Type I dentin dysplasia: report of two cases.
Dentin dysplasia is a rare developmental disturbance of dentin affecting approximately 1:100,000 people. It has been classified as an autosomal dominant disease. Two distinct forms of dentin dysplasia have been described. As more cases of dentin dysplasia were reported these categories seemed inadequate; subclassification of type I dentin dysplasia were proposed based on root length and the presence or not of a pulpal remnant. This paper presents two cases demonstrating the classic features of type I dentin dysplasia in the mixed and permanent dentitions and discusses the suggested subclassifications. The authors suggest that while differences in root length may be useful in determining treatment options, thinking of these variables as separate types of dentin dysplasia is not warranted at this time. Justification of a subcategory of type I dentin dysplasia should be based on a different disease process, different histology, significantly different symptoms, or different etiologies, and until researchers can clearly prove from a genetic or chromosomal standpoint that the subcategories are separate entities, we should accept, as we do for many other genetic disorders, that some patients are more severely affected than others.


Calcium phosphate cement augmentation of cancellous bone screws can compensate for the absence of cortical fixation.
An obvious means to improve the fixation of a cancellous bone screw is to augment the surrounding bone with cement. Previous studies have shown that bone augmentation with Calcium Phosphate (CaP) cement significantly improves screw fixation. Nevertheless, quantitative data about the optimal distribution of CaP cement is not available. The present study aims to show the effect of cement distribution on the screw fixation strength for various cortical thicknesses and to determine the conditions at which cement augmentation can compensate for the absence of cortical fixation in osteoporotic bone. In this study, artificial bone materials were used to mimic osteoporotic cancellous bone and cortical bone of varying thickness. These bone constructs were used to test the fixation strength of cancellous bone screws in different cortical thicknesses and different cement augmentation depths. The cement distribution was measured with microCT. The maximum pullout force was measured experimentally. The microCT analysis revealed a pseudo-conic shape distribution of the cement around the screws. While the maximum pullout strength of the screws in the artificial bone only was 30±7N, it could increase up to approximately 1000N under optimal conditions. Cement augmentation significantly increased pullout force in all cases. The effect of cortical thickness on pullout force was reduced with increased cement augmentation depth. Indeed, cement augmentation without cortical fixation increased pullout forces over that of screws without cement augmentation but with cortical fixation. Since cement augmentation significantly increased pullout force in all cases, we conclude that the loss of cortical fixation can be compensated by cement augmentation.


Reservoirs of HIV-1 in vivo: implications for antiretroviral therapy.
The eradication of HIV-1 from infected individuals remains the ultimate goal of all anti-HIV therapeutics. Although highly active antiretroviral therapy (HAART) has led to a profound decrease in morbidity and mortality in infected people by suppressing HIV replication, the virus continues to evolve slowly during therapy even when patients achieve below detectable levels of HIV in plasma. HIV-1 persists in latently infected memory CD4+ T cells and there is minimal decay of HIV in this compartment despite prolonged HAART. Various other reservoirs and sanctuary sites harboring HIV are also established in vivo during antiretroviral therapy. Collectively these sites represent a major impediment to the eradication of HIV-1. This review presents a detailed overview of various reservoir sites in vivo, and discusses their impact on the success and failure of HAART for HIV patients. In addition, it addresses the effect of sub-optimal drug concentrations on reservoir establishment and outlines future therapeutic strategies to counteract these reservoirs and sanctuaries.


Random segment deletion based on IS31831 and Cre/loxP excision system in Corynebacterium glutamicum.
A simple and random genome deletion method combining insertion sequence (IS) element IS31831 and the Cre/loxP excision system generated 42 Corynebacterium glutamicum mutants (0.2-186 kb). A total of 393.6 kb (11.9% of C. glutamicum R genome) coding for 331 genes was confirmed to be nonessential under standard laboratory conditions. The deletion strains, generated using only two vectors, varied not only in their lengths but also the location of the deletion along the C. glutamicum R genome. By comparing and analyzing the generated deletion strains, identification of nonessential genes, the roles of genes of hitherto unknown function, and gene-gene interactions can be easily and efficiently determined.


Towards the realization of the quantum chemistry approach to tunneling photoionization processes in strong laser fields.
Based on Keldysh's theory, we investigate the possibility to use the molecular orbital theoretic approach for calculating the tunneling photoionization rates of molecules. As a demonstration, we concentrate on the 1s state of the hydrogen atom as the initial state.


[The development and clinical application of an easily carried Chinese electrocardiographic auto-diagnostic apparatus].
The 8090 single chip has been used as main core to complete the automatic process, such as controlling electrocardiographer, collecting information, measuring parameters, analysis, diagnosis, and printing Chinese report.


Survival statistics for multiple primaries in head and neck cancer.
The recognition of a second primary carcinoma in a patient with known head and neck cancer is considered a poor prognostic sign. However, its true implication for patient survival is not known. A retrospective 10-year study showed that second primary malignancies developed in 207 of 875 patients. Second primary malignancies were most commonly associated with glottic index tumors, followed by floor of mouth tumors. The second primary was most likely to occur at a time interval of 1.5 years from diagnosis of the index tumor. Second primary neoplasms were more likely to develop in patients whose original head and neck tumor was stage I or II, or whose histopathology showed well or moderately well differentiation. Patients with head and neck cancer in whom a second upper aerodigestive tract tumor develops have a 75% chance of 1-year survival, but only a 25% chance of 5-year survival. The average time from diagnosis of second primary to the time of death was 2.3 years. If we are to increase the survival time of our patients with head and neck cancer, we must consider that a second primary will develop in one of four patients. We must therefore consider the high risk of second primary malignancy when formulating the original treatment plan for a patient manifesting his or her first head and neck cancer.


[Pancreatic cancer stem cell].
Prognosis of pancreatic cancer remains dismal due to the resistance against conventional therapies. Metastasis and massive invasion toward surrounding organs hamper radical resection. Small part of entire cancer cells reveal resistance against chemotherapy or radiotherapy, increased tumorigenicity and migratory phenotype. These cells are called as cancer stem cells, as a counter part of normal stem cells. In pancreatic cancer, several cancer stem cell markers have been identified, which enabled detailed characterization of pancreatic cancer stem cells. Recent researches clarified that conventional chemotherapy itself could increase cancer cells with stem cell-phenotype, suggesting the necessity of cancer stem cell-targeting therapy. Based on these observations, pancreatic cancer stem cell-targeting therapies have been tested, which effectively eliminated cancer stem cell fraction and attenuated cancer progression in experimental models. Clinical efficacy of these therapies need to be evaluated, and cancer stem cell-targeting therapy will contribute to improve the prognosis of pancreatic cancer.


Increase in the incidence of parotid gland tumors in the years 2005-2014.
Salivary gland tumours account for 3-6% of tumours of the head and neck. About 80% of salivary gland tumors occur in parotid glands, 10-17% of which are malignant The aim of the study was to assess whether there is an upward trend in cancer incidence within the parotid glands, with particular emphasis on cancers. 322 patients underwent surgery and 328 parotid gland tumours were removed in the years 2005-2014 at the Department of Laryngology and Laryngological Oncology of the Upper Silesian Medical Centre in Katowice-Ochojec. Clinical, histopathological and statistical analyses of the removed parotid gland tumours were performed. A significant increase in the incidence of benign tumours, especially mixed and Warthin tumours, was demonstrated. There was no significant increase in the number of malignant tumours over the analysed period of time.


Short communication: Early-lactation, but not mid-lactation, bovine lactoferrin preparation increases epithelial barrier integrity of Caco-2 cell layers.
Bovine lactoferrin is an important milk protein with many health-promoting properties, including improving intestinal barrier integrity. Dysfunction of this barrier, commonly referred to as "leaky gut," has been linked to inflammatory and autoimmune diseases. With some processing techniques, lactoferrin isolated from milk collected at the start of the milking season (early lactation) may have lower purity than that isolated from milk collected during the rest of the milking season (mid-lactation) and could result in differences in bioactivity based on the stage of lactation. We compared reversed-phase HPLC chromatographs of early-lactation and mid-lactation preparations and found that both had large chromatograph peaks at the time predicted for lactoferrin. The notable difference between the 2 chromatographs was a much larger peak in the early-lactation lactoferrin sample that was determined to be angiogenin. Angiogenin was first identified due to its ability to induce new blood vessel formation, but is now known to be involved in numerous physiological processes. Then, we compared the effects of early-lactation and mid-lactation lactoferrin preparations in 2 bioassays: trans-epithelial electrical resistance (TEER), a measure of intestinal barrier integrity, and peripheral blood mononuclear cell cytokine secretion, a measure of immune-stimulatory properties. We found that early-lactation lactoferrin increased TEER across Caco-2 cell layers compared with control from 10 to 48 h, mid-lactation lactoferrin did not alter TEER. We also found that early-lactation lactoferrin reduced the amount of IL-8 produced by peripheral blood mononuclear cells (compared with those treated with control medium) to a greater extent than mid-lactation lactoferrin. A pro-inflammatory chemokine, IL-8 is also known to decrease barrier function. These results suggest that the decrease in IL-8 production in the presence of early-lactation lactoferrin may be the mechanism by which it increases TEER. The anti-inflammatory effect of early-lactation lactoferrin may be related to the presence of angiogenin, which is known to suppress inflammatory responses. This work indicates that products rich in angiogenin may have intestinal health benefits, and further work to investigate this is warranted.


Investigating the environmental factors affecting the toxicity of silver nanoparticles in Escherichia coli with dual fluorescence analysis.
Flow cytometric investigation of the toxic effects of nanoparticles on bacteria is highly challenging and not sensitive due to the interference of aggregated nanoparticles: aggregated nanoparticles and bacteria are similar in size. In this study, an optimized dual fluorescence flow cytometric analysis was developed using PI-Lac::GFP (propidium iodide stained Escherichia coli (lac::GFP)) to monitor the toxicity of silver nanoparticles (AgNPs). As compared with single fluorescence analysis, the dual fluorescence analysis enabled more accurate evaluation of the toxic effects of AgNPs. We used this dual fluorescence analysis to investigate how AgNPs toxicity was affected by two typical environmental factors, divalent metal ions and surfactants. Our data revealed that Cu(2+) and SDS significantly enhanced the toxicity of AgNPs in a dose-dependent manner. SDS enhanced the toxicity of both AgNPs and Ag(+) ions, whereas Cu(2+) increased the toxicity of AgNPs but not dissolved Ag(+) ions. Our results suggest that this dual fluorescence analysis can be used to evaluate the toxicity of AgNPs accurately and sensitively.


