Two new species of Peromyscus (Cricetidae: Neotominae) from the Transverse Volcanic Belt of Mexico.
Specimens of the Peromyscus boylii species group distributed in the western and northeastern montane regions of Michoacán, México, historically have been assigned to P. levipes. Previous studies indicated that these specimens possessed mitochondrial DNA haplotypes that were distinct from both P. levipes and P. kilpatricki, a recently named species in the P. boylii species group from northeastern Michoacán and western Morelos. Herein karyotypic, DNA sequence, and morphological data were analyzed from those populations to evaluate their taxonomic affinity. Karyotypic data indicated that individuals from western Michoacán (Dos Aguas and Aguililla) and from a newly discovered population in northeastern Michoacán (Zinapécuaro) were chromosomally similar to P. carletoni (FN = 68) but distinct from other taxa assigned to the P. boylii species group. Analyses of cranial characteristics indicated that, relative to other species in the P. boylii species group, two morphologically distinct groups were present that corresponded to the Dos Aguas/Aguililla and Zinapécuaro populations, respectively. The latter population, although represented by a small sample size (n = 5 specimens), appeared to exhibit some trenchant morphological distinctions compared with other cryptic species in the P. boylii group. Phylogenetic analyses (parsimony, Bayesian, and likelihood) of DNA sequences obtained from the mitochondrial cytochrome-b gene indicated that although the individuals from Dos Aguas/Aguililla and Zinapécuaro formed a sister group relationship, they formed monophyletic clades that differed genetically (2.54%)-a level approaching that seen between other sister species of Peromyscus. Further, the Dos Aguas/Aguililla and Zinapécuaro clade was more closely aligned with a clade containing representatives of P. carletoni and P. levipes instead of with those from closer geographic proximities (P. kilpatricki) located in eastern Michoacán. Together, these results indicated that these two populations seemingly represent two undescribed species in the P. boylii species group for which we propose the names Peromyscus greenbaumi for populations in western Michoacán (circa Dos Aguas and Aguililla) and Peromyscus ensinki for populations in northeastern Michoacán (circa Zinapécuaro).


Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1.
The voltage-gated KCNQ2/3 and KCNQ3/5 K(+) channels regulate neuronal excitability. We recently showed that KCNQ2/3 and KCNQ3/5 channels are regulated by the ubiquitin ligase Nedd4-2. Serum- and glucocorticoid-regulated kinase-1 (SGK-1) plays an important role in regulation of epithelial ion transport. SGK-1 phosphorylation of Nedd4-2 decreases the ability of Nedd4-2 to ubiquitinate the epithelial Na(+) channel, which increases the abundance of channel protein in the cell membrane. In this study, we investigated the mechanism(s) of SGK-1 regulation of M-type KCNQ channels expressed in Xenopus oocytes. SGK-1 significantly upregulated the K(+) current amplitudes of KCNQ2/3 and KCNQ3/5 channels approximately 1.4- and approximately 1.7-fold, respectively, whereas the kinase-inactive SGK-1 mutant had no effect. The cell surface levels of KCNQ2-hemagglutinin/3 were also increased by SGK-1. Deletion of the KCNQ3 channel COOH terminus in the presence of SGK-1 did not affect the K(+) current amplitude of KCNQ2/3/5-mediated currents. Coexpression of Nedd4-2 and SGK-1 with KCNQ2/3 or KCNQ3/5 channels did not significantly alter K(+) current amplitudes. Only the Nedd4-2 mutant (S448A)Nedd4-2 exhibited a significant downregulation of the KCNQ2/3/5 K(+) current amplitudes. Taken together, these results demonstrate a potential mechanism for regulation of KCNQ2/3 and KCNQ3/5 channels by SGK-1 regulation of the activity of the ubiquitin ligase Nedd4-2.


Service Integration Across Sectors in Europe: Literature and Practice.
To meet the needs of vulnerable people, the integration of services across different sectors is important. This paper presents a preliminary review of service integration across sectors in Europe. Examples of service integration between social services, health, employment and/or education were studied. A further aim of the study was to improve conceptual clarity regarding service integration across sectors, using Minkman's Developmental Model for Integrated Care (DMIC) as an analytical framework. The study methods comprised a literature review (34 articles) and a survey of practice examples across Europe (44 practices). This paper is based on a more comprehensive study published in 2016. The study demonstrates that although the focus of integration across sectors is often on social services and health care, other arrangements are also frequently in place. The review shows that integration may be either tailored to a particular target group or designed for communities in general. Although systems to monitor and evaluate social service integration are often present, they are not yet fully developed. The study also highlights the importance of good leadership and organizational support in integrated service delivery. The study shows that the DMIC can work as a conceptual framework for the analysis of service integration across sectors. However, as this is an exploratory study, further in-depth case studies are required to deepen our understanding of the processes involved in service integration across sectors.


Maturation of cochlear nonlinearity as measured by distortion product otoacoustic emission suppression growth in humans.
The growth of distortion product otoacoustic emission (DPOAE) suppression follows a systematic, frequency-dependent pattern. The pattern is consistent with direct measures of basilar-membrane response growth, psychoacoustic measures of masking growth, and measures of neural rate growth. This pattern has its basis in the recognized nonlinear properties of basilar-membrane motion and, as such, the DPOAE suppression growth paradigm can be applied to human neonates to study the maturation of cochlear nonlinearity. The objective of this experiment was to investigate the maturation of human cochlear nonlinearity and define the time course for this maturational process. Normal-hearing adults, children, term-born neonates, and premature neonates, plus a small number of children with sensorineural hearing loss, were included in this experiment. DPOAE suppression growth was measured at two f2 frequencies (1500 and 6000 Hz) and three primary tone levels (55-45, 65-55, and 75-65 dB SPL). Slope of DPOAE suppression growth, as well as an asymmetry ratio (to compare slope for suppressor tones below and above f2 frequency), were generated. Suppression threshold was also measured in all subjects. Findings indicate that both term-born neonates and premature neonates who have attained term-like age, show non-adult-like DPOAE suppression growth for low-frequency suppressor tones. These age effects are most evident at f2 = 6000 Hz. In neonates, suppression growth is shallower and suppression thresholds are elevated for suppressor tones lower in frequency than f2. Additionally, the asymmetry ratio is smaller in neonates, indicating that the typical frequency-dependent pattern of suppression growth is not present. These findings suggest that an immaturity of cochlear nonlinearity persists into the first months of postnatal life. DPOAE suppression growth examined for a small group of hearing-impaired children also showed abnormalities.


Cerebrospinal Fluid Studies in Kenyan Children with Severe Falciparum Malaria.
The pathogenesis of the neurological complications of Plasmodium falciparum malaria is unclear. We measured proteins and amino acids in paired plasma and cerebrospinal fluid (CSF) samples in children with severe falciparum malaria, to assess the integrity of the blood brain barrier (BBB), and look for evidence of intrathecal synthesis of immunoglobulins, excitotoxins and brain damage. METHODS: Proteins of different molecular sizes and immunoglobulins were measured in paired CSF and plasma samples in children with falciparum malaria and either impaired consciousness, prostrate, or seizures. RESULTS: The ratio of CSF to plasma albumin (Q(alb)) exceeded the reference values in 42 (51%) children. The CSF concentrations of the excitotoxic amino acid aspartate and many non-polar amino acids, except alanine, were above the reference value, despite normal plasma concentrations. IgM concentrations were elevated in 21 (46%) and the IgM index was raised in 22 (52%). Identical IgG oligoclonal bands were found in 9 (35%), but only one patient had an increase in the CSF IgG without a concomitant increase in plasma indicating intrathecal synthesis of IgG. CONCLUSIONS: This study indicates that the BBB is mildly impaired in some children with severe falciparum malaria, and this impairment is not confined to cerebral malaria, but also occurs in children with prostrate malaria and to a lesser extent the children with malaria and seizures. There is evidence of intrathecal synthesis of immunoglobulins in children with malaria, but this requires further investigation. This finding, together with raised level of excitotoxic amino acid aspartate could contribute to the pathogenesis of neurological complications in malaria.


[Predictive information of basic indices of biochemical status of a man in evaluating the tolerance to acute hypoxia].
Under simulation of acute hypoxic hypoxia with participating the volunteers (men) there has been studied the predictor significance of the biochemical indices characterising an intensity of lipoperoxidation process, hormonal status and level of fermentemia. It is indicated that the following indices, namely, LDH, a [symbol: see text]-DPDH, MPD, secondary products of POL, SOD, insulin, cAMP and cAMP/cGMP have the prognostic validity. The revealed combination of the reliable relations was approximated by the equations of one-factor regression. As this takes place, the analysis of the presented dependencies between tolerance for hypoxia and biochemical indices allowed one to recognize the most probable mechanisms of resistance to the effect of this factor. The performed discrimination analysis for 6 biochemical variables (cAMP, LDH, SOD, MPO, MDA, TC) made it possible to create discriminant equations and to formulate the decisive rules to class the individuals into the ranks with different tolerance to the oxygen deficiency. The high informative capacity of the mentioned approach is recommended by the authors for a more wide use when developed the expert system to evaluate the human functional state as applied to the effect of extreme environmental factors and activity.


