Studies on the primary structure of short polysaccharides using SEC MALDI mass spectroscopy.
The introduction of size-exclusion chromatography (SEC) analysis of polysaccharides prior to MALDI mass spectroscopy accounts for the determination of the molecular mass of the repeating unit when neutral homopolymers are investigated. In the case of natural polysaccharides characterised by more complicated structural features (presence of non-carbohydrate substituents, charged groups, etc.), this mass value usually is in agreement with more than one sugar composition. Therefore, it is not sufficient to give the correct monosaccharidic composition of the polysaccharide investigated. To solve this problem, MALDI spectra were recorded on the permethylated sample and post-source decay experiments were performed on precursor ions. In this way, the composition (in terms of Hex, HexNAc, etc.), size and sequence of the repeating unit were determined.


Confocal Laser Microscopy for in vivo Intraoperative Application: Diagnostic Accuracy of Investigator and Machine Learning Strategies.
Confocal laser microscopy (CLM) is one of the optical techniques that are promising methods of intraoperative in vivo real-time tissue examination based on tissue fluorescence. However, surgeons might struggle interpreting CLM images intraoperatively due to different tissue characteristics of different tissue pathologies in clinical reality. Deep learning techniques enable fast and consistent image analysis and might support intraoperative image interpretation. The objective of this study was to analyze the diagnostic accuracy of newly trained observers in the evaluation of normal colon and peritoneal tissue and colon cancer and metastasis, respectively, and to compare it with that of convolutional neural networks (CNNs). Two hundred representative CLM images of the normal and malignant colon and peritoneal tissue were evaluated by newly trained observers (surgeons and pathologists) and CNNs (VGG-16 and Densenet121), respectively, based on tissue dignity. The primary endpoint was the correct detection of the normal and cancer/metastasis tissue measured by sensitivity and specificity of both groups. Additionally, positive predictive values (PPVs) and negative predictive values (NPVs) were calculated for the newly trained observer group. The interobserver variability of dignity evaluation was calculated using kappa statistic. The F1-score and area under the curve (AUC) were used to evaluate the performance of image recognition of the CNNs' training scenarios. Sensitivity and specificity ranged between 0.55 and 1.0 (pathologists: 0.66-0.97; surgeons: 0.55-1.0) and between 0.65 and 0.96 (pathologists: 0.68-0.93; surgeons: 0.65-0.96), respectively. PPVs were 0.75 and 0.90 in the pathologists' group and 0.73-0.96 in the surgeons' group, respectively. NPVs were 0.73 and 0.96 for pathologists' and between 0.66 and 1.00 for surgeons' tissue analysis. The overall interobserver variability was 0.54. Depending on the training scenario, cancer/metastasis tissue was classified with an AUC of 0.77-0.88 by VGG-16 and 0.85-0.89 by Densenet121. Transfer learning improved performance over training from scratch. Newly trained investigators are able to learn CLM images features and interpretation rapidly, regardless of their clinical experience. Heterogeneity in tissue diagnosis and a moderate interobserver variability reflect the clinical reality more realistic. CNNs provide comparable diagnostic results as clinical observers and could improve surgeons' intraoperative tissue assessment.


Participant Reactions to a Literacy-Focused, Web-Based Informed Consent Approach for a Genomic Implementation Study.
Clinical genomic implementation studies pose challenges for informed consent. Consent forms often include complex language and concepts, which can be a barrier to diverse enrollment, and these studies often blur traditional research-clinical boundaries. There is a move toward self-directed, web-based research enrollment, but more evidence is needed about how these enrollment approaches work in practice. In this study, we developed and evaluated a literacy-focused, web-based consent approach to support enrollment of diverse participants in an ongoing clinical genomic implementation study. Methods: As part of the Cancer Health Assessments Reaching Many (CHARM) study, we developed a web-based consent approach that featured plain language, multimedia, and separate descriptions of clinical care and research activities. CHARM offered clinical exome sequencing to individuals at high risk of hereditary cancer. We interviewed CHARM participants about their reactions to the consent approach. We audio recorded, transcribed, and coded interviews using a deductively and inductively derived codebook. We reviewed coded excerpts as a team to identify overarching themes. Results: We conducted 32 interviews, including 12 (38%) in Spanish. Most (69%) enrolled without assistance from study staff, usually on a mobile phone. Those who completed enrollment in one day spent an average of 12 minutes on the consent portion. Interviewees found the information simple to read but comprehensive, were neutral to positive about the multimedia support, and identified increased access to testing in the study as the key difference from clinical care. Conclusions: This study showed that interviewees found our literacy-focused, web-based consent approach acceptable; did not distinguish the consent materials from other online study processes; and valued getting access to testing in the study. Overall, conducting empirical bioethics research in an ongoing clinical trial was useful to demonstrate the acceptability of our novel consent approach but posed practical challenges.


Recruitment of Oligoclonal Viral-Specific T cells to Kill Human Tumor Cells Using Single-Chain Antibody-Peptide-HLA Fusion Molecules.
Tumor progression is often associated with the development of diverse immune escape mechanisms. One of the main tumor escape mechanism is HLA loss, in which human solid tumors exhibit alterations in HLA expression. Moreover, tumors that present immunogenic peptides via class I MHC molecules are not susceptible to CTL-mediated lysis, because of the relatively low potency of the tumor-specific CLTs. Here, we present a novel cancer immunotherapy approach that overcomes these problems by using the high affinity and specificity of antitumor antibodies to recruit potent antiviral memory CTLs to attack tumor cells. We constructed a recombinant molecule by genetic fusion of a cytomegalovirus (CMV)-derived peptide pp65 (NLVPMVATV) to scHLA-A2 molecules that were genetically fused to a single-chain Fv Ab fragment specific for the tumor cell surface antigen mesothelin. This fully covalent fusion molecule was expressed in E. coli as inclusion bodies and refolded in vitro. The fusion molecules could specifically bind mesothelin-expressing cells and mediate their lysis by NLVPMVATV-specific HLA-A2-restricted human CTLs. More importantly, these molecules exhibited very potent antitumor activity in vivo in a nude mouse model bearing preestablished human tumor xenografts that were adoptively transferred along with human memory CTLs. These results represent a novel and powerful approach to immunotherapy for solid tumors, as demonstrated by the ability of the CMV-scHLA-A2-SS1(scFv) fusion molecule to mediate specific and efficient recruitment of CMV-specific CTLs to kill tumor cells.


An approach to leg and foot ulcers: a brief overview.
Legs and feet are susceptible to ulcer formation. Three main types of lower extremity ulcers are venous, arterial, and neurotropic. Ulcer care should include treatment of the underlying cause, moist interactive healing, and quality of life (pain control). If the ulcer shows no signs of healing in 6 to 12 weeks, the wound should be biopsied, the diagnosis confirmed, and a plan of care instituted. In certain instances, biologicals may be used. A graphical representation of an approach to ulcer care, in addition to common differential diagnoses of leg ulcers, is presented.


PSYCHIATRIC DISORDERS IN AUTOIMMUNE ENCEPHALITIS - LITERATURE REVIEW.
Autoimmune encephalitis (AE) is a non-infectious inflammatory disease caused by the presence of autoantibodies directed against neuronal surface or intracellular antigens. Its incidence in Western countries is about 0.8 per 100,000 people. AE requires differentiation primarily with psychiatric diseases, but it also requires oncological vigilance. On the other hand, in the case of an acute episode of psychosis, differentiation with AE should always be pursued. This paper discusses the most common psychiatric disorders that occur in autoimmune encephalitis.


Epispadias and the associated embryopathies: genetic and developmental basis.
The abnormalities in the urogenital organs are frequently observed as human developmental diseases. Among such diseases, the defects in the upper part of external genitalia are rather rare named epispadias. The cleft in the dorsal part of external genitalia often reaches to the urethra. In general, the urogenital abnormalities accompany defects in the adjacent tissues and organs. The ventral body wall and bladder can also be affected in the patients with dorsal defects of the external genitalia. Therefore, such multiple malformations are often classified as bladder exstrophy and epispadias complex (BEEC). Because of the lower frequency of such birth defects and their early embryonic development, animal models are required to analyze the pathogenic mechanisms and the functions of responsible genes. Mutant mouse analyses on various signal cascades for external genitalia and body wall development are increasingly performed. The genetic interactions between growth factors such as bone morphogenetic proteins (Bmp) and transcription factors such as Msx1/2 and Isl1 have been suggested to play roles for such organogenesis. The significance of epithelial-mesenchymal interaction (EMI) is suggested during development. In this review, we describe on such local interactions and developmental regulators. We also introduce some mutant mouse models displaying external genitalia-body wall abnormalities.


Gender-Specific Acaricidal Properties and Sexual Transmission of Spirotetramat in Two-Spotted Spider Mite (Tetranychidae: Acariformes).
Two-spotted spider mite, Tetranychus urticae Koch (Tetranychidae: Acariformes), is one of the most important agricultural pests in the world. Their populations have a tendency of rapidly developing resistance to acaricides, making it necessary to have a variety of active ingredients for sustainable chemical control of this pest. We investigated acaricidal properties of a relatively new insecticide spirotetramat using its commercial formulation, Movento Energy. Spirotetramat applied at concentrations equivalent to the field rates of 78 and 90 g ai/ha had a strong negative effect on the survival of the treated T. urticae, with ca. 95% of females and ca. 65% of males dying after the treatment. Spirotetramat appeared to interfere with female reproductive system. Many of the dead treated females had eggs stuck in the oviduct and protruding from their bodies. Surviving treated females did not lay eggs. Furthermore, untreated females that mated with treated males did not produce female offspring and displayed the symptoms of spirotetramat poisoning. Toxic effects continued manifesting themselves after female mites were transferred from treated onto untreated plant culture. Contrary to previous studies, contact toxicity was also detected. None of the treated immature stages survived to adulthood. Based on these results, spirotetramat may be a good option for integrated pest management in crops that are simultaneously affected by sucking insects and spider mites and in pesticide rotation sequences that are a part of integrated resistance management programs.


