aprepitant's potential utility as a drug for depression is complicated by >99.9% protein binding and both enzyme inhibition and induction of CYP3A4. A population-based PK model developed from a pilot Phase 1B trial in 19 HIV-infected patients (125 or 250 mg/d aprepitant for 2 weeks) was modified to account for enzyme induction and impact of an exposure enhancer on CYP3A4 metabolism. Likelihood of clinical success in depression was assessed based on achievement of target trough plasma concentration and evaluated using Monte Carlo simulation. Scenarios were generated for varying daily dose (375, 625, 750 and 875 mg), pharmacokinetic variability, exposure enhancement (EE), duration (2 and 6 months) and sample size (n=12 and 24/arm). Daily dosing of ≥ 625 mg with EE yielded desirable troughs (based on in vitro infectivity experiments) of > 2.65 ug/mL for the majority of virtual patients simulated. Results are dependent on the degree of exposure enhancement and extent of enzyme induction. Actual threshold exposure requirements for aprepitant in HIV-associated depression are unknown though preclinical evidence supports trough levels > 2.65 ug/mL. If 100% NK1r blockage is necessary for efficacy, doses of 875 mg (625 mg with EE) or higher may be required. The benefit of aprepitant on innate immunity(natural killer cells) and absence of negative effects onex vivo neutrophil chemotaxis alleviates concerns regarding drug dependent inhibition (DDI)-mediated infection risk.


α-Linolenic acid and exercise training independently, and additively, decrease blood pressure and prevent diastolic dysfunction in obese Zucker rats.
α-linolenic acid (ALA) and exercise training both attenuate hyperlipidaemia-related cardiovascular derangements, however, there is a paucity of information pertaining to their mechanisms of action when combined. We investigated both the independent and combined effects of exercise training and ALA consumption in obese Zucker rats, aiming to determine the potential for additive improvements in cardiovascular function. ALA and exercise training independently improved cardiac output, end-diastolic volume, left ventricular fibrosis and mean blood pressure following a 4 week intervention. Combining ALA and endurance exercise yielded greater improvements in these parameters, independent of changes in markers of oxidative stress or endogenous anti-oxidants. We postulate that divergent mechanisms of action may explain these changes: ALA increases peripheral vasodilation, and exercise training stimulates angiogenesis. Although α-linolenic acid (ALA) and endurance exercise training independently attenuate hyperlipidaemia-related cardiovascular derangements, there is a paucity of information pertaining to their mechanisms of action and efficacy when combined as a preventative therapeutic approach. Therefore, we used obese Zucker rats to investigate the independent and combined effects of these interventions on cardiovascular disease. Specifically, animals were randomly assigned to one of the following groups: control diet-sedentary, ALA supplemented-sedentary, control diet-exercise trained or ALA supplemented-exercise trained. Following a 4 week intervention, although the independent and combined effects of ALA and exercise reduced (P < 0.05) the serum free/esterified cholesterol ratio, only the ALA supplemented-exercise trained animals displayed a reduction in the content of both serum free and esterified cholesterol. Moreover, although ALA and endurance training individually increased cardiac output, stroke volume and end-diastolic volume, as well as reduced left ventricle fibrosis, mean blood pressure and total peripheral resistance, these responses were all greater following the combined intervention (ALA supplemented-exercise trained). These effects occurred independent of changes in oxidative phosphorylation proteins, markers of oxidative stress or endogenous anti-oxidant capacity. We propose that the beneficial effects of a combined intervention occur as a result of divergent mechanisms of action elicited by ALA and endurance exercise because only exercise training increased the capillary content in the left ventricle and skeletal muscle, and tended to decrease protein carbonylation in the left ventricle (P = 0.06). Taken together, our data indicate that combining ALA and endurance exercise provides additional improvements in cardiovascular disease risk reduction compared to singular interventions in the obese Zucker rat.


ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.
Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.


Dopamine and glutamate in Huntington's disease: A balancing act.
Huntington's disease (HD) is caused by a CAG repeat expansion in exon 1 of the HD gene resulting in a long polyglutamine tract in the N-terminus of the protein huntingtin. Patients carrying the mutation display chorea in early stages followed by akinesia and sometimes dystonia in late stages. Other major symptoms include depression, anxiety, irritability or aggressive behavior, and apathy. Although many neuronal systems are affected, dysfunction and subsequent neurodegeneration in the basal ganglia and cortex are the most apparent pathologies. In HD, the primary hypothesis has been that there is an initial overactivity of glutamate neurotransmission that produces excitotoxicity followed by a series of complex changes that are different in the striatum and in the cortex. This review will focus on evidence for alterations in dopamine (DA)-glutamate interactions in HD, concentrating on the striatum and cortex. The most recent evidence points to decreases in DA and glutamate neurotransmission as the HD phenotype develops. However, there is some evidence for increased DA and glutamate functions that could be responsible for some of the early HD phenotype. Significant evidence indicates that glutamate and dopamine neurotransmission is affected in HD, compromising the fine balance in which DA modulates glutamate-induced excitation in the basal ganglia and cortex. Restoring the balance between glutamate and dopamine could be helpful to treat HD symptoms.


Lower gastrointestinal bleeding.
Lower gastrointestinal bleeding remains an important medical emergency. Most lower gastrointestinal bleeding is now known to come from angiodysplasia or diverticular disease. Accurate angiographic and colonoscopic diagnosis may lead to a better focus for treatment and improved survival.


The complete nucleotide sequences of the cloned hepatitis B virus DNA; subtype adr and adw.
The complete nucleotide sequences of two different subtypes (adr and adw) of hepatitis B virus (HBV) DNA cloned in E. coli were determined. The sequence of the viral genome of the adr clone was 3188 nucleotides long, and that of the adw clone was 3200 nucleotides long. The adr and adw clones differed from the reported cloned ayw HBV DNA (3182 nucleotides long) in 11.2% and 10.0% of nucleotides, respectively. Heterogeneity of the HBV genome in the clones with the same subtype was observed.


Antioxidative and Angiogenic Hyaluronic Acid-Based Hydrogel for the Treatment of Peripheral Artery Disease.
Peripheral arterial disease (PAD) is a progressive atherosclerotic disorder characterized by blockages of the arteries supplying the lower extremities. Ischemia initiates oxidative damage and mitochondrial dysfunction in the legs of PAD patients, causing injury to the tissues of the leg, significant decline in walking performance, leg pain while walking, and in the most severe cases, nonhealing ulcers and gangrene. Current clinical trials based on cells/stem cells, the trophic factor, or gene therapy systems have shown some promising results for the treatment of PAD. Biomaterial matrices have been explored in animal models of PAD to enhance these therapies. However, current biomaterial approaches have not fully met the essential requirements for minimally invasive intramuscular delivery to the leg. Ideally, a biomaterial should present properties to ameliorate oxidative stress/damage and failure of angiogenesis. Recently, we have created a thermosensitive hyaluronic acid (HA) hydrogel with antioxidant capacity and skeletal muscle-matching stiffness. Here, we further optimized HA hydrogels with the cell adhesion peptide RGD to facilitate the development of vascular-like structures in vitro. The optimized HA hydrogel reduced intracellular reactive oxygen species levels and preserved vascular-like structures against H2O2-induced damage in vitro. HA hydrogels also provided prolonged release of the vascular endothelial growth factor (VEGF). After injection into rat ischemic hindlimb muscles, this VEGF-releasing hydrogel reduced lipid oxidation, regulated oxidative-related genes, enhanced local blood flow in the muscle, and improved running capacity of the treated rats. Our HA hydrogel system holds great potential for the treatment of the ischemic legs of patients with PAD.


Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function.
INK4a/ARF tumor suppressor locus encodes two protein products, INK4a and ARF, essential for controlling tumorigenesis and mutated in more than half of human cancers. There is no resemblance between the two proteins: their coding regions are assembled by alternative splicing of two mutually exclusive 5' exons into a constitutive one containing overlapping out-of-phase reading frames. We show that the dual-coding arrangement conflicts with the high cost of mutations within INK4a/ARF. Unexpectedly, the locus evolves rapidly and asymmetrically, with ARF accumulating the majority of amino acid replacements. Rapid evolution drives both INK4a and ARF proteins out of sync with other members of the RB and p53 tumor suppressor pathways, both of which are controlled by the locus. Yet, the asymmetric behavior may be an intrinsic property of dual-coding exons: INK4a/ARF closely mimics the evolution of 90 newly identified genes with similar dual-coding structure. Thus, the strong link between mutations in INK4a/ARF and cancer may be a direct consequence of the architecture of the locus.