Clinical Validation of a Novel High-Sensitivity Cardiac Troponin I Assay for Early Diagnosis of Acute Myocardial Infarction.
Clinical performance of the novel high-sensitivity cardiac troponin I (Siemens-hs-cTnI-Centaur) assay is unknown. We aimed to clinically validate the Siemens-hs-cTnI-Centaur assay and develop 0/1-h and 0/2-h algorithms. We enrolled patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction (AMI). Final diagnoses were centrally adjudicated by 2 independent cardiologists including all clinical information twice: first, using serial hs-cTnT (Roche-Elecsys, primary analysis); second, using hs-cTnI (Abbott-Architect, secondary analysis) measurements in addition to the clinically applied (hs)-cTn. Siemens-hs-cTnI-Centaur was measured at presentation, 1 h, and 2 h. The primary objective was a direct comparison of diagnostic accuracy, quantified by the area under the ROC curve (AUC), of Siemens-hs-cTnI-Centaur vs the 2 established hs-cTn assays (Roche-hs-cTnT-Elecsys, Abbott-hs-cTnI-Architect). Secondary objectives included the development of Siemens-hs-cTnI-Centaur-specific 0/1-h and 0/2-h algorithms. AMI was the final diagnosis in 318 of 1755 (18%) patients (using Roche-hs-cTnT-Elecsys for adjudication). The AUC at presentation for Siemens-hs-cTnI-Centaur was 0.94 (95% CI, 0.92-0.96) and comparable with 0.95 (95% CI, 0.93-0.97) for Roche-hs-cTnT-Elecsys and 0.93 (95% CI, 0.90-0.96) for Abbott-hs-cTnI-Architect. Applying the derived Siemens-hs-cTnI-Centaur 0/1-h algorithm to the validation cohort, 46% of patients were ruled out (sensitivity, 99.1%; 95% CI, 95.3-100), and 18% of patients were ruled in (specificity, 94.1%; 95% CI, 91.8-95.9). The Siemens-hs-cTnI-Centaur 0/2-h algorithm ruled out 55% of patients (sensitivity, 100%; 95% CI, 94.1-100), and ruled in 18% of patients (specificity, 96.0%; 95% CI, 93.1-97.9). Findings were confirmed in the secondary analyses using serial measurements of Abbott-hs-cTnI-Architect for adjudication. Diagnostic accuracy and clinical utility of the novel Siemens-hs-cTnI-Centaur assay are high and comparable with the established hs-cTn assays. ClinicalTrials.gov Identifier: NCT00470587.


Structural proteins of Herpesvirus saimiri.
Herpesvirus saimiri particles were purified from productively infected owl monkey kidney cell cultures, and the virion polypeptides were analyzed by polyacrylamide gel electrophoresis. A total of 21 predominant proteins were found in lysates of H. saimiri 11 particles by Coomassie blue staining or by [35S]methionine labeling and autoradiography; all proteins were between 160,000 and 12,000 daltons in size. They are most probably virion constituents, as most of them were precipitated by immune sera, and no dominant proteins of equivalent sizes were found in mock-infected cultures. Four glycoproteins (gp 155/160, gp 128, gp 84/90, gp 55) and three polypeptides that appeared not to be glycosylated (p71, p35, p28) were assigned to the envelope or matrix of virions, whereas at least four phosphoproteins (pp132, pp118, pp55, pp13) and ten polypeptides without apparent secondary modification (p155/160, p106, p96, p67, p53, p36, p32, p15, p14, p12) were found in the nucleocapsid fraction. Analysis of virion proteins from different H. saimiri strains did not reveal appreciable differences in the migration behavior of most polypeptides, including all glycoproteins; however, determination of a strain-specific size pattern was possible for three of four phosphoproteins. The overall similarity in protein architecture of H. saimiri strains obviously does not reflect the variability in biology, such as oncogenic properties. In comparison, DNA sequence divergences appear to remain a better taxonomic criterion for strain distinction.


Small element array algorithm for correcting phase aberrations using near-field signal redundancy. Part II: experimental results.
For part I see ibid., vol.47, p.29 (2000). A small element array algorithm for phase-aberration correction using near-field signal redundancy was proposed in part I. Using this algorithm, subarrays are formed to narrow the transmitted and received beams when collecting common midpoint signals, so that angle-dependent aberration profiles across the array can be measured. In this paper, this algorithm is tested on data collected from a phantom with a non-isoplanatic aberrator attached to the front surface of a phased array. The aberrator is made from cast room temperature vulcanizing (RTV) silicone rubber, which has a sound velocity of about 1.02 mm.micros(-1). Results show that the subarray technique can be used to measure and correct angle-dependent, phase-aberration profiles. The theoretical results regarding the performance of several implementation methods for dynamic near-field delay correction on subarrays are also experimentally tested using data from a phantom.


Antidromic Analog Signaling.
Analog signaling describes the use of graded voltage changes as signals in the axonal compartment. Analog signaling has been described originally in invertebrates but more recent work has established its presence in the mammalian brain (Alle and Geiger, 2006; Shu et al., 2006). In recent years, many different groups have contributed to the understanding of the physiological significance of analog signaling from a cellular perspective (for a recent review the reader may take a look at the work by Zbili and Debanne, 2019 in this Frontiers in Neuroscience Special Issue). The great majority of the experimental work related to analog signaling, however, concerns the propagation of subthreshold voltage changes from the soma to the axon. Much less attention has been paid to the propagation of subthreshold voltage changes in the opposite direction, from the axon to the soma, or to the propagation of local signals within the axon. In this mini review we will describe these other variants of analog signaling that we call here "antidromic" coupling and "local" coupling.


[Diagnostic accuracy of mammography and mammoscintigraphy in multifocal breast cancer].
The aim of the study was to compare accuracy of conventional mammography and mammoscintigraphy with the 99mTc-Technetril in the detection of multicentric (MC) breast cancer. A total of 135 women (mean age 52 years) with unilateral simple breast lesions at clinical examination underwent preoperative mammography and mammoscintigraphy. Data of diagnostic procedure were compared with histopathologic analysis in all cases. The present of MC breast cancer was proven in 11 of 135 cases (8%). Mammography detected only one of 11 multicentric cases, while mammoscintigraphy-9 of 11 cases. Mammography showed a 9.1% and 93.5% sensitivity and specificity rates for the detection of multicentric breast cancer, respectively. The overall sensitivity and specificity rates for the detection of the form were 81.8% and 91.1% for mammoscintigraphy, respectively. Confirmation of the distinction between two methods has been attained by Bayesian probability calculation. Mammoscintigraphy proved a more highly sensitive diagnostic method than mammography in the detection and preoperative assessment of MC breast cancer and may contribute to changing surgical management in some cases.


[Pathologic findings of small cell lung cancer (SCLC) after chemotherapy--analysis of 48 cases].
From 1980 to 1986, resected specimens from 48 SCLC patients after chemotherapy were studied pathologically. According to the pathologic changes, they were divided into four degrees: 1. The primary lesion disappeared and was replaced by fibrosis (6 cases, 12.5%); 2. Scanty residual cancer tissues were seen by microscopy (6 cases, 12.5%); 3. Degeneration and necrosis with fibrosis were present but active cancer tissues in small areas were found (18 cases, 37.5%), and 4. There was mild degeneration or no obvious changes (18 cases, 37.5%). Five specimens were examined by electron microscopy. The effect of chemotherapy in the primary lesion is more marked than that in the metastatic lymph nodes. The relationship between pathologic changes and response of chemotherapy and pathologic staging; comparison of clinical and pathologic staging and the prognosis of lymph node metastasis are discussed.


Interstitial granulomatous dermatitis and arthritis revealing oesophageal carcinoma.
Interstitial granulomatous dermatitis and arthritis (IGDA) is an uncommon clinicopathological condition that may occur in association with a number of systemic disorders. We present a novel case of IGDA in association with oesophageal squamous cell carcinoma (SCC). A 67-year-old man with a 3-month history of arthritis presented with several erythematous indurated plaques on his lateral trunk and arms. An oesophagogastroduodenoscopy showed an irregular mass 20 mm in size in the proximal third of the oesophagus, and on histopathological examination of a biopsy, the mass was identified as a poorly differentiated SCC. Histopathological examination of a skin biopsy found features consistent with interstitial granulomatous dermatitis. The combination of clinicopathological correlation and laboratory findings led to the diagnosis of IGDA. This association has not been previously described, to our knowledge.


Cell Therapy for Anal Sphincter Incontinence: Where Do We Stand?
Anal sphincter incontinence is a chronic disease, which dramatically impairs quality of life and induces high costs for the society. Surgery, considered as the best curative option, shows a disappointing success rate. Stem/progenitor cell therapy is pledging, for anal sphincter incontinence, a substitute to surgery with higher efficacy. However, the published literature is disparate. Our aim was to perform a review on the development of cell therapy for anal sphincter incontinence with critical analyses of its pitfalls. Animal models for anal sphincter incontinence were varied and tried to reproduce distinct clinical situations (acute injury or healed injury with or without surgical reconstruction) but were limited by anatomical considerations. Cell preparations used for treatment, originated, in order of frequency, from skeletal muscle, bone marrow or fat tissue. The characterization of these preparations was often incomplete and stemness not always addressed. Despite a lack of understanding of sphincter healing processes and the exact mechanism of action of cell preparations, this treatment was evaluated in 83 incontinent patients, reporting encouraging results. However, further development is necessary to establish the correct indications, to determine the most-suited cell type, to standardize the cell preparation method and to validate the route and number of cell delivery.


MicroRNA-17-5p post-transcriptionally regulates p21 expression in irradiated betel quid chewing-related oral squamous cell carcinoma cells.
Betel nut chewing is associated with oral cavity cancer in Taiwan. OC3 is an oral carcinoma cell line that was established from cells collected from a long-term betel nut chewer who does not smoke. After we found that microRNA-17-5p (miR-17-5p) is induced in OC3 cells, we used this cell line to examine the biological role(s) of this microRNA in response to exposure to ionizing radiation. A combined SYBR green-based real-time PCR and oligonucleotide ligation assay was used to examine the expression of the miR-17 polycistron in irradiated OC3 cells. The roles of miR-17-5p and p21 were evaluated with specific antisense oligonucleotides (ODN) that were designed and used to inhibit their expression. Expression of the p21 protein was evaluated by Western blotting. The clonogenic assay and annexin V staining were used to evaluate cell survival and apoptosis, respectively. Cells in which miR-17-5p was stably knocked down were used to create ectopic xenografts to evaluate in vivo the role of miR-17-5p. A radiation dose of 5 Gy significantly increased miR-17-5p expression in irradiated OC3 cells. Inhibition of miR-17-5p expression enhanced the radiosensitivity of the OC3 cells. We found that miR-17-5p downregulates radiation-induced p21 expression in OC3 cells and, by using a tumor xenograft model, it was found that p21 plays a critical role in increasing the radiosensitivity of OC3 cells in vitro and in vivo. miR-17-5p is induced in irradiated OC3 cells and it downregulates p21 protein expression, contributing to the radioresistance of OC3 cells.