Can anticoagulation therapy in cerebral venous thrombosis associated with Behçet's disease be stopped without relapse?
There is as yet no consensus on the treatment of cerebral venous thrombosis (CVT) in Behçet's disease, and the place of anticoagulation is also still being debated. This report is of a series of seven patients with Behçet's disease (BD)-associated CVT, for which anticoagulation was stopped, and discusses the possibility of stopping anticoagulation during follow-up while receiving optimal treatment for BD. The diagnosis of BD was established during follow-up, which lasted a median of 120 [range: 60-1490] days after CVT diagnosis. The median duration of anticoagulation therapy was 29.5 months. On stopping anticoagulation, concomitant treatment then included colchicine, steroids and azathioprine, all introduced after BD was diagnosed. With a median follow-up of 25 months after anticoagulation interruption, only one relapse of CVT was observed. No relapse of CVT or other venous thrombosis was observed in the six patients treated by steroids associated with an immunosuppressant or colchicine. Our results emphasize that corticosteroids are essential for the treatment of BD-associated CVT, and that anticoagulant therapy may be safely stopped during follow-up in the presence of optimal BD treatment (steroids alone or with immunosuppressive drugs).


Neural input modulates osmotically stimulated release of vasopressin into the supraoptic nucleus.
The effects of lesioning of the anteroventral third ventricle (AV3V) region on vasopressin (VP) release into the supraoptic nucleus (SON) and blood in response to central and systemic osmotic stimulation were determined. Microdialysis probes were implanted bilaterally within the SON of male urethan-anesthetized rats with sham or AV3V lesions. Osmotic stimuli were administered intraperitoneally (3.5 M NaCl, 600 microliters/100 g body wt) and then via the microdialysis probes (1 M NaCl-artificial cerebrospinal fluid). AV3V lesions attenuated the response to systemic osmotic stimulation. The lesioned rats showed no increase in intranuclear VP release and reduced plasma VP (increase of 42.6 +/- 8.4 vs. 78.0 +/- 16.4 pg/ml) and blood pressure responses (7.1 +/- 2.3 vs. 19.6 +/- 3.2 mmHg) to intraperitoneal NaCl. In contrast, the endocrine and cardiovascular responses to direct osmotic stimulation of the nucleus were as seen in previous studies and seemed to be unaffected by the lesion. These results show that lesion of the AV3V region interrupts neuronal inputs which trigger VP secretion from the posterior pituitary as well as release into the extracellular compartment of the SON.


[Ovine enzootic abortion: seroprevalence in Switzerland using a competitive enzyme-linked immunosorbent assay (cELISA)].
The present study gives an overview over the seroprevalence of ovine enzootic abortion in Switzerland. 639 sheep flocks out of eight cantons in Switzerland were examined by a competitive enzyme linked immunosorbent assay (cELISA) for antibodies against Chlamydophila abortus (Chlamydia psittaci serotype 1), the agent causing ovine enzootic abortion. The eight cantons included Aargau, Bern, Zürich, Appenzell-Ausserrhoden, Appenzell-Innerrhoden and Fribourg, the Vallais and the Graubünden. They were representative for 57% of the Swiss sheep flocks and for 60% of Swiss sheep population. In total, almost 19% (118) of the examined flocks were seropositive. Seroprevalence was the highest in Graubünden with 41%; this requires further examination and the evaluation of the need for a monitoring and controlling program. The examination of pooled sera made it possible to test a large number of samples with a reasonable amount of work. Higher sensitivity (92.9%) and specificity (97.6%) than the complement fixation test (CFT) in combination with testing of pooled sera makes the cELISA to be an usuable tool for serological screening on flock level.


Patients with an abnormal chest radiograph and latent tuberculosis.
Patients with latent tuberculosis characterized by a positive tuberculin (purified protein derivative) skin test and radiographic evidence of fibronodular changes or silicosis are at increased risk for the development of active tuberculosis. Before preventive therapy is initiated, the radiographic abnormalities must be differentiated from those representing active disease. According to recommendations from the American Thoracic Society and the Centers for Disease Control and Prevention, patients with latent tuberculosis who exhibit fibronodular changes or silicosis on chest radiographs should be given either isoniazid alone for one year or the combination of isoniazid and rifampin for four months, preferably with pyrazinamide for the first two months. Patients with similar radiographic findings and sputum or culture evidence of active tuberculosis require full multidrug therapy.


Peritoneal carcinomatosis after prophylactic oophorectomy in familial ovarian cancer syndrome.
A woman who was at high risk for ovarian cancer because of a strongly positive family history underwent prophylactic oophorectomy, but subsequently developed and died of intraabdominal carcinomatosis. One small focus of adenocarcinoma was found on the ovarian surface in serial sections performed retrospectively on the resected ovaries. This case study emphasizes the importance of thorough histologic examination for familial ovarian cancer syndrome, including serial sectioning of the specimens removed in prophylactic oophorectomy.


The CXCR4/SDF-1 chemokine axis: a potential therapeutic target for bone metastases?
Chemokines and chemokine receptors play diverse roles in homeostasis. The chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 have critical functions in the immune, circulatory, and central nervous systems and have also been implicated in tumor biology and metastasis. Here we review the current data regarding the role of the CXCR4/SDF-1 chemokine axis in the development of bone metastases, derived from tumor models of breast or prostate cancers. There is substantial evidence that CXCR4 and SDF-1 directly influence the survival and proliferation of tumor cells. In regards to bone metastases, the CXCR4/SDF-1 axis also appears to facilitate tumor cell recruitment to the bone marrow microenvironment via a homing mechanism. This makes disruption of the chemokine axis an attractive therapeutic target for the prevention of tumor cell spread to bone. However, within the bone microenvironment, SDF-1 and CXCR4 appear to have conflicting roles. While genetic disruption of CXCR4 enhances osteoclast activity and therefore stimulates tumor cell growth in the bone - likely via release of bone-derived growth factors - SDF-1 has been shown to have either a stimulatory effect or no effect on osteoclasts. In short, the effects of the CXCR4/SDF-1 axis on tumor cell growth within the bone are not yet fully defined. Further, there are theoretical risks that blockade of this chemokine axis could impair immune function or mobilize tumor cells leading to other sites of metastasis. As such, caution should be taken when designing therapeutic strategies targeting this chemokine axis.


Faculty perception of clinical value of five commonly used orthopedic tests.
The purpose of this study is to examine the perceptions of the value of five orthopedic tests (straight leg raise, Braggard's test, Kemp's test, Valsalva maneuver, and Patrick's fabere test) in the diagnosis of specific neuromusculoskeletal conditions among the chiropractic faculty at a large chiropractic college. This is an observational study that employed a survey of 41 academic and clinic faculty members with a Doctor of Chiropractic degree. Of the 12 posed questions, only five demonstrated statistically significant consistency (positive straight leg raise for the presence of disc pathology, positive Valsalva maneuver for the presence of disc pathology, negative Valsalva maneuver to rule out disc pathology, negative Braggard's test to rule out the presence of disc pathology, and positive Patrick's fabere test for the presence of hip joint pathology). Subgroup analysis demonstrated that the school of graduation may be the only predictor of consistency. There were strong indications that faculty members were not consistent in their perception of the value for common orthopedic tests for diagnosing specific conditions. In an evidence-based model of education, there should be a consensus among academic and clinical faculty in order for the students to learn, integrate, and apply in practice what they have learned in the classroom. Active intervention in the academic process is required to accomplish necessary change.


The effect of hypertension on the apparent diffusion coefficient values of kidneys.
The purpose of this study was to diagnose hypertension- induced renal microvascular dysfunction using renal diffusion magnetic resonance imaging (MRI) and to identify any correlation between blood pressure level and apparent diffusion coefficient (ADC) values. The study included 77 consecutive patients (41 women and 36 men). The patients were divided into 4 groups according to their blood pressure level. Group 1 consisted of normotensive control patients; group 2, pre-hypertensive patients; group 3, stage 1 hypertensive patients; and group 4, stage 2 hypertensive patients. All patients underwent transverse diffusion-weighted multi-section echo-planar MRI. In the transverse ADC maps, rectangular regions of interest were placed in the cortex at 3 sites (upper, middle, and lower pole) of each kidney. The ADCs of the kidneys were calculated separately for low, average, and high b values to enable the differentiation of the relative influence of the perfusion fraction and true diffusion. In addition, a multi-slab balanced turbo field-echo magnetic resonance angiographic technique (without the use of a contrast agent) was used to exclude renal artery stenosis. There was no statistically significant difference between the groups in age, and no significant correlation between the ADC values of both kidneys and blood pressure level in each group (P > 0.05). In addition, the ADC values of patients with microalbuminuria did not differ from those of the other patients (P > 0.05). CONCLUSION Despite the end-organ damage caused by hypertension, renal microvascular functions were preserved and hypertension did not affect ADC values.


Species composition and seasonal abundance of sandflies (Diptera: Psychodidae: Phlebotominae) in coffee agroecosystems.
The composition and seasonal occurrence of sandflies were investigated in coffee agroecosystems in the Soconusco region of Chiapas, Mexico. Insect sampling was performed on three plantations located at different altitudes: Finca Guadalupe Zajú [1,000 m above sea level (a.s.l.)], Finca Argovia (613 m a.s.l.) and Teotihuacán del Valle (429 m a.s.l.). Sandflies were sampled monthly from August 2007-July 2008 using three sampling methods: Shannon traps, CDC miniature light traps and Disney traps. Sampling was conducted for 3 h during three consecutive nights, beginning at sunset. A total of 4,387 sandflies were collected during the course of the study: 2,718 individuals in Finca Guadalupe Zajú, 605 in Finca Argovia and 1,064 in Teotihuacán del Valle. The Shannon traps captured 94.3% of the total sandflies, while the CDC light traps and Disney traps captured 4.9% and 0.8%, respectively. More females than males were collected at all sites. While the number of sandflies captured was positively correlated with temperature and relative humidity, a negative correlation was observed between sandfly numbers and rainfall. Five species of sandflies were captured: Lutzomyia cruciata , Lutzomyia texana , Lutzomyia ovallesi , Lutzomyia cratifer / undulata and Brumptomyia sp. Lu. cruciata , constituting 98.8% of the total, was the most abundant species. None of the captured sandflies was infected with Leishmania spp.


