Immunocytochemical localization of cyclic guanosine monophosphate-dependent protein kinase in endocrine tissues.
Antisera have been produced against purified soluble cyclic guanosine monophosphate (cGMP) dependent-protein kinase (ATP: protein phosphotransferase EC 18.104.22.168) isolated from bovine lung. No cross-reactivity was observed between the antisera and structurally related components of cAMP-dependent protein kinases (cAMP kinase), as judged by the immunodiffusion and immunoprecipitation techniques. Immunocytochemical specificity was determined by absorption of antisera with pure antigen. The distribution of cGMP kinase has been examined in several rat tissues, using an indirect immunofluorescence technique, and compared with the immunocytochemical distribution of cGMP. In skeletal muscle, cGMP kinase was localized primarily to A bands on the muscle fiber and along the Z line in I band regions. Densitometric determinations of immunoperoxidase staining indicated that absorbance over A band areas was greater than absorbance over the I band regions. In small intestine, cGMP kinase is distributed primarily along the villus brush border membrane. In testis, cGMP kinase is observed in several cell types adjacent to the seminiferous tubular wall, including Sertoli cells and spermatogonia, as well as in association with meiotic chromosomes of pachytene spermatocytes. In the cortex of the adrenal glands from dexamethasone-suppressed rats, chronic ACTH treatment induced an increase in cGMP kinase fluorescence in nuclei. In each of the tissues examined, a striking correlation was observed between the distribution of cGMP kinase and cGMP, supporting the hypothesis that cGMP-mediated actions occur via cGMP kinases.


Ultra-High Frequency Self-Focusing Ultrasonic Sensors with Half-Concave Geometry for Visualization of Mouse Brain Atrophy.
Ultra-high frequency (>100 MHz) acoustic waves feature biocompatibility and high sensitivity and allow biomedical imaging and acoustic tweezers. Primarily, excellent spatial resolution and broad bandwidth at ultra-high frequency is the goal for pathological research and cell selection at the cellular level. Here, we propose an efficient approach to visualize mouse brain atrophy by self-focused ultrasonic sensors at ultra-high frequency with ultra-broad bandwidth. The numerical models of geometry and theoretically predicted acoustic parameters for half-concave piezoelectric elements are calculated by the differential method, which agrees with measured results (lateral resolution: 24 μm, and bandwidth: 115% at -6 dB). Compared with the brain slices of 2-month-old mouse, the atrophy visualization of the 6-month-old mouse brain was realized by C-mode imaging with an acoustic microscopy system, which is a potential prospect for diagnosis and treatment of Alzheimer's disease (AD) combined with neuroscience. Meanwhile, the acoustic properties of the brain slices were quantitatively measured by the acoustic microscopy. These encouraging results demonstrate the promising application for high-resolution imaging in vitro biological tissue with ultra-high frequency self-focusing ultrasonic sensors.


Ascetoaxinus quatsinoensis sp. et gen. nov. (Bivalvia: Thyasiroidea) from Vancouver Island, with notes on Conchocele Gabb, 1866, and Channelaxinus Valentich-Scott & Coan, 2012.
Ascetoaxinus quatsinoensis sp. et gen. nov. is described from deep waters off the coast of Vancouver Island, British Columbia, Canada. The shell of this species is quite unusual in that the margin of the lunule is distinctly scalloped, a feature not reported previously for the Thyasiroidea. Further investigation led to the discovery of another similarly scalloped shell, represented by the unique type specimen of Cryptodon