Long-term effects of alprazolam on memory: a 3.5 year follow-up of agoraphobia/panic patients.
Benzodiazepines (BZs) can impair explicit memory after a single dose and also when taken repeatedly for treatment of anxiety disorders. A previous study with agoraphobia/panic patients found that the BZ alprazolam impaired memory during an 8-week treatment and residual impairments were still manifest several weeks after drug withdrawal (Curran et al. 1994). The present study followed up the same group of patients 3.5 years after treatment to determine whether those memory impairments persisted. Thirty-one patients, 15 who had originally been treated with alprazolam and 16 with placebo, were assessed on a battery of psychometric tests and self-rating scales. Ex-alprazolam patients performed at the same levels as ex-placebo patients on the memory task and on other objective tests. Performance levels of both groups were similar to pre-treatment baselines, however there were differences in subjective ratings whereby ex-alprazolam patients rated themselves as less attentive and clear headed and more incompetent and clumsy than ex-placebo patients. Explicit memory impairments found while patients were taking alprazolam and weeks after drug withdrawal did not persist 3.5 years later. We suggest that the memory impairments observed in our previous study weeks after withdrawal of alprazolam were not residual effects of alprazolam but rather were due to the drug's interference with practice effects on the tests and habituation of anxiety over repeated exposure to the test situation.


What does morphokinetics add to embryo selection and in-vitro fertilization outcomes?
Time lapse technology represents a new tool in the in-vitro fertilization (IVF) laboratory. It can aid the embryologist in the detection of objective and quantifiable markers associated with embryo viability and implantation. The purpose of this review is to explain how embryo morphokinetics can be used as an adjunct to standard morphological assessment and to evaluate its potential value to improve IVF outcomes. Several algorithms have been developed. Some utilize early kinetic markers, whereas others rely more on later stages of embryo development. Even though over a handful of randomized control trials are in progress, at this point, only one has been published demonstrating a significant increase in implantation rates and ongoing pregnancy rates when selecting embryos on the basis of a combination of morphological assessment and morphokinetics. We believe that standard morphological assessment should remain the gold standard to initiate embryo evaluation; however, if possible, it can be complemented with the use of morphokinetics. This new approach will allow the embryologist to perform a more accurate and objective embryo selection and therefore reduce the number of embryos transferred while maintaining or even improving clinical results.


Preferential dimethylation of histone H4 lysine 20 by Suv4-20.
Post-translational modifications of histone tails direct nuclear processes including transcription, DNA repair, and chromatin packaging. Lysine 20 of histone H4 is mono-, di-, or trimethylated in vivo, but the regulation and significance of these methylations is poorly understood. The SET domain proteins PR-Set7 and Suv4-20 have been implicated in mono- and trimethylation, respectively; however, enzymes that dimethylate lysine 20 have not been identified. Here we report that Drosophila Suv4-20 is a mixed product specificity methyltransferase that dimethylates approximately 90% and trimethylates less than 5% of total H4 at lysine 20 in S2 cells. Trimethylation, but not dimethylation, is reduced in Drosophila larvae lacking HP1, suggesting that an interaction with HP1 regulates the product specificity of Suv4-20 and enrichment of trimethyllysine 20 within heterochromatin. Similar to the Drosophila enzyme, human Suv4-20h1/h2 enzymes generate di- and trimethyllysine 20. PR-Set7 and Suv4-20 are both required for normal levels of methylation, suggesting they have non-redundant functions. Alterations in the level of lysine 20 methylation following knock-down or overexpression of Suv4-20 did not affect lysine 16 acetylation, revealing that these two modifications are not competitive in vivo. Depletion of Suv4-20h1/h2 in HeLa cells impaired the formation of 53BP1 foci, suggesting dimethyllysine 20 is required for a proper DNA damage response. Collectively, the data indicate that Suv4-20 generates nearly ubiquitous dimethylation that facilitates the DNA damage response and selective trimethylation that is involved in heterochromatin formation.


Clostridium perfringens in poultry: an emerging threat for animal and public health.
The incidence of Clostridium perfringens-associated necrotic enteritis in poultry has increased in countries that stopped using antibiotic growth promoters. Necrotic enteritis and the subclinical form of C. perfringens infection in poultry are caused by C. perfringens type A, producing the alpha toxin, and to a lesser extent type C, producing both alpha toxin and beta toxin. Some strains of C. perfringens type A produce an enterotoxin at the moment of sporulation and are responsible for foodborne disease in humans. The mechanisms of colonization of the avian small intestinal tract and the factors involved in toxin production are largely unknown. It is generally accepted, however, that predisposing factors are required for these bacteria to colonize and cause disease in poultry. The best known predisposing factor is mucosal damage, caused by coccidiosis. Diets with high levels of indigestible, water-soluble non-starch polysaccharides, known to increase the viscosity of the intestinal contents, also predispose to necrotic enteritis. Standardized models are being developed for the reproduction of colonization of poultry by C. perfringens and the C. perfringens-associated necrotic enteritis. One such model is a combined infection with Eimeria species and C. perfringens. Few tools and strategies are available for prevention and control of C. perfringens in poultry. Vaccination against the pathogen and the use of probiotic and prebiotic products has been suggested, but are not available for practical use in the field at the present time. The most cost-effective control will probably be achieved by balancing the composition of the feed.


How do patients with HIV perceive their general practitioners?
To study the perceptions of patients with HIV of their general practitioners in terms of knowledge, abilities, confidence, and satisfaction. Questionnaire survey of inpatients, outpatients, and members of a self help group. Two city hospitals, three outpatient clinics, and one AIDS self help group in Munich and Berlin, Germany. All 402 patients available between 1 September 1988 and 31 May 1989. General practitioners' attitudes towards the patients' HIV status; patients' experience of treatment rejection; reception in the general practitioner's office; the doctor's perceived knowledge about HIV and AIDS. 394 of 402 patients consented to interview; 87% were registered with a general practitioner and 91% of those indicated that the doctor was aware of their HIV diagnosis. The overwhelming majority of patients (94%) had a friendly or at least neutral reception in the general practitioner's surgery and only six patients' general practitioner changed his or her behaviour for the worse because of the HIV diagnosis. Two thirds of patients said they would consult first with their primary care doctor for a physical problem, but only 13% would do so for psychological problems. Over a third of the patients did not routinely inform other doctors or medical staff about their HIV status, but there was no significant correlation between this concealment and ever having been rejected by a doctor (7%) or a dentist (12%). Most patients expressed a high degree of satisfaction with their general practitioners in terms of confidential issues, attitudes, knowledge, and management.


T-cell levels are prognostic in mantle cell lymphoma.
The purpose of this study was to investigate the impact of T-cell subsets on pathologic and clinical features including disease outcome in mantle cell lymphoma (MCL). Cell populations were investigated using flow cytometry in diagnostic MCL (n = 153) and reactive (n = 26) lymph node biopsies. Levels of tumor cells, T cells, T-cell subsets, and the CD4:CD8 ratio were assessed and related to pathologic and clinical parameters. MCL cases with diffuse and nodular histologic subtypes showed lower levels of T cells, especially CD4(+) T cells, than those with mantle zone growth pattern. Both CD3 and CD4 levels were lower in the nodular subtype than in mantle zone (P = 0.007; P = 0.003) and in the diffuse compared with the nodular subtype (P = 0.022; P = 0.015). The CD4:CD8 ratios were inversely correlated to tumor cell proliferation (P = 0.003). Higher levels of CD3(+) and CD4(+) T cells and higher CD4:CD8 ratios were associated with indolent disease (P = 0.043, 0.021, and 0.003 respectively). In univariate analysis, a high CD4:CD8 ratio, but not the histologic subtype, was correlated to longer overall survival (OS). In multivariate analysis, the CD4:CD8 ratio correlated with OS independently of Mantle Cell Lymphoma International Prognostic Index (MIPI) and high p53 expression (P = 0.023). CD3(+), CD8(+), and particularly CD4(+) T-cell levels are higher in indolent MCL and decrease with more aggressive histology as reflected by a diffuse growth pattern. High CD4:CD8 ratio correlated independently of other high-risk prognostic factors with longer OS, suggesting a prognostic role for T cells in MCL.


A framework for modeling the growth and development of neurons and networks.
The development of neural tissue is a complex organizing process, in which it is difficult to grasp how the various localized interactions between dividing cells leads relentlessly to global network organization. Simulation is a useful tool for exploring such complex processes because it permits rigorous analysis of observed global behavior in terms of the mechanistic axioms declared in the simulated model. We describe a novel simulation tool, CX3D, for modeling the development of large realistic neural networks such as the neocortex, in a physical 3D space. In CX3D, as in biology, neurons arise by the replication and migration of precursors, which mature into cells able to extend axons and dendrites. Individual neurons are discretized into spherical (for the soma) and cylindrical (for neurites) elements that have appropriate mechanical properties. The growth functions of each neuron are encapsulated in set of pre-defined modules that are automatically distributed across its segments during growth. The extracellular space is also discretized, and allows for the diffusion of extracellular signaling molecules, as well as the physical interactions of the many developing neurons. We demonstrate the utility of CX3D by simulating three interesting developmental processes: neocortical lamination based on mechanical properties of tissues; a growth model of a neocortical pyramidal cell based on layer-specific guidance cues; and the formation of a neural network in vitro by employing neurite fasciculation. We also provide some examples in which previous models from the literature are re-implemented in CX3D. Our results suggest that CX3D is a powerful tool for understanding neural development.


Enhanced signals from chiral molecules via molecular coherence.
One of the most widely used chiroptical spectroscopic methods for studying chiral molecules is Raman optical activity; however, the chiral Raman optical activity signal is extremely weak. Here, we theoretically examine enhanced chiral signals in a system with strongly prepared molecular coherence. We show that the enhanced chiral signal due to strong molecular coherence is up to four orders of magnitude higher than that of the spontaneous Raman optical activity. We discuss several advantages of studying the heterodyned signal obtained by combining the anti-Stokes signal with a local oscillator. The heterodyning allows direct measurement of the ratio of the chiral and achiral parameters. Taking advantage of the molecular coherence and heterodyne detection, the coherent anti-Stokes Raman scattering technique opens up a new potential application for investigation of biomolecular chirality.