Angiotensin-converting enzyme: zinc- and inhibitor-binding stoichiometries of the somatic and testis isozymes.
The blood pressure regulating somatic isozyme of angiotensin-converting enzyme (ACE) consists of two homologous, tandem domains each containing a putative metal-binding motif (HEXXH), while the testis isozyme consists of just a single domain that is identical with the C-terminal half of somatic ACE. Previous metal analyses of somatic ACE have indicated a zinc stoichiometry of 1 mol of Zn2+/mol of ACE and inhibitor-binding studies have found 1 mol of inhibitor bound/mol of enzyme. These and other data have indicated that only one of the two domains of somatic ACE is catalytically active. We have repeated the metal and inhibitor-binding analyses of ACE from various sources and have determined protein concentration by quantitative amino acid analysis on the basis of accurate polypeptide molecular weights that are now available. We find that the somatic isozyme in fact contains 2 mol of Zn2+ and binds 2 mol of lisinopril (an ACE inhibitor) per mol of enzyme, whereas the testis isozyme contains 1 mol of Zn2+ and binds 1 mol of lisinopril. In the case of somatic ACE, the second equivalent of inhibitor binds to a second zinc-containing site as evidenced by the ability of a moderate excess of inhibitor to protect both zinc ions against dissociation. However, active site titration with lisinopril assayed by hydrolysis of furanacryloyl-Phe-Gly-Gly revealed that 1 mol of inhibitor/mol of enzyme abolished the activity of either isozyme, indicating that the principal angiotensin-converting site likely resides in the C-terminal (testicular) domain of somatic ACE and that binding of inhibitor to this site is stronger than to the second site.(ABSTRACT TRUNCATED AT 250 WORDS)


Which biopsychosocial variables contribute to more weight gain in depressed persons?
Depression appears to be associated with weight gain. Little is known about whether this association is independent of, or partly due to, several biopsychosocial variables. This study aims to investigate which biopsychosocial variables contribute to weight gain over a 4-year period in persons with major depressive disorder (MDD) or high depressive symptoms. Data from 1658 adults who participated in the Netherlands Study of Depression and Anxiety were used. Baseline depression was measured with a DSM-IV based psychiatric interview and with a depressive symptom measure. Four year weight gain was classified as stable weight (within 5% gain or loss) versus weight gain (>5% gain). Twenty-one baseline psychological, lifestyle and biological variables and antidepressant use were considered as potential contributing variables. In sociodemographic adjusted models, MDD and depressive symptoms were associated with subsequent weight gain. None of the biopsychosocial variables or antidepressants was associated with weight gain, thus did not contribute to the observed increased weight gain risk in depression, except for alcohol intake and TCA use. Future research should explore other potential factors that may be responsible for the increased risk for subsequent weight gain in depression, e.g. unhealthy dietary patterns or eating styles, or underlying intrinsic factors such as genetics.


Designing pairwise interactions that stabilize open crystals: Truncated square and truncated hexagonal lattices.
Using a recently introduced formulation of the ground-state inverse design problem for a targeted lattice [W. Piñeros et al., J. Chem. Phys. 144, 084502 (2016)], we discover purely repulsive and isotropic pair interactions that stabilize low-density truncated square and truncated hexagonal crystals, as well as promote their assembly in Monte Carlo simulations upon isochoric cooling from a high-temperature fluid phase. The results illustrate that the primary challenge to stabilizing very open two-dimensional lattices is to design interactions that can favor the target structure over competing stripe microphases.


Neonatal withdrawal syndrome after chronic maternal drinking of mate.
The premature newborn of a mother who reported drinking mate during pregnancy presented with increased jitteriness and irritability, high-pitched cry, hypertonia in the limbs, and brisk tendon reflexes consistent with neonatal withdrawal syndrome. High concentrations of caffeine and theobromine were detected in various maternal and neonatal biological matrices (placenta, cord serum, neonatal urine, maternal and neonatal hair, meconium, and breast milk), demonstrating both acute and chronic prenatal and postnatal exposure to these methylxanthines, contained in high amounts in homemade mate. Symptoms progressively disappeared at 84 hours of age, although intermittent irritability was still present when the infant was discharged at 24 days of age. Fluctuating caffeine (and theobromine) content in different breast milk feeds likely generated the baby's irritability, due to either the physiological stimulatory effects of the methylxanthines or postnatal withdrawal syndrome as the substances cleared from the body. The mother was strongly advised to initiate a considerable, progressive, constant reduction of mate consumption to a maximum of 2 cups a day for the duration of breastfeeding.


Recombinant human papillomavirus type 16 E7 protein as a model antigen to study the vaccine potential in control and E7 transgenic mice.
The early genes E6 and E7 of human papillomavirus type 16 (HPV16) are consistently and exclusively expressed in HPV16-induced cancer lesions and play major roles in the development and maintenance of the malignant phenotype. Because this protein is a good example of a tumor-associated antigen, we have used E7 as a model antigen to test the potential of an experimental vaccine as an immunotherapeutic approach. In this study, we used a murine E7-expressing tumor model (TC1 cells) to assess effects of an E7-based vaccine on tumor growth. We show that vaccination with the E7 protein, formulated in the SmithKline Beecham Biologicals proprietary adjuvants (SBAS 1 and SBAS 2), leads to the rejection of pre-established tumors. Tumor rejection was associated with the induction of a strong systemic T helper 1 response, including CTLs, and the presence of an inflammatory infiltrate within the regressing tumor. Because most identified tumor-associated antigens are self antigens rather viral antigens, we used E7 transgenic mice to evaluate the E7-based vaccine in conditions where E7 is a self antigen. Transgenic mice, which constitutively and specifically express the E7 HPV16 gene in the thyroid epithelium, rapidly develop thyroid goiters and, after several months, thyroid carcinomas. We show that E7-specific antibodies and CD4 T helper responses can be obtained by vaccinating E7 transgenic mice, although a CTL response was not detected. Despite the absence of measurable CTL responses, vaccination still reduced the growth of pre-established TC1 tumors, although less efficiently than in nontransgenic animals, but was unable to suppress or delay the development of the spontaneous thyroid pathology.


Modulation transfer function of photographic emulsion: the small-angle approximation in radiative transfer theory.
The modulation transfer function (MTF) of photographic emulsion can be conveniently represented by an expression derived from the theory of radiative transfer. Small-angle scattering is assumed to simplify the transfer equation and a Gaussian model is used to represent the forward lobe of the scattering phase function. The MTF depends on such variables as emulsion thickness, crystal size and concentration, relative refractive index, and the wavelength of incident light. The experimental results show that the Gaussian model adequately represents the phase function and also that useful MTF predictions are possible in the spatial frequency bandwidth 0-40 cycles/mm for AgBr crystals in a gelatin matrix.


Alpha 1-adrenergic receptor induced subsensitivity and supersensitivity in rabbit iris-ciliary body. Effects on myo-inositol trisphosphate accumulation, arachidonate release, and prostaglandin synthesis.
Topical treatment of the rabbit eye with three successive doses of 2% epinephrine resulted in attenuation of the in vitro drug response of the alpha 1-adrenoceptor-mediated phosphoinositide hydrolysis system and of alpha 1-adrenergic receptor-mediated contraction in the iris. In contrast, sympathetic denervation of the eye resulted in potentiation of these responses. Desensitized tissues showed a significant decrease in epinephrine-induced myo-inositol trisphosphate (IP3) accumulation, 1,2-diacylglycerol (DG) formation, measured as phosphatidate, arachidonic acid (AA) liberation, measured by radiochromatography, prostaglandin (PG) E2 release, measured by radiochromatography and radioimmunoassay, and muscle contraction. Adrenergic desensitization of the eye resulted in attenuation of: The polyphosphoinositide response in the iris, measured both as loss of 32P-radioactivity from phosphatidylinositol 4,5-bisphosphate (PIP2) and as IP3 accumulation; the epinephrine-stimulated liberation of AA, from membrane phosphoinositides and other phospholipids, and PGE2 release in the iris; and the epinephrine-induced muscle contraction in the iris dilator. This adrenergic desensitization of the eye is reversible. Surgical sympathetic denervation, previously found to increase alpha 1-adrenoceptor mediated accumulation of IP3 and contraction, increased AA liberation. Dexamethasone blocked the epinephrine-induced liberation of AA and PG release, both in vivo and in vitro. These data support the hypothesis that changes in the activity of the alpha 1-adrenergic receptor-mediated phosphoinositide hydrolysis system and its derived second messengers may underlie the mechanism of adrenergic subsensitivity and supersensitivity in the iris-ciliary body. How much the desensitization of alpha 1-adrenergic receptor-mediated responses contribute to the therapeutic action of epinephrine in the eye remains to be determined.


A retrospective bacteriological study of mycobacterial infections in patients with acquired immune deficiency syndrome (AIDS).
The main species of mycobacteria isolated in 51 patients with acquired immune deficiency syndrome (AIDS) admitted to the Clinical Hospital of UNICAMP (Teaching Hospital) in 1996, were studied retrospectively by recording the isolation site and signs of pathogenesis. Of these isolates, 31 (55%) were M.tuberculosis and 20 (45%) M.avium complex. Strains of M.tuberculosis isolated in 1996, 1997, and 1998, originating from 42 patients who had AIDS, were tested for susceptibility to isoniazid and rifampicin. Of these, 34 (81%) were susceptible to both drugs tested, 4 (10%) were resistant to isoniazid and susceptible to rifampicin, 2 (5%) were susceptible to isoniazid and resistant to rifampicin, and 2 (5%) were resistant to both rifampicin and isoniazid. We conclude that, in Brazil, M. avium complex infections in AIDS are more common than has been previously suggested; i.e., almost as frequent as M.tuberculosis infections. Approximately 20% of M.tuberculosis strains showed resistance to rifampicin and/or isoniazid. Further distribution of information regarding how to treat the disease in AIDS patients is needed.


Microbiological and molecular characterization of nosocomial and community Staphylococcus aureus isolates.
This study aimed to evaluate the incidence of Staphylococcus aureus infections in different departments of Belcolle Hospital in Viterbo and the surrounding area between January 2003 and June 2008. Isolates of methicillin-resistant S. aureus (MRSA) recovered in this time interval were characterized by microbiological and molecular methods to evaluate the reliability of simple criteria to distinguish between hospital-acquired and community-acquired isolates. MRSA accounted for 33% of all S. aureus, with a significantly higher prevalence in isolates from nosocomial infections. MRSA isolates were assayed by PCR for the presence of 13 genes associated with virulence, agr type and SCCmec type. Cumulative data were analysed by partial least square discriminant analysis and a clear correlation was demonstrated between genetic profiles and classification of isolates as hospital or community acquired according to simple temporal criteria. Nosocomial MRSA isolates from blood samples showed significantly higher genetic diversity than other nosocomial isolates. Our data confirm the existence of significant differences between community- and hospital-acquired MRSA isolates.