Purple Napiergrass (Pennisetum purpureum Schumach) Hot Water Extracts Ameliorate High-Fat Diet-Induced Obesity and Metabolic Disorders in Mice.
Purple Pennisetum (Pennisetum purpureum Schumach), a hybrid between Taihucao No. 2 and the local wild species of purple Pennisetum, has dark red stems and leaves due to its anthocyanin content. This study explores the potential of purple napiergrass extracts (PNE) in alleviating obesity and metabolic disorders induced by a high-fat diet in mice, where 50% of the caloric content is derived from fat. Mice were orally administered low-dose or high-dose PNE alongside a high-fat diet. Experimental findings indicate that PNE attenuated weight gain, reduced liver, and adipose tissue weight, and lowered blood cholesterol, triglyceride, low-density lipoprotein, and blood sugar levels. Stained sections showed that PNE inhibited lipid accumulation and fat hypertrophy in the liver. Immunoblotting analysis suggested that PNE improved the inflammatory response associated with obesity, dyslipidemia, and hyperglycemia induced by a high-fat diet. Furthermore, PNE potentially functions as a PPAR-γ agonist, increasing the adiponectin (ADIPOQ) concentration and suppressing inflammatory factors, while elevating the anti-inflammatory factor interleukin-10 (IL-10) in the liver. PNE-treated mice showed enhanced activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways and increased fatty acid oxidation and liver lipolysis. In conclusion, this study elucidated the mechanisms underlying the anti-inflammatory, PI3K/Akt, and AMPK pathways in a high-fat diet-induced obesity model. These findings highlight the potential of PNE in reducing weight, inhibiting inflammation, and improving blood sugar and lipid levels, showing the potential for addressing obesity-related metabolic disorders in humans.


Screening of inmates transferred to Spain reveals a Peruvian prison as a reservoir of persistent Mycobacterium tuberculosis MDR strains and mixed infections.
It is relevant to evaluate MDR-tuberculosis in prisons and its impact on the global epidemiology of this disease. However, systematic molecular epidemiology programs in prisons are lacking. A health-screening program performed on arrival for inmates transferred from Peruvian prisons to Spain led to the diagnosis of five MDR-TB cases from one of the biggest prisons in Latin America. They grouped into two MIRU-VNTR-clusters (Callao-1 and Callao-2), suggesting a reservoir of two prevalent MDR strains. A high-rate of overexposure was deduced because one of the five cases was coinfected by a pansusceptible strain. Callao-1 strain was also identified in 2018 in a community case in Spain who had been in the same Peruvian prison in 2002-5. A strain-specific-PCR tailored from WGS data was implemented in Peru, allowing the confirmation that these strains were currently responsible for the majority of the MDR cases in that prison, including a new mixed infection.


Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes.
Determining the full complement of protein-coding genes is a key goal of genome annotation. The most powerful approach for confirming protein-coding potential is the detection of cellular protein expression through peptide mass spectrometry (MS) experiments. Here, we mapped peptides detected in seven large-scale proteomics studies to almost 60% of the protein-coding genes in the GENCODE annotation of the human genome. We found a strong relationship between detection in proteomics experiments and both gene family age and cross-species conservation. Most of the genes for which we detected peptides were highly conserved. We found peptides for >96% of genes that evolved before bilateria. At the opposite end of the scale, we identified almost no peptides for genes that have appeared since primates, for genes that did not have any protein-like features or for genes with poor cross-species conservation. These results motivated us to describe a set of 2001 potential non-coding genes based on features such as weak conservation, a lack of protein features, or ambiguous annotations from major databases, all of which correlated with low peptide detection across the seven experiments. We identified peptides for just 3% of these genes. We show that many of these genes behave more like non-coding genes than protein-coding genes and suggest that most are unlikely to code for proteins under normal circumstances. We believe that their inclusion in the human protein-coding gene catalogue should be revised as part of the ongoing human genome annotation effort.


Phagocytosis, germination and killing of Bacillus subtilis spores presenting heterologous antigens in human macrophages.
Bacillus subtilis is a Gram-positive spore-bearing bacterium long used as a probiotic product and more recently regarded as an attractive vehicle for delivering heterologous antigens to be used for mucosal vaccination. This report describes the in vitro interaction between human macrophages and B. subtilis spores displaying the tetanus toxin fragment C or the B subunit of the heat-labile toxin of Escherichia coli on their surface in comparison to spores of the parental strain. Recombinant and parental B. subtilis spores were similarly internalized by human macrophages, at a frequency lower than 2.5%. Inside macrophages, nearly all spores germinated and were killed within 6 h. Using germination-defective spores and inhibiting spore germination inside macrophages, evidence was produced that only germinated spores were killed by human macrophages and that intracellular spore germination was mediated by an alanine-dependent pathway. The germinated spores were killed by macrophages before any round of cell duplication, as estimated by fluorescence microscopy analysis of macrophages infected with spores carrying the gfp gene fused to abrB, a B. subtilis gene shown here to be expressed at the transition between outgrowth and vegetative growth. Monitoring of macrophage infection never revealed cytotoxic effects being exerted by B. subtilis spores. These in vitro data support the hypothesis that B. subtilis spores may potentially be used as a suitable and safe vehicle for administering heterologous antigens to humans.


Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone.
Almost exactly 100years ago Osborne and colleagues demonstrated that restricting the food intake of a small number of female rats extended their lifespan. In the 1930s experiments on the impact of diet on lifespan were extended by Slonaker, and subsequently McCay. Slonaker concluded that there was a strong impact of protein intake on lifespan, while McCay concluded that calories are the main factor causing differences in lifespan when animals are restricted (Calorie restriction or CR). Hence from the very beginning the question of whether food restriction acts on lifespan via reduced calorie intake or reduced protein intake was disputed. Subsequent work supported the idea that calories were the dominant factor. More recently, however, this role has again been questioned, particularly in studies of insects. Here we review the data regarding previous studies of protein and calorie restriction in rodents. We show that increasing CR (with simultaneous protein restriction: PR) increases lifespan, and that CR with no PR generates an identical effect. None of the residual variation in the impact of CR (with PR) on lifespan could be traced to variation in macronutrient content of the diet. Other studies show that low protein content in the diet does increase median lifespan, but the effect is smaller than the CR effect. We conclude that CR is a valid phenomenon in rodents that cannot be explained by changes in protein intake, but that there is a separate phenomenon linking protein intake to lifespan, which acts over a different range of protein intakes than is typical in CR studies. This suggests there may be a fundamental difference in the responses of insects and rodents to CR. This may be traced to differences in the physiology of these groups, or reflect a major methodological difference between 'restriction' studies performed on rodents and insects. We suggest that studies where the diet is supplied ad libitum, but diluted with inert components, should perhaps be called dietary or caloric dilution, rather than dietary or caloric restriction, to distinguish these potentially important methodological differences.


Morinda citrifolia noni water extract enhances innate and adaptive immune responses in healthy mice, ex vivo, and in vitro.
Although Morinda citrifolia (noni) has long been used in traditional medicines for human diseases, its molecular and cellular mechanism of immunostimulatory ability to improve human health under normal healthy conditions is not fully elucidated. This study aimed to investigate the in vitro and in vivo immunostimulatory activity of M. citrifolia fruit water extract treated with enzymes (Mc-eWE). In vitro studies revealed that Mc-eWE stimulated the cells by inducing nitric oxide (NO) production and the expression of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). The immunostimulatory activity was mediated by activation of NF-κB and AP-1. Ex vivo studies showed that Mc-eWE stimulated splenocytes isolated from mice by inducing NO production and expression of immunostimulatory cytokines and by downregulating the expression of the immunosuppressive cytokine IL-10 without cytotoxicity. In vivo demonstrated that Mc-eWE induced immunostimulation by modulating populations of splenic immune cells, especially by increasing the population of IFN-γ+ NK cells. Mc-eWE enhanced the expression of inflammatory genes and immunostimulatory cytokines and inhibited the expression of IL-10 in the mouse splenocytes and sera. Taken together, these results suggest that Mc-eWE plays an immunostimulatory role by activating innate and adaptive immune responses.


Bilirubin and Stroke Risk Using a Mendelian Randomization Design.
Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans. The 14 single-nucleotide polymorphisms (SNPs) (<10-7) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNPs selected from the top SNPs. Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNPs (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found. There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.


Changes in DNA during meiosis in a repair-deficient mutant (rad 52) of yeast.
The kinetic patterns of DNA synthesis in wild-type (RAD+) and rad 52 mutants of yeast, which exhibit high levels of synchrony during meiosis, are comparable. However, RAD 52 mutants accumulate single-strand breaks in parental DNA during the DNA synthesis period. Thus, the product of the RAD 52 gene has a role in meiotic DNA metabolism, as well as in the repair of DNA damage during mitotic growth. The observed breaks may be unresolved recombination intermediates.


[Calcium regulation of the short-term plasticity of the cholinoreceptors in neurons RPa3 and LPa3 of the edible snail].
Pharmacological influences, changing intracellular content of Ca2+, reversibly change the speed and depth of extinction of the input current of the Helix RPa3 and LPa3 neurones, elicited by a repeated iontophoretic application of acetylcholine to the soma. Suppression by extracellular medium, devoid of Ca2+ and by verapamyl (100-150 mumol/l) of Ca2+ input to the cell, induced by cholinoreceptors activation, reversibly weakens the extinction. Raise of intracellular Ca2+ level by blockade with ruthenium red (5-10 mumol/l) of specific Ca2+ transport by mitochondria and by mobilization with caffeine (1-4 mmol/l) of Ca2+, deposited by endoplasmic reticulum, accelerates and intensifies the extinction. The obtained results testify that the short-term cholinoreceptors plasticity of the above neurones is positively controlled by Ca2+ entering the cell by chemically controlled ion channels and mobilized from intracellular Ca-depot.