Interpretive time-frequency analysis of genomic sequences.
Time-Frequency (TF) analysis has been extensively used for the analysis of non-stationary numeric signals in the past decade. At the same time, recent studies have statistically confirmed the non-stationarity of genomic non-numeric sequences and suggested the use of non-stationary analysis for these sequences. The conventional approach to analyze non-numeric genomic sequences using techniques specific to numerical data is to convert non-numerical data into numerical values in some way and then apply time or transform domain signal processing algorithms. Nevertheless, this approach raises questions regarding the relative magnitudes under numeric transforms, which can potentially lead to spurious patterns or misinterpretation of results. In this paper, using the notion of interpretive signal processing (ISP) and by redefining correlation functions for non-numeric sequences, a general class of TF transforms are extended and applied to non-numerical genomic sequences. The technique has been successfully evaluated on synthetic and real DNA sequences. The proposed framework is fairly generic and is believed to be useful for extracting quantitative and visual information regarding local and global periodicity, symmetry, (non-) stationarity and spectral color of genomic sequences. The notion of interpretive time-frequency analysis introduced in this work can be considered as the first step towards the development of a rigorous mathematical construct for genomic signal processing.


Nine-, but Not Four-Days Heat Acclimation Improves Self-Paced Endurance Performance in Females.
Although emerging as a cost and time efficient way to prepare for competition in the heat, recent evidence indicates that "short-term" heat acclimation (<7 days) may not be sufficient for females to adapt to repeated heat stress. Furthermore, self-paced performance following either short-term, or longer (>7 days) heat acclimation has not been examined in a female cohort. Therefore, the aim of this study was to investigate self-paced endurance performance in hot conditions following 4- and 9-days of a high-intensity isothermic heat acclimation protocol in a female cohort. Eight female endurance athletes (mean ± SD, age 27 ± 5 years, mass 61 ± 5 kg, VO2peak 47 ± 6 ml⋅kg⋅min-1) performed 15-min self-paced cycling time trials in hot conditions (35°C, 30%RH) before (HTT1), and after 4-days (HTT2), and 9-days (HTT3) isothermic heat acclimation (HA, with power output manipulated to increase and maintain rectal temperature (T rec) at ∼38.5°C for 90-min cycling in 40°C, 30%RH) with permissive dehydration. There were no significant changes in distance cycled (p = 0.47), mean power output (p = 0.55) or cycling speed (p = 0.44) following 4-days HA (i.e., from HTT1 to HTT2). Distance cycled (+3.2%, p = 0.01; +1.8%, p = 0.04), mean power output (+8.1%, p = 0.01; +4.8%, p = 0.05) and cycling speed (+3.0%, p = 0.01; +1.6%, p = 0.05) were significantly greater in HTT3 than in HTT1 and HTT2, respectively. There was an increase in the number of active sweat glands per cm2 in HTT3 as compared to HTT1 (+32%; p = 0.02) and HTT2 (+22%; p < 0.01), whereas thermal sensation immediately before HTT3 decreased ("Slightly Warm," p = 0.03) compared to ratings taken before HTT1 ("Warm") in 35°C, 30%RH. Four-days HA was insufficient to improve performance in the heat in females as observed following 9-days HA.


The implications of age and comorbidity on survival following epithelial ovarian cancer: summary and results from a Centers for Disease Control and Prevention study.
Advances in treatment have improved ovarian cancer survival for most women, although less for the elderly. We report on this disparity and add further evidence about the relationship among age, comorbidity, and survival after ovarian cancer. To examine age and comorbidity, Centers for Disease Control and Prevention (CDC)-funded cancer registries examined 2367 women residing in New York and Northern California diagnosed with epithelial ovarian cancer (1998-2000). Subjects were identified through tumor registries, treatment data were supplemented with physician survey, and comorbidity was identified through hospital discharge database linkages. Proportional hazards modeling was used to estimate the risk of death by age and comorbidity, adjusting for clinical and sociodemographic factors. Crude survival at 1 year and 3 years was 71.9% and 50.1%, respectively. Within stage, age-specific survival rates were lower in the oldest groups, particularly for those with advanced disease. For age 75+, 3-year survival was 13% vs. 50% in those <35 (stage IV). For all stages, women without comorbidity had higher survival rates than those with comorbidity. Older age and comorbidity were both associated with advanced stage and less aggressive treatment. The adjusted risk of death was 40%, and it was 80% higher for the 65-74 and 75+ groups, respectively, compared to women 35-64 (p<0.00). Comorbidity increased the risk of death by 40% (p<0.00). This study confirmed the independent adverse effects of age and comorbidity on survival following ovarian cancer. As the population ages, the co-occurrence of ovarian cancer and comorbidity will increase. Further work identifying critical conditions that impact survival could potentially inform complex treatment decisions.


Carbon uptake by mature Amazon forests has mitigated Amazon nations' carbon emissions.
Several independent lines of evidence suggest that Amazon forests have provided a significant carbon sink service, and also that the Amazon carbon sink in intact, mature forests may now be threatened as a result of different processes. There has however been no work done to quantify non-land-use-change forest carbon fluxes on a national basis within Amazonia, or to place these national fluxes and their possible changes in the context of the major anthropogenic carbon fluxes in the region. Here we present a first attempt to interpret results from ground-based monitoring of mature forest carbon fluxes in a biogeographically, politically, and temporally differentiated way. Specifically, using results from a large long-term network of forest plots, we estimate the Amazon biomass carbon balance over the last three decades for the different regions and nine nations of Amazonia, and evaluate the magnitude and trajectory of these differentiated balances in relation to major national anthropogenic carbon emissions. The sink of carbon into mature forests has been remarkably geographically ubiquitous across Amazonia, being substantial and persistent in each of the five biogeographic regions within Amazonia. Between 1980 and 2010, it has more than mitigated the fossil fuel emissions of every single national economy, except that of Venezuela. For most nations (Bolivia, Colombia, Ecuador, French Guiana, Guyana, Peru, Suriname) the sink has probably additionally mitigated all anthropogenic carbon emissions due to Amazon deforestation and other land use change. While the sink has weakened in some regions since 2000, our analysis suggests that Amazon nations which are able to conserve large areas of natural and semi-natural landscape still contribute globally-significant carbon sequestration. Mature forests across all of Amazonia have contributed significantly to mitigating climate change for decades. Yet Amazon nations have not directly benefited from providing this global scale ecosystem service. We suggest that better monitoring and reporting of the carbon fluxes within mature forests, and understanding the drivers of changes in their balance, must become national, as well as international, priorities.


The effect of different depth planes during a manual tracking task in three-dimensional virtual reality space.
Unlike ballistic arm movements such as reaching, the contribution of depth information to the performance of manual tracking movements is unclear. Thus, to understand how the brain handles information, we investigated how a required movement along the depth axis would affect behavioral tracking performance, postulating that it would be affected by the amount of depth movement. We designed a visually guided planar tracking task that requires movement on three planes with different depths: a fronto-parallel plane called ROT (0), a sagittal plane called ROT (90), and a plane rotated by 45° with respect to the sagittal plane called ROT (45). Fifteen participants performed a circular manual tracking task under binocular and monocular visions in a three-dimensional (3D) virtual reality space. As a result, under binocular vision, ROT (90), which required the largest depth movement among the tasks, showed the greatest error in 3D. Similarly, the errors (deviation from the target path) on the depth axis revealed significant differences among the tasks. Under monocular vision, significant differences in errors were observed only on the lateral axis. Moreover, we observed that the errors in the lateral and depth axes were proportional to the required movement on these axes under binocular vision and confirmed that the required depth movement under binocular vision determined depth error independent of the other axes. This finding implies that the brain may independently process binocular vision information on each axis. Meanwhile, the required depth movement under monocular vision was independent of performance along the depth axis, indicating an intractable behavior. Our findings highlight the importance of handling depth movement, especially when a virtual reality situation, involving tracking tasks, is generated.


Health care insurance, financial concerns in accessing care, and delays to hospital presentation in acute myocardial infarction.
Little is known about how health insurance status affects decisions to seek care during emergency medical conditions such as acute myocardial infarction (AMI). To examine the association between lack of health insurance and financial concerns about accessing care among those with health insurance, and the time from symptom onset to hospital presentation (prehospital delays) during AMI. Multicenter, prospective study using a registry of 3721 AMI patients enrolled between April 11, 2005, and December 31, 2008, at 24 US hospitals. Health insurance status was categorized as insured without financial concerns, insured but have financial concerns about accessing care, and uninsured. Insurance information was determined from medical records while financial concerns among those with health insurance were determined from structured interviews. Prehospital delay times (< or = 2 hours, > 2-6 hours, or > 6 hours), adjusted for demographic, clinical, and social and psychological factors using hierarchical ordinal regression models. Of 3721 patients, 2294 were insured without financial concerns (61.7%), 689 were insured but had financial concerns about accessing care (18.5%), and 738 were uninsured (19.8%). Uninsured and insured patients with financial concerns were more likely to delay seeking care during AMI and had prehospital delays of greater than 6 hours among 48.6% of uninsured patients and 44.6% of insured patients with financial concerns compared with only 39.3% of insured patients without financial concerns. Prehospital delays of less than 2 hours during AMI occurred among 36.6% of those insured without financial concerns compared with 33.5% of insured patients with financial concerns and 27.5% of uninsured patients (P < .001). After adjusting for potential confounders, prehospital delays were associated with insured patients with financial concerns (adjusted odds ratio, 1.21 [95% confidence interval, 1.05-1.41]; P = .01) and with uninsured patients (adjusted odds ratio, 1.38 [95% confidence interval, 1.17-1.63]; P < .001). Lack of health insurance and financial concerns about accessing care among those with health insurance were each associated with delays in seeking emergency care for AMI.


[Position paper of the Italian Society of Cardiology (SIC) on COVID-19 vaccine priority in patients with cardiovascular diseases].
In over a year, the COVID-19 pandemic caused 2.69 million deaths and 122 million infections. Social isolation and distancing measures have been the only prevention available for months. Scientific research has done a great deal of work, developing in a few months safe and effective vaccines against COVID-19. In the European Union, nowadays, four vaccines have been authorized for use: Pfizer-BioNTech, Moderna, ChAdOx1 (AstraZeneca/Oxford), Janssen (Johnson & Johnson), and three others are currently under rolling review.Vaccine allocation policy is crucial to optimize the advantage of treatment preferring people with the highest risk of contagion. These days the priority in the vaccination program is of particular importance since it has become clear that the number of vaccines is not sufficient for the entire Italian population in the short term. Cardiovascular diseases are frequently associated with severe COVID-19 infections, leading to the worst prognosis. The elderly population suffering from cardiovascular diseases is, therefore, to be considered a particularly vulnerable population. However, age cannot be considered the only discriminating factor because in the young-adult population suffering from severe forms of heart disease, the prognosis, if affected by COVID-19, is particularly ominous and these patients should have priority access to the vaccination program. The aim of this position paper is to establish a consensus on a priority in the vaccination of COVID-19 among subjects suffering from different cardiovascular diseases.