Prognostic value of serum acute-phase proteins in dogs with parvoviral enteritis.
To evaluate the acute-phase protein response in dogs with parvoviral enteritis as predictor of the clinical outcome. Canine parvovirus infection was diagnosed based on the compatible clinical findings and confirmed by the canine parvovirus antigen test in 43 dogs of less than six months of age. Blood samples for complete blood cell count and acute-phase proteins (C-reactive protein, haptoglobin, ceruloplasmin and albumin) were collected before treatment. Twenty-three dogs died during or after treatment (non-survival) and the rest recovered (survival). Five healthy dogs were enrolled as control. Serum C-reactive protein, ceruloplasmin and haptoglobin levels in dogs with parvoviral enteritis were higher (P<0·001, P<0·01 and P<0·001, respectively), but serum albumin was lower (P<0·001) than those in controls. Mean C-reactive protein and ceruloplasmin values in non-survival were higher (P<0·01) than those for survival dogs. C-reactive protein was found to be superior to ceruloplasmin, haptoglobin and albumin for distinguishing survival from non-survival dogs. Values higher than 92·4 mg/l for C-reactive protein had a sensitivity of 91% to predict mortality. The magnitude of the increase in serum acute-phase proteins in dogs with parvoviral enteritis could be a useful indicator of the prognosis of the disease. In acute-phase proteins, C-reactive protein is a potent predictor of mortality in dogs with parvoviral enteritis.


Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab.
To investigate the effect of aflibercept 2.0 mg in cases resistant to ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment. To evaluate the anatomic and visual effect of intravitreal aflibercept 2.0 mg in cases of exudative age-related macular degeneration (AMD) with persistent fluid on optical coherence tomography (OCT) despite regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment at 1 and 6 months. Retrospective review at Ophthalmic Consultants of Boston, Boston, Massachusetts, USA of exudative AMD cases with persistent fluid on regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment switched to intravitreal aflibercept 2.0 mg treatment and followed for 6 months. Tabulated data included details of prior treatments, best available visual acuity, central subfoveal thickness on registered spectral domain OCT before and after aflibercept injection centred on the anatomic fovea and macular description before and after aflibercept injection. A total of 353 eyes with exudative AMD were switched to aflibercept during the study period. Of these, 28 eyes in 28 patients had persistent fluid after an average of 20 regular ranibizumab/bevacizumab injections (range 7-37). At 1 month, 89% (25 eyes) showed anatomic improvement and 18% (five eyes) were dry after a single aflibercept injection. Central subfoveal thickness improved from 295 to 272 microns (p<0.001) after one aflibercept injection. After an average of 4.4 aflibercept injections (range 3-6) over 6 months, the central subfoveal thickness remained improved (274 microns, p=0.008); 64% (18 eyes) showed anatomic improvement and a quarter of eyes (25%, seven eyes) were dry. Visual acuity did not improve at 1 month (logarithm of minimum angle of resolution (logMAR) 0.54, Snellen 20/69, p=0.64) or 6 months (logMAR 0.57, Snellen 20/76, p=0.49). Treatment was well tolerated with no adverse events reported. A significant proportion of exudative AMD cases with persistent fluid on OCT despite regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment respond anatomically to aflibercept 2.0 mg. Visual acuity did not improve. Aflibercept may be beneficial anatomically in cases of exudative AMD treated with persistent fluid on ranibizumab and/or bevacizumab.


Skin Cancer Excision Is More Efficient and Cost Effectivein a Specialist Secondary Care Service.
Aim To compare the relative efficiencies of skin excisions in primary and secondary care. Methods We compared the benign: malignant ratio for specimens referred by General Practice, General Surgery and the Skin Cancer Service to the regional pathology laboratory over one month. We used cost minimization analysis to compare the relative efficiencies of the services. Results 620 excisions were received: 139 from General Practice, 118 from General Surgery and 363 from the Skin Cancer Service. The number (%) of malignant lesions was 13 (9.4%) from General Practice, 18 (15.2%) from General Surgery and 137 (37.7%) from the Skin Cancer Service. Excision was cheaper in General Practice at €84.58 as compared to €97.49 in the hospital day surgical unit. However, the cost per malignant lesion excised was €1779.80 in general practice versus €381.78 in the Skin Cancer Service. Conclusion Our results indicate that moving skin cancer treatment to General Practice may result in an excess of benign excisions and therefore be both less efficient and less cost effective.


A randomized controlled trial of hypnosis compared with biofeedback for adults with chronic low back pain.
Chronic low back pain (CLBP) is common and results in significant costs to individuals, families and society. Although some research supports the efficacy of hypnosis for CLBP, we know little about the minimum dose needed to produce meaningful benefits, the roles of home practice and hypnotizability on outcome, or the maintenance of treatment benefits beyond 3 months. One hundred veterans with CLBP participated in a randomized, four-group design study. The groups were (1) an eight-session self-hypnosis training intervention without audio recordings for home practice; (2) an eight-session self-hypnosis training intervention with recordings; (3) a two-session self-hypnosis training intervention with recordings and brief weekly reminder telephone calls; and (4) an eight-session active (biofeedback) control intervention. Participants in all four groups reported significant pre- to post-treatment improvements in pain intensity, pain interference and sleep quality. The hypnosis groups combined reported significantly more pain intensity reduction than the control group. There was no significant difference among the three hypnosis conditions. Over half of the participants who received hypnosis reported clinically meaningful (≥ 30%) reductions in pain intensity, and they maintained these benefits for at least 6 months after treatment. Neither hypnotizability nor amount of home practice was associated significantly with treatment outcome. The findings indicate that two sessions of self-hypnosis training with audio recordings for home practice may be as effective as eight sessions of hypnosis treatment. If replicated in other patient samples, the findings have important implications for the application of hypnosis treatment for chronic pain management.


Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity.
Rats selectively bred for inborn low capacity of running (LCR) display a series of poor health indices, whereas rats selected for high capacity of running (HCR) display a healthy profile. We hypothesized that selection of low aerobic capacity over generations leads to a phenotype with increased diastolic Ca(2+) leak that trigger arrhythmia. We used rats selected for HCR (N = 10) or LCR (N = 10) to determine the effect of inborn aerobic capacity on Ca(2+) leak and susceptibility of ventricular arrhythmia. We studied isolated Fura-2/AM-loaded cardiomyocytes to detect Ca(2+) handling and function on an inverted epifluorescence microscope. To determine arrhythmogenicity, we did a final experiment with electrical burst pacing in Langendorff-perfused hearts. Ca(2+) handling was impaired by reduced Ca(2+) amplitude, prolonged time to 50% Ca(2+) decay and reduced sarcoplasmic reticulum (SR) Ca(2+) content. Impaired Ca(2+) removal was influenced by reduced SR Ca(2+) ATP-ase 2a (SERCA2a) function and increased sodium/Ca(2+) exchanger (NCX) in LCR rats. Diastolic Ca(2) leak was 87% higher in LCR rats. The leak was reduced by CaMKII inhibition. Expression levels of phosphorylated threonine 286 CaMKII levels and increased RyR2 phosphorylation at the serine 2814 site mechanistically support our findings of increased leak in LCR. LCR rats had significantly higher incidence of ventricular fibrillation. Selection of inborn low aerobic capacity over generations leads to a phenotype with increased risk of ventricular fibrillation. Increased phosphorylation of CaMKII at serine 2814 at the cardiac ryanodine receptor appears as an important mechanism of impaired Ca(2+) handling and diastolic Ca(2+) leak that results in increased susceptibility to ventricular fibrillation.


Update on Management and Outcomes of Congenital Diaphragmatic Hernia.
Infants with congenital diaphragmatic hernia (CDH) benefit from comprehensive multidisciplinary teams that have experience in caring for the unique and complex issues associated with CDH. Despite prenatal referral to specialized high-volume centers, advanced ventilation strategies and pulmonary hypertension management, and extracorporeal membrane oxygenation, mortality and morbidity remain high. These infants have unique and complex issues that begin in fetal and infant life, but persist through adulthood. Here we will review the literature and share our clinical care pathway for neonatal care and follow up. While many advances have occurred in the past few decades, our work is just beginning to continue to improve the mortality, but also importantly the morbidity of CDH.


Cognitive functioning in patients with nonfunctioning pituitary adenoma before and after endoscopic endonasal transsphenoidal surgery.
Patients with nonfunctioning pituitary adenomas (NFPAs) can suffer from cognitive dysfunction. However, the literature on longitudinal cognitive follow-up of patients undergoing endoscopic endonasal transsphenoidal surgery (EETS) is limited. This study was performed to investigate perioperative cognitive status and course in patients with NFPAs. Patients underwent computerized neuropsychological assessment 1 day before (n = 45) and 3 months after (n = 36) EETS. Performance in 7 domains was measured with a computerized test battery (CNS Vital Signs) and standardized using data from a healthy control group. The authors conducted analyses of cognitive performance at both time points and changes pre- to post-ETSS on a group and an individual level. Linear multiple regression analyses were employed to investigate predictors of cognitive performance. On average, patients scored significantly lower in 6 of 7 cognitive domains before and after surgery than controls. Impairment proportions were significantly higher among patients (56% before surgery, 63% after surgery) than among controls. Patients showed no change over time in group-level (mean) performance, but 28% of individual patients exhibited cognitive improvement and 28% exhibited cognitive decline after surgery. Hormonal deficiency showed a positive correlation with verbal memory before surgery. Postoperative performances in all cognitive domains were predicted by preoperative performances. Cognitive impairment was present before and after EETS in over half of NFPA patients. Individual patients showed diverse postoperative cognitive courses. Monitoring of cognitive functioning in clinical trajectories and further identification of disease-related and psychological predictors of cognition are warranted.