An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China.
Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Since only limited data on the Chinese population, which is the largest in the world, is available, we conducted an epidemiological study on the prevalence and risk factors of AF in mainland China. This population-based study conducted by cluster sampling comprised 29079 participants forming 14 cohorts from 13 provinces across China, where the population was nearly 1 billion. Every participant underwent electrocardiogram and physical examinations and responded to the interviewer-led questionnaire(s). Univariate and multiple statistical analyses were conducted to explore the relationship between AF prevalence and risk factors. The age-standardized prevalence of AF in China (>or=30 y) was 0.65%, and it increased with age. Men showed a higher prevalence of AF than women (0.91% [age-standardized, 0.66%] vs. 0.65% [0.63%], P = 0.013); several significant risk factors (age, hyperthyroidism, coronary heart disease, and rheumatic heart disease) were identified for AF in the general population. Stroke prevalence was much higher in AF patients than in non-AF people (12.95% vs. 2.28%, P < 0.001). AF was confirmed to be a significant independent risk factor for stroke prevalence in the studied population (OR = 2.776, [1.814, 4.248], P < 0.001). We found that AF patients received poor treatment (2.7%, warfarin; 39.7%, aspirin). This study conducted on a large sample size demonstrates that AF prevalence in mainland China is slightly lower than that in Western countries and similar to that in Asian areas, and confirms that AF is a serious public health problem in China. We identified several potential risk factors, but their associations with AF still need to be further studied.


Plasma Bmi1 mRNA as a potential prognostic biomarker for distant metastasis in colorectal cancer patients.
Bmi1 is overexpressed in gastrointestinal cancers, including colorectal cancer (CRC); however, its role as a non-invasive biomarker in CRC has not been established. The aim of this study was to compare the plasma Bmi1 mRNA levels prior to and following curative resection of the primary tumor in CRC patients and to determine their association with the clinicopathological parameters. The plasma Bmi1 mRNA level was measured by quantitative polymerase chain reaction and expressed as cycle threshold value. There was no significant difference between the overall pre- and postoperative plasma Bmi1 mRNA level (31.73±2.63 vs. 31.93±2.88, respectively; P=0.614) in 45 CRC patients. However, when grouped into non-metastatic and metastatic CRC patients, the postoperative Bmi1 transcript level was found to be significantly lower compared to the preoperative level in patients with non-metastatic CRC (32.13±2.677 31.44±2.764, respectively; P=0.041), whereas there was a trend towards a higher postoperative Bmi1 transcript level compared to the preoperative level in the metastatic counterpart (30.85±3.916 vs. 33.27±0.718, respectively; P=0.164). Furthermore, when the patients were categorized into two groups according to their plasma Bmi1 postoperative vs. preoperative level status, we observed that patients without a reduction in the postoperative plasma Bmi1 mRNA levels exhibited a significantly higher rate of distant metastasis following primary resection (P=0.017) and a significantly worse prognosis regarding disease-free survival (P=0.016) when compared to the reduced postoperative plasma Bmi1 level counterparts. In conclusion, plasma Bmi1 mRNA levels may serve as a non-invasive biomarker for monitoring occult metastasis and predicting the development of distant metastasis.


Thyroxine-binding globulin in patients with chronic hepatitis B virus infection: different implications in hepatitis and hepatocellular carcinoma.
To determine serum thyroxine-binding globulin (TBG) levels, we used radioimmunoassay, and compared the results obtained with other tests in 231 patients with chronic hepatitis B virus infection to evaluate its clinical implications. All of these patients were hepatitis B surface antigen (HBsAg)-positive. Among them, 38 patients had hepatocellular carcinoma (HCC), 18 had chronic persistent hepatitis, 70 had chronic lobular or active hepatitis (grouped as CAH), 31 had active cirrhosis (AC), 25 had inactive cirrhosis, 20 had decompensated cirrhosis, and 29 were "healthy" HBsAg carriers. Twenty-seven patients with acute hepatitis, 12 with cancer metastasis to the liver, and 81 normal adults served as disease or normal controls. The results showed that serum TBG level increased significantly in patients with CAH, AC, or HCC. Serum TBG did not correlate with albumin or bilirubin level, but correlated with alanine aminotransferase (ALT) positively in patients with CAH (p less than 0.001) and negatively in patients with HCC (p less than 0.01) (slope difference p less than 0.05). Serial determination of serum TBG and ALT also showed parallel changes in 15 patients with CAH, but not in nine patients with HCC. In contrast, the fall and rise of serum TBG levels in patients with HCC coincided with tumor resection and recurrence. The data suggest that serum TBG elevation in patients with hepatitis activity is the result of hepatocellular damage, whereas that in patients with HCC is due to increased synthesis. Whether serum TBG elevation without concomitant rise of ALT could be used as a marker of HCC awaits further study.


Expression and mutational analysis of MET in human solid cancers.
MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) regulate a variety of cellular functions, many of which can be dysregulated in human cancers. Activated MET signaling can lead to cell motility and scattering, angiogenesis, proliferation, branching morphogenesis, invasion, and eventual metastasis. We performed systematic analysis of the expression of the MET receptor and its ligand HGF in tumor tissue microarrays (TMA) from human solid cancers. Standard immunohistochemistry (IHC) and a computerized automated scoring system were used. DNA sequencing for MET mutations in both nonkinase and kinase domains was also performed. MET was differentially overexpressed in human solid cancers. The ligand HGF was widely expressed in both tumors, primarily intratumoral, and nonmalignant tissues. The MET/HGF likely is functional and may be activated in autocrine fashion in vivo. MET and stem cell factor (SCF) were found to be positively stained in the bronchioalevolar junctions of lung tumors. A number of novel mutations of MET were identified, particularly in the extracellular semaphorin domain and the juxtamembrane domain. MET-HGF pathway can be assayed in TMAs and is often overexpressed in a wide variety of human solid cancers. MET can be activated through overexpression, mutation, or autocrine signaling in malignant cells. Mutations in the nonkinase regions of MET might play an important role in tumorigenesis and tumor progression. MET would be an important therapeutic antitumor target to be inhibited, and in lung cancer, MET may represent a cancer early progenitor cell marker.


The influence of identity elements on the aminoacylation of tRNA(Arg) by plant and Escherichia coli arginyl-tRNA synthetases.
Identity elements determine the accurate recognition between tRNAs and aminoacyl-tRNA synthetases. The arginine system from yeast and Escherichia coli has been studied extensively in the past. However, information about the enzymes from higher eukaryotes is limited and plant aminoacyl-tRNA synthetases have been largely ignored in this respect. We have designed in vitro tRNA transcripts, based on the soybean tRNA(Arg) primary structure, aiming to investigate its specific aminoacylation by two recombinant plant arginyl-tRNA synthetases and to compare this with the enzyme from E. coli. Identity elements at positions 20 and 35 in plants parallel those previously established for bacteria. Cryptic identity elements in the plant system that are not revealed within a tRNA(Arg) consensus sequence compiled from isodecoders corresponding to nine distinct cytoplasmic, mitochondrial and plastid isoaccepting sequences are located in the acceptor stem. Additionally, it has been shown that U20a and A38 are essential for a fully efficient cognate E. coli arginylation, whereas, for the plant arginyl-tRNA synthetases, these bases can be replaced by G20a and C38 with full retention of activity. G10, a constituent of the 10:25:45 tertiary interaction, is essential for both plant and E. coli activity. Amino acid recognition in terms of discriminating between arginine and canavanine by the arginyl-tRNA synthetase from both kingdoms may be manipulated by changes at different sites within the tRNA structure.


Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma.
Lapatinib, an orally administered small-molecule tyrosine kinase inhibitor targeting epidermal growth factor receptors (EGFR) and Her2/Neu, has been widely accepted in the treatment of breast cancer. In this study, we found that lapatinib induced cytotoxicity in human hepatoma Huh7, HepG2 and HA22T cells. For the mode of cell death, we found lapatinib induced a higher percent of dead cells and a lower percent of hypodiploid cells, suggesting non-apoptotic cell death in lapatinib-treated hepatoma cells. Moreover, lapatinib-induced autophagy in hepatoma cells was confirmed by the detection of autophagic LC3-II conversion, the up-regulation of autophagy-related proteins, and the down-regulation of p62 by immunoblotting. Autophagic cell death was demonstrated by images of punctuated LC3 patterns, a higher percent of acridine orange positive cells, as well as a partial rescue of cell death by autophagy inhibitor 3-methyladenine or chloroquine. We also found massive vacuoles in lapatinib-treated hepatoma cells by electronic microscopy. In addition, the shRNA of knocked-down autophagy-related proteins rescued the hepatoma cells from lapatinib-induced growth inhibition. We also demonstrated a reduction of tumorigenesis by lapatinib in vivo. In conclusion, lapatinib induced autophagic cell death and the growth of human hepatoma cells. Our study provides potential cancer therapies by using lapatinib as a treatment for hepatoma.


Hyperleptinemia is associated with CRP, but not apolipoprotein E, and is reduced by exercise training.
The purpose of this study was to examine whether leptin levels affect the response of leptin to exercise training (ET) and whether this is also affected by C-reactive protein (CRP) or the three common Apolipoprotein E genotypes (APOE). Ninety-seven (male = 45, female = 52) sedentary individuals underwent 6 months of supervised ET. Blood was sampled before the initiation of ET, and again 24 and 72 hr after completion of the final training session. ET resulted in a small reduction in body mass (80.47 ± 18.03 vs 79.42 ± 17.34 kg, p < .01). Leptin was reduced 24 hr after the final exercise session (p < .01), but returned to normal after 72 hr (p > .05)--Pre: 13.51 ± 12.27, 24hr: 12.14 ± 12.34, 72 hr: 12.98 ± 11.40 ng/ml. The most hyperleptinemic individuals had a greater initial response, which was sustained through to 72 hr after the final session in the pooled study population (p < .01), and in both males (p < .05) and females (p < .05) separately. CRP was related to leptin independently of body weight and positively related to the reductions in leptin. APOE genotype was not related to leptin levels and did not affect the response to ET. Leptin levels may only be reduced by ET in those with hyperleptinemia. In addition, both the initial extent of hyperleptinemia and the subsequent reduction in leptin may be related to low grade chronic systemic inflammation.