Factors contributing to the lack of human immunodeficiency virus type 1 (HIV-1) transmission in HIV-1-discordant partners.
Correlates of resistance to infection by human immunodeficiency virus type 1 (HIV-1) are important for defining potential therapeutic interventions and for prophylactic vaccination. In this study, 11 couples discordant in their HIV-1 infection status were prospectively evaluated for the presence of protective factors. Behavioral characteristics of all subjects entailed a high risk of transmission. Cytotoxic T lymphocyte (CTL) responses against viruses isolated from the infected partner, and against laboratory virus isolates, were detected in 5 (45%) of 11 HIV-negative partners, including a CCR5Delta32-homozygous and a heterozygous subject. No CTL responses were observed in 6 control unexposed subjects. Marked variation in lymphocyte susceptibility to viral infection was noted. Resistance attributable to major histocompatibility complex discordance or anti-major histocompatibility complex antibodies was not identified. These results suggest that a combination of factors, including cellular immunity, viral characteristics, and coreceptor integrity, may be involved in the persistent nontransmission of HIV.


Electroacupuncture improves memory and protects neurons by regulation of the autophagy pathway in a rat model of Alzheimer's disease.
Acupuncture is a potential therapy for Alzheimer's disease (AD), but its clinical effects and underlying mechanisms are not fully understood. Emerging evidence suggests autophagy is involved in β-amyloid (Aβ) clearance. We hypothesised that electroacupuncture (EA) treatment of AD involves the autophagy pathway in rats. We injected 2μl Aβ1-40 bilaterally into the hippocampi of 42 rats to establish AD. Rats remained untreated (AD group, n=14) or received 24 EA treatments at GV20+BL23 over 28 days from day 7 post-injection with/without co-treatment with 3-methyladenine (3-MA), an autophagy inhibitor (AD+EA+3-MA and AD+EA groups, respectively, n=14 each). Cognitive function was evaluated by Morris water maze (MWM) testing. Hippocampi were examined by transmission electron microscopy (TEM) and stained with haematoxylin and eosin/transferase dUTP nick end labelling (TUNEL) to assess neuronal morphology/apoptosis, respectively. Protein expression of Beclin-1, LC3 and Aβ1-40 was examined. In the MWM test, the AD+EA group showed an improvement in parameters consistent with improved learning/memory compared to untreated AD rats, and 3-MA attenuated these effects. EA mitigated cellular apoptosis resulting from Aβ infusion in the CA1 region and enhanced LC3II/LC3I ratios and Beclin-1 expression. Numerous autophagosome precursors and enlarged autophagosomes were observed by TEM in the hippocampi of EA-treated rats. Reduced Aβ levels, and co-localisation of Aβ and LC3II, were observed following EA treatment by immunofluorescence staining. EA+3-MA treated rats had much higher TUNEL-positive neurons, lower LC3II/LC3I ratios and Beclin-1 expression, and elevated Aβ levels compared with EA alone. EA reduces neuronal apoptosis, enhances degradation of Aβ, and improves learning/memory in AD rats by upregulating the autophagy pathway.


Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves.
The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo-determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates.


Macropharyngodon pakoko, a new species of wrasse (Teleostei: Labridae) endemic to the Marquesas Islands, French Polynesia.
A new species of wrasse, Macropharyngodon pakoko, is described from the Marquesas Islands, bringing the total number of species of the genus Macropharyngodon to 12. Macropharyngodon pakoko was found at depths from 0-42 m and is endemic to the Marquesas Islands. Macropharyngodon pakoko is similar to M. meleagris, which is widely distributed from the central and western Pacific to Cocos-Keeling in the Indian Ocean, but differs genetically and in several coloration characters: males with irregularly curved black humeral blotch with incomplete iridescent blue border; inverted irregular "U"- shaped band on the cheek; a small black spot at the upper base of the pectoral fin; and background color of the body greenish with faint bluish black spots on each scale. Females lack black pigment on the chest posterior to the ventral attachment of the gill membranes; reddish black blotches on the body are widely spaced, particularly on the head where they are more reddish and half the size of those on body; caudal fin with small, bright yellow spots arranged in narrow vertical bands with pale interspaces; pelvic fins pale with three reddish yellow cross-bands; a small black spot at the upper base of the pectoral fin; and small reddish spots along the base of the anal fin. Juveniles have irregular black blotches on the body, a small black spot instead of an ocellus posteriorly on the dorsal fin and lack large black spots and ocellus on the anal fin.


Localization of musicogenic epilepsy to Heschl's gyrus and superior temporal plane: case report.
Musicogenic epilepsy (ME) is an extremely rare form of the disorder that is provoked by listening to or playing music, and it has been localized to the temporal lobe. The number of reported cases of ME in which intracranial electroencephalography (iEEG) has been used for seizure focus localization is extremely small, especially with coverage of the superior temporal plane (STP) and specifically, Heschl's gyrus (HG). The authors describe the case of a 17-year-old boy with a history of medically intractable ME who underwent iEEG monitoring that involved significant frontotemporal coverage as well as coverage of the STP with an HG depth electrode anteriorly and a planum temporale depth electrode posteriorly. Five seizures occurred during the monitoring period, and a seizure onset zone was localized to HG and the STP. The patient subsequently underwent right temporal neocortical resection, involving the STP and including HG, with preservation of the mesial temporal structures. The patient remains seizure free 1 year postoperatively. To the authors' knowledge, this is the first reported case of ME in which the seizure focus has been localized to HG and the STP with iEEG monitoring. The authors review the literature on iEEG findings in ME, explain their approach to HG depth electrode placement, and discuss the utility of STP depth electrodes in temporal lobe epilepsy.


Exposure to the environmentally relevant fungicide Maneb: Studying toxicity in the soil nematode Caenorhabditis elegans.
Maneb is a manganese-containing ethylene bisdithiocarbamate fungicide and is still commonly used as no cases of resistance have been documented. However, studies have shown that Maneb exposure has neurodegenerative potential in mammals, resulting in symptoms affecting the motor system. Despite its extensive use, structural elucidation of Maneb has only recently been accomplished by our group. This study aimed to examine the bioavailability of Maneb, the quantification of oxidative stress-related endpoints and neurotransmitters employing pure Maneb, its metabolites and structural analogues, in the model organism Caenorhabditis elegans. Exposure to Maneb did not increase the bioavailability of Mn compared to manganese chloride, although Maneb was about 8 times more toxic with regard to lethality. Maneb generated not significantly reactive oxygen and nitrogen species (RONS) but decreased the ATP level while increasing the amount of glutathione and its oxidized form in a dose-dependent manner. Nevertheless, an alteration in the neurotransmitter homeostasis of dopamine, acetylcholine, and gamma-butyric acid (GABA) was observed as well as morphological changes in the dopaminergic neurons upon Maneb exposure, which underlines the assumption of the neurotoxic potential of Maneb. This study showed that Maneb exhibits effects based on a combined interaction of the ligand and manganese.


Racial disparities in stage-specific gastric cancer: analysis of results from the Surveillance Epidemiology and End Results (SEER) program database.
The incidence of gastric cancer is declining in western countries but continues to represent a serious health problem worldwide, especially in Asia and among Asian Americans. This study aimed to investigate ethnic disparities in stage-specific gastric cancer, including differences in incidence, treatment and survival. The cohort study was analyzed using the data set of patients with gastric cancer registered in the Surveillance, Epidemiology, and End Results (SEER) program from 2004 to 2013. Among 54,165 patients with gastric cancer, 38,308 were whites (70.7%), 7546 were blacks (13.9%), 494 were American Indian/Alaskan Natives (0.9%) and 7817 were Asians/Pacific Islanders (14.4%). Variables were patient demographics, disease characteristics, surgery/radiation treatment, overall survival (OS) and cause specific survival (CSS). Asians/Pacific Islanders demonstrated the highest incidence rates for gastric cancer compared with other groups and had the greatest decline in incidence during the study period (13.03 to 9.28 per 100,000/year), as well as the highest percentage of patients with American Joint Committee on Cancer (AJCC) early stage gastric cancer. There were significant differences between groups in treatment across stages I-IV (all p<0.001); Asians/Pacific Islanders had the highest rate of surgery plus radiation (45.1%). Significant differences were found in OS and CSS between groups (p<0.001); OS was highest among Asians/Pacific Islanders. Multivariate analysis revealed that age, race, grade, stage, location, and second primary cancer were valid prognostic factors for survival. Marked ethnic disparities exist in age-adjusted incidence of primary gastric cancer, with significant differences between races in age, gender, histological type, grade, AJCC stage, location, second cancer, treatment and survival.


Probing atomic ordering and multiple twinning in metal nanocrystals through their vibrations.
Control of nanocrystal (NC) crystallinity currently raises great interest because of its potential benefits in both physics modeling and technological applications. Advances in methods for synthesizing perfect single-crystalline NCs are recent, so that the effect of crystallinity on NC properties has received only limited study and still needs to be properly investigated. Here, we report that crystallinity of gold NCs dramatically modifies their vibrations. Using low-frequency Raman scattering, we clearly demonstrate that single-domain NCs vibrate differently than their multiply twinned counterparts, through the splitting of the quadrupolar vibrations, which is only observed for the former. Using the resonant ultrasound approach, we calculate the vibrational frequencies of a gold sphere and show that elastic anisotropy induces a lift of degeneracy of the quadrupolar mode in good agreement with our experimental measurements. These findings open up challenging perspectives on using Raman spectroscopy to characterize nanocrystallinity.