Large differences in the organization of palliative care in nursing homes in six European countries: findings from the PACE cross-sectional study.
To be able to provide high-quality palliative care, there need to be a number of organizational structures available in the nursing homes. It is unclear to what extent such structures are actually present in nursing homes in Europe. We aim to examine structural indicators for quality of palliative care in nursing homes in Europe and to evaluate the differences in terms of availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives. A PACE cross-sectional study (2015) of nursing homes in Belgium, England, Finland, Italy, the Netherlands and Poland. Nursing homes (N = 322) were selected in each country via proportional stratified random sampling. Nursing home administrators (N = 305) filled in structured questionnaires on nursing home characteristics. Organization of palliative care was measured using 13 of the previously defined IMPACT structural indicators for quality of palliative care covering four domains: availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives. We calculated structural indicator scores for each country and computed differences in indicator scores between the six countries. Pearson's Chi-square test was used to compute the p-value of each difference. The availability of specialist palliative care teams in nursing homes was limited (6.1-48.7%). In Finland, Poland and Italy, specialist advice was also less often available (35.6-46.9%). Up to 49% of the nursing homes did not provide a dedicated contact person who maintained regular contact with the resident and relatives. The 24/7 availability of opioids for all nursing home residents was low in Poland (37.5%). This study found a large heterogeneity between countries in the organization of palliative care in nursing homes, although a common challenge is ensuring sufficient structural access to specialist palliative care services. Policymakers and health and palliative care organizations can use these structural indicators to identify areas for improvement in the organization of palliative care.


Absorption, distribution and excretion of beta-cyclodextrin and glucosyl-beta-cyclodextrin in rats.
The absorption, distribution and excretion of intravenously and orally administered beta-cyclodextrin (beta-CD) and glucosyl (G)-beta-CD in rats were studied using HPLC with pulsed amperometric detection. Within 10 h after intravenous administration, unchanged beta-CD and G-beta-CD recovered in urine were about 90% of each dose. The nephritic accumulation of G-beta-CD after the intravenous administration of G-beta-CD was slightly lower than that of beta-CD using the same treatment. The maximum plasma concentrations of beta-CD and G-beta-CD after the oral administration of CDs (500 mg/kg) were observed within 40 min. After oral administration, 0.6% of beta-CD and 0.3% of G-beta-CD were excreted in urine. The pharmacokinetic behaviour of both CDs after the intravenous administration of CDs (50 mg/kg) was almost the same. Furthermore, the inclusion complexes of estriol and betamethasone with CDs were prepared, and their absorption was evaluated after oral administration in rats. The plasma concentrations of CDs after oral administration of drug-CD complexes were significantly decreased in comparison with those after the oral administration of CDs alone. On the other hand, the plasma concentrations of drugs after the oral administration of drug-CD complexes were higher than those after the administration of drugs alone.


Taylor's law for exponentially growing local populations linked by migration.
We consider the dynamics of a collection of n>1 populations in which each population has its own rate of growth or decay, fixed in continuous time, and migrants may flow from one population to another over a fixed network, at a rate, fixed over time, times the size of the sending population. This model is represented by an ordinary linear differential equation of dimension n with constant coefficients arrayed in an essentially nonnegative matrix. This paper identifies conditions on the parameters of the model (specifically, conditions on the eigenvalues and eigenvectors) under which the variance of the n population sizes at a given time is asymptotically (as time increases) proportional to a power of the mean of the population sizes at that given time. A power-law variance function is known in ecology as Taylor's Law and in physics as fluctuation scaling. Among other results, we show that Taylor's Law holds asymptotically, with variance asymptotically proportional to the mean squared, on an open dense subset of the class of models considered here.


Factors that affect the outcome of peripheral arterial embolization.
To find the factors that significantly affected prognosis in patients with peripheral arterial thromboembolism, we reviewed a 12-year experience at two hospitals. Sixty-one patients had 67 embolectomies. Operative treatment and management preserved the limbs in 75.8%. Mortality was 22.4%. Outcome was favorably affected when age was less than 60 years and when arteriosclerotic heart disease was absent, and was adversely affected when common femoral emboli were present and hematocrit level elevated. Duration of symptoms did not affect outcome. Our treatment of patients with peripheral embolism is based on the effect of certain intrinsic factors on the formation of distal thrombus. These factors may be more important than duration of symptoms. Immediate, complete heparinization is recommended to arrest thrombosis, and to allow both for proper emphasis on treatment on the often-associated cardiopathy and for attention to hydration and acid-base balance. This preoperative plan of therapy should produce maximal limb salvage with reduced operative mortality.


Kinetic mechanism of the hydrogen-oxidizing hydrogenase from soybean nodule bacteroids.
The kinetic mechanism of the unidirectional H2-oxidizing hydrogenase from soybean nodule bacteroids has been investigated with highly purified enzyme. Measurements of the Km for H2 vary from 0.97 to 2.6 microM, and the Km for methylene blue varies from 6 to 17 microM. With H2 and methylene blue as substrates, the initial velocity patterns are intersecting. High levels of methylene blue are inhibitory (KI =2.4 mM): the inhibition is competitive vs. H2. CO is a competitive inhibitor of H2 (KI = 157 microM) and noncompetitive vs. methylene blue. O2 inactivates the enzyme (t 1/2 approximately 1 h) but also is a reversible inhibitor of hydrogenase activity upon short exposure to low concentrations. Inhibition by O2 is uncompetitive vs. H2 and noncompetitive vs. methylene blue. Hydrogenase was not inhibited by C2H2; preincubation under C2H2 inactivates the enzyme. Reduced methyl and benzyl viologens support low rates of H2 evolution by the hydrogenase. The Km for reduced methyl viologen is 11 microM. H2 is a potent inhibitor of H2 evolution: the inhibition is noncompetitive vs. reduced methyl viologen. The hydrogenase will catalyze a low rate of exchange in the reaction between D2 and H2O to form both HD and H2. We propose a two-site ping-pong mechanism for the enzyme in which H2 is reversibly activated at one site and e- carriers interact at the second site.


Histamine-free diet: treatment of choice for histamine-induced food intolerance and supporting treatment for chronic headaches.
Histamine-induced food intolerance is not IgE-mediated. Skin-prick testing and specific IgE to food allergens are typically negative. Food rich in histamine or red wine may cause allergy-like symptoms such as sneezing, flush, skin itching, diarrhoea and even shortness of breath. The suspected reason is a diminished histamine degradation based on a deficiency of diamine oxidase. As diamine oxidase cannot be supplemented, a histamine-free diet was implemented to reduce histamine intake. Forty-five patients with a history of suffering from intolerance to food or wine (n = 17) and chronic headache (n = 28) were put on the diet over months to years. Fish, cheese, hard cured sausages, pickled cabbage and alcoholic beverages had to be avoided. Complaint intensity and drug-use per week prior to and 4 weeks after a histamine-free diet were compared. After 4 weeks on the diet 33/45 patients improved considerably (P < 0.01), eight of them had total remission. In 12/45 patients, however, no changes in symptoms were observed. Symptoms of food or wine intolerance significantly decreased (P < 0.02; treatment of choice), headaches decreased in frequency (P < 0.001), duration and intensity. After eating histamine-rich food symptoms were reproducible and could be eliminated by anti-histamines in most patients. These data indicate the role of histamine in food and wine intolerance and that histamine-rich food causes a worsening of symptoms in patients suffering from chronic headaches. Results obtained support the hypothesis of a deficiency of diamine oxidase in patients with intolerance to food or wine.


[Ciprofloxacin in the treatment of patients with brucellosis].
With the aim to estimate the clinical and immunological efficiency of the ciprofloxacin (cifloxinal) 105 patients with acute (51), subacute (19) and chronic (35) brucellosis were studied. Control group (17 patients with acute and 30 patients with chronic brucellosis) have been treated with combination of two antibiotics: doxycycline and rifampicin. Ciprofloxacin in a dose 500 mg bid within 14 days in acute stage and 20 days in chronic stage of disease essentially reduced duration of local inflammatory processes of brucellosis with simultaneous treatment of the chronic infection focus, provides good proximate and distant outcomes of treatment. Ciprofloxacin can be considered as an alternative drug for the treatment of brucellosis, more effective (clinically and immunologically) than a combination of two antibiotics: doxycycline and rifampicin.


RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704.
To confirm whether a previously observed association between RECQ1 A159C variant and clinical outcome of resectable pancreatic cancer patients treated with preoperative chemoradiation is reproducible in another patient population prospectively treated with postoperative chemoradiation. Patients were selected, according to tissue availability, from eligible patients with resected pancreatic cancer who were enrolled on the NRG Oncology Radiation Therapy Oncology Group 9704 trial of 5-fluorouacil (5-FU)-based chemoradiation preceded and followed by 5-FU or gemcitabine. Deoxyribonucleic acid was extracted from paraffin-embedded tissue sections, and genotype was determined using the Taqman method. The correlation between genotype and overall survival was analyzed using a Kaplan-Meier plot, log-rank test, and multivariate Cox proportional hazards models. In the 154 of the study's 451 eligible patients with evaluable tissue, genotype distribution followed Hardy-Weinberg equilibrium (ie, 37% had genotype AA, 43% AC, and 20% CC). The RECQ1 variant AC/CC genotype carriers were associated with being node positive compared with the AA carrier (P=.03). The median survival times (95% confidence interval [CI]) for AA, AC, and CC carriers were 20.6 (16.3-26.1), 18.8 (14.2-21.6), and 14.2 (10.3-21.0) months, respectively. On multivariate analysis, patients with the AC/CC genotypes were associated with worse survival than patients with the AA genotype (hazard ratio [HR] 1.54, 95% CI 1.07-2.23, P=.022). This result seemed slightly stronger for patients on the 5-FU arm (n=82) (HR 1.64, 95% CI 0.99-2.70, P=.055) than for patients on the gemcitabine arm (n=72, HR 1.46, 95% CI 0.81-2.63, P=.21). Results of this study suggest that the RECQ1 A159C genotype may be a prognostic or predictive factor for resectable pancreatic cancer patients who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation. Further study is needed in patients treated with gemcitabine to determine whether an association exists.


Transfer of the Epstein-Barr virus genes coding for small RNAs to human lymphoid cells with a vector carrying a dominant selectable marker.
Epstein-Barr virus (EBV)-negative, Burkitt-like lymphoma-derived cells were transformed with a transducing vector (pSV2-gpt) containing the Escherichia coli gene coding for xanthine-guanine phosphoribosyltransferase (XGPRT) and with a derivative of PSV2-gpt that carries the genes for the EBV-associated small RNAs on the EcoRI J fragment of B95-8 EBV DNA inserted at the unique EcoRI site (pJ-gpt). Cells transformed with PSV2-gpt and pJ-gpt express the E. coli gpt gene to approximately the same extent, judged by determinations of the XGPRT activity of cell extracts. Blot hybridisation experiments with restriction endonuclease-cleaved DNA from the transformants have revealed the presence of vector DNA sequences in the cells, at least some of which are most probably integrated into high mol. wt. chromosomal DNA. Northern blot hybridisation analysis of cytoplasmic RNA from pJ-gpt-transformed cells revealed the presence of an EcoRI J DNA complementary RNA species of the same size as the EBV DNA-encoded small RNAs found in EBV-transformed cells.


Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor.
Small intestinal neuroendocrine tumors (SINET) are the commonest malignancy of the small intestine; however, underlying pathogenic mechanisms remain poorly characterized. Whole-genome and -exome sequencing has demonstrated that SINETs are mutationally quiet, with the most frequent known mutation in the cyclin-dependent kinase inhibitor 1B gene (CDKN1B) occurring in only ∼8% of tumors, suggesting that alternative mechanisms may drive tumorigenesis. The aim of this study is to perform genome-wide molecular profiling of SINETs in order to identify pathogenic drivers based on molecular profiling. This study represents the largest unbiased integrated genomic, epigenomic, and transcriptomic analysis undertaken in this tumor type. Here, we present data from integrated molecular analysis of SINETs (n = 97), including whole-exome or targeted CDKN1B sequencing (n = 29), HumanMethylation450 BeadChip (Illumina) array profiling (n = 69), methylated DNA immunoprecipitation sequencing (n = 16), copy-number variance analysis (n = 47), and Whole-Genome DASL (Illumina) expression array profiling (n = 43). Based on molecular profiling, SINETs can be classified into three groups, which demonstrate significantly different progression-free survival after resection of primary tumor (not reached at 10 years vs. 56 months vs. 21 months, P = 0.04). Epimutations were found at a recurrence rate of up to 85%, and 21 epigenetically dysregulated genes were identified, including CDX1 (86%), CELSR3 (84%), FBP1 (84%), and GIPR (74%). This is the first comprehensive integrated molecular analysis of SINETs. We have demonstrated that these tumors are highly epigenetically dysregulated. Furthermore, we have identified novel molecular subtypes with significant impact on progression-free survival.


Gastric varices and hepatic encephalopathy: treatment with vascular plug and gelatin sponge-assisted retrograde transvenous obliteration--a primary report.
To evaluate technical safety, clinical safety, and effectiveness of vascular plug-assisted retrograde transvenous obliteration (RTO) for treatment of gastric varices (GV) and hepatic encephalopathy (HE). This retrospective study was approved by the institutional review board; written informed consent was waived. From April 2009 to December 2011, 20 patients (13, GV; seven, HE) who had undergone vascular plug-assisted RTO were retrospectively evaluated. After retrograde transvenous placement of a vascular plug in the left adrenal vein or gastrorenal shunt, subsequent gelatin-sponge embolization of both gastrorenal shunt and GV was performed. Follow-up computed tomography (CT) and upper gastrointestinal tract endoscopy were performed; clinical and laboratory data were collected to evaluate primary (technical success, complications, clinical success) and secondary (change of liver function by using the Child-Pugh score, worsening of esophageal varices) end points. Laboratory data before and after vascular plug-assisted RTO were compared (paired-sample t test). Placement of the vascular plug and subsequent gelatin-sponge embolization were technically successful in all 20 patients, with no procedure-related complications. Follow-up CT within 1 week after vascular plug-assisted RTO showed complete thrombosis of GV and gastrorenal shunts in all patients. Clinical symptoms of HE completely resolved in all seven patients with HE; mean serum NH3 level of 127.4 μmol/L ± 58 (standard deviation) before vascular plug-assisted RTO decreased significantly to 28.1 μmol/L ± 9.8 within 1 week after vascular plug-assisted RTO (P = .002). Eighteen patients who underwent follow-up longer than 2 months showed complete obliteration of GV and gastrorenal shunts at CT and endoscopy. There were no cases of variceal bleeding or HE during mean follow-up of 422 days. Improvement in Child-Pugh score was observed in 12 of 18 (67%) patients 1 month after vascular plug-assisted RTO. Worsening of esophageal varices was observed in four (22%) patients at mean follow-up of 9.4 months. Vascular plug-assisted RTO is technically simple and safe and seems to be clinically effective for treatment of GV and HE.


Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa.
Cyclooxigenase (COX) is the rate-limiting enzyme for the conversion of arachidonic acid (AA) to prostaglandins (PGs). Two isoforms of COX have been identified: COX-1 is constitutively expressed in many cells and is involved in cell homeostasis, angiogenesis and cell-cell signalling; COX-2 is not expressed in normal condition however it is strongly expressed in inflammation. The oral cavity is constantly exposed to physical and chemical trauma that could lead to mucosal reactions such as hyperplasia, dysplasia and cancer. Early diagnosis is the most important issue to address for a positive outcome of oral cancer; therefore it would be useful to identify molecular markers whose expression is associated with the various stages of oral cancer progression. Since COX enzyme has been involved, with different mechanisms, in the development and progression of malignancies we decided to investigate the expression and localization of COX-1 and COX-2 in normal human oral mucosa and three different pathologies (hyperplasia, dysplasia and carcinoma) by immunohistochemistry and RT-PCR. COX-1 mRNA and protein have been detected already in normal oral mucosa and their expression progressively increases from normal samples towards hyperplasia, dysplasia and finally carcinoma. On the contrary, COX-2 is not expressed in the normal tissue, starts to be expressed in hyperplasia, reaches the maximum activation in dysplasia and then starts to be downregulated in carcinoma.


A systematic review of worldwide data on tinea capitis: analysis of the last 20 years.
Dermatophyte infections are the most common fungal infections in humans; among them, tinea capitis (TC) - the most contagious fungal infection - is caused by anthropophilic, zoophilic and geophilic dermatophytes. The purpose of this systematic review was to determine the different aetiological variants involved in TC and the overall epidemiology of the causes of this infection in the last two decades. We searched the MEDLINE (PubMed) and Embase databases for articles published from July 2000 to August 2019 using the following search terms: 'Tinea capitis', 'Africa', 'America', 'Asia', 'Europe', 'Oceania', and the names of the countries on each continent. The flow of information through the different phases in this systematic review was depicted using a PRISMA flow diagram, which mapped the number of records identified, included and excluded, and the reasons for exclusion. Our findings indicate that the frequency of different aetiologic agents of TC in the reported studies varied globally, from 0.4-87.7% in Africa, 0.2-74.0% in North America, 0.0-91.2% in Eastern Asia, 0.0-69.0% in Eastern Europe and 2.9-86.4% in Oceania. Microsporum canis is the most frequent reported zoophilic agent worldwide, while Trichophyton violaceum and Trichophyton tonsurans are the predominant anthropophilic agents. Over time, the frequency of these latter fungal infections has increased globally, and these fungi have become the major species globally. Anthropophilic transmission - the most prevalent type of transmission - could be explained by two factors: (i) the socioeconomic status of affected countries and population groups with associated risk factors and (ii) movement of populations importing new causes of infection to areas where they had not been encountered previously. We observed that intercontinental migration and travel; globalization; environmental, climatic and ecological changes; and accelerated evolution of health technologies may influence the observed epidemiological changes and, consequently, contributed to the variations in the global status of TC.


THetA: inferring intra-tumor heterogeneity from high-throughput DNA sequencing data.
Tumor samples are typically heterogeneous, containing admixture by normal, non-cancerous cells and one or more subpopulations of cancerous cells. Whole-genome sequencing of a tumor sample yields reads from this mixture, but does not directly reveal the cell of origin for each read. We introduce THetA (Tumor Heterogeneity Analysis), an algorithm that infers the most likely collection of genomes and their proportions in a sample, for the case where copy number aberrations distinguish subpopulations. THetA successfully estimates normal admixture and recovers clonal and subclonal copy number aberrations in real and simulated sequencing data. THetA is available at http://compbio.cs.brown.edu/software/.


[Experimental validation of the administration into the body of the lipids from therapeutic muds by means of vibration].
Infrared and ultraviolet spectroscopy were used to study the ability of therapeutic mud lipids to penetrate through the animal skin when compress or vibration were used. Vibrophoresis appeared to be 1.5-fold more effective compared to compress in improving skin permeability. It promotes entering the body for biologically active compounds containing heteroatoms: oxygen, nitrogen, sulfur, phosphorus, high-molecular acids, spirits, ethers, chlorophils, sulpho- and phospholipids.


Recurrent transverse myelitis after lumbar spine surgery: a case report.
A case of recurrent idiopathic transverse myelitis occurring after surgery is reported. To present a case of idiopathic transverse myelitis recurring after surgery and to heighten awareness for the diagnosis and management of this disorder. Transverse myelitis presenting with acute spinal pain and neurologic deficit must be considered along with structural causes of myelopathy by the spine specialist. This intramedullary spinal cord disorder may be caused by parainfectious and postvaccinal sequelae, multiple sclerosis, spinal cord ischemia, autoimmune disorders, and paraneoplastic syndromes. These various etiologies are often difficult to differentiate. However, a patient's history, clinical course, MRI studies, and laboratory findings often allow such classification. Determination of etiology provides pertinent information regarding potential recurrence, treatment, and prognosis. The patient history, physical examination, radiologic and laboratory studies, and pertinent literature were reviewed. Thoracolumbar myelitis developed in the reported patient 6 weeks after lumbar spine surgery during an otherwise uncomplicated postoperative recovery. The workup did not identify a specific cause, and the patient recovered to ambulatory status. However, 4 months after surgery, acute transverse myelitis developed again, this time affecting the cervical spinal cord. Despite aggressive intervention with corticosteroids, the patient has remained nonambulatory with severe neurologic residua. In spite of an extensive workup, a definitive cause was not determined, although an autoimmune etiology was suspected. The patient has stabilized without recurrence using immunosuppressant therapies. Acute transverse myelitis is an intramedullary spinal cord disorder that may present to the spine specialist during the postoperative period. This diagnosis requires swift and aggressive diagnostic and treatment intervention. Although sometimes difficult, establishment of causation may help to determine therapy and prognosis.