Increasing knowledge of Cymbiapophysa Gabriel & Sherwood, 2020 (Araneae, Theraphosidae): general distribution, key to species, and three new species from Ecuador.
Three new species of Cymbiapophysa Gabriel & Sherwood, 2020 are described from south, central, and north-western Ecuador, showing the wide range of distribution that this genus has in Ecuador and its biogeographical provinces. These three new species are easily differentiated from other congeners based on keel morphology of the male palpal bulb. Supplementary information about the locality of C.magna Sherwood, Gabriel, Brescovit & Lucas, 2021 is provided, alongside additional data on morphology and some commentaries about the general distribution and biogeography of Cymbiapophysa. Additionally, a taxonomic key for males of Cymbiapophysa species is presented, based on the palpal bulb morphology.


Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1alpha.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcriptional factor which is activated by hypoxia and associated with cell survival, proliferation and drug resistance. Recent studies have shown that the down-stream molecules of the epidermal growth factor receptor (EGFR) signal are involved in the hypoxia-dependent or -independent HIF-1alpha protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1alpha expression. In our data, treatment of gefitinib suppressed induced HIF-1alpha by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1alpha mRNA. The effect of gefitinib on down-regulation of HIF-1alpha was reversed by transfection of constitutively active form of Akt. The cellular response to gefitinib was similar in both normoxia and hypoxia condition. However, the response to conventional chemotherapeutic drugs decreased >50% under hypoxia condition and they did not change HIF-1alpha expression. In addition, the suppression of HIF-1alpha using siRNA overcame partially hypoxia-induced drug resistance. In conclusion, gefitinib was able to circumvent hypoxia-induced drug resistance suggesting that the effective suppression of HIF-1alpha by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.


Developing substrate-based small molecule fluorescent probes for super-resolution fluorescent imaging of various membrane transporters.
Super-resolution imaging technology has been a powerful tool for revealing fine biological structures and functions. Its high-quality imaging always needs highly accurate labeling. Here, by exploiting the high specificity and affinity of natural substrates to transporters, we developed one set of substrate-based small molecule fluorescent probes for labeling membrane transporters. A glucose-based probe (Glu-probe) and tyrosine-based probe (Tyr-probe) were synthesized as two examples. Confocal imaging showed that the Glu-probe could label glucose transporters on live cells by being stuck into the binding site. Compared with antibody-probe labeling, the labeling advantages of the Glu-probe were revealed. High specificity of the Glu-probe or Tyr-probe was examined by a colocalization experiment and glucose replacement or amino acid (AA) blocking. The synthetic probes were also tested on imaging HeLa cells to confirm their wide labeling application. Additionally, we found that membrane transporters were mostly in the clustered state on cellular membranes, changing their assembly pattern to regulate the transport effectiveness. These results suggest that the substrate-based probes can serve as valuable tools for investigating the spatial information of membrane transporters.


Fire and brimstone: the microbially mediated formation of elemental sulfur nodules from an isotope and major element study in the paleo-Dead Sea.
We present coupled sulfur and oxygen isotope data from sulfur nodules and surrounding gypsum, as well as iron and manganese concentration data, from the Lisan Formation near the Dead Sea (Israel). The sulfur isotope composition in the nodules ranges between -9 and -11‰, 27 to 29‰ lighter than the surrounding gypsum, while the oxygen isotope composition of the gypsum is constant around 24‰. The constant sulfur isotope composition of the nodule is consistent with formation in an 'open system'. Iron concentrations in the gypsum increase toward the nodule, while manganese concentrations decrease, suggesting a redox boundary at the nodule-gypsum interface during aqueous phase diagenesis. We propose that sulfur nodules in the Lisan Formation are generated through bacterial sulfate reduction, which terminates at elemental sulfur. We speculate that the sulfate-saturated pore fluids, coupled with the low availability of an electron donor, terminates the trithionate pathway before the final two-electron reduction, producing thionites, which then disproportionate to form abundant elemental sulfur.


3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism.
The prototypic cannabinoid type 1 (CB₁) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB₁-selective compounds and explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. Several notable patterns emerged. First, most of the analogs exhibited CB₁ selectivity, with many lacking affinity for the CB₂ receptor. Affinity tended to be better when [³H]5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [³H](-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP55,940), was used as the binding radioligand. Second, many of the analogs produced an agonist-like profile of effects in mice (i.e., suppression of activity, antinociception, hypothermia, and immobility); however, their potencies were not well correlated with their CB₁ binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ⁹-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB₁⁻/⁻ mice, and they failed to stimulate guanosine-5'-O-(3-[³⁵S]thio)-triphosphate binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB₁-selective cannabinoids that produce agonist-like effects in mice through a non-CB₁, non-CB₂ mechanism.


Coexistence of a bradycardia- and tachycardia-dependent bundle branch block.
Aberrant ventricular conduction is a rare phenomenon as compared with the more frequently occurring antrioventricular conduction disturbances. It leads to widening of the QRS complex, which is either due to a complete or functional block in one of the bundle branches or a block within the intramyocardial conduction system itself. Mechanisms that are potentially involved in the genesis of aberrant ventricular conduction are sudden shortening of cycle length (tachycardia-dependent phase III), antegrade block with retrograde concealed conduction, or bradycardia-dependent block (enhanced phase IV). In this paper, we present a patient with aberrant ventricular conduction with the occurrence of a tachycardia-dependent, as well as a bradycardia-dependent bundle branch block, which is an even rarer phenomenon.


Low oxygen microenvironment and cardiovascular remodeling: Role of dual L/N.type Ca2+ channel blocker.
Patients exposed to chronic sustained hypoxia frequently develop cardiovascular disease risk factors to ultimately succumb to adverse cardiovascular events. In this context, the present study intends to assess the role of cilnidipine (Cil), a unique calcium channel blocker that blocks both L-type and N-type calcium channels, on cardiovascular pathophysiology in face of chronic sustained hypoxia exposure. The study involved Wistar strain albino rats. The group-wise allocation of the experimental animals is as follows - Group 1, control (21% O2); Group 2, chronic hypoxia (CH) (10% O2, 90% N); Group 3, Cil + 21% O2; and Group 4, CH (10% O2, 90% N) + Cil (CH + Cil). Cardiovascular hemodynamics, heart rate variability, and endothelial functions (serum nitric oxide [NO], serum endothelial nitric oxide synthase [NOS3], and serum vascular endothelial growth factor [VEGF]) were assessed. Cardiovascular remodeling was studied by histopathological examination of the ventricular tissues, coronary artery (intramyocardial), and elastic and muscular arteries. Normalized wall index of the coronary artery was also calculated. The results demonstrated altered cardiovascular hemodynamics, disturbed cardiovascular autonomic balance, increased levels of VEGF and NOS3, and decreased bioavailability of NO on exposure to chronic sustained hypoxia. The histopathological examination further pointed toward cardiovascular remodeling. Treatment with Cil ameliorated the cardiovascular remodeling and endothelial dysfunction induced by CH exposure, which may be due to its blocking actions on L/N-type of calcium channels, indicating the possible therapeutic role of Cil against CH-induced cardiovascular pathophysiology.


Suppression of the SOS-inducing activity of mutagenic heterocyclic amine, Trp-P-1, by triterpenoid from Uncaria sinensis in the Salmonella typhimurium TA1535/pSK1002 Umu test.
The methanol extract from Uncaria sinensis showed a suppressive effect on umu gene expression of the SOS response in Salmonella typhimurium TA1535/pSK1002 against the mutagen 3-amino-1,4-dimethyl-5H-pyrido[4,3b]indole (Trp-P-1), which requires liver metabolizing enzymes. The methanol extract from U. sinensis was re-extracted with hexane, CH2Cl2, BuOH, and water, respectively. CH2Cl2 extract showed a suppressive effect. A suppressive compound 1 in CH2Cl2 extract was isolated by SiO2 column chromatography. Compound 1 was identified as ursolic acid by IR, electron ionization EI-MS, and NMR spectroscopy. Suppressive effects of ursolic acid (1) and its derivatives, methyl ursolate (1M), acetylursolic acid (1A), and methyl acetylursolate (1MA), were determined in the umu test. These compounds suppressed 61.3, 37.7, 71.5, and 37.8% of the Trp-P-1-induced SOS response at a concentration of 0.4 micromol/mL, respectively. The ID50 values of compounds 1 and 1A were 0.17 and 0.20 micromol/mL. In addition, these compounds were assayed with the activated Trp-P-1. Suppressive effects on activated Trp-P-1 were decreased as compared with those of Trp-P-1.