Generation and characterization of mutant cell lines defective in gamma-secretase processing of Notch and amyloid precursor protein.
Several type I integral membrane proteins, such as the Notch receptor or the amyloid precursor protein, are cleaved in their intramembrane domain by a gamma-secretase enzyme, which is carried within a multiprotein complex. These cleavages generate molecules that are involved in intracellular or extracellular signaling. At least four transmembrane proteins belong to the gamma-secretase complex: presenilin, nicastrin, Aph-1, and Pen-2. It is still unclear whether these proteins are the only components of the complex and whether a unique complex is involved in the different gamma-secretase cleavage events. We have set up a genetic screen based on the permanent acquisition or loss of an antibiotic resistance depending on the presence of an active gamma-secretase able to cleave a Notch-derived substrate. We selected clones deficient in gamma-secretase activity using this screen on mammalian cells after random mutagenesis. We further analyzed two of these clones and identified previously undescribed mutations in the nicastrin gene. The first mutation abolishes nicastrin production, and the second mutation, a point mutation in the ectodomain, abolishes nicastrin maturation. In both cases, gamma-secretase activity on Notch and APP is impaired.


[Molecular aspects of pharmacological activity of naltrexone and naloxone].
Naltrexone and naloxone, being competitive antagonists of opioid receptors, have found therapeutic applications in medicine. The experiments with mutant receptors showed that many amino acid residues within transmembrane domains play an important role in binding these drugs. Using the site-directed mutagenesis technique, it was established that even single mutations (replacing single amino acid residues) can significantly modify the affinity of antagonists to receptors, sometimes even imparting agonist-like properties to the compounds studied. Chronic administration of naltrexone and naloxone leads to an increase in the density of opioid receptors and in the sensitivity to agonists. This hypersensitivity and overdose risk in heroin abusers after chromic naltrexone treatment are discussed.


Beyond PEGylation: Alternative surface-modification of nanoparticles with mucus-inert biomaterials.
Mucus is a highly hydrated viscoelastic gel present on various moist surfaces in our body including the eyes, nasal cavity, mouth, gastrointestinal, respiratory and reproductive tracts. It serves as a very efficient barrier that prevents harmful particles, viruses and bacteria from entering the human body. However, the protective function of the mucus also hampers the diffusion of drugs and nanomedicines, which dramatically reduces their efficiency. Functionalisation of nanoparticles with low molecular weight poly(ethylene glycol) (PEGylation) is one of the strategies to enhance their penetration through mucus. Recently a number of other polymers were explored as alternatives to PEGylation. These alternatives include poly(2-alkyl-2-oxazolines), polysarcosine, poly(vinyl alcohol), other hydroxyl-containing non-ionic water-soluble polymers, zwitterionic polymers (polybetaines) and mucolytic enzymes. This review discusses the studies reporting the use of these polymers or potential application to facilitate mucus permeation of nanoparticles.


The changing uses of accuracy in science communication.
Tracing its historical trajectories, this article explores the preoccupation with accuracy in science communication research and explores the resurgence in the present century of concerns about accuracy, balance and impartiality in public communication of science. It is argued that many of the original insights from news and journalism research are still relevant and important if re-formulated in constructionist terms about voice, access and claims-making, and asking, in whose interest? Key to this is also the recognition of a radically changing - technologically, economically and professionally - media and communications environment, with implications for science journalism and a very different dynamic regarding the range and type of actors involved in discursively constructing opinions and information about controversial science and expertise. The article concludes with proposals for future emphases and directions in research broadly concerned with accuracy in science communication.


The incidence of induced abortion in Kinshasa, Democratic Republic of Congo, 2016.
In the Democratic Republic of Congo, the penal code prohibits the provision of abortion. In practice, however, it is widely accepted that the procedure can be performed to save the life of a pregnant woman. Although abortion is highly restricted, anecdotal evidence indicates that women often resort to clandestine abortions, many of which are unsafe. However, to date, there are no official statistics or reliable data to support this assertion. Our study provides the first estimates of the incidence of abortion and unintended pregnancy in Kinshasa. We applied the Abortion Incidence Complications Method (AICM) to estimate the incidence of abortion and unintended pregnancy. We used data from a Health Facilities Survey and a Prospective Morbidity Survey to determine the annual number of women treated for abortion complications at health facilities. We also employed data from a Health Professionals Survey to calculate a multiplier representing the number of abortions for every induced abortion complication treated in a health facility. In 2016, an estimated 37,865 women obtained treatment for induced abortion complications in health facilities in Kinshasa. For every woman treated in a facility, almost four times as many abortions occurred. In total, an estimated 146,713 abortions were performed, yielding an abortion rate of 56 per 1,000 women aged 15-49. Furthermore, more than 343,000 unintended pregnancies occurred, resulting in an unintended pregnancy rate of 147 per 1,000 women aged 15-49. Increasing contraceptive uptake can reduce the number of women who experience unintended pregnancies, and as a consequence, result in fewer women obtaining unsafe abortions, suffering abortion complications, and dying needlessly from unsafe abortion. Increasing access to safe abortion and improving post-abortion care are other measures that can be implemented to reduce unsafe abortion and/or its negative consequences, including maternal mortality.


Keratin species in type II pneumocytes in culture and during lung injury.
A detailed understanding of alveolar epithelial cell transitions during remodeling after lung injury requires the identification of specific markers. We have developed a panel of monoclonal antibodies against species of the intermediate filament protein, keratin. These individual species are recognized markers of the state of differentiation of various epithelial cells. These and complementary protein analytic methods have been applied to studies of isolated, enriched Type II pneumocyte preparations as well as to normal and injured lung tissues. Monoclonal antibody 24A3, initially raised against Morris hepatoma 7777 keratins, decorated a filament network in isolated cultured rat Type II pneumocytes by indirect immunofluorescence; it reacts by 2-dimensional polyacrylamide gel immunoblot procedures with an acidic, 46,000-dalton keratin. Monoclonal antikeratin antibodies AE1 and AE3, raised against human epidermal keratins, reacted poorly with isolated Type II cells; however, AE3 reacted by immunoblot technique with the 55,000-dalton keratin subclass. The bronchial epithelium reacted intensely with 24A3 as well as with a mix of AE1 plus AE3 in ethanol-fixed, paraffin-embedded sections of normal and injured rat lung. Alveolar regions of normal lung reacted poorly with all 3 antibodies, however, as visualized by light microscopy. At the same time, very large, presumptive epithelial cells in the alveolar regions stained intensely with 24A3 3 days after intratracheal instillation of bleomycin, whereas thin cells lining the alveoli in injured regions were intensely reactive 14 days after bleomycin treatment. These elongated cells may represent Type II pneumocytes in the process of converting to Type I cells.


The ectomesenchymal chondromyxoid tumor: a review.
The ectomesenchymal chondromyxoid tumor is a relatively recently described neoplasm that appears to involve uniquely the oral cavity, particularly the tongue. Thirty well-accepted cases have been reported since the initial description of this lesion in 1995. While a wide age range (9-78 years) has been documented, most of these tumors are diagnosed from the third to sixth decades of life. No sex predilection is seen. The size of the neoplasm is typically <2 cm, and most affect the anterior dorsal tongue. The duration of the lesion was difficult to gauge, probably due to the asymptomatic nature of the process. Some tumors, however, were well documented to have been present for as long as 10-20 years. Histopathologically, the ectomesenchymal chondromyxoid tumor is characterized by a well circumscribed, but unencapsulated, lobular growth pattern. Varying degrees of cellularity are noted, with the lesional cells often set in a myxoid, chondroid or hyalinized background. Immunohistochemical studies reveal positivity of the lesional cells for antibodies directed against glial fibrillary acidic protein, cytokeratins, S-100 protein and CD-57 in the majority of tumors. Treatment consists of conservative surgical excision, and while recurrence is possible, it has been noted in <10% of reported cases.


Emergence of organized bursting in clusters of pancreatic beta-cells by channel sharing.
Pancreatic beta-cells in an intact Islet of Langerhans exhibit bursting electrical behavior. The Chay-Keizer model describes this using a calcium-activated potassium (K-Ca) channel, but cannot account for the irregular spiking of isolated beta-cells. Atwater I., L. Rosario, and E. Rojas, Cell Calcium. 4:451-461, proposed that the K-Ca channels, which are rarely open, are shared by several cells. This suggests that the chaotic behavior of isolated cells is stochastic. We have revised the Chay-Keizer model to incorporate voltage clamp data of Rorsman and Trube and extended it to include stochastic K-Ca channels. This model can describe the behavior of single cells, as well as that of clusters of cells tightly coupled by gap junctions. As the size of the clusters is increased, the electrical activity shows a transition from chaotic spiking to regular bursting. Although the model of coupling is over-simplified, the simulations lend support to the hypothesis that bursting is the result of channel sharing.


Elevated ozone alters soybean-virus interaction.
Increasing concentrations of ozone (O(3)) in the troposphere affect many organisms and their interactions with each other. To analyze the changes in a plant-pathogen interaction, soybean plants were infected with Soybean mosaic virus (SMV) while they were fumigated with O(3). In otherwise natural field conditions, elevated O(3) treatment slowed systemic infection and disease development by inducing a nonspecific resistance against SMV for a period of 3 weeks. During this period, the negative effect of virus infection on light-saturated carbon assimilation rate was prevented by elevated O(3) exposure. To identify the molecular basis of a soybean nonspecific defense response, high-throughput gene expression analysis was performed in a controlled environment. Transcripts of fungal, bacterial, and viral defense-related genes, including PR-1, PR-5, PR-10, and EDS1, as well as genes of the flavonoid biosynthesis pathways (and concentrations of their end products, quercetin and kaempherol derivatives) increased in response to elevated O(3). The drastic changes in soybean basal defense response under altered atmospheric conditions suggest that one of the elements of global change may alter the ecological consequences and, eventually, coevolutionary relationship of plant-pathogen interactions in the future.


Hierarchical Mechanical Transduction of Precision-Engineered DNA Hydrogels with Sacrificial Bonds.
Engineering the response to external signals in mechanically switchable hydrogels is important to promote smart materials applications. However, comparably little attention has focused on embedded precision mechanisms for autonomous nonlinear response in mechanical profiles in hydrogels, and we lack understanding of how the behavior from the molecular scale transduces to the macroscale. Here, we design a nonlinear stress-strain response into hydrogels by engineering sacrificial DNA hairpin loops into model network hydrogels formed from star-shaped building blocks. We characterize the force-extension response of single DNA hairpins and are able to describe how the specific topology influences the nonlinear mechanical behavior at different length scales. For this purpose, we utilize force spectroscopy as well as microscopic and macroscopic deformation tests. This study contributes to a better understanding of designing nonlinear strain-adaptive features into hydrogel materials.