Abnormal levels of plasma hormones in men with prostate cancer: evidence toward a "two-disease" theory.
The 24-hr mean plasma concentrations of 13 hormones or hormone metabolites (cortisol, testosterone, dihydrotestosterone, dehydroisoandrosterone, dehydroisoandrosterone sulfate, androsterone, androsterone sulfate, estrone, thyroxine, triiodothyronine, LH, FSH, and prolactin) were measured in 16 rigorously screened patients (aged 55-80) with stage C or D prostate cancer and 36 normal men. Nine of the hormones showed no abnormalities in the patients but four (testosterone, dihydrotestosterone, cortisol, and estrone) showed abnormalities. Testosterone and dihydrotestosterone, which, respectively, decreased with age and showed no change with age in the normal men, rose sharply with age in the patients. The patients' curves crossed the normal curves at about age 65; patients 65 or above showed normal values while patients under age 65 showed significantly subnormal levels of both hormones: testosterone averaged 282 ng/dl in patients vs 434 ng/dl in controls (P less than 0.0001) and dihydrotestosterone averaged 70 ng/dl in patients vs 99 ng/dl in controls (P less than 0.01). Cortisol, which was age invariant in the normal men, fell sharply with age in the patients; patients under 65 had significantly elevated levels (10.1 vs 6.9 micrograms/dl; P less than 0.0001), while patients 65 or older had normal levels. Estrone levels were age invariant in both patients and controls, but the mean level in patients was markedly elevated (81 vs 47 pg/ml in controls; P less than 0.001). The cortisol/testosterone ratio almost completely separated prostate cancer patients under 65 from normal men, but did not discriminate patients 65 or older from normal. The findings indicate that prostate cancer patients under 65 differ markedly in their endogenous hormonal pattern from patients 65 or older. This leads us to propose a "two-disease" theory of prostate cancer, with possible differences in genetic factors and prognosis.


New chemotherapeutics in malignant mesothelioma: effects on cell growth and IL-6 production.
The benefits of chemotherapy can be assessed in terms of tumour shrinkage, prolongation of life or simply palliation of symptoms. In the study reported here, in vitro correlates of these parameters were sought as a rational guide to the choice of newer agents in the clinic. The cytotoxicity and effects on IL-6 production of ten chemotherapy agents representing four different classes of drugs were tested against a panel of five mesothelioma cell lines. The mesothelioma cells were more sensitive to the action of irinotecan (and its active metabolite SN38) and gemcitabine than the control cell lines. Gemcitabine and to a lesser extent irinotecan inhibited the secretion of the proinflammatory cytokine IL-6 at concentrations of each drug that produced only small decreases in cell viability. This effect was not seen in cells treated with docetaxel or vindesine. Higher doses of gemcitabine and irinotecan caused a surge in IL-6 release and this was not due to release of intracellular stores of IL-6 through lysis of the cells. These results suggest that irinotecan and gemcitabine are not only more likely to be active against mesothelioma than other new chemotherapy agents but may also produce a palliative effect in nonresponders to these agents by decreasing the secretion of IL-6.


Outcomes of Newborns with Prenatal Ventricular Asymmetry not Requiring Neonatal Surgical Intervention: a 22-Year Retrospective Single-Center Study.
To assess the outcomes of neonates prenatally diagnosed with ventricular asymmetry and not operated on within the neonatal period and to determine the risk factors for left heart obstruction occurrence at follow-up. All neonates with prenatal asymmetry of the ventricles, diagnosed from August 1993 to July 2015, not operated on within the neonatal period, were retrospectively included in the study. Left heart echocardiographic measurements at birth and at last follow-up were collected and compared. Left heart anomaly included isthmus and/or aortic valve and/or mitral valve obstruction. There were a total of 34 newborns included in the study. The median follow-up was 2 years. There was no death. Eleven patients were operated on at a median age of three months; seven of them had an obstruction of the left heart (five coarctations of the aorta, one sub-aortic and aortic valve stenosis, and one mitral stenosis). Estimated freedom of left heart surgery was 80% at 6 months and 75% at 10 years. The main risk factor for progression to a left heart anomaly was a hypoplasia of the aortic isthmus (p = 0.0003), while the presence of a left superior vena cava was more frequent in these patients although the difference was not significant. Patients with an aortic isthmus z-score below - 2 at the closure of arterial duct are at risk of later coarctation and therefore follow-up should be extended to at least 3 months. Furthermore, the prenatal ventricular asymmetry does not only identify patients at risk of coarctation but also of other left heart anomalies. This last point should be a better approach with future parents to improve prenatal counseling on a more complex postnatal diagnostic than a simple isolated coarctation.


Use of adjunctive treatments in improving patient outcome in Fournier's gangrene.
Fournier's gangrene is a polymicrobial necrotising soft tissue infection (NSTI) affecting the perineum and scrotum. It is rapidly progressive and destructive, and is associated with high morbidity and mortality. Management protocol includes prompt diagnosis, early institution of antibiotic therapy and adequate wound debridement, usually requiring multiple operations. The resultant defect can be left to heal by secondary intention, or surgical coverage can be undertaken. We report Fournier's gangrene in a 60-year-old diabetic man and his successful treatment with skin grafting, which utilised a multidisciplinary approach and adjuncts, including negative-pressure wound therapy and hyperbaric oxygen therapy. We also review the literature related to these adjuncts and discuss their usefulness in the management of NSTIs.


In vitro biomechanical comparison of locking compression plate fixation and limited-contact dynamic compression plate fixation of osteotomized equine third metacarpal bones.
To compare monotonic biomechanical properties and fatigue life of a broad locking compression plate (LCP) fixation with a broad limited contact dynamic compression plate (LC-DCP) fixation to repair osteotomized equine third metacarpal (MC3) bones. In vitro biomechanical testing of paired cadaveric equine MC3 with a mid-diaphyseal osteotomy, stabilized by 1 of 2 methods for fracture fixation. Cadaveric adult equine MC3 bones (n=12 pairs). MC3 were divided into 3 groups (4 pairs each) for: (1) 4-point bending single cycle to failure testing; (2) 4-point bending cyclic fatigue testing; and (3) torsional single cycle to failure testing. The 8-hole, 4.5 mm LCP was applied to the dorsal surface of 1 randomly selected bone from each pair. One 8-hole, 4.5 mm LC-DCP) was applied dorsally to the contralateral bone from each pair. All plates and screws were applied using standard ASIF techniques. All MC3 bones had mid-diaphyseal osteotomies. Mean test variable values for each method were compared using a paired t-test within each group. Significance was set at P<.05. Mean yield load, yield bending moment, composite rigidity, failure load and failure bending moment, under 4-point bending, single cycle to failure, of the LCP fixation were significantly greater than those of the LC-DCP fixation. Mean cycles to failure for 4-point bending was significantly greater for the LCP fixation compared with LC-DCP fixation. Mean yield load, mean composite rigidity, and mean failure load under torsional testing, single cycle to failure was significantly greater for the broad LCP fixation compared with the LC-DCP fixation. The 4.5 mm LCP was superior to the 4.5 mm LC-DCP in resisting the static overload forces (palmarodorsal 4-point bending and torsional) and in resisting cyclic fatigue under palmarodorsal 4-point bending. The results of this in vitro study may provide information to aid in the selection of a biological plate for the repair of equine long bone fractures.


Aconitine-induced writhing as a method for assessing aspirin-like analgesic activity.
A painful writhing syndrome is produced by aconitine when given intraperitoneally. It is similar to that induced by other chemical agent viz. phenylquinone, acetic acid, and bradykinin. Aconitine writhing is quick to appear, shows greater frequency and longer duration than that induced by other agents. The nonnarcotic analgesics more selectively antagonize the aconitine writhing than orally-administered narcotic analgesics. Thus the aconitine writhing method is a very suitable method for the selective screening of the aspirin type of analgesic agent.


Synovial sarcoma of the soft palate: report of a case.
A case of primary synovial sarcoma of the soft palate is reported in a 19 year old man who was in good health and free of recurrence one year after operation. Radiation therapy was selected and a dose of 7600 rads was given. The presence of hyaluronic acid was investigated using the critical electrolyte concentration method. The tumor was considered histogenetically to be derived from undifferentiated mesenchymal tissue.


Phase II study of rDNA alpha-2 interferon (INTRON A) in patients with multiple myeloma utilizing an escalating induction phase.
Twenty previously treated patients with multiple myeloma were treated with rDNA human alpha-2 interferon (INTRON A) in a phase II trial. Patients received an induction phase of therapy consisting of 3-100 X 10(6) IU/m2 iv given every other day pending myelosuppression. Patients then received 10 X 10(6) IU/m2 three times a week sc. In patients not responding to the iv and sc protocol, prednisone (20 mg orally) was given with each dose of INTRON A to determine whether additional responses could be produced and whether toxicity could be reduced. During the sc phases of therapy, INTRON A was escalated pending hematologic and nonhematologic toxicity. Three partial remissions were achieved in patients receiving the initial iv/sc therapy, and one additional patient responded when prednisone was added (durations of remission, 5, 6, 8, and 9 months). Myelosuppression was the dose-limiting toxic effect in both the iv and sc phases of therapy. Constitutional symptoms (flu-like) were seen in the majority of patients, but were tolerable. With the utilization of prednisone, flu-like symptoms were reduced in frequency and degree. Escalation of the dose of INTRON A was possible in the majority of patients when prednisone was added; however, only one patient (of seven) responded to combination therapy. INTRON A can produce remissions in 20% of patients with previously treated multiple myeloma. No improvement in the response rate was achieved utilizing a high-dose induction program. Although the dose of INTRON A could be escalated when prednisone was added, the response rate was not enhanced.