A retrospective review of mucocutaneous infections by human herpesvirus 1 and 2 in an urban population in Malaysia.
This is a 10-year retrospective review of mucocutaneous infection by human herpesvirus 1 (HHV1) and human herpesvirus 2 (HHV2) carried out by the virus diagnostic unit of University Malaya Medical Centre (UMMC). A total of 504 specimens from UMMC and a private clinic in the same city (KLSC) were tested; 198 samples from patients with oral lesions and 306 from patients with genital lesions. HHV1 was found to be responsible for 98.4% of oral lesions whereas HHV2 was the cause of 83.6% of all genital lesions. Detailed analysis showed no statistical difference by age group, race or gender among the patients with oral and genital lesions. Two laboratory methods were used in this study. Of the total 504 specimens tested, 18.0% specimens were positive by direct immunofluorescence (IF), 55.0% by virus isolation and 56.5% when both methods were used in combination. Although IF can provide a more rapid diagnosis, it is, however, less sensitive and can be attributed partly to inadequate collection of specimens.


IgE-Mediated Reaction to Metamizole: Evaluation of a Patient with Severe Anaphylaxis.
Metamizole, a non-steroidal anti-inflammatory drug with weak anti-inflammatory and spasmolytic effects, is used as an analgesic and antipyretic agent. Many adverse reactions to metamizole, such as early or late-onset systemic reactions and bone marrow suppression, have been identified. In this report, we present a case of systemic reaction after the application of parenteral metamizole (Novalgin(®) ampoule; Sanofi Aventis, İstanbul, Turkey) and discuss the mechanism underlying the reaction.


Assessing the nature and mix of offences among serious adolescent offenders.
Much of the research on specialisation in offending tends to show that offending careers are marked by more versatile than specific criminal activity. One key limitation of this research has been that very few studies have used both official records and self-reports to study the longitudinal mix of offences. This study uses longitudinal data to examine the mixture of offences during mid-adolescence and into early adulthood, a key transitionary period of the life course, using both self-reports and official records. Data from 1354 serious adolescent offenders are used to study the mixture of offences over a 7-year period. The results point strongly to the conclusion that generality is typical and specialisation is exceptional.


Endovascular repair of ruptured aneurysms of the infrarenal abdominal aorta: feasibility and results.
Endovascular repair may represent an interesting alternative to open surgery for ruptured abdominal aortic aneurysms (AAA). This study evaluated the feasibility and short-term results of endovascular repair of ruptured AAA at our center. Between April 2004 and December 2005, all patients admitted to our center for a ruptured AAA were considered for endovascular repair. Patients whose hemodynamic status was too unstable to permit a preoperative CT scan and patients with an unfavorable anatomy for endovascular repair underwent open surgery. Endovascular repair consisted in emergency placement of an aorto-uni-iliac endograft associated with a crossover femoro-femoral bypass and deployment of an occluder in the contralateral common iliac artery. Follow-up postoperative CT scans were obtained 1, 6, 12 and 18 months after intervention and then annually. Data concerning diagnosis, the operative risk, treatment, and follow-up were collated prospectively in a registry and were analyzed on an intention-to-treat basis. Between April 2004 and December 2005, 17 patients were admitted to our Department for a ruptured AAA. Ten patients (59 %) underwent emergency endovascular repair and were included in this study (8 men and 2 women, mean age 81 years, range 51-97). The mean duration of the operation was 167 +/- 37 min. The mean blood transfusion volume was 3 700 +/- 1 400 mL. The mean duration of hospitalization was 19 days (range: 9-60). Mortality at day 30 was 20% (2 patients): one death occurred on day 2 due to multi-organ failure in an 80-year-old patient and another death occurred on day 2 owing to myocardial infarction in an 87-year-old patient. Mean follow-up was 6 months. Late mortality occurred in 2 cases. No endoleaks were observed during follow-up. Our initial results using endografts for the repair of ruptured AAA were satisfactory, with a feasibility of 59% and an operative mortality of 20%. Randomized studies are necessary to determine the true value of endovascular repair of ruptured AAA compared to conventional open repair.


Deletion of the glycosyltransferase bgsB of Enterococcus faecalis leads to a complete loss of glycolipids from the cell membrane and to impaired biofilm formation.
Deletion of the glycosyltransferase bgsA in Enterococcus faecalis leads to loss of diglucosyldiacylglycerol from the cell membrane and accumulation of its precursor monoglucosyldiacylglycerol, associated with impaired biofilm formation and reduced virulence in vivo. Here we analyzed the function of a putative glucosyltransferase EF2890 designated biofilm-associated glycolipid synthesis B (bgsB) immediately downstream of bgsA. A deletion mutant was constructed by targeted mutagenesis in E. faecalis strain 12030. Analysis of cell membrane extracts revealed a complete loss of glycolipids from the cell membrane. Cell walls of 12030ΔbgsB contained approximately fourfold more LTA, and 1H-nuclear magnetic resonance (NMR) spectroscopy suggested that the higher content of cellular LTA was due to increased length of the glycerol-phosphate polymer of LTA. 12030ΔbgsB was not altered in growth, cell morphology, or autolysis. However, attachment to Caco-2 cells was reduced to 50% of wild-type levels, and biofilm formation on polystyrene was highly impaired. Despite normal resistance to cationic antimicrobial peptides, complement and antibody-mediated opsonophagocytic killing in vitro, 12030ΔbgsB was cleared more rapidly from the bloodstream of mice than wild-type bacteria. Overall, the phenotype resembles the respective deletion mutant in the bgsA gene. Our findings suggest that loss of diglucosyldiacylglycerol or the altered structure of LTA in both mutants account for phenotypic changes observed. In summary, BgsB is a glucosyltransferase that synthesizes monoglucosyldiacylglycerol. Its inactivation profoundly affects cell membrane composition and has secondary effects on LTA biosynthesis. Both cell-membrane amphiphiles are critical for biofilm formation and virulence of E. faecalis.


Leprosy: Medical views of leviticus rabba.
This article discusses chapters 15 and 16 of the ancient midrash (allegorical commentary) Leviticus Rabba (IV -V AD) and its view of leprosy. The phenomenon of Biblical leprosy is here not investigated from a paleo-pathological point of view. The focus lies on its physiological, aetiological, pathological and therapeutic aspects as represented in Leviticus Rabba. It is argued that the medical views of Leviticus Rabba show a certain resemblance to some of the view of the Hippocratic School, notably with respect to humoral theory, the belief in the correspondence between the macrocosm and the individual microcosm, and the notion of paideia as a way of healing. Finally, it is shown that the ancient myth of the two floods (of water and of fire) is connected to the understanding of leprosy in Leviticus Rabba.


Effects of corticosteroid plus long-acting beta2-agonist on the expression of PD-L1 in double-stranded RNA-induced lung inflammation in mice.
Airway viral infections cause the exacerbations of asthma and chronic obstructive pulmonary disease. PD-L1, also known as B7-H1, is an immune-checkpoint molecule that plays a role in an escape mechanism of viruses from the host immune systems. This escape may be associated with the persistence of viral infection and the exacerbation of the underlying diseases. In a study in vitro, we have shown that corticosteroids plus long-acting beta2-agonists (LABAs) attenuate the upregulation of PD-L1 on airway epithelial cells stimulated with an analog of viral double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C). To address its biological relevance in vivo, we investigated the effect of corticosteroid plus LABA on the expression of PD-L1 in double-stranded RNA-induced lung inflammation in mice. Mice were intratracheally administered with poly I:C. The expression of PD-L1 on the lung cells was assessed by flow cytometry and inflammation was assessed for bronchoalveolar lavage fluid (BALF). Independent as well as combination effects of ciclesonide and indacaterol were examined. Administration of low dose poly I:C upregulated the expression of PD-L1, induced neutrophilia and increased keratinocyte-derived chemokine (KC), macrophage inflammatory protein-1β (MIP-1β), and IL-6 in BALF. The upregulation of PD-L1, neutrophilic inflammation and increase of KC were suppressed by ciclesonide plus indacaterol, but not by either when administered independently. Although the upregulation of PD-L1 by high dose poly I:C was suppressed by ciclesonide plus indacaterol, neutrophilia and increased KC, MIP-1β, and IL-6 in BALF were not attenuated. Ciclesonide plus indacaterol attenuate double-stranded RNA-induced upregulation of PD-L1 in the lungs.


Cystic Fibrosis in Ukraine: age, origin and tracing of the delta F508 mutation.
Seven already known CF mutations were searched in 170 unrelated cystic fibrosis patients from different regions of Ukraine. Their frequencies in this sample were: delta F508-50%, 1677delTA-0.3% (10th exon), R553X-0.6%, G551D-0.3% (11th exon), R334W-0.6% (7th exon). 1154insTC (7th exon) and S549I (11th exon) were not found. Heterozygotes for delta F508 were searched in 865 healthy volunteers from different Ukranian regions. Their frequencies ranged from 1:28 to 1:70. We report here unpublished population data from Ukraine in order to discuss the origin, evolution and dispersion of chromosomes bearing the delta F508 mutation. Selection in terms of heterozygote advantage is also discussed.