Neurobiology of nutrition and obesity.
In the course of evolution, the need to eat has powerfully shaped biological structure and function. As a result, nutrient-depletion signals strongly activate neural mechanisms that orchestrate foraging, appetitive, and ingestive behaviors and at the same time instigate an internal energy savings mode through autonomic, endocrine, and peripheral cellular mechanisms. Although the hypothalamus and brainstem play crucial roles in the initiation and coordination of these responses, it is the integrated action of a much more complex and distributed neural system that is engaged in this fundamental survival reflex. In our modern, media-driven and mechanized environment of plenty, it is particularly important to recognize the neural systems responsible for learning and memory, reward, emotions and mood, decision-making and choice, and dealing with stress. These neural systems appear to powerfully assist the hypothalamic regulator in defending the lower limits of body weight, but they do little in overcoming its inherent weakness to defend over-nutrition and the upper limits of body weight and adiposity. The challenge is to define the role of these extrahypothalamic brain structures involved in the cognitive, rewarding, and emotional aspects of ingestive and physical activity behaviors and their relationship to the homeostatic regulator, and to assess the capacity of these mechanisms in predisposing to obesity.


Compensating effects of urea and trimethylamine-N-oxide on the heteroassociation of α-chymotrypsin and soybean trypsin inhibitor.
An assay for the determination of the equilibrium constant for heteroassociation of α-chymotrypsin and soybean trypsin inhibitor via fluorescence depolarization is described. Results obtained at neutral pH in saline buffer were consistent with prior determinations via sedimentation equilibrium and static light scattering. The dependence of the association equilibrium constant upon the concentrations of urea and trimethylamine-N-oxide (TMAO) added individually and in mixtures was determined at several temperatures. It was found that subdenaturing concentrations of urea decrease the extent of heteroassociation and that added TMAO increases the extent of heteroassociation. The effects of both cosolutes in mixtures upon the equilibrium heteroassociation of α-chymotrypsin and soybean trypsin inhibitor appear to be additive. A thermodynamic analysis of the combined results is presented.


Impact of Cosmetics on the Surface Properties of Silicone Hydrogel Contact Lenses.
This study evaluated the impact of various cosmetics on the surface properties of silicone hydrogel (SiHy) contact lens materials. In this in vitro experiment, 7 SiHy contact lens materials were coated with 1 of 9 cosmetics, including common hand creams (3), eye makeup removers (3), and mascaras (3). Dark-field microscopy images were taken to determine pixel brightness (PB) after cosmetic exposure, which describes the visible surface deposition (n=6 for each lens type), with a higher PB indicating increased deposition. The sessile drop technique was used to determine the advancing contact angle (CA). Measurements were repeated for both methods after a single peroxide-based cleaning cycle. Pixel brightness was significantly higher for mascara-coated lenses compared with the other cosmetic products (P<0.01). The peroxide-based lens care solution removed most deposits from the nonwaterproof mascara for 4 lens types, whereas deposits remained relatively unchanged for 1 waterproof mascara (P>0.05). Hand creams and makeup remover had minimal impact on PB. Changes in CA measurements after cosmetic application were highly lens dependent. Hand creams caused primarily a decrease in CA for 5 of the 7 lens types, whereas 1 of the waterproof mascaras caused a significant increase of 30 to 50° for 3 lens types. Some mascara-lens combinations resulted in increased CA and PB, which could have an impact on in vivo lens performance. Nonwaterproof mascara was mostly removed after a cleaning cycle. Further research is needed to understand the clinical implications for SiHy lens wearers using cosmetics.


Characteristics and outcome of children with renal tumors in the Netherlands: The first five-year's experience of national centralization.
Around 6% of all childhood malignancies represent renal tumors, of which a majority includes Wilms tumor (WT). Although survival rates have improved over the last decades, specific patients are still at risk for adverse outcome. In the Netherlands, since 2015, pediatric oncology care for renal tumors has been centralized in the Princess Máxima Center for Pediatric Oncology. Here, we describe experiences of the first 5 years of centralized care and explore whether this influences the epidemiological landscape by comparing data with the Netherlands Cancer Registry (NCR). We identified all patients <19 years with a renal mass diagnosed between 01-01-2015 and 31-12-2019 in the Princess Máxima Center. Epidemiology, characteristics and management were analyzed. We identified 164 patients (including 1 patient who refused consent for registration), in our center with a suspicion of a renal tumor. The remaining 163 cases included WT (n = 118)/cystic partially differentiated nephroblastoma (n = 2)/nephrogenic rests only (n = 6) and non-WT (n = 37). In this period, the NCR included 138 children, 1 17-year-old patient was not referred to the Princess Máxima Center. Central radiology review (before starting treatment) was performed in 121/163 patients, and central pathology review in 148/152 patients that underwent surgery. Treatment stratification, according to SIOP/EpSSG protocols was pursued based on multidisciplinary consensus. Preoperative chemotherapy was administered in 133 patients, whereas 19 patients underwent upfront surgery. Surgery was performed in 152 patients, and from 133 biomaterial was stored. Centralization of care for children with renal tumors led to referral of all but 1 new renal tumor cases in the Netherlands, and leads to referral of very rare subtypes not registered in the NCR, that benefit from high quality diagnostics and multidisciplinary decision making. National centralization of care led to enhanced development of molecular diagnostics and other innovation-based treatments for the future.


Analysis of arm trajectories of everyday tasks for the development of an upper-limb orthosis.
Spatiotemporal arm and body movements of able-bodied subjects performing nine everyday tasks were recorded for the purpose of guiding the development of an upper-limb orthosis. To provide a user the opportunity to carry out these tasks with natural movements, the orthosis should allow replication of the measured trajectories. We outline the orthosis architecture, which supports the user's upper arm and forearm, and analyze the movement data to obtain orthosis design specifications. Trajectories were obtained using six-degree-of-freedom magnetic position sensors affixed to the wrist, elbow, shoulder, trunk and head. Elbow trajectory data were decomposed into ranges along the principle Cartesian axes to provide a generally useful envelope measure. The smallest Cartesian parallel-piped that contained the elbow trajectories for most tasks was approximately 30 cm front/back, 15 cm side/side, and 17 cm up/down. A rough lower bound estimate obtained by asking subjects to repeat the tasks while minimizing elbow movement substantially reduced movement in the up/down and side/side dimensions. Elbow angles were generally in the range 50 degrees-150 degrees, and the angle of the forearm with respect to vertical was 10 degrees-110 degrees. Raw trajectory data may be downloaded from www://asel.udel.edu/robotics/orthosis/range.h tml.


Influence of Pre-reproductive Maternal Enrichment on Coping Response to Stress and Expression of c-Fos and Glucocorticoid Receptors in Adolescent Offspring.
Environmental enrichment (EE) is an experimental setting broadly used for investigating the effects of complex social, cognitive, and sensorimotor stimulations on brain structure and function. Recent studies point out that parental EE experience, even occurring in the pre-reproductive phase, affects neural development and behavioral trajectories of the offspring. In the present study we investigated the influences of pre-reproductive EE of female rats on maternal behavior and adolescent male offspring's coping response to an inescapable stressful situation after chronic social isolation. For this purpose female Wistar rats were housed from weaning to breeding age in enriched or standard environments. Subsequently, all females were mated and housed in standard conditions until offspring weaning. On the first post partum day (ppd 1), mother-pup interactions in undisturbed conditions were recorded. Further, after weaning the male pups were reared for 2 weeks under social isolation or in standard conditions, and then submitted or not to a single-session Forced Swim Test (FST). Offspring's neuronal activation and plastic changes were identified by immunohistochemistry for c-Fos and glucocorticoid receptors (GRs), and assessed by using stereological analysis. The biochemical correlates were measured in the hippocampus, amygdala and cingulate cortex, structures involved in hypothalamic-pituitary-adrenocortical axis regulation. Enriched dams exhibited increased Crouching levels in comparison to standard reared dams. In the offspring of both kinds of dams, social isolation reduced body weight, decreased Immobility, and increased Swimming during FST. Moreover, isolated offspring of enriched dams exhibited higher levels of Climbing in comparison to controls. Interestingly, in the amygdala of both isolated and control offspring of enriched dams we found a lower number of c-Fos immunopositive cells in response to FST and a higher number of GRs in comparison to the offspring of standard dams. These results highlight the profound influence of a stressful condition, such as the social isolation, on the brain of adolescent rats, and underline intergenerational effects of maternal experiences in regulating the offspring response to stress.


The Effects of Orientation of Lumbar Facet Joints on the Facet Joint Contact Forces: An In Vitro Biomechanical Study.
A biomechanical human cadaveric study. The aim of this study was to measure L2-L3 facet joint contact forces in a flexibility test using thin film electroresistive sensors, and facet joint orientation on computed tomographic (CT) scan images, to examine the effects of orientation of lumbar facet joint on the facet joint contact forces. Biomechanically, the bilateral facet joints play a critical role in maintaining stability of the lumbar spine. The effect of orientation of lumbar facet joints on the contact forces remains unknown. Eight human cadaveric lumbar spine specimens (L2-L3) were tested by applying a pure moment of ±7.5 Nm in three directions of loading (flexion-extension, lateral bending, and axial rotation) with and without a follower preload of 300 N. The orientation of the lumbar facet joints at the L2-L3 was measured on axial CT scans. Bilateral facet contact forces were measured during flexibility tests using thin film electroresistive sensors (Tekscan 6900). The average total peak facet loads was 66 N in axial rotation, 27 N in extension, and 20 N in lateral bending under a pure moment. Under a pure moment with a follower preload of 300 N, the average total peak facet loads was 53 N in axial rotation, 43 N in extension, and 24 N in lateral bending. The facet joint forces were correlated positively and significantly with the orientation in all directions with and without a compressive follower preload (P < 0.05). In addition, the facet joint contact forces at neutral position with a follower preload were correlated positively with the orientation (rs = 0.759, P = 0.001). This study identified that the greater coronal orientation of lumbar facet joints is, the higher the facet joint contact forces are. 3.


Interferometric Imaging Using Shared Quantum Entanglement.
Quantum entanglement-based imaging promises significantly increased resolution by extending the spatial separation of optical collection apertures used in very-long-baseline interferometry for astronomy and geodesy. We report a tabletop entanglement-based interferometric imaging technique that utilizes two entangled field modes serving as a phase reference between two apertures. The spatial distribution of a simulated thermal light source is determined by interfering light collected at each aperture with one of the entangled fields and performing joint measurements. This experiment demonstrates the ability of entanglement to implement interferometric imaging.