Covid-fatigued? A longitudinal study of Norwegian older adults' psychosocial well-being before and during early and later stages of the COVID-19 pandemic.
As the pandemic continues, many older adults are facing prolonged isolation and stress while having less access to traditional ways of coping. There is widespread concern that the situation is increasingly taking its toll on older adults' psychological and social well-being. We use linear mixed models to examine psychosocial impacts and predictors thereof among older Norwegians in early and later stages of the pandemic. Longitudinal data were collected online in the Norwegian Counties Public Health Survey right before the pandemic and in June and November-December 2020 in two counties (baseline n = 4,104; age 65-92). Outcomes include loneliness (single item, UCLA3), psychological ill-being (worried, anxious, depressed), and psychological well-being (satisfied, engaged, happy). From before to three months into the pandemic men's psychosocial well-being remained stable, whereas women's slightly declined. Five months later we observe broad and substantial declines in psychosocial well-being. These impacts disproportionately affect women (all outcomes) and single and older individuals (loneliness only) and are not moderated by educational level, urbanicity, or whether self or partner are reported "at risk" due to health problems. Pre-pandemic low social support and high psychological distress predict relatively improved psychosocial well-being. Older Norwegians seemed to manage the pandemic's early stage without clear psychosocial impacts. However, we observe notably compromised well-being during the second wave of COVID-19 in late 2020. Lessons learned about the nature and distribution of the psychosocial impacts of prolonged health-threats and social distancing provide valuable knowledge for intervention design during this and future pandemics.


Effect of alpha lipoic acid in a porcine in-stent restenosis model.
The aim of this study was to investigate the effect of alpha lipoic acid (α-LA) on a porcine in-stent restenosis (ISR) model. In protocol 1, porcine vascular smooth muscle cells (PVSMC) were stimulated by granulocyte-colony stimulating factor (G-CSF) in the presence or absence of α-LA. MTT (3-[4,5-dimethylthiazole-2-yl] 2,5-diphenyl tetrazolium bromide) assay and western blotting were used to determine the cell growth inhibitory rate and anti-inflammatory effect associated with nuclear factor-κb (NF-κb) and extracellular signal-regulated kinase (ERK). In protocol 2, 28 days after balloon overdilation injuries, 24 bare metal stents were placed in coronary artery of 12 pigs. The pigs were randomly divided to receive control diet with or without α-LA (100 mg/kg). In protocol 3, 8 control stents and 8 α-LA coated stents were randomly implanted in 2 coronary arteries of 8 pigs and follow-up coronary angiogram and histopathologic assessment were performed 4 weeks after stenting. Protocol 1. The proliferation of PVSMC was inhibited and protein expression of NF-κb and ERK were attenuated by α-LA pretreatment. Protocol 2. On histopathologic analysis, the neointimal area (4.0+/-1.0 mm(2) vs. 1.5+/-0.7 mm(2), p<0.001) and histopathologic area of stenosis (66.7+/-10.7% vs. 24.2+/-9.7%, p<0.001) were reduced in the α-LA feeding group compared to controls. Protocol 3. On histopathologic analysis, the neointimal area (3.9+/-0.8 mm(2) vs. 1.0+/-0.4 mm(2), p<0.001), and the histopathologic area of stenosis (67.1+/-8.8% vs. 17.4+/-10.0%, p<0.001) were reduced in the α-LA coated stent group compared to the control stent group. α-LA feeding and α-LA coated stents inhibit neointimal hyperplasia in porcine ISR, possibly through inhibiting the activation of NF-κb pathway and proliferation of PVSMC.


Factors associated with dairy calf health in automated feeding systems in the Upper Midwest United States.
Automated calf feeding systems are becoming more common on US dairy farms. The objective of this study was to evaluate calf health in these systems and to identify risk factors associated with adverse health outcomes on farms in the Upper Midwest United States. Over an 18-mo period on bimonthly farm visits to 38 farms, calves (n = 10,179) were scored for attitude, ear, eye, and nasal health, as well as evidence of diarrhea (hide dirtiness score of perianal region, underside of the tail, and tailhead). For all health score categories, a score of 0 represented an apparently healthy animal. Rectal temperatures were taken in calves scoring a ≥2 in any category, and those with a temperature >39.4°C were categorized as having a fever (n = 550). Associations were determined between farm-level variables and health scores to identify risk factors for higher (worse) scores. All health outcomes were associated with season of measurement, with fall and winter seasons increasing the odds of a high health score or detected fever. High bacterial counts measured in the milk or milk replacer were associated with increased odds for higher attitude and ear scores, and higher odds for calves having a detected fever. Higher peak milk allowance (L/d) was associated with lower hide dirtiness score, whereas a longer period of time (d) to reach peak milk allowance was associated with increased odds of higher scores for attitude, ear, eye, and hide dirtiness, as well as fever. Higher fat content in milk was associated with increased odds of high eye score. Less space per calf (m2/calf) was associated with higher ear and eye scores, whereas larger group sizes were associated with increased odds of higher nasal score and decreased odds of higher hide dirtiness score. Rectangular pen shape was associated with decreased odds of higher eye score. Absence of a positive pressure ventilation tube was associated with increased odds of having a calf detected with a fever. Based on these results, we hypothesize that these factors could be managed to improve health outcomes for dairy calves on automated feeding systems.


Perinatal pathologic examination of nonintact, second-trimester fetal demise specimens: the value of standardization.
Management of second-trimester intrauterine fetal demise via dilation and evacuation results in nonintact specimens for pathologic examination. Surgical pathology examination is often mandated; however, evidence on expected findings and specimen evaluation guidelines are lacking. To assess pathologic findings of nonintact, second-trimester fetal demise specimens, through comparison of anatomic abnormalities identified on standardized perinatal examination to individualized general pathology examinations. Single institution, retrospective chart review of 14- to 24-week gestational size fetal demise cases was conducted from May 2006 to October 2010. Suspected abnormalities, chromosomal and pathologic diagnoses were collected. A general surgical pathology examination occurred between May 2006 and October 2008, while a perinatal pathologist examined specimens between October 2008 and October 2010. Statistical analysis consisted of t tests and χ(2) tests by Stata/SE 12.1. One hundred eighteen specimens were included and mean gestational size was 16.0 weeks (standard deviation, 1.6 weeks). Perinatal pathologic evaluation diagnosed significantly more abnormalities than did general pathologic examination (77.3% [34 of 44] versus 9.5% [7 of 75], P < .001). Forty-eight abnormalities were identified: 77.0% (n = 37) were placental and 23.0% (n = 11) were fetal. Chromosomal analysis was done on 73.7% (n = 87 of 118) with 12.6% (n = 11 of 87) showing abnormalities. Among aneuploid specimens, the perinatal pathologist confirmed abnormalities in 66.7% (n = 4 of 6) of cases while general pathologists confirmed abnormalities in 0% (n = 0 of 5) (P = .02). Systematic surgical pathology examination of nonintact, second-trimester fetal demise specimens yields increased information on fetal or placental abnormalities, which may be clinically useful. Institutions with high-risk obstetrical practices and dilation and evacuation providers should consider integrating a standardized perinatal checklist into educational and practice guidelines.


Comparison between milk deprivation and oral rehydration with a glucose-glycine-electrolyte formulation in diarrhoeic and transported calves.
Treatment of diarrhoeic calves by oral administration of a glucose-glycine-electrolyte solution (GGES) was compared with milk deprivation (water given instead) and with no treatment (milk-fed controls). The diarrhoea followed challenge with enteropathogenic Escherichia coli. The GGES group showed a significantly lower mortality (5 per cent) in comparison with the controls (37 per cent). The milk-deprived group had a slightly lower mortality (30 per cent) in comparison with the controls. The milk deprived group showed a significantly prolonged duration of diarrhoea in survivors compared with the control group, while the GGES group did not differ significantly from the controls. Calves arriving on farms were allocated randomly to either GGES or to an alternative control treatment (usually partial milk deprivation). The incidence of diarrhoea during the subsequent two weeks was significantly less in the GGES group. Clotting of milk by rennet was impaired by addition with either water or an alkaline electrolyte solution but was enhanced by dilution with GGES.


Large-scale genomics unveil polygenic architecture of human cortical surface area.
Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ∼2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h(2)∼0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N=466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.


Executive summary: opportunities for action and impact to address HIV and AIDS in adolescents.
The global HIV epidemic in adolescents is not controlled, and this group has not received sufficient attention in programming and research efforts addressing HIV prevention, treatment, and care. A global technical consultation on adolescents and HIV addressing services and research gaps was convened by United Nations Children's Fund and the London School of Hygiene and Tropical Medicine in July 2013. Proceedings from this meeting are presented in this issue of the Supplement. Several reviews highlight poor levels of coverage of critical HIV prevention, treatment, and care interventions for adolescents, disparities in HIV prevalence among adolescent girls, and low-risk perceptions associated with risk behaviors among key risk groups. Others underscore the significance of clear national targets and strengthening data, government involvement, enhanced systems capacity and policy, engagement of community and adolescent social networks, and of mobile and internet technologies to the success of interventions for adolescents. Finally, reviews identified several efficacious interventions for adults that could benefit from operational research to inform optimizing implementation in adolescents and how to do so with maximal cost efficiency and impact on the epidemic. Addressing the adolescent gap in the response to the HIV epidemic is essential to a more sustainable and effective response and is critical to overall adolescent health and well-being. The global community has the means and the responsibility to put measures in place to make AIDS-free survival the reality for children in this second decade of life.


Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2).
CaMKK2 signals through AMPK-dependent and AMPK-independent pathways to trigger cellular outputs including proliferation, differentiation, and migration, resulting in changes to metabolism, bone mass accrual, neuronal function, hematopoiesis, and immunity. CAMKK2 is upregulated in tumors including hepatocellular carcinoma, prostate, breast, and gastric cancer, and genetic deletion in myeloid cells results in increased antitumor immunity in several syngeneic models. Validation of the biological roles of CaMKK2 has relied on genetic deletion or small molecule inhibitors with activity against several biological targets. We sought to generate selective inhibitors and degraders to understand the biological impact of inhibiting catalytic activity and scaffolding and the potential therapeutic benefits of targeting CaMKK2. We report herein selective, ligand-efficient inhibitors and ligand-directed degraders of CaMKK2 that were used to probe immune and tumor intrinsic biology. These molecules provide two distinct strategies for ablating CaMKK2 signaling in vitro and in vivo.


PclA, a pneumococcal collagen-like protein with selected strain distribution, contributes to adherence and invasion of host cells.
Analysis of Streptococcus pneumoniae sequenced genomes revealed a region present only in selected strains consisting of two ORFs: a putative cell wall anchored protein and a putative transcriptional regulator. The cell wall anchored protein contains large regions of collagen-like repeats, the number of which varies between strains. We have therefore named this protein PclA for pneumococcal collagen-like protein A. The second gene, spr1404, encodes a putative transcriptional regulator. We examined the strain distribution of these two genes among a collection of clinical isolates from invasive pneumococcal disease and found them to be present in 39% of the strains examined. Strains were either positive for both genes or lacked both, with the two genes always present together in the same location of the genome. RT-PCR analysis revealed that pclA is transcribed in vitro, even in the absence of spr1404. Single deletion mutants lacking either gene were not attenuated in a mouse model of invasive pneumonia. However, the pclA mutant was defective in adherence and invasion of host cells in vitro.