Stages That Lead to Drop Depinning and Onset of Motion.
In this paper, we consider drops that are subjected to a gradually increasing lateral force and follow the stages of the motion of the drops. We show that the first time a drop slides as a whole is when the receding edge of the drop is pulled by the advancing edge (the advancing edge drags the receding edge). The generality of this phenomenon includes sessile and pendant drops and spans over various chemically and topographically different cases. Because this observation is true for both pendant and sessile cases, we exclude hydrostatic pressure as its reason. Instead, we explain it in terms of the wetting adaptation and interfacial modulus, that is, the difference in the energies of the solid interface at the advancing and receding edges. At the receding edge, a slight motion exposes to the air a recently wetted solid surface whose molecules had reoriented to the liquid and will take time to reorient back to the air. This results in a high surface energy at the solid-air interface which pulls on the triple line, that is, inhibits the motion of the receding edge. On the other hand, at the advancing edge, a slight advancement does not change the nature of the solid interfacial molecules outside the drop, and the advancing side's sliding can continue. Moreover, the solid molecules under the drop at the advancing edge take time to reorient, and hence, their configuration is not yet adapted for the liquid and therefore not adapted for retention of the advancing edge. Therefore, in sliding-drop experiments, the advancing edge moves before the receding one, typically a few times before the receding edge moves. For the same reason, the last motion of the receding edge usually happens as a result of the advancing edge pulling on it.


Ornithinicoccus hortensis gen. nov., sp. nov., a soil actinomycete which contains L-ornithine.
Two Gram-positive coccoid, non-motile bacteria with L-ornithine as diagnostic diamino acid of the peptidoglycan and an interpeptide bridge of L-Orn<--Gly(1,2)<--D-Glu were isolated from a sample of garden soil. The major menaquinone is MK-8(H4). 13-methyl and 12-methyl tetradecanoic acids are the predominant fatty acids. The polar lipids are phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylserine and two unknown phospholipids. Mycolic acids are absent. The DNA base composition is 72 mol% G + C. Recent comparative 16S rDNA studies revealed that strains HKI 0125T and HKI 0131 represent a novel lineage adjacent to the family Intrasporangiaceae of the order Actinomycetales but distinct from the previously described genera of this family. On the basis of the genotypic, chemotaxonomic, morphological and physiological characteristics of these two isolates it is proposed to classify HKI 0125T and HKI 0131 in a new genus and species for which the name Ornithinicoccus hortensis gen. nov., sp. nov. is proposed. The type strain is HKI 0125T (= DSM 12335T).


A new mechanism for hydroxyl radical production in irradiated nanoparticle solutions.
The absolute yield of hydroxyl radicals per unit of deposited X-ray energy is determined for the first time for irradiated aqueous solutions containing metal nanoparticles based on a "reference" protocol. Measurements are made as a function of dose rate and nanoparticle concentration. Possible mechanisms for hydroxyl radical production are considered in turn: energy deposition in the nanoparticles followed by its transport into the surrounding environment is unable to account for observed yield whereas energy deposition in the water followed by a catalytic-like reaction at the water-nanoparticle interface can account for the total yield and its dependence on dose rate and nanoparticle concentration. This finding is important because current models used to account for nanoparticle enhancement to radiobiological damage only consider the primary interaction with the nanoparticle, not with the surrounding media. Nothing about the new mechanism appears to be specific to gold, the main requirements being the formation of a structured water layer in the vicinity of the nanoparticle possibly through the interaction of its charge and the water dipoles. The massive hydroxyl radical production is relevant to a number of application fields, particularly nanomedicine since the hydroxyl radical is responsible for the majority of radiation-induced DNA damage.


Providing a stable methodological basis for comparing transcript abundance of developing embryos using microarrays.
High throughput methods deliver large amount of data serving to describe the physiological treatment that is being studied. In the case of microarrays, there would be a clear benefit to integrate the published data sets. However, the numerous methodological discrepancies between microarray platforms make this comparison impossible. This incompatibility is magnified when considering the peculiar context of transcript management in early embryogenesis. The total RNA content is known to profoundly fluctuate during development. In addition, the mRNA population is subjected to poly(A) tail shortening and elongating events, a characteristic of stored and recruited messengers. These intrinsic factors need to be considered when interpreting any transcript abundance profiles during early development. As a consequence, many methodological details affect microarray platform performances and prevent compatibility. In an effort to maximize our microarray platform performance, we determined the various sources of variation for every one of the main steps leading to the production of microarray data. The five main steps involved in sample preparation were evaluated, as well as conditions for post-hybridization validation by qRT-PCR. These determinations were essential for the implementation of standardized procedures for our Research Network but they can also provide insight into the compatibility issues that the microarray community is now facing.


Executive and theory-of-mind contributions to event-based prospective memory in children: exploring the self-projection hypothesis.
In two studies, 4- to 6-year-olds were asked to name pictures of animals for the benefit of a watching hand puppet (the ongoing task) but to refrain from naming and to remove from view any pictures of dogs (the prospective memory [PM] task). Children also completed assessments of verbal ability, cognitive inhibition, working memory, and false-belief understanding (both studies), empathy (Study 1 only), and performance on false-sign tests that matched the false-belief tests in narrative content and structure (Study 2 only). Both studies found that inhibition and false-belief performance made unique contributions to the variance in PM, although in Study 1 the influence of inhibition was evident only when children needed to withhold naming. Study 2 further demonstrated that false-belief performance was the only reliable predictor of whether children remembered to return to the researcher an object that had been loaned to them prior to the picture-naming game. Both experiments uncovered moderate relations between PM and chronological age, but such relations were rarely significant after taking account of cognitive ability. We consider the implications of the findings for (a) current views regarding frontal/executive contributions to PM development and (b) the suggestion that the same brain network underlies various forms of mental self-projection, including envisioning the future and understanding the minds of other people.


Development of a CRISPR/Cas9 system for high efficiency multiplexed gene deletion in Rhodosporidium toruloides.
The oleaginous yeast Rhodosporidium toruloides is considered a promising candidate for production of chemicals and biofuels thanks to its ability to grow on lignocellulosic biomass, and its high production of lipids and carotenoids. However, efforts to engineer this organism are hindered by a lack of suitable genetic tools. Here we report the development of a CRISPR/Cas9 system for genome editing in R. toruloides based on a fusion 5S rRNA-tRNA promoter for guide RNA (gRNA) expression, capable of greater than 95% gene knockout for various genetic targets. Additionally, multiplexed double-gene knockout mutants were obtained using this method with an efficiency of 78%. This tool can be used to accelerate future metabolic engineering work in this yeast.


Association of chronic alcoholic liver and pancreatic disease: a prospective study.
Seventy-two chronic alcoholics, 40 (all males) with chronic pancreatitis and 32 (23 males and nine females) with liver cirrhosis, were submitted to liver biopsy, endoscopic retrograde cholangiopancreatography and secretin-caerulein test in order to assess a possible liver involvement in chronic pancreatitis and viceversa, and to evaluate the existence of any relationship between the diseases of these two organs. Chronic pancreatitis patients were younger than cirrhotic patients and drank more than the cirrhotic females. Twenty-nine of the 40 patients had abnormal liver histology, five had micronodular cirrhosis and were older than the others. No relationship was found between the degree of pancreatic impairment and the type of liver injury. Five liver cirrhosis patients had an endoscopic retrograde cholangiopancreatography picture consistent with chronic pancreatitis; two were females with an alcohol intake lower than the one of the other females. In conclusion the association of chronic pancreatitis and liver cirrhosis was observed in a minority of cases, with the same percentage in the two groups, even if the cirrhotic subjects were older than the pancreatitics. Therefore we can postulate that different factors have roles in the pathogenesis of alcoholic cirrhosis and of chronic alcoholic pancreatitis. The association of the two diseases in two women with a relatively low alcohol intake supports this hypothesis.


Maternal exposure to bisphenol A during pregnancy interferes ovaries development of F1 female mice.
This study was conducted to investigate the effects of maternal exposure bisphenol A (BPA) on ovaries development of F1 female mice. The BPA exposure model of pregnant mice was prepared by intragastric administration of BPA at the doses of 0, 2.5, 5, 10, 20, 40 mg kg-1 d-1 at gestation day (GD) 0.5-17.5. The ovarian index of the offspring mice was calculated at postnatal day (PND) 21 and PND 56. The results showed that BPA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg significantly increased the abortion rate of the pregnant mice, and each dose of BPA significantly reduced the survival rate of the pups (P < 0.01 or P < 0.05). Besides, there was a non-monotonic dose-response relationship between serum hormone, ovarian receptor levels and BPA in F1 females at both PND 21 and 56. BPA increased the ovarian/uterine index in F1 females at both PND 21 and 56, increased the mRNA relative transcript levels of ovarian ERα, PgR and DNA methyltransferase (DNMT) in F1 females at PND 21, while decreased at PND 56 (P < 0.01 or P < 0.05). BPA also increased the relative expression of caspase-7, caspase-9, bax, inhibited the relative expression of bcl-2 in F1 females at both PND 21 and 56, and increased the apoptosis rate in the ovaries in F1 mice at PND 56 (P < 0.01). The number of follicles in the ovary was increased in F1 females at PND 21, and the ovaries were significantly atrophied when sexual maturity (PND 56). Our results indicated that BPA could disturb the contents of DNMT and make reproductive injury to the offspring females.