Intravenous feeding of the rat with short chain fatty acid esters. II. Monoacetoacetin.
Acetoacetic acid is oxidized independent of carnitine transport into the cell mitochondria and its monoglyceride is a water soluble compound. The latter was examined as an intravenous nutrient. The monoglyceride of acetoacetic acid was prepared from the acid anhydride, diketene, and glycerol and was found to be totally miscible with water. The nutritional properties of monoacetoacetin were investigated by continuous intravenous infusion of 25 or 50 g/kg body weight per day into ad libitum fed rats. The response of these animals was compared to normal and food restricted rats. All experimental animals survived the 7 day study period in good health and were free of detectable physiological and behavioral abnormalities. The test rats demonstrated weight gain dependent on the infusion rate while on an inadequate spontaneous oral food intake diet. Ketonuria, hyperketonemia and monoglyceride excretion in the urine accompanied the infusion of monoacetoacetin and were dependent on the infusion load. At 50 g/kg per day total plasma ketones were found to be comparable with the infusion load. At 50 g/kg per day total plasma ketones were found to be comparable with the maximum level obtained in fasted rats, but the acetoacetate concentration was relatively higher than in fasting. This was consistant with ketosis derived from the hydrolysis of the monoglyceride. It was concluded from these results that monoacetoacetin might be an asset for intravenous nutrition.


A rapid and sensitive method to detect specific human lymphocyte antigen (HLA) class II alleles associated with celiac disease.
Celiac disease (CD) is a complex disorder triggered by gluten affecting genetically predisposed individuals. More than 90% of patients carry human lymphocyte antigen (HLA)-DQ2 (DQA1*05, DQB1*02) and/or HLA-DQ8 (DQA1*03, DQB1*0302). We propose the use of the DQ-CD Typing kit that allows identification of the HLA class II alleles (DQA1*0201,*03,*05, DQB1*02,*0302, DRB1*03,*04,*07) selected to be informative in the CD risk evaluation and of a second kit, namely DQ-CD Zygosis, for DQB1*02 homozygosity determination. The study was performed on a cohort of 100 individuals previously HLA typed with commercial kits. Fresh blood or previously extracted DNA was amplified in a unique PCR program using allele-specific primers and visualized on agarose gel. DNA amplification yielded strong and clear products without non specific signals or ghost bands. All the samples showed the expected alleles in accordance with the previous HLA typing. The DQ-CD Typing and Zygosis kits are fast, simple, economical and accurate tools that can be used to determinate the HLA-DQ2/DQ8 status in laboratory practice addressed for the diagnosis of CD. Molecular HLA testing is considered a valid support in the confirmation/exclusion of CD, especially in high-risk groups, such as CD relatives, or when serological and histological data are ambiguous.


Efficacy of a skin tear education program: improving the knowledge of nurses practicing in acute care settings.
We sought to evaluate the knowledge base of acute care registered nurses (RNs) regarding skin tears and the efficacy of an online educational program designed to improve their knowledge of skin tears including (1) predisposing factors; (2) identification and assessment of skin tears using the Payne-Martin Classification System; and (3) preventive care, treatment, and documentation. This was a prospective quasi-experimental education intervention study. Four hundred sixteen acute care RNs from 2 affiliated hospitals participated in the study. They comprised approximately 20% of more than 2,000 nurses employed by Atlantic Health. These nurses worked in critical care, medical-surgical, and specialty units and varied in age, level of education, work experience, and years in nursing. A Web-based educational program was provided for over 4 months on our intranet service, which was available to all RN staff 24-hours-a-day, 7-days-a-week. The educational program was subdivided into 3 sections: (1) identification and assessment, (2) classification and differentiation, and (3) treatment. Nurses' knowledge of skin tears improved following the Web-based educational program. Following completion of the identification and assessment of skin tears section, participants were better able to identify and correctly assess skin tears (mean scores 99.1% vs 97.1%, P < .001). Participants also achieved greater knowledge of the differentiation between categories I, II, and III skin tears (mean scores 94.9% vs 83.4%, P < .001) and knowledge of treatment (mean score 93.7% vs 73.8%, P < .001). Our Web-based skin tear educational program was effective in improving nurses' knowledge regarding skin tear identification and assessment, classification and differentiation, and treatment.


Systematic mutational mapping of sites on human interferon-beta-1a that are important for receptor binding and functional activity.
A systematic mutational analysis of human interferon-beta-1a (IFN-beta) was performed to identify regions on the surface of the molecule that are important for receptor binding and for functional activity. The crystal structure of IFN-beta-1a was used to design a panel of 15 mutant proteins, in each of which a contiguous group of 2-8 surface residues was mutated, in most instances to alanine. The mutants were analyzed for activity in vitro in antiviral and in antiproliferation assays, and for their ability to bind to the type I IFN (ifnar1/ifnar2) receptor on Daudi cells and to a soluble ifnar2 fusion protein (ifnar2-Fc). Abolition of binding to ifnar2-Fc for mutants A2, AB1, AB2, and E established that the ifnar2 binding site on IFN-beta comprises parts of the A helix, the AB loop, and the E helix. Mutations in these areas, which together define a contiguous patch of the IFN-beta surface, also resulted in reduced affinity for binding to the receptor on cells and in reductions in activity of 5-50-fold in functional assays. A second receptor interaction site, concluded to be the ifnar1 binding site, was identified on the opposite face of the molecule. Mutations in this region, which encompasses parts of the B, C, and D helices and the DE loop, resulted in disparate effects on receptor binding and on functional activity. Analysis of antiproliferation activity as a function of the level of receptor occupancy allowed mutational effects on receptor activation to be distinguished from effects on receptor binding. The results suggest that the binding energy from interaction of IFN-beta with ifnar2 serves mainly to stabilize the bound IFN/receptor complex, whereas the binding energy generated by interaction of certain regions of IFN-beta with ifnar1 is not fully expressed in the observed affinity of binding but instead serves to selectively stabilize activated states of the receptor.


Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: incidence and mortality in a controlled trial (Finland).
Epidemiological studies have suggested a protective effect of vegetables and fruits on urinary tract cancer but the possible protective nutrients are unknown. We studied the effect of alpha-tocopherol (a form of vitamin E) and beta-carotene supplementation on urinary tract cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. A total of 29,133 male smokers aged 50-69 years from southwestern Finland were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or a placebo daily for 5-8 years (median 6.1 years). Incident urothelial cancers (bladder, ureter, and renal pelvis; n = 169) and renal cell cancers (n = 102) were identified through the nationwide cancer registry. The diagnoses were centrally confirmed by review of medical records and pathology specimens. The supplementation effects were estimated using a proportional hazards model. Neither alpha-tocopherol nor beta-carotene affected the incidence of urothelial cancer, relative risk 1.1 (95% confidence interval (CI) 0.8-1.5) and 1.0 (95% CI 0.7-1.3), respectively, or the incidence of renal cell cancer, relative risk 1.1 (95% CI 0.7-1.6) and 0.8 (95% CI 0.6-1.3), respectively. Long-term supplementation with alpha-tocopherol and beta-carotene has no preventive effect on urinary tract cancers in middle-aged male smokers.


Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus versus Alzheimer's Disease and Subcortical Ischemic Vascular Disease: A Systematic Review.
The diagnostic workup of idiopathic normal pressure hydrocephalus (iNPH) can be challenging due to an overlap in symptoms and neuroimaging features with other disorders. Despite a growing interest, a cerebrospinal fluid (CSF) biomarker profile in iNPH has not yet been identified. To determine the CSF biomarkers with the greatest evidence for differentiating iNPH from the most common differential diagnoses, Alzheimer's disease (AD) and subcortical ischemic vascular disease (SIVD). A systematic literature search was conducted in PubMed to identify relevant articles up to July 2018 using the following MESH-terms: "Cerebrospinal fluid", "diagnos*", "hydrocephalus, normal pressure". Relevant data were extracted to assess the risk of bias in the included studies. Twenty-five studies including 664 patients with iNPH, 502 with AD, 57 with SIVD, 81 with other disorders, and 338 healthy controls (HC) were included. They investigated the diagnostic value of 92 CSF biomarkers. Most evidence existed for amyloid-β 42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) in iNPH versus AD and HC: Aβ42 did not differ between iNPH and AD, but was lower than in HC subjects. T-tau and p-tau were lower in iNPH versus AD on a level comparable to HC subjects. There was moderate or limited evidence for 62 and 88 biomarkers, respectively. Several plausible biases characterize the literature including small sample sizes and inconsistent diagnostic criteria. T-tau and p-tau may differentiate iNPH from AD and Aβ42 from HC. A combination of these biomarkers may improve the diagnostic accuracy in iNPH.


Comparison of the effects of diltiazem and aspirin on platelet aggregation in cats.
Platelet aggregation in response to collagen (1 or 3 micrograms/ml), arachidonic acid (10(-2) M), and adenosine diphosphate (ADP, 2 microM) was compared in healthy cats treated with diltiazem (approximately 2 mg/kg body weight, q 8 hrs for 10 doses), aspirin (approximately 21 mg/kg body weight [1 baby aspirin], q 72 hrs for three doses), or a combination of diltiazem and aspirin. Baseline values obtained prior to treatment served as controls. Addition of arachidonic acid to blood resulted in an impedance change (i.e., aggregation) with time in samples from the nontreated cats and the cats treated with diltiazem, but the addition had no effect in blood from cats treated with aspirin alone or with a combination of diltiazem and aspirin. Platelet aggregation in response to either concentration of collagen or to ADP was not altered by any treatment. Secretion of adenosine triphosphate (ATP) from the platelets was measured when the aggregating agent was 3 micrograms/ml collagen; secretion was not affected by any treatment.