Exploring complex networks by means of adaptive walkers.
Finding efficient algorithms to explore large networks with the aim of recovering information about their structure is an open problem. Here, we investigate this challenge by proposing a model in which random walkers with previously assigned home nodes navigate through the network during a fixed amount of time. We consider that the exploration is successful if the walker gets the information gathered back home, otherwise no data are retrieved. Consequently, at each time step, the walkers, with some probability, have the choice to either go backward approaching their home or go farther away. We show that there is an optimal solution to this problem in terms of the average information retrieved and the degree of the home nodes and design an adaptive strategy based on the behavior of the random walker. Finally, we compare different strategies that emerge from the model in the context of network reconstruction. Our results could be useful for the discovery of unknown connections in large-scale networks.


Both CLIC4 and CLIC5A activate ERM proteins in glomerular endothelium.
The chloride intracellular channel (CLIC) 5A is expressed at very high levels in renal glomeruli, in both endothelial cells (EC) and podocytes. CLIC5A stimulates Rac1- and phosphatidylinositol (4,5)-bisphosphate-dependent ERM (ezrin, radixin, moesin) activation. ERM proteins, in turn, function in lumen formation and in the development of actin-based cellular projections. In mice lacking CLIC5A, ERM phosphorylation is profoundly reduced in podocytes, but preserved in glomerular EC. Since glomerular EC also express CLIC4, we reasoned that, if CLIC4 activates ERM proteins like CLIC5A, then CLIC4 could compensate for the CLIC5A loss in glomerular EC. In glomeruli of CLIC5-deficient mice, CLIC4 expression was upregulated and colocalized with moesin and ezrin in glomerular EC, but not in podocytes. In cultured glomerular EC, CLIC4 silencing reduced ERM phosphorylation and cytoskeletal association, and expression of exogenous CLIC4 or CLIC5A rescued ERM de-phosphorylation due to CLIC4 silencing. In mice lacking either CLIC4 or CLIC5, ERM phosphorylation was retained in glomerular EC, but, in mice lacking both CLIC4 and CLIC5, glomerular EC ERM phosphorylation was profoundly reduced. Although glomerular EC fenestrae developed normally in dual CLIC4/CLIC5-deficient mice, the density of fenestrae declined substantially by 8 mo of age, along with the deposition of subendothelial electron-lucent material. The dual CLIC4/CLIC5-deficient mice developed spontaneous proteinuria, glomerular cell proliferation, and matrix deposition. Thus CLIC4 stimulates ERM activation and can compensate for CLIC5A in glomerular EC. The findings indicate that CLIC4/CLIC5A-mediated ERM activation is required for maintenance of the glomerular capillary architecture.


Minimally invasive cervical pedicle screw fixation via the posterolateral approach for metastatic cervical spinal tumors.
To avoid lateral misplacement of midcervical pedicle screws, we developed a method for Minimally Invasive Cervical Pedicle Screw (MICEPS) fixation via a posterolateral approach. This intramuscular approach allows for horizontal pedicle screw insertion and reduced intraoperative bleeding. We reviewed our initial experience with MICEPS fixation for patients with cervical metastases. This study included 18 consecutive patients who received cervical spinal surgery for metastatic tumor. We treated 12 patients with conventional cervical pedicle screw fixation, and 6 patients with the MICEPS fixation technique. Average follow-up was 14 months (range 3 to 34). We inserted 117 pedicle screws using the navigation system. Average fusion area was 4.9 vertebrae (range 3 to 8). Alpha-angles between a line perpendicular to the posterior cortex of the vertebral body and the screw trajectory in the transverse plane were also measured. The average surgical time was 250 min (range 151 to 420 min) with the conventional pedicle screw fixation and 234 min (range 154 to 300 min) with the MICEPS fixation. The average total blood loss was 780 mL (range, 180-1430 mL) in the conventional pedicle screw fixation group and 180 mL (range, 70-400 mL) in the MICEPS fixation group. At the level of midcervical (C3-5), average alpha-angles was 52 degrees (range 43 to 62) in MICEPS fixation group, and 39 degrees (range 19 to 55) in conventional cervical pedicle screw group. The MICEPS fixation technique uses an intramuscular approach, which is minimally invasive and reduces intraoperative bleeding. Intramuscular approach allows for horizontal pedicle screw insertion, and reduced critical screw deviation.


Effect of lupeol on antioxidants and xenobiotic enzymes in N-Butyl-N-(4-hydroxybutyl) nitrosamine induced bladder carcinogenesis in experimental rats.
Urothelial carcinoma of the bladder is a common malignancy ranked 9th with an estimated 356,600 new cases diagnosed annually worldwide. The study showed the protective effects of Lupeol in N-Butyl-N-(4-hydroxybutyl) nitrosamine induced bladder carcinogenesis in in vivo experimental model. Forty male healthy wistar rats were selected randomly divided into four groups. Group I rats served as healthy control. Group II rats were treated with BBN (150 mg/gavage/twice a week) for 8 weeks. Group III rats were treated with BBN + Lupeol [ Lupeol (50 mg/kg bw/day) treatment was started 1 week prior to the BBN treatment, and it was orally administered for 8 weeks]. Group IV rats were treated with Lupeol alone (50 mg/kg bw/day) for 8 weeks. All the experimental rats were maintained and euthanized at 32nd week. Serum and bladder tissues were collected and examined for biochemical parameters, serum markers and histopathological evaluation. Preventive (BBN + Lupeol) group modulates the activity of antioxidant enzymes such as Superoxide dismutase, Catalase, Reduced glutathione, Glutathione Peroxidase, Thiobarbituric acid reactive substances (TBARS) and drug metabolizing enzymes such as Cytochrome P450, Cytochrome b5, NADPH Cytochrome c reductase, NADPH- Quinone Oxidoreductase 1 and Glutathione-S-transferase when compared to BBN treated rats. Serological markers such as Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) were significantly (P<0.05) decreased in preventive lupeol treated groups. Lupeol supplementation protects BBN induced bladder carcinogenesis in experimental rats by its antioxidant, anti-inflammatory and antiproliferative properties.


Radiographic features of knee and hip osteoarthritis represent characteristics of an individual, in addition to severity of osteoarthritis.
To evaluate to what extent radiographic features of knees and hips that are normally related to osteoarthritis (OA) represent characteristics of an individual in addition to OA severity. We studied a cohort of individuals (n = 1002) with very early signs of hip and knee OA, from the Cohort Hip and Cohort Knee (CHECK) study. Baseline radiographs were evaluated by digital analyses, using Holy's and Knee Images Digital Analysis (KIDA) software, providing distinct quantitative measures of radiographic OA features. In addition, conventional Kellgren and Lawrence (KL) grading was performed. Digital parameters were evaluated for correlations within participants between contralateral (left vs. right hip and left vs. right knee), ipsilateral (e.g. left hip vs. left knee), and diagonal joints (e.g. left hip vs. right knee). Analyses were performed separately for participants with KL grade 0-I and those with evident radiographic OA (KL grade II-III). Regression analyses determined whether demographic characteristics were related to radiographic features. Correlations between digital parameters and KL grade were moderate, and within each KL grade large variation was found. Within participants strong correlations were found for digital parameters between joints in individuals with KL grade 0-I (R = 0.60-0.89), strongest for contralateral comparison, but no statistically significant correlations were found for participants with KL grade II-III. The demographic characteristics age, gender, height, and weight were, to a limited extent (R(2) = 0.01-0.20) but statistically significant, related to radiographic characteristics. Using digital analyses of radiographic OA, strong correlations between joints within participants were found. These correlations diminished when OA became evident. This has implications for monitoring joint damage in (very) early OA with digital analyses.


Perinephric abscess: the missed diagnosis.
Perinephric abscess is a life-threatening but treatable process. Most infections of the perinephric space occur as a result of extension of an ascending urinary tract infection, commonly in association with nephrolithiasis or urinary tract obstruction. A large portion of the mortality is the result of failure to diagnose this entity in a timely fashion. This failure may be because of the frequently obscure or nonspecific nature of the clinical presentation. Blood cultures as well as urine cultures may fail to identify correctly the bacterial pathogens responsible for the abscess. Perinephric abscess should be considered in the differential diagnosis of any patient presenting with a urinary tract infection that fails to respond promptly to antibiotic therapy, particularly in those known to have anatomical abnormalities of the urinary tract or diabetes mellitus. Consideration of this diagnosis should enter into the differential diagnosis of fever with abdominal pain or flank pain. Early recognition of perinephric abscess and prompt drainage, either percutaneously or surgically, in combination with appropriate antibiotic coverage, should reduce dramatically the morbidity and mortality from this infection.


Serum Lipid Concentrations and FADS Genetic Variants in Young Mexican College Students: The UP-AMIGOS Cohort Study.
Recent genome-wide association studies in the Mexican population have identified several genetic loci associated with blood lipid levels in adults. However, studies focusing on the fatty acid desaturase (FADS) gene cluster have been understudied in this population, even though it seems associated with lipid profiles in other ethnicities. The aim of this study was to test associations between single nucleotide polymorphisms (SNPs) in the FADS cluster (rs174546, rs1535, rs174548, rs174550, rs174450, and rs174618) and serum lipid profiles in young Mexicans. Anthropometrics, serum lipid profiles, and FADS SNPs were measured in 998 subjects in the UP-AMIGOS cohort study. Genotype-phenotype (total cholesterol [TC], triglyceride [TG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and very-low-density lipoprotein [VLDL]) associations were assessed using PLINK adjusted for sex, age, and body mass index (BMI). Among 6 FADS SNPs, we found that carriers of the C-allele of the FADS1-rs174546 showed a significant association with lower TG concentrations (β = -12.6 mg/dL, p = 0.009) and lower VLDL concentrations (β = -2.52 mg/dL, p = 0.005). We found that rs174546, rs1535, and rs174550 were in high linkage disequilibrium (r2 > 0.80). There were no significant associations between rs174550, rs174548, and rs174618 and lipid profiles. A genetic variant in the FADS1 (rs174546) gene is a major contributor of plasma TG and VLDL concentrations in healthy young Mexicans.