The Importance of Frailty in the Assessment of Influenza Vaccine Effectiveness Against Influenza-Related Hospitalization in Elderly People.
Influenza is an important cause of morbidity and mortality among older adults. Even so, effectiveness of influenza vaccine for older adults has been reported to be lower than for younger adults, and the impact of frailty on vaccine effectiveness (VE) and outcomes is uncertain. We aimed to study VE against influenza hospitalization in older adults, focusing on the impact of frailty. We report VE of trivalent influenza vaccine (TIV) in people ≥65 years of age hospitalized during the 2011-2012 influenza season using a multicenter, prospective, test-negative case-control design. A validated frailty index (FI) was used to measure frailty. Three hundred twenty cases and 564 controls (mean age, 80.6 and 78.7 years, respectively) were enrolled. Cases had higher baseline frailty than controls (P = .006). In the fully adjusted model, VE against influenza hospitalization was 58.0% (95% confidence interval [CI], 34.2%-73.2%). The contribution of frailty was important; adjusting for frailty alone yielded a VE estimate of 58.7% (95% CI, 36.2%-73.2%). VE was 77.6% among nonfrail older adults and declined as frailty increased. Despite commonly held views that VE is poor in older adults, we found that TIV provided good protection against influenza hospitalization in older adults who were not frail, though VE diminished as frailty increased. NCT01517191.


Photophysiological functions of visual pigments.
In order to gain a fundamental understanding of functions of a visual pigment, i.e., photoreception and phototransduction, it is essential to elucidate the molecular structure of visual pigment, its photochemical behavior and connection of the pigment to the molecular physiological amplification mechanism for excitation of a visual cell. A rhodopsin, a rod visual pigment, is composed of an 11-cis-retinal bound with an apo-protein, opsin, through a protonated Schiff-base. Competitive inhibition of beta-ionone on regeneration of rhodopsin from an 11-cis-retinal and cattle opsin demonstrated the existence of a hydrophobic linkage between the beta-ionone ring of the retinal and the hydrophobic region of opsin. Owing to these two linkages, the 11-cis-retinal is fixed in an opsin cleft. As a result, it is endowed with new physiological functions as a chromophore of rhodopsin; the change of 11-cis-retinal (lambda max = 369 nm, epsilon = 26,400) to rhodopsin (lambda max = about 500 nm, epsilon = 40,600) brings not only a spectral shift from near ultraviolet to visible regions and an intensification of the molecular extinction coefficient, but also an increase of a quantum yield of 11-cis-retinal to all-trans form. High quantum yield of rhodopsin suggests rapid formation of the first photoproduct. Study of the first photoproduct was accelerated by the finding of bathorhodopsin, which was formed by irradiation at liquid nitrogen temperatures. The change of rhodopsin to bathorhodopsin has been inferred to be due to a photoisomerization of the chromophore from 11-cis to a twisted all-trans form. This isomerization hypothesis has been verified by the following experimental results. Irradiation of 7-cis- and 9-cis-rhodopsins at liquid nitrogen temperature produced the same bathorhodopsin as that from 11-cis-rhodopsin, indicating that the chromophore of bathorhodopsin should be in all-trans or transoid form. 7-Membered-rhodopsin, in which the rotation of 11-12 double bond of the retinylidene chromophore is locked, did not form bathorhodopsin by excitation of picosecond laser photolysis. This fact indicates that bathorhodopsin is a product formed by photoisomerization of the chromophore. Rhodopsin showed a positive circular dichroism (CD) in the visible while bathorhodopsin showed a remarkable negative CD. The reversal of the sign of CD indicates that not only large conformational change of the retinylidene chromophore occurs during the conversion of rhodopsin to bathorhodopsin, but also the direction of twist of the chromophore reverses. It is inferred that the chromophore of bathorhodopsin is a twisted trans form.(ABSTRACT TRUNCATED AT 400 WORDS)


Changes in 3 beta-hydroxy- delta 5-steroid dehydrogenase activity in granulosa tissue during the ovulatory cycle of the laying hen (Gallus domesticus).
The object of this study was to examine changes in the activity of granulosa 3 beta-hydroxy-delta 5-steroid dehydrogenase during the ovulatory cycle of the domestic fowl. The enzyme activity in granulosa tissue from the largest follicle increased significantly during the period 8-14 h before an expected ovulation. The increase in activity occurs before the preovulatory surge of LH and near the time of lights off. During the 4-8 h period before an ovulation, i.e. the time of maximal plasma LH concentrations, 3 beta-hydroxy-delta 5-steroid dehydrogenase activity decreased in granulosa tissue from the largest follicle. This observation is explained by proposing that the enzyme is inhibited by the large amounts of progesterone found in the tissue at this time. The results indicate that important biochemical changes are taking place within granulosa tissue of the largest ovarian follicle before the preovulatory LH surge.


Molecular analysis of Culex quinquefasciatus larvae responses to Lysinibacillus sphaericus Bin toxin.
Lysinibacillus sphaericus produces the mosquito larvicidal binary toxin consisting of BinA and BinB, which are both required for toxicity against Culex and Anopheles larvae. The molecular mechanisms behind Bin toxin-induced damage remain unexplored. We used whole-genome microarray-based transcriptome analysis to better understand how Culex larvae respond to Bin toxin treatment at the molecular level. Our analyses of Culex quinquefasciatus larvae transcriptome changes at 6, 12, and 18 h after Bin toxin treatment revealed a wide range of transcript signatures, including genes linked to the cytoskeleton, metabolism, immunity, and cellular stress, with a greater number of down-regulated genes than up-regulated genes. Bin toxin appears to mainly repress the expression of genes involved in metabolism, the mitochondrial electron transport chain, and the protein transporter of the outer/inner mitochondrial membrane. The induced genes encode proteins linked to mitochondrial-mediated apoptosis and cellular detoxification including autophagic processes and lysosomal compartments. This study is, to our knowledge, the first microarray analysis of Bin toxin-induced transcriptional responses in Culex larvae, providing a basis for an in-depth understanding of the molecular nature of Bin toxin-induced damage.


Perspectives on research in gynecologic oncology.
Gynecologic cancers present unusual opportunities to explore the fruits of well-designed clinical trials to assess the value of existing treatment using a combined modality approach soon after diagnosis. Cancers of the ovary and uterus have well-defined, familiar natural histories. Pathways of spread are clear and reasons for treatment failure are often blatantly obvious. In the case of ovarian cancer, regional treatment with surgery and radiotherapy has been relatively ineffective and generally has not improved the survival statistics in the last two decades. Spread of tumor cells widely throughout the abdominal cavity outside radiation or surgical fields, even in patients with apparently early disease, is the obvious reason. Studies are underway to assess the impact of long-term postoperative adjuvant chemotherapy with L-phenylalanine mustard, an alkylating agent effective in patients with advanced disease, in early stages of ovarian cancer following surgery and or x-irradiation. The search is on for more effective drugs, or combinations of drugs, that could subsequently serve as more effective adjuvant treatments. In carcinoma of the uterine cervix, chemotherapy as an adjunct to surgery and/or radiotherapy in patients with localized, or locally inoperable disease has been poorly evaluated; little data are available and the value of many established drugs in patients with metastatic cervical cancer is undermined. Some recent evidence suggests the use of hydroxyurea, a drug that by itself is not effective in controlling tumor, may enhance the effect of radiotherapy in patients with Stage II disease. Uterine fundal cancer is often successfully treated by surgery alone. The data for the use of pre- or postoperative radiotherapy are open to considerable question. While the relative nontoxic progesterone compounds are effective in a small but significant fraction of patients with advanced uterine cancer, no properly designed clinical trial has truly evaluated their role as postoperative adjuncts in patients who have resectable tumor but a definite high risk of recurrence. Systemic chemotherapy has been rarely used with any consistency against this tumor but, even so, some chemotherapeutic leads, such as the use of adriamycin, are worthy of exploration. The absence of useful information on systemic treatment of gynecologic malignancies can be traced to the excessive rigid compartmentalization of medical practice. Only recently have investigators of all persuasions begun to explore and exploit some of the therapeutic opportunities, which have been available for some time.


Immediate implant placement into posterior sockets with or without buccal bone dehiscence defects: A retrospective cohort study.
To evaluate bone reconstruction and soft tissue reactions at immediate implants placed into intact sockets and those with buccal bone dehiscence defects. Fifty-nine internal connection implants from four different manufacturers were immediately placed in intact sockets(non-dehiscence group, n=40), and in alveoli with buccal bone dehiscence defects: 1) Group 1(n= N10), the defect depth measured 3-5 mm from the gingival margin. 2) Group 2(n=9), the depth ranged from 5mm to 7mm. The surrounding bony voids were grafted with deproteinized bovine bone mineral (DBBM) particles. Cone beam computed tomography(CBCT) was performed immediately after surgery (T1), and at 6 months later(T2). Radiographs were taken at prosthesis placement and one year postloading(T3). Soft tissue parameters were measured at baseline (T0), prosthesis placement and T3. No implants were lost during the observation period. For the dehiscence groups, the buccal bone plates were radiographically reconstructed to comparable horizontal and vertical bone volumes compared with the non-dehiscence group. Marginal bone loss occurred between the time of final restoration and 1-year postloading was not statistically different(P=0.732) between groups. Soft tissue parameters did not reveal inferior results for the dehiscence groups. Within the limitations of this study, flapless implant placement into compromised sockets in combination with DBBM grafting may be a viable technique to reconstitute the defected buccal bone plates due to space maintenance and primary socket closure provided by healing abutments and bone grafts. Immediate implants and DBBM grafting without using membranes may be indicated for sockets with buccal bone defects.