Synthesis and characterization of a carboranyl-tetrabenzoporphyrin.
An expeditious synthetic route to a carboranyl-substituted tetrabenzoporphyrin is reported. The absorption and emission spectra of water-soluble tetrabenzoporphyrin 4 are distinct from those of a known carboranylporphyrin (5). Both tetrabenzoporphyrin 4 and porphyrin 5 were found to be non-toxic toward V79 hamster lung fibroblast cells at 300 microM, using an MTT assay. The X-ray structure of a Cu(II)-carboranyl-tetrabenzoporphyrin is presented and discussed.


Glioblastoma Multiforme with Hypodipsic Hypernatremia in a Seven-Month-Old Golden Retriever.
Primary hypodipsic hypernatremia is a rarely reported disease in dogs. Reported underlying causes associated with this disease in dogs include congenital malformations, encephalitis, intracranial neoplasia, and pressure atrophy of the hypothalamus secondary to hydrocephalus. The dog in this report had an infiltrative neoplastic disorder, likely causing damage to the hypothalamic osmoreceptors responsible for the thirst generation. The neoplastic process was identified histopathologically as glioblastoma multiforme, an unusual tumor to occur in a dog this young. A tumor of the central nervous system causing physical destruction of the osmoreceptors has rarely been reported in dogs and none of the previously reported cases involved a glial cell tumor.


Infective endocarditis in children.
The clinical manifestations, infective microorganisms, underlying diseases, complications and prognosis of infective endocarditis (IE) were studied in 17 current patients. Data were compared with 101 previous cases reported in Japan. Most patients with IE (110/118 = 93.2%) had underlying heart diseases. IE was noted most often in patients with ventricular septal defect (VSD) and tetralogy of Fallot. The incidence of post operative endocarditis was high (29.4% in the present series and 9.0% in the overall series), too. Streptococcus viridans, Staphylococcus aureus and GNB were the most common etiologic agents with incidences of 28.8% (34/118), 25.4% (30/118) and 9.3% (11/118), respectively. Almost half of the deaths from IE were caused by s. aureus. The mortality was 11.9% (14/118) in both series. The death rate from candida albicans was 100%, from s. aureus 33.3% (10/30) and from str. viridans 5.9% (2/34) in both series. Culture negative patients accounted for 11.9% (14/118) in both series. Complications which did not involve the valves were noted in one patient with cerebral emboli and in two patients with pulmonary infarction in the present series. Cerebral emboli phenomena were seen 8 cases of the overall series, 4 of whom died.


Induction of cytochromes P-450 2B and 3A in mice following the dietary administration of the novel cognitive enhancer linopirdine.
The effects of the novel cognitive enhancer linopirdine [3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one] on hepatic cytochromes P-450 (CYP) and linopirdine metabolism were determined in female mice fed 0, 10, 50, and 250 mg/kg/day of linopirdine in the diet for 4, 7, 14, and 28 days. Linopirdine induced CYP maximally by day 4 only at the highest dose, as demonstrated by significant (p < 0.05) increases in total spectral CYP and liver weight. SDS-PAGE revealed induced 52 kDa microsomal protein(s), identified as CYP2B and 3A by immunoblotting. Linopirdine also increased the rates of reactions selectively catalyzed by CYP2B and 3A (pentoxyresorufin O-dealkylation, benzphetamine N-demethylation, erythromycin N-demethylation, and testosterone 2 beta-, 6 beta-, 16 beta-hydroxylation), 1.7- to 3.0-fold vs. control, similar to increases produced by the prototypical CYP2B and 3A inducers phenobarbital and dexamethasone. No increase in microsomal CYP1A or 2E levels was demonstrated by immunoblotting or selective substrate assays. CYP induction increased the metabolism of linopirdine. The area under the plasma concentration-time curve of linopirdine after a 250 mg/kg/day dose decreased 11-fold from day 1-28, and microsomes from a parallel 250 mg/kg/day group metabolized linopirdine 1.9-fold faster than control (p < 0.05). This autoinduction was due primarily to the induced CYP3A, because antibodies recognizing CYP3A inhibited the microsomal metabolism of linopirdine by 85%, whereas antibodies to CYP2B were not inhibitory. In summary, the dietary consumption of 250 mg/kg/day of linopirdine by female mice coinduced CYP2B and 3A maximally by day 4, and resulted in an increased rate of metabolism of linopirdine, predominantly due to CYP3A.


Renal lesions in estuarine fishes collected from the Elizabeth River, Virginia.
The renal lesions of five species of estuarine fishes from the heavily polluted Elizabeth River, Virginia, and the nearby, less polluted Nansemond River were studied grossly and microscopically. No gross lesions were observed but microscopic lesions occurred in renal tissue. Mesangial sclerosis occurred in hogchoker, and mesangiolysis occurred in both hogchoker and spot. Glomerular lesions in spot and hogchoker were more frequent in Elizabeth River samples than in Nansemond River samples. Tubular lesions occurred in both Nansemond River and Elizabeth River sciaenids and hogchoker; the prevalence of these lesions was higher in Elizabeth River sciaenids but equal in hogchoker. All lesions in toadfish were found only in fish from the Elizabeth River.


Standard deviations and correlations of GC levels in DNA sequences.
In a DNA sequence that exhibits long-range correlations, standard deviations among the GC levels of its segments can be up to an order of magnitude higher than in a sequence consisting of independent, identically distributed nucleotides. Conversely, plots of inter-segment standard deviations vs. segment length reveal quantitative information about the correlations present in a sequence. We present and discuss formulae that relate long-range (power-law) correlations between the nucleotides of a sequence to the expected standard deviations of the GC levels of its segments, and to the correlations between them.


The Effects of a Genital Vibratory Stimulation Device on Sexual Function and Genital Sensation.
The aim of this study was to evaluate the effectiveness of a genital vibratory stimulation device in improving sexual function in women with arousal and orgasm disorders. In this single-arm, prospective study, baseline and 1- and 3-month assessments were performed to evaluate women with sexual arousal and/or orgasmic disorders, who received therapy using a genital vibratory stimulation device. Sexual function, satisfaction, and distress were evaluated using the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale, and the Female Intervention Efficacy Index questionnaires. Genital sensation was evaluated using quantitative sensory testing. Seventy women, aged 19 to 64 years, were evaluated from October 2009 to August 2013. Forty-seven (67.1%) and 37 (52.9%) women completed 1- and 3-month follow-ups, respectively. The FSFI arousal and orgasm domain scores and total FSFI scores improved at 1 and 3 months (P < 0.001 for all outcomes). Mean (SD) total FSFI scores increased from 20.04 (4.65) (baseline) to 25.03 (5.21) (1 month) to 26.66 (5.42) (3 months; both Ps < 0.0001). Female Sexual Distress Scale scores reflected significantly decreased distress at 1 (P = 0.0006) and 3 (P < 0.0001) months compared with baseline and at 3 months compared with 1 month (P = 0.03). Neurological sensation was increased at all genital sites at 1 and 3 months (P < 0.0001 for all). After adjustment for age, there was a significant interaction between arousal domain scores and clitoral and right labial sensation. At 3 months, perceptions of increased vaginal lubrication, orgasm, and genital sensation were reported by 67.5%, 65.0%, and 82.5% of the participants. No major adverse events were noted. Genital vibratory stimulation device use resulted in uniform improvements in sexual function, satisfaction, sexually related distress and genital sensation.


Expression of nestin and chromogranin in regeneration zones of rat pancreas.
The particular signals that start and orchestrate the regeneration process in pancreas are not well understood yet. We aimed to investigate the expression of nestin and chromogranin A in pancreatic regeneration zones and a secondary objective, we assessed the efficiency of pancreatic duct ligation method in creation of a pancreatic regeneration model in rats. Partial (90%) pancreatectomy and pancreatic duct ligation were performed in Wistar rats, in order to create pancreatic regeneration models. Pancreatic tissues were examined histologically. Expression profiles were investigated by immunohistochemistry for nestin and chromogranin A. Nestin and chromogranin A expressions were observed in regeneration zones. Pancreatic regenerations zones were seen in pancreatic duct ligation group samples as well as partial pancreatectomy group. Nestin was expressed prominently in acinoductular metaplasia cells in regeneration zones. This was best demonstrated in the samples of pancreatic duct ligation group. In the subsequent sections of nestin positive sites, cytoplasmic positivity with chromogranin A was observed. This study confirms that nestin and chromogranin A can be detected in neogenesis-evoked pancreatic tissue, particularly in the acinoductular epithelium. Nestin and chromogranin A may be important markers to identify pancreatic stem cells. Pancreatic duct ligation can be used for creating pancreatic regeneration model in rats. Chromogranin A, Nestin, Pancreas, Regeneration, Stem cells.


A 1064-nm Neodymium-doped Yttrium Aluminum Garnet Picosecond Laser for the Treatment of Hyperpigmented Scars.
Pigmentation is one of the few major characteristics according to which scars are evaluated. Data on the treatment of the hyperpigmented component of scars are sparse. The authors aimed at evaluating the efficacy of the fractional 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) picosecond laser in the treatment of the hyperpigmented component of scars. Sixteen patients with hyperpigmented scars underwent 3 to 8 treatment sessions at 3- to 6-week intervals with the 1,064-nm Nd:YAG picosecond laser (PicoWay, Candela, Resolve handpiece). The treatment response was evaluated by 2 noninvolved dermatologists on a global assessment scale (GAS) of 1 to 4. A Mexameter quantitatively evaluated the melanin content of the scar before and after laser treatments. The average GAS score of the 2 noninvolved dermatologists was 3.31 ± 0.57. The patients assessed their level of tolerance as good or excellent and their satisfaction level as moderate or high. The Mexameter showed that the melanin index decreased considerably (by 39.11 ± 11.58%) in all patients after treatment. The fractionated nonablative picosecond Nd:YAG laser was effective for the treatment of the hyperpigmented component of scars.