Comparison of volatile release in tomatillo and different varieties of tomato during chewing.
The release of volatiles from tomatillos (Physalis ixocarpa Brot.) and tomatoes in the mouthspace and nosespace was measured in real-time using selected ion flow tube mass spectrometry (SIFT-MS). (Z)-3-Hexenal, (E)-2-hexenal, hexanal, and 1-penten-3-one increased, while isobutyl alcohol, nonanal, and methylbutanal showed no significant change in the first 30 s of chewing. Cherry tomato released more (E)-2-hexenal, (Z)-3-hexenal, and 1-penten-3-one than tomatillo, Roma tomato, and vine-ripened tomato during chewing. The proportion of the average concentration of volatiles in the mouthspace after swallowing to before swallowing (MSas/MSbs) varied from 2.8% to 73.9% between different volatiles and varieties. Methylbutanal, hexanal, and nonanal were retained at a higher percentage in the mouth after swallowing than (Z)-3-hexenal, (E)-2-hexenal, 1-penten-3-one, and isobutyl alcohol. The proportion of the average volatile concentration in the mouthspace, to the headspace in a glass container (MS/HS) of 1-penten-3-one, hexanal, methylbutanal, and nonanal, and the proportion of nosespace to headspace (NS/HS) for 1-penten-3-one, hexanal, (Z)-3-hexenal, and nonanal was significantly higher in tomatillo than in tomatoes. There was no difference between tomatoes of different varieties in NS/HS ratio. The real-time volatile release from tomatillos and tomatoes was measured and compared. The information obtained on the dynamic generation of volatile compounds provides a better understanding of volatile release in the headspace of tomatillo and tomatoes. The compounds and their volatile release patterns were similar for the tomatillo and tomatoes. The green aldehydes released during chewing were not significantly higher than most tomato varieties, except for Roma tomatoes. Cherry tomato released relatively more volatiles during chewing, whereas Roma tomatoes were generally poor in mouthspace volatiles. The lingering of volatiles in the mouth after swallowing was different for different volatiles and varieties, which may appear as a sensory difference detected by consumers.


Sutureless versus conventional bioprostheses for aortic valve replacement in severe symptomatic aortic valve stenosis.
Sutureless aortic valves are a novel option for aortic valve replacement. We sought to demonstrate noninferiority of sutureless versus standard bioprostheses in severe symptomatic aortic stenosis. The Perceval Sutureless Implant Versus Standard-Aortic Valve Replacement is a prospective, randomized, adaptive, open-label trial. Patients were randomized (March 2016 to September 2018) to aortic valve replacement with a sutureless or stented valve using conventional or minimally invasive approach. Primary outcome was freedom from major adverse cerebral and cardiovascular events (composite of all-cause death, myocardial infarction, stroke, or valve reintervention) at 1 year. At 47 centers (12 countries), 910 patients were randomized to sutureless (n = 453) or conventional stented (n = 457) valves; mean ages were 75.4 ± 5.6 and 75.0 ± 6.1 years, and 50.1% and 44.9% were female, respectively. Mean ± standard deviation Society of Thoracic Surgeons scores were 2.4 ± 1.7 and 2.1 ± 1.3, and a ministernotomy approach was used in 50.4% and 47.3%, respectively. Concomitant procedures were performed with similar rates in both groups. Noninferiority was demonstrated for major adverse cerebral and cardiovascular events at 1 year, whereas aortic valve hemodynamics improved equally in both groups. Use of sutureless valves significantly reduced surgical times (mean extracorporeal circulation times: 71.0 ± 34.1 minutes vs 87.8 ± 33.9 minutes; mean crossclamp times: 48.5 ± 24.7 vs 65.2 ± 23.6; both P < .0001), but resulted in a higher rate of pacemaker implantation (11.1% vs 3.6% at 1 year). Incidences of perivalvular and central leak were similar. Sutureless valves were noninferior to stented valves with respect to major adverse cerebral and cardiovascular events at 1 year in patients undergoing aortic valve replacement (alone or with coronary artery bypass grafting). This suggests that sutureless valves should be considered as part of a comprehensive valve program.


Study of nasal exhaled nitric oxide levels in diagnosis of allergic rhinitis in subjects with and without asthma.
The measure of fractional exhaled nitric oxide (FENO) in the airways is a useful tool to guide the diagnosis and titration of inhaled corticosteroids in patients with asthma. However, its role in diagnosis of allergic rhinitis (AR), especially in subjects with asthma, is not well established. To study the cutoff of nasal FENO in the diagnosis of subjects with AR and AR-asthma compared to age-matched subjects without AR or asthma and its correlations with the clinical and functional characteristics. The study was cross sectional and descriptive. Subjects were grouped into control subjects, AR, and AR-asthma, based on the inclusion criteria. Exhaled NO (nasal FENO, bronchial FENO, and alveolar concentration of NO) was measured by multiple flow electro-luminescence device. Six hundred twenty-eight subjects were included: 217 control subjects (children: n=98, 10±4 years; adults: n=119, 50±16 years), 168 subjects with AR (children: n=54, 10±3 years; adults: n=114, 49±15 years), and 243 subjects with AR-asthma (children: n=115, 10±3 years; adults: n=128, 51±14 years). Nasal peak inspiratory flow and peak expiratory flow were lower in subjects with AR and AR-asthma than in control subjects (P<0.01 and P<0.01; and P<0.05 and P<0.01, respectively). Nasal FENO levels were significantly higher in subjects with AR and AR-asthma than in control subjects (1614±629 and 1686±614 ppb vs 582±161 ppb; P<0.001 and P<0.001, respectively). In subjects with AR non-asthma, the cutoffs of nasal FENO for those diagnosed with AR were 775 ppb in children, 799 ppb in adults, and 799 in the general population (sensitivity: 92.68%, 92.63%, and 92.65%, respectively; specificity: 91.67%, 95.00%, and 96.87%, respectively). In subjects with AR-asthma, the cutoffs of nasal FENO were higher, especially in asthma children (1458 ppb; sensitivity: 72.97% and specificity: 95.83%). Nasal FENO measurement is a useful technique for the diagnosis of AR in subjects with and without asthma.


Prediction of locally advanced bladder tumor using preoperative clinical parameters.
Staging of bladder cancer (BC) still remains a challenge. In conjunction with imaging, there is a critical need for accessible and cost-effective predictors to evaluate the existence of locally advanced disease. Our aim was to determine the role of preoperative clinical parameters in predicting locally advanced cT3/4 and/or cN+ in BC. Single-center data consisting of 32 patients were collected prospectively and eligible for the final analysis. The demographics data, presence of hydronephrosis, and results of renal function test (blood urea nitrogen [BUN] and serum creatinine [SCr]) were analyzed between the groups. Analysis of the receiver-operating characteristics curve was performed to determine the optimal cutoff value, sensitivity, and specificity of the preoperative clinical parameters, whereas multivariate logistic regression was used to assess the predictive analysis. According to preoperative computed tomography imaging, 17 (53.1%) out of 32 patients with BC had locally advanced disease. Preoperative hydronephrosis and renal insufficiency as indicated by BUN and SCr levels were independently associated with the presence of locally advanced disease (P < 0.05). Multivariate analysis confirmed that the presence of preoperative hydronephrosis and higher level of BUN and SCr were the independent predictors of locally advanced BC (Odds ratio [OR] =6.6; 95% confidence interval [CI]: 1.40-31.05; P = 0.017; OR = 6.6; 95% CI: 1.40-31.05; P = 0.017; OR = 18.67; 95% CI: 3.16-110.29; P = 0.001, respectively). No further variables were statistically significant. Preoperative assessment of hydronephrosis and renal insufficiency was able to predict locally advanced stage risk of BC cT3/4 and/or cN+; thus, preoperative staging might be improved. However, further studies are required to corroborate these findings.


Lipid-lowering update 2001. Aggressive new goals.
To review the central role of cholesterol in coronary artery disease (CAD), underscore the need for identifying patients at high risk of CAD, and discuss treatment of dyslipidemias. Current literature (1995-2000) was searched via MEDLINE using the MeSH headings "cholesterol," "risk reduction," and "statins." Recommendations in this paper are based mainly on the results of large randomized controlled trials. Preference was given to more recent articles, clinically relevant articles, and landmark clinical trials. Lipid lowering, and specifically low-density lipoprotein lowering, has been repeatedly shown in large clinical trials to improve survival dramatically and reduce cardiac events in both primary and secondary prevention. Identifying those at highest risk for future cardiac events is critical because these patients will benefit most from aggressive modification of risk factors. The definition of high risk has been expanded to include patients with diabetes mellitus and peripheral vascular disease, as well as those with established CAD. A full lipid profile is required for these patients to assess risk and develop a lipid-lowering strategy with proven effectiveness. With the advent of powerful, efficacious, and well tolerated cholesterol-modifying therapies, lipid normalization should be a mandate for all physicians caring for patients with established CAD and patients at risk of developing CAD.


From bacterial killing to immune modulation: Recent insights into the functions of lysozyme.
Lysozyme is a cornerstone of innate immunity. The canonical mechanism for bacterial killing by lysozyme occurs through the hydrolysis of cell wall peptidoglycan (PG). Conventional type (c-type) lysozymes are also highly cationic and can kill certain bacteria independently of PG hydrolytic activity. Reflecting the ongoing arms race between host and invading microorganisms, both gram-positive and gram-negative bacteria have evolved mechanisms to thwart killing by lysozyme. In addition to its direct antimicrobial role, more recent evidence has shown that lysozyme modulates the host immune response to infection. The degradation and lysis of bacteria by lysozyme enhance the release of bacterial products, including PG, that activate pattern recognition receptors in host cells. Yet paradoxically, lysozyme is important for the resolution of inflammation at mucosal sites. This review will highlight recent advances in our understanding of the diverse mechanisms that bacteria use to protect themselves against lysozyme, the intriguing immunomodulatory function of lysozyme, and the relationship between these features in the context of infection.