Neonatal spongioform myelinopathy after restricted application of hexachlorophane skin disinfectant.
At least four out of 97 low birth weight (less than 1750 g) newborn infants who had received only limited skin disinfection with 3% hexachlorophane (HCP) emulsion developed spongioform myelinopathy in association with detectable amounts of HCP in their brains. These four cases were found in a post-mortem survey of 20 out of the 27 infants who died. Another nine of these infants had detectable amounts of HCP in the brain but no myelinopathy. It is at present not possible to define a 'safe" level of exposure to 3% HCP emulsion for small preterm infants in the first 2 weeks of life.


Activator anion binding site in pyridoxal phosphorylase b: the binding of phosphite, phosphate, and fluorophosphate in the crystal.
It has been established that phosphate analogues can activate glycogen phosphorylase reconstituted with pyridoxal in place of the natural cofactor pyridoxal 5'-phosphate (Change YC. McCalmont T, Graves DJ. 1983. Biochemistry 22:4987-4993). Pyridoxal phosphorylase b has been studied by kinetic, ultracentrifugation, and X-ray crystallographic experiments. In solution, the catalytically active species of pyridoxal phosphorylase b adopts a conformation that is more R-state-like than that of native phosphorylase b, but an inactive dimeric species of the enzyme can be stabilized by activator phosphite in combination with the T-state inhibitor glucose. Co-crystals of pyridoxal phosphorylase b complexed with either phosphite, phosphate, or fluorophosphate, the inhibitor glucose, and the weak activator IMP were grown in space group P4(3)2(1)2, with native-like unit cell dimensions, and the structures of the complexes have been refined to give crystallographic R factors of 18.5-19.2%, for data between 8 and 2.4 A resolution. The anions bind tightly at the catalytic site in a similar but not identical position to that occupied by the cofactor 5'-phosphate group in the native enzyme (phosphorus to phosphorus atoms distance = 1.2 A). The structural results show that the structures of the pyridoxal phosphorylase b-anion-glucose-IMP complexes are overall similar to the glucose complex of native T-state phosphorylase b. Structural comparisons suggest that the bound anions, in the position observed in the crystal, might have a structural role for effective catalysis.


Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden.
Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We identified 6217 PV, 2838 ET, 1172 MF, and 812 MPN unclassifiable (NOS) patients diagnosed in Sweden, 43 550 controls, and first-degree relatives of cases (n = 24 577) and controls (n = 99 542). Using a marginal survival model, we calculated relative risks (RRs) and 95% confidence intervals as measures of familial aggregation. Relatives of MPN patients had significantly increased risks of PV (RR = 5.7; 3.5-9.1), ET (RR = 7.4; 3.7-14.8), and MPN NOS (RR = 7.5; 2.7-20.8). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings, compatible with a model of recessive genetic inheritance, which can be confirmed only by identifying the susceptibility gene(s). Mean age at MPN diagnosis was not different (P = .20) for affected relatives of cases (57.5 years) versus controls (60.6 years), and risk of MPN by age was not different for parents versus offspring of MPN cases (P = .10), providing no support for anticipation. Relatives of MPN patients had a borderline increased risk of chronic myeloid leukemia (CML; RR = 1.9; 0.9-3.8; P = .09). Our findings of 5- to 7-fold elevated risk of MPNs among first-degree relatives of MPN patients support the hypothesis that common, strong, shared susceptibility genes predispose to PV, ET, MF, and possibly CML.


Perceived Susceptibility to Cervical Cancer among African American Women in the Mississippi Delta: Does Adherence to Screening Matter?
Although preventive measures have greatly decreased the national burden of cervical cancer, racial/ethnic and geographic disparities remain, including the disproportionate incidence and mortality among African American women in the Mississippi Delta. Along with structural barriers, health perceptions and cultural beliefs influence participation in cervical screening. This study examined perceived susceptibility to cervical cancer among African American women in the Delta across three groups: 1) women attending screening appointments (screened), 2) women attending colposcopy clinic following an abnormal Papanicolaou test (colposcopy), and 3) women with no screening in 3 years or longer (unscreened/underscreened). Data were collected during a study assessing the feasibility/acceptability of self-collected sampling for human papillomavirus (HPV) testing as a cervical screening modality. A questionnaire assessed demographics, health care access, and cervical cancer knowledge and beliefs (including perceived susceptibility). Participants were asked, "Do you think you are at risk for cervical cancer?", and responses included yes, no, and I don't know. Multinomial logistic regression models compared variables associated with answers among each group. Of 524 participants, one-half did not know if they were at risk of cervical cancer (50%) or HPV exposure (53%). Between the unscreened/underscreened (n = 160), screened (n = 198), and colposcopy (n = 166) groups, age (p < .001), education (p = .02), and perceived risk of HPV exposure (p < .01) differed. Older age and younger age at first intercourse (unscreened/underscreened), family history and screening recommendations (screened), and family history and perceived risk of HPV exposure (colposcopy) were associated with perceived susceptibility to cervical cancer. Differences in the perceived susceptibility to cervical cancer exist between African American women in the Delta. Understanding these variations can help in developing strategies to promote screening among this population with a high burden of disease.


The challenging diagnosis of Cronkhite-Canada syndrome in the upper gastrointestinal tract: a series of 7 cases with clinical follow-up.
Cronkhite-Canada syndrome is a rare protein-losing enteropathy, classically characterized by ectodermal changes and gastrointestinal polyposis. The etiology remains obscure but immune dysregulation may be important. The diagnosis of Cronkhite-Canada syndrome in the upper gastrointestinal tract is challenging, frequently resulting in delayed patient management. In this study, we described the initial clinical presentations, upper gastrointestinal endoscopic appearances, clinical follow-up, and histologic diagnoses in 7 patients who were subsequently diagnosed with Cronkhite-Canada syndrome. Histology slides were reviewed, and IgG4 immunohistochemical analysis was performed. The most common initial endoscopic impressions were antral malignancy and gastric infection, but gastroduodenal polyposis was not described. On histologic review, the main findings in the gastric mucosa were a prominent mucosal edema, a mixed inflammatory infiltrate rich in eosinophils, and architectural changes with gland dilatation and withering. In the duodenal mucosa, total or subtotal duodenal villous atrophy, inflammation, crypt distortion, and increased apoptotic bodies were the most common features. Three patients died of the disease, and 4 patients were asymptomatic at a mean follow-up of 3.5 years. No intestinal malignancy had been diagnosed. In 2 patients foci of dysplasia in colonic polyps were identified. In only 1 patient, a significant increase in IgG4-positive plasma cells was observed in a colonic polyp. In summary, we found that patients with Cronkhite-Canada syndrome have histologic features commonly found in other immune disorders of the gastrointestinal tract that may help in establishing the diagnosis and further supports the hypothesis that Cronkhite-Canada syndrome may represent an immune dysregulation syndrome, different from IgG4-related disease.


Intensity-modulated radiation therapy in head and neck cancers: The Mallinckrodt experience.
The purpose of the study was to investigate the feasibility and the optimization of tomotherapy-based intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer. From February 1997 to November 1997, 17 patients with squamous cell carcinoma of the head and neck were treated with IMRT. Patients were immobilized with a noninvasive mask and treated using a serial tomotherapy device on a 6 MV linear accelerator. Treatment planning was performed on a Peacock inverse planning system and prescription optimization was used to achieve the best plan for target coverage and parotid sparing. The treatment planning system process has a dosimetric characteristic of delivering different doses to different target structures simultaneously in each daily treatment; therefore, the biological equivalent dose was implemented using the linear-quadratic model to adjust the total dose to the target volume receiving a daily dose of less than 1.9 Gy. All eight patients with gross disease (six in the nasopharynx, two in the tonsil) and one patient with recurrent nasopharyngeal carcinoma received concurrent cisplatin chemotherapy. Six postoperative patients were treated with irradiation alone. Median follow-up was 2.2 years (range 2.6-1.8 years). All patients completed the prescribed treatment without unexpected interruption. Acute side effects were comparable to those of patients treated with conventional beam arrangements during the same period. No patient required gastrostomy during irradiation. The preliminary experience showed that the noninvasive immobilization mask yielded high positioning reproducibility for our patients. To spare the parotid gland, which is in the proximity of the target, a fraction of the target volume may not receive the prescribed dose. In the best-achievable plan of our studied cohort, only 27% +/- 8% of parotid gland volumes were treated to more than 30 Gy, while an average of 3.3% +/- 0.6% of the target volume received less than 95% of the prescribed dose. This is mainly related to the steep dose gradient in the region where the target abuts the parotid gland. The inverse planning system allowed us the freedom of weighting normal tissue-sparing and target coverage to select the best-achievable plan. Local control was achieved in eight patients with gross tumor; six were treated postoperatively. Of three reirradiated patients, two had symptomatic improvement but persistent disease, and one is without evidence of disease. In summary, a system for patient immobilization, setup verification, and dose optimization for head and neck cancer with parotid sparing without significantly compromising target coverage is being implemented for a tomotherapy-based IMRT plan at the Mallinckrodt Institute of Radiology. The initial clinical experience in tumor control is promising, and no severe adverse acute side effects have been observed. Further refining of delivery technology and the inverse planning system, gaining clinical experience to address target definition and dose inhomogeneity within the targets, and understanding the partial volume effect on normal tissue tolerance are needed for IMRT to excel in the treatment of head and neck cancer. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 92-103, (2000).