Brain edema after carotid revascularization: benign syndrome or prelude to hemorrhage?
Brain edema (BE) post carotid revascularization (CR) is considered a benign presentation of the hyperperfusion syndrome. Its physiopathology has been related to production of vasogenic edema that tends to progressive spontaneous resolution. Its relation with post-CR hemorrhage remains unclear. Three cases of BE post-CR are described and compared to controls. Clinical evolution, medical management, and plain-CT and perfusion-CT (PCT) results are analysed. Two cases of BE had a benign course, with a progressive resolution of edema and disappearance of neurologic deficits. Effective blood pressure control was achieved in these patients. The third case suffered massive hemorrhage 24h after initial BE and died. This patient reached peak systolic levels of 220 mmHg before conversion to hemorrhage. Plain-CT and PCT findings were similar in the three patients with BE. CT showed signs of hemispheric brain swelling ipsilateral to CR. PCT showed low MTT and high CBF values on the hemisphere ipsilateral to CR compared to the contralateral hemisphere, with symmetric CBV values. Plain-CT and PCT in controls showed no abnormalities. BE post CR can be reversible but may also herald a hemorrhagic complication. A common physiopathology of post-CR BE and hemorrhage is suggested by PCT findings, related to failure of auto-regulation and secondary blood-brain-barrier dysfunction. Spontaneous resolution of BE post-CR should not be routinely expected in clinical practice. Conversion to hemorrhage might be related with deficient blood pressure control and secondary rupture of the already damaged vessel wall.


[Hemagglutinating activity of various viruses on trypsinized erythrocytes].
Mengo, Vesicular stomatitis and Semliki forest viruses titered with trypsin modified mouse, goose, pigeon and human erythrocytes show HA titers 2-32 fold higher than with the same untreated cells.


Thoracic and cardiovascular interventions after orthotopic heart transplantation.
The long-term outcome of orthotopic heart transplantation is limited by the development of cardiac allograft vasculopathy, rejection, infection, and malignancy. After heart transplantation, we treated patients with thoracic and cardiovascular diseases: preexisting coronary artery sclerosis in 2 patients, cardiac allograft vasculopathy in 19, valvular disease in 3, mycotic ascending aortic aneurysm in 2, superior vena cava stenosis in 2, and lung neoplasm in 10 patients. We successfully performed coronary artery bypass grafting for preexisting coronary artery sclerosis, valve replacement for valvular disease, and patch enlargement for superior vena cava stenosis. Percutaneous transluminal coronary angioplasty for cardiac allograft vasculopathy achieved excellent initial results, but the incidence of restenosis was high (67%). One patient who underwent coronary artery bypass grafting for cardiac allograft vasculopathy died immediately after operation. Graft replacement was performed for mycotic aortic aneurysm, but 1 patient required reoperation because of recurrent aneurysm. The long-term survival rate in patients undergoing surgical resection for lung neoplasm was poor (50%). The need for thoracic and cardiovascular interventions in patients after heart transplantation was low (4.7%). Use of the appropriate procedures can improve the long-term survival after heart transplantation.


Self-association of the major protein component of bovine serum high density lipoprotein.
The major protein component of bovine high density lipoprotein was investigated in solution by fluorescence polarization and ultracentrifugal techniques. A fluorescent derivative of this protein with 1-dimethylaminonaphthalene-5-sulfonyl chloride was employed in the fluorescence experiments. Over the concentration range from 5-10(-7) M to 5-10(-4) M of the protein monomer at pH values from 2 to 11 and ionic strengths from 0.03 to 2.0, at 23 degrees C, the major protein of bovine high density lipoproteinapoprotein (Apo-HOL-I) was found to exist in a stable aggregated form. The aggregate was not affected by dioxane additions of up to 20% nor by Triton X-100 to 0.2%, but dissociated readily in the presence of 0.07% sodium dodecylsulfate or 6 M urea. At concentrations below 5-10(-7) M, dissociation of the protein aggregate started spontaneously and continued down to 10(-8) M, the lowest measurable concentration. Several physiocochemical properties of the major protein of bovine high density lipoprotein were determined in the stable aggregate form. Molecular weight was 104 000 from ultracentrifugal analysis and 80 000 from gel-filtration. Rotational relaxation time was 115 ns at 25 degrees C, and s-0 20,w was 4.78 s. The results suggest very strong protein-protein interactions (Kd less than 10(-7) M) that are not electrostatic in nature. Hydrophobic interactions of a magnitude that could be affected by 20% dioxane or 0.2% Triton X-100 detergent are also excluded. There is saturation of the interaction sites by the aggregation of a few protein monomer units possibly to form a tetramer which is moderately asymmetric (1:4 axial ratio, assuming an ellipsoid of revolution) and relatively rigid. The strong protein-protein interactions in this pure apolipoprotein suggest the possibility of competition of inter-protein associations with protein-lipid interactions in in vitro lipid binding or lipoprotein reconstitution experiments.


Monitoring for potential adverse effects of prenatal gene therapy: use of large animal models with relevance to human application.
Safety is an absolute prerequisite for introducing any new therapy, and the need to monitor the consequences of administration of both vector and transgene to the fetus is particularly important. The unique features of fetal development that make it an attractive target for gene therapy, such as its immature immune system and rapidly dividing populations of stem cells, also mean that small perturbations in pregnancy can have significant short- and long-term consequences. Certain features of the viral vectors used, the product of the delivered gene, and sometimes the invasive techniques necessary to deliver the construct to the fetus in utero have the potential to do harm. An important goal of prenatal gene therapy research is to develop clinically relevant techniques that could be applied to cure or ameliorate human disease in utero on large animal models such as sheep or nonhuman primates. Equally important is the use of these models to monitor for potential adverse effects of such interventions. These large animal models provide good representation of individual patient-based investigations. However, analyses that require defined genetic backgrounds, high throughput, defined variability and statistical analyses, e.g. for initial studies on teratogenic and oncogenic effects, are best performed on larger groups of small animals, in particular mice. This chapter gives an overview of the potential adverse effects in relation to prenatal gene therapy and describes the techniques that can be used experimentally in a large animal model to monitor the potential adverse consequences of prenatal gene therapy, with relevance to clinical application. The sheep model is particularly useful to allow serial monitoring of fetal growth and well-being after delivery of prenatal gene therapy. It is also amenable to serially sampling using minimally invasive and clinically relevant techniques such as ultrasound-guided blood sampling. For more invasive long-term monitoring, we describe telemetric techniques to measure the haemodynamics of the mother or fetus, for example, that interferes minimally with normal animal behaviour. Implanted catheters can also be used for serial fetal blood sampling during gestation. Finally, we describe methods to monitor events around birth and long-term neonatal follow-up that are important when considering human translation of this therapy.


Lead in human bones. Investigations on an occupationally non-exposed population in southern Bavaria (F.R.G.). II. Children.
The concentration of lead in three different bones (pelvic bone, cortical part of the mid-femur, petrous portion of the temporal bone) of 82 children who died in 1984 was determined by graphite furnace atomic absorption spectrometry. Three age classes were selected: less than 1 year (n = 25); 1-6 years (n = 18); 10-20 years (n = 35). The Pb content of all three types of bone increased steadily with age, and was most pronounced in the temporal bone. The differentiation of the bones with respect to the Pb concentration, as seen in adults, increased from babies (geom. mean, temporal bone 0.33 mg/kg wet wt., femur 0.33, pelvic bone 0.26) to pre-school children (0.62; 0.74; 0.49) and to youths (1.76: 1.18; 0.63). Babies showed no dependence of the Pb concentration in bone on sex. For pre-school children, in all three bones the concentration of Pb in girls was higher, while for youths, the concentration in males exceeded that found in females. In any sub-group the bones from urban children showed on average higher Pb concentrations than those from rural areas. For the mid-femur, and the age class 10-20 years, this difference was statistically significant. No difference was seen in the mean Pb concentration in bones of SIDS (sudden infant death syndrome) and non-SIDS babies, but in the temporal bone the distribution of the Pb concentrations for the SIDS group was significantly greater than that of the control babies.2off


Diamine oxidase: an overview of historical, biochemical and functional aspects.
This article is a review of the historical, biochemical, and functional aspects of the enzyme diamine oxidase (DAO). The amine oxidase DAO, formerly called histaminase, is found in various tissues, but is especially active in the intestinal mucosa. Its function is the oxidative deaminating of several polyamines, essential substances for cell proliferation. DAO is thus a regulating enzyme in rapidly proliferating tissues such a bone marrow and intestinal mucosa. Results from several studies have demonstrated that both ornithine decarboxylase (ODC) and DAO activity rise during adaptive hyperplasia seen after small bowel resection. The ODC-dependent increase in polyamine content and subsequent increase in cell proliferative activity is probably downregulated locally in the villus tip by the increased DAO activity. DAO is normally present in very small amounts in the circulation and its basal plasma levels are positively correlated with the maturity and integrity of the intestinal mucosa. After intravenous administration of heparin, DAO is released from its capillary binding sites in the lamina propria into the peripheral circulation. Measurement of postheparin DAO release enhances its sensitivity and is now extensively studied to assess its value as follow-up or screening test for several enteropathies. Measuring basal as well as postheparin DAO levels has potential relevance following small bowel transplantation. Rejection of the small bowel graft leads to mucosal damage, which could conceivably lead to changes in DAO activity.


Bones in motion: Ontogeny of craniofacial development in sympatric arctic charr morphs.
The impressive diversity in the feeding apparatus often seen among related fish species clearly reflects differences in feeding modes and habitat utilization. Such variation can also be found within species. One example of such intraspecific diversity is the Arctic charr in Lake Thingvallavatn, where four distinct morphs coexist: two limnetic, with evenly protruding jaws, and two benthic, with subterminal lower jaws. We used these recently evolved morphs to study the role of ontogenetic variation in shaping craniofacial diversity. The segmental development of the pharyngeal arches and the order of events in craniofacial development is the same as has been described for teleosts, emphasizing the conserved nature of this process. However, our morphometric analyses reveal differences between morphs. Hatching is accompanied by increase in size and allometric shape changes in Arctic charr. Ontogenetic trajectories of craniofacial shape also differ significantly between morphs. The results point to hatching as a significant developmental event in Arctic charr and possibly other fishes. Also, the developmental origins of limnetic and benthic specializations in the craniofacial elements of Arctic charr may stem from events around hatching. This calls for investigations of the mechanisms and consequences of hatching, in the context of development and evolution. Developmental Dynamics 244:1168-1178, 2015. © 2015 Wiley Periodicals, Inc.


Impact of microRNAs in resistance to chemotherapy and novel targeted agents in non-small cell lung cancer.
Despite recent advances in understanding the cancer signaling pathways and in developing new therapeutic strategies, non-small cell lung cancer (NSCLC) shows grim prognosis and high incidence of recurrence. Insufficient disruption of oncogenic signaling and drug resistance are the most common causes of tumor recurrence. Drug resistance, intrinsic or acquired, represents a main obstacle in NSCLC therapeutics by limiting the efficacy both of conventional chemotherapeutic compounds and new targeted agents. Therefore, novel and more innovative approaches are required for treatment of this tumor. MicroRNAs (miRNAs) are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing mRNA degradation or translational repression. Accumulating evidence suggests that impairment of candidate miRNAs may be involved in the acquisition of tumor cell resistance to conventional chemotherapy and novel biological agents by affecting the drug sensitivity of cancer cells. The modulation of these miRNAs, using antagomiRs or miRNA mimics, can restore key gene networks and signaling pathways, and optimize anticancer therapies by inhibition of tumor cell proliferation and increasing the drug sensitivity. Therefore, miRNA-based therapeutics provides an attractive anti-tumor approach for developing new and more effective individualized therapeutic strategies, improving drug efficiency, and for predicting the response to different anticancer drugs. In this review, we present an overview on the role of miRNAs in resistance mechanisms of NSCLC, discussing the main studies on the aberrations in apoptosis, cell cycle and DNA damage repair pathways, as well as in novel drug targets.


Presence of calmodulin in human platelet cytoskeletons and its concentration change upon activation of platelets.
We found that a small, reproducible amount of calmodulin is present in the cytoskeleton of human platelets. Triton-insoluble materials (cytoskeletons), which were prepared by centrifugation at 1000 X g for 10 min of platelets after lysis by Triton X-100, stimulated cyclic AMP phosphodiesterase activity in the presence of Ca2+ but not in the presence of the calcium chelator, EGTA, or the calmodulin antagonist, trifluoperazine. The activation of the enzyme was also obtained after heating Triton-insoluble materials. An alkaline glycerol polyacrylamide gel electrophoresis of fractions obtained after gel filtration of solubilized Triton residues showed a protein band which had a faster electrophoretic mobility in the absence than in the presence of Ca2+. Upon thrombin activation of platelets, calmodulin in the Triton-insoluble cytoskeletons increased rapidly parallel to actin, actin-binding protein and myosin. With other stimulants such as collagen, epinephrine and ADP, similar results were obtained but with slower association of these proteins with cytoskeletons. However, after treatment with the Ca2+-ionophore A23187, calmodulin, actin and actin-binding protein in Triton residues decreased rapidly, whereas the association of myosin increased. Thus, calmodulin seems to be associated with actin filaments rather than myosin filaments, and may be involved in the generation of contractile force in the cell.


The effect of vaccination on undetected persistence of foot-and-mouth disease virus in cattle herds and sheep flocks.
The importance of carrier animals (those in whom virus persists after recovery from disease or acute infection) and their potential role in the spread of disease remain open questions within foot-and-mouth disease epidemiology. Using simple probabilistic models we attempt to quantify the effect of emergency vaccination--and especially the time of application--on the likely number of such animals, using data from challenge experiments on both cattle and sheep to determine the probability of persistence in diseased and subclinically infected animals. We show that the number of persistently infected animals in a group is predominantly determined by the number of animals initially infected on premises--the high variability of which ultimately limits the accuracy of any predictions of carrier numbers based upon transmission models. Furthermore, results suggest that, within a cattle herd, carrier numbers may be increased if challenge occurs shortly after vaccination. We show that the quality of inspection is the principal factor influencing whether or not carrier herds occur and that, by reducing clinical signs, the application of vaccination in regularly checked stock also results in an increase in undetected persistently infected animals. Where clinical detection would be poor regardless of the use of vaccination (i.e. particularly in sheep), vaccination will result in a reduction in the probability of a group containing undetected carriers: otherwise there is a benefit only if vaccination is applied sufficiently far in advance of any challenge. The implications of the results for serosurveillance are discussed, including the requisite test sensitivity and practices for successful implementation.


Development and rapid dissemination of Merkel-cell carcinomatosis following therapy with fludarabine and rituximab for relapsing follicular lymphoma.
This report deals with an unusual case of a patient with follicular small cleaved lymphocytic lymphoma who developed Merkel-cell carcinoma soon after receiving chemoimmunotherapy with a fludarabine-containing regimen and rituximab. The presentation of the Merkel-cell carcinoma in this patient was atypical because of the absence of dermal involvement and the very rapid clinical progression. In the light of recent reports which suggest a possible link between the immunocompromised state and the development of Merkel-cell carcinoma, the atypical presentation seen in this patient may indeed imply a possible link between the therapy given and the development of Merkel-cell carcinoma. To the best of our knowledge, this is the first documentation of Merkel-cell carcinoma appearing in a patient soon after treatment with fludarabine and/or rituximab.


The pH-unrelated influence of salt, temperature and manganese on aroma formation by Staphylococcus xylosus and Staphylococcus carnosus in a fermented meat model system.
The influence of manganese (0.01-0.1-1.0 microg/g), temperature (15-24 degrees C) and salt (3-4% w/w) on volatile formation in model minces inoculated with Pediococcus pentosaceus and either Staphylococcus xylosus or Staphylococcus carnosus was studied in a full factorial experiment. In order to study the direct, pH-unrelated effect of the parameters, data were analysed by use of multiple linear regression and partial least-squares regression both before and after transformation of the volatile responses into pH-orthogonal (pH-unrelated) responses. By using the pH-orthogonalised data, the overall interpretability of the experiment was increased, and new cause-and-effect relations were suggested. Approximately 50% of the total variance in volatile levels was due to differences caused by S. xylosus and S. carnosus, and another 30% was related to differences in pH development. The remaining 20% covered pH-orthogonal effects of manganese, temperature and salt plus the experimental noise. From this, it was concluded that most of the variation in volatile profiles caused by manganese, temperature and salt was in fact directly or indirectly caused by changes in lactic acid bacterial activity and pH.


High-throughput solvent assisted ionization inlet for use in mass spectrometry.
In this work we developed a multiplexed analysis platform providing a simple high-throughput means to characterize solutions. Automated analyses, requiring less than 5 s per sample without carryover and 1 s per sample, accepting minor cross contamination, was achieved using multiplexed solvent assisted ionization inlet (SAII) mass spectrometry (MS). The method involves sequentially moving rows of pipet tips containing sample solutions in close proximity to the inlet aperture of a heated mass spectrometer inlet tube. The solution is pulled from the container into the mass spectrometer inlet by the pressure differential at the mass spectrometer inlet aperture. This sample introduction method for direct injection of solutions is fast, easily implemented, and widely applicable, as is shown by applications ranging from small molecules to proteins as large as carbonic anhydrase (molecular weight ca. 29,000). MS/MS fragmentation is applicable for sample characterization. An x,y-stage and common imaging software are incorporated to map the location of components in the sample wells of a microtiter plate. Location within an x,y-array of different sample solutions and the relative concentration of the sample are displayed using ion intensity maps.


A study, by electron microscopy, of the specific uptake of alpha-fetoprotein by mouse embryonic fibroblasts in relation to in vitro aging, and by human mammary epithelial tumour cells in comparison with normal donors' cells.
A covalent conjugate of alpha-foetoprotein (AFP) and horseradish peroxidase (HRP) has been used to follow the internalization pathway of this serum protein in early and late passages of primary cultures of mouse embryonic fibroblasts as well as in a spontaneously immortalized cell line. AFP, as transferrin (Tf) used in parallel as a control, are endocytosed through coated pits and vesicles and move then to endosomes in every case; in cells of the late passages, at least a part of the internalized proteins would be routed to lysosomes. Cells of three different established human mammary cancer lines (MCF-7, Evsa-T, T-47D) internalize AFP-HRP through coated pits and vesicles. Such localization of the conjugate is practically never detected in normal human mammary epithelial cells in primary culture. Taken together, these results are in agreement with the view that AFP receptors are expressed at the surface of proliferating mouse embryonic fibroblasts and human mammary epithelial cancer cells but absent from the surface of normal human mature cells of the same origin.


Bilateral origin of the internal thoracic artery from the third part of the subclavian artery: a case report.
The routine use of the internal thoracic artery (ITA) as a conduit in coronary artery bypass grafting surgery has highlighted the need to appreciate this vessel's anatomic variations. The usual origin of this vessel is from the first part of the subclavian artery, occasionally from the second and rarely from the third. Henriques-Pino and Prates described a unilateral origin from the third part on the left and Vorster et al on the right. Our cadaveric case report presents an unusual bilateral origin of the ITA arising from the third part of the subclavian artery in a 25-year-old Black South African female. The ITA arose from the ventral aspect, 7.3 cm on the right side and 8.5 cm on the left side from the origin of the subclavian artery, and inclined acutely inferiorly and medially, anterior to the distal attachment of the scalenus anterior m., followed the inner border of the first rib for a short distance and, thereafter, continued its usual course in the thorax. This appears to be the first case report presenting a bilateral origin of the ITA from the third part of the subclavian artery.


Shedding Light on the Diversity of Surfactant Interactions with Luminol Electrochemiluminescence for Bioanalysis.
Luminol is a major probe for chemiluminescence (CL) and electrochemiluminescence (ECL) detection technologies in (bio)analysis. Surfactants are added to ECL assay cocktails to enhance signals or are present, owing to given bioassay protocols, yet little is known regarding their effects on luminol ECL. In-depth understanding is provided here through a broad study with bioanalytically relevant surfactants (cationic, anionic, and nonionic), four common electrode materials, and two luminol derivatives. Naturally, in ECL, surface effects are dominant; however, bulk solution, diffusion, and luminescence-stabilization processes also contribute significantly to the overall reaction. It was found that in contrast to CL the effect surfactants have on luminol ECL cannot be linked to general surfactant characteristics such as ionic nature, hydrophilic lipophilic balance (HLB) value, and critical micellar concentration (CMC). Instead, surfactants act in an all-encompassing mechanism, including surface electrochemistry, their solution and interfacial phases, and the chemical luminescence pathway. This leads to dramatic differences in signals obtained, ranging from 5-fold increases to total quenching. Within this complexity, we defined six guiding principles that are extrapolated from the underlying mechanisms and selection guides for surfactant, electrode, and environmental condition combinations. Those will now assist in developing highly sensitive luminol-ECL-based bioassays, because the surfactant selection can be based not only on properties needed for the assay protocol but also on identifying the optimal electrode-surfactant pair to maximize detection efficiency.


Immunosuppressive effects of rubidatum in mice.
To study the effect of rubidatum (Rub) on immune function in normal mice. Serum lysozyme concentration (SLC) was measured using micrococcus lysodiekticus as a substrate. Delayed type hypersensitivity (DTH) was determined by measuring the thickness of the right hind footpad 24 h after the injection of 1 x 10(8) washed sRBC (50 microL 10% sRBC). Serum hemolysin concentration was determined by OD measuring at A540 after the serum was treated with 2-mercaptoethanol. Phagocytic function of peripheral leukocyte (Leu) were determined by the incorporated radioactivity of [3H]TdR. The hemolytic activity of plaque forming cell (PFC) was determined by measuring the lymphocytemediated hemolysis of sheep red blood cell in vitro. T- and B-lymphocyte transformation (TLT and BLT) were induced by phytohemagglutinin (PHA) and lipopolysacharide (LPS) respectively and measured by the incorporation of [3H]TdR. Rub 125, 500, 2000 mg.kg-1.d-1 p.o. to BALB/c (or NIH) mice decreased the SLC; inhibited the phagocytosing functions of peripheral leukocytes; diminished the hemolytic activity of PFC; decreased the HC50; inhibited the DTH reaction; and showed inhibitory effects on TLT and BLT. Rub has immunosuppressive effects on immune system in mice by affecting M phi, T, and B lymphocyte, which suggests that Rub has inhibitory effects on both nonspecific and specific immune function.


Redox poise and metabolite changes in bread wheat seeds are advanced by priming with hot steam.
Fast and uniform germination is key to agricultural production and can be achieved by seed 'priming' techniques. Here, we characterised the responses of bread wheat (Triticum aestivum L.) seeds to a hot steam treatment ('BioFlash'), which accelerated water uptake, resulting in faster germination and seedling growth, typical traits of primed seed. Before the completion of germination, metabolite profiling of seeds revealed advanced accumulation of several amino acids (especially cysteine and serine), sugars (ribose, glucose), and organic acids (glycerate, succinate) in hot steam-treated seeds, whereas sugar alcohols (e.g. arabitol, mannitol) and trehalose decreased in all seeds. Tocochromanols (the 'vitamin E family') rose independently of the hot steam treatment. We further assessed shifts in the half-cell reduction potentials of low-molecular-weight (LMW) thiol-disulfide redox couples [i.e. glutathione disulfide (GSSG)/glutathione (GSH) and cystine/cysteine], alongside the activities of the reactive oxygen species (ROS)-processing enzyme superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase. Upon the first 4 h of imbibition, a rapid conversion of LMW disulfides to thiols occurred. Completion of germination was associated with a re-oxidation of the LMW thiol-disulfide cellular redox environment, before more reducing conditions were re-established during seedling growth, accompanied by an increase in all ROS-processing enzyme activities. Furthermore, changes in the thiol-disulfide cellular redox state were associated to specific stages of wheat seed germination. In conclusion, the priming effect of the hot steam treatment advanced the onset of seed metabolism, including redox shifts associated with germination and seedling growth.


Decreased beta2-adrenergic receptor density on peripheral blood mononuclear cells in myasthenia gravis.
Beta2-adrenergic receptors (beta2AR) are present on both lymphocytes and skeletal muscle cells. Antibodies and T cells that react with these receptors are present in patients with myasthenia gravis (MG). Immune reactivity against the beta2AR may thus modify both the immune and the muscle functions in MG. In this study, we analysed the density and affinity of beta2AR on peripheral blood mononuclear cells using a radioligand binding assay. The density (Bmax) of the receptor on cells from patients with MG was significantly lower than that on cells from patients with other neurological disorders and healthy individuals. The affinity (Kd) of the receptor and the concentration of the second messenger, cAMP, in the cells did not differ between the groups. Serum antibodies against beta2AR were demonstrated in 22% of 27 MG patients vs. 0% of 26 healthy controls. Incubation of cells with serum or purified IgG containing antibodies against the beta2AR resulted in a decline in ligand binding of the receptor in samples from three out of five patients. Thus, this study suggests that a downregulation of the beta2AR may occur in MG. This downregulation might be of importance in the patho-genesis of the disease and its symptoms.


Protective effects of polysaccharides from Lilium lancifolium on streptozotocin-induced diabetic mice.
In this study, the protective effect of Lilium lancifolium polysaccharides (LLP) on streptozotocin (STZ)-induced diabetic mice and possible mechanism were investigated. The diabetic mice were administered with LLP for 28 days. The results showed that oral administration of LLP could significantly decrease blood glucose level and increase body weight loss in STZ-induced diabetic mice. LLP also significantly increased the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) and decreased the level of malondialdehyde (MDA) in serum, liver, and kidney in STZ-induced diabetic mice. Moreover, histopathological examination showed that LLP could markedly improve the structure integrity of pancreatic islet tissue in STZ-induced diabetic mice. However, LLP had no significant effect on organ weight of liver and pancreas of diabetic mice, but significantly decreased kidney weight compared with diabetic control mice. This study suggested that LLP had hypoglycemic and antioxidant properties and could provide protective effect on STZ-induced diabetic mice.


Effects of clindamycin and gentamicin and other antimicrobial combinations against enterococci in an experimental model of intra-abdominal abscess.
A model was developed to permit direct assessment of antibiotic efficacy against Enterococcus species in experimental intra-abdominal abscess. Abscesses yielded Enterococcus faecalis in pure culture. Antimicrobials were delivered by precisely controlled continuous intravenous infusion. After five days of therapy, ampicillin alone or in combination with gentamicin reduced residual bacterial titers from 7.93 +/- 1.05 (untreated) to 3.51 +/- 1.07 and 3.52 +/- 0.81 log10 colony forming units per gram, respectively. Both the clindamycin and gentamicin combination (6.49 +/- 1.33) and metronidazole and gentamicin combination (6.79 +/- 0.90) significantly suppressed the growth of enterococci (p less than 0.01). Combined clindamycin and aztreonam was ineffective, as were any of the agents used alone (except ampicillin). These results may explain, in part, the clinical efficacy of certain drug combinations against the enterococcal component of polymicrobial abscesses despite the apparent lack of in vitro activity of individual agents.


Changes in autobiographical memory specificity following cognitive behavior therapy and pharmacotherapy for major depression.
An important cognitive marker of clinical depression is a reduced ability to be specific in recalling personal memories, a phenomenon coined 'overgeneral memory'. Overgeneral memory is considered as a stable cognitive trait that is intrinsically linked with depression and independent of mood state. Previous studies show that autobiographical memory is modifiable. This study investigated whether autobiographical memory is differentially affected by treatment type. Depressed patients were randomly assigned to receive either cognitive behavior therapy (CBT) for depression or pharmacotherapy (PHT). The proportion of categoric memories decreased and the proportion of specific memories increased following both types of treatments, adding support to the view that overgeneral memory is modifiable. CBT also had a greater impact on reducing extended overgeneral memories compared to PHT. The results from the current study are important in that they show that overgeneral memory can be targeted and modified through brief treatment. The clinical significance of the finding that there was a greater decrease in extended memories in the CBT group is unclear.


Effect of cystic fibrosis exacerbations on neutrophil function.
In cystic fibrosis (CF), inflammation is caused by persistent bacterial infection from Pseudomonas aeruginosa and Burkholderia cenocepacia in the lung and is characterised by the persistent infiltration of massive numbers of neutrophils which leads to lung injury. The aim of this present study was to investigate the effects of CF exacerbations on the reactivity of peripheral blood neutrophils compared to data from a normal healthy control population. Peripheral blood neutrophils were isolated from control subjects and CF patients before and after an exacerbation of their lung disease. Isolated neutrophils were stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA) and the rate of superoxide generation and elastase activity measured and compared with neutrophils from healthy age-matched controls. Neutrophils from CF patients spontaneously generated higher levels of superoxide after resolution of the exacerbation compared to control neutrophils. The stimulated generation of superoxide from control neutrophils was not significantly different from neutrophils isolated from CF patients either before or after resolution of the CF exacerbation. Neutrophils from CF patients spontaneously released more elastase than control neutrophils but released less elastase than control neutrophils in response to fMLP. The stimulated release of elastase from neutrophils was not significantly different before compared to after resolution of the exacerbation. Neutrophils from CF patients displayed a different pattern of response than those from control subjects; however, CF exacerbations did not appear to modulate neutrophil function.


Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells.
The RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) pathway plays a pivotal role in various cellular responses, including cellular growth, differentiation, survival and motility. Constitutive activation of the ERK pathway has been linked to the development and progression of human cancers. Here, we reported that mitogen-activated protein kinase phosphatase (MKP)-3, a negative regulator of ERK1/2, lost its expression particularly in the protein level, was significantly correlated with high ERK1/2 activity in primary human ovarian cancer cells using quantitative reverse transcription-polymerase chain reaction and western blot analyses. Intriguingly, the loss of MKP3 protein was associated with ubiquitination/proteosome degradation mediated by high intracellular reactive oxygen species (ROS) accumulation such as hydrogen peroxide in ovarian cancer cells. Functionally, short hairpin RNA knock down of endogenous MKP3 resulted in increased ERK1/2 activity, cell proliferation rate, anchorage-independent growth ability and resistance to cisplatin in ovarian cancer cells. Conversely, enforced expression of MKP3 in MKP3-deficient ovarian cancer cells significantly reduced ERK1/2 activity and inhibited cell proliferation, anchorage-independent growth ability and tumor development in nude mice. Furthermore, the enforced expression of MKP3 succeeded to sensitize ovarian cancer cells to cisplatin-induced apoptosis in vitro and in vivo. These results suggest a molecular mechanism by which the accumulation of ROS during ovarian cancer progression may cause the degradation of MKP3, which in turn leads to aberrant ERK1/2 activation and contributes to tumorigenicity and chemoresistance of human ovarian cancer cells.


Total intravenous anesthesia for improvement of intraoperative monitoring of somatosensory evoked potentials during aneurysm surgery.
Two anesthetic regimens for monitoring somatosensory evoked potentials (SEPs) during intracranial aneurysm surgery were compared. Eighty-four sequential cases of intracranial aneurysms were operated on employing SEP monitoring. The first group of 22 cases was anesthetized with "balanced anesthesia" and the second group of 62 cases received total intravenous anesthesia (TIVA) consisting of propofol and alfentanil. In the TIVA group, the amplitude of early cortical SEP responses (N20-P25, or P40-N50) was significantly higher than that of responses in the balanced anesthesia group. In median nerve SEPs, the averaged amplitude of N20-P25 was 3.22 microV with TIVA and 1.69 microV with balanced anesthesia (P = 0.006). Similarly, posterior tibial nerve SEPs showed a P40-N50 response of 1.85 microV and 1.00 microV, respectively (P = 0.017). The superior signal-to-noise ratio obtained with TIVA allowed more frequent and reliable intraoperative SEP recordings than was possible with balanced anesthesia, resulting in rapid and reliable feedback for the surgeon. In 19% of median nerve SEPs recorded with TIVA, the cortical responses were over 5 microV in amplitude, so that reproducible N20-P25 responses were obtainable by averaging only 10 to 50 serial responses, that is, two to three recordings per minute. The higher amplitude of posterior tibial nerve SEPs recorded with TIVA made monitoring during surgery for anterior communicating artery aneurysms possible in all cases. This was not always the case with balanced anesthesia. The late deflection of median nerve SEPs (N30) was more frequently observed with TIVA.(ABSTRACT TRUNCATED AT 250 WORDS)


An improved single-round PCR leads to rapid and highly sensitive detection of Pneumocystis spp.
In order to standardize a polymerase chain reaction (PCR)-based method of Pneumocystis detection, we describe the development of an improved PCR method that targets the Pneumocystis mtLSUrRNA gene. Design of a new primer pair and PCR program with suitable parameters and optimization resulted in a simpler and faster single-round amplification assay. The sensitivity of the novel Pneumocystis genus-specific PCR proved comparable to the reference nested PCR. The improvement that this new PCR assay offers in the detection and epidemiological studies of Pneumocystis spp. infection in research laboratories is discussed.


The epidemiology of infant injuries and alarming health disparities.
Injury epidemiology is the underappreciated foundation of injury prevention and control strategies. Given the substantial disparity of infant injury-related mortality between African Americans (AA) and whites in our region, we sought to better understand the epidemiology of infant injury-related mortality rates. Our trauma database was reviewed for all infant injuries over a 10-year period. The mortality rates were analyzed based on race, mechanism, and health insurance type. From 1995 to 2004, 1270 infants were identified. Sixty-nine percent were white, 26% AA, and 5% were other. Overall mortality was 4.8%. There were significant disparities in mortality comparing AA to whites: overall, 9.6% vs 2.8%*; abuse, 15% vs 4%*; suffocation, 100% vs 55%* (*P < .05). Although 75% of AA vs 40% of whites were insured by Medicaid, when separated by insurance type, the disparity in mortality rates between races remained significant. African-American infants have 3.5 times increased risk of death from preventable injuries compared to white infants. This disparity persists despite controlling for type of health insurance, a surrogate for socioeconomic status. Understanding these disparities and developing injury-prevention programs targeting high-risk mechanisms of injury such as abuse and suffocation among AA is critical toward eventually eliminating these preventable deaths.


Integrating mental health services into primary care for HIV-infected pregnant and non-pregnant women: Whole Life--a theoretically derived model for clinical care and outcomes assessment.
Poor women of color who are disproportionately both infected and affected by HIV/AIDS also face multiple lifestyle and psychosocial burdens that complicate effective delivery of health care, thereby contributing to their poorer prognosis. Addressing these factors within the context of HIV/AIDS primary care for women is the aim of Whole Life, a program to integrate mental health services into primary care for HIV-infected pregnant and non-pregnant women. Whole Life utilizes a theoretically derived clinical services model that provides data for both clinical care and patient outcomes research within the constraints of a clinical setting. During a woman's first two clinic visits, data are gathered in structured interviews with standardized instruments-adapted for relevance to the population-that meet clinical and service needs, as well as measure components of the Whole Life model. Interviews are conducted by existing front-line staff who have been trained in using these instruments to gather information typically recorded in clinical notes. The implementation of Whole Life to date clearly demonstrates the feasibility of mental health-primary care services integration in a publicly funded HIV primary care clinic serving poor women of color.


On-chip magnetic bead microarray using hydrodynamic focusing in a passive magnetic separator.
Implementing DNA and protein microarrays into lab-on-a-chip systems can be problematic since these are sensitive to heat and strong chemicals. Here, we describe the functionalization of a microchannel with two types of magnetic beads using hydrodynamic focusing combined with a passive magnetic separator with arrays of soft magnetic elements. The soft magnetic elements placed on both sides of the channel are magnetized by a relatively weak applied external magnetic field (21 mT) and provide magnetic field gradients attracting magnetic beads. Flows with two differently functionalized magnetic beads and a separating barrier flow are introduced simultaneously at the two channel sides and the centre of the microfluidic channel, respectively. On-chip experiments with fluorescence labeled beads demonstrate that the two types of beads are captured at each of the channel sidewalls. On-chip hybridization experiments show that the microfluidic systems can be functionalized with two sets of beads carrying different probes that selectively recognize a single base pair mismatch in target DNA. By switching the places of the two types of beads it is shown that the microsystem can be cleaned and functionalized repeatedly with different beads with no cross-talk between experiments.


Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol.
Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the beta-adrenergic receptor-blocking agent celiprolol in healthy volunteers. In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or grapefruit juice. In addition, 200 mL of water or grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0-33)] of celiprolol was 80% greater (P <.05) than in the placebo phase. During the grapefruit juice phase, the mean AUC(0-33) and peak plasma concentration values of celiprolol were reduced to about 13% (P <.001) and 5% (P <.001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P <.05) and decreased by 85% by grapefruit juice (P <.001). Hemodynamic variables did not differ between the phases. Itraconazole almost doubles but grapefruit juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the grapefruit juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The grapefruit juice-celiprolol interaction is probably of clinical relevance.


Lung transplantation in patients with cystic fibrosis and Mycobacterium abscessus infection.
Mycobacterium abscessus lung disease is difficult to treat and has been considered a strong relative contraindication to lung transplantation. We performed double lung transplantation in three cystic fibrosis patients with ongoing, and a fourth with recent treatment for Mycobacterium abscessus lung infection. Despite prolonged antibiotic courses and adjustment of immunosuppressive therapy the first three patients developed skin infection and abscesses. At follow-up after 1, 3, 5 and 7years respectively no patient had evidence of M abscessus infection and all had stable lung function. Lung transplantation in patients with M abscessus lung infection is feasible but may involve severe complications.


[What therapeutic benefits are there in the early diagnosis of metastases in patients with breast carcinoma?].
Early detection and curative treatment of metastasis of breast cancer is seldom. Local surgery and radiation could be helpful. The survival time was sometimes not a psychological advantage for the patients with early detection of metastasis.


Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies.
Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivo using a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicin/rapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicin/rapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours.


Enhanced reduction of C-N multiple bonds using sodium borohydride and an amorphous nickel catalyst.
Amorphous nickel powder (Ni(0)) was utilised as a catalyst under mild, aqueous, basic conditions for enhancing the sodium borohydride-mediated reduction of C-N multiple bonds such as oximes, imines, hydrazones and nitriles to produce the corresponding amines in good to excellent yields.


Material properties of the human cranial vault and zygoma.
The material properties of cortical bone from the diaphyses of long bones (e.g., the femur and tibia) vary by direction, such that bone is stiffer and stronger along its long axis. This configuration improves the abilities of these structures to resist axial compressive loads coupled with bending. As in long bones, cortical bone from the cranial vault is subject to mechanical loads from various orofacial functions and the contraction of attached muscles. However, experimental studies suggest that the resulting bone strains are at least an order of magnitude smaller than those found in the midshafts of the femur or tibia. The characteristics of the three-dimensional elastic properties of cortical bone are largely unexplored in regions of low bone strain, including the cranial vault, in which little is known regarding cortical structure and function. In the present study we examined variations in the cortical microstructure and material properties of the bone of the human cranial vault, including the parietal, frontal, temporal, and occipital bones. A facial bone, the zygoma, was also included to contrast the properties of the cranial vault with another craniofacial intramembranous bone that experiences larger strains. Cortical specimens from the outer cortical plate of the cranial vault were removed from 15 frozen human crania. We measured cortical thicknesses and densities, and determined the primary direction of stiffness within the bone specimens prior to ultrasonic testing to determine their elastic properties. There were statistically significant differences in elastic properties between bones and, in some cases, sites within bones, which for most variables were clustered by bone or region. In striking contrast to this pattern, elastic moduli in the direction of primary stiffness were larger in cortical regions underlying muscle attachments than in regions without muscle attachments. Few sites in the cranial vault or zygoma showed a consistent orientation of the material axes among individuals, although specimens from many regions had directional differences similar to those in cortical bone from the mandible, femur, or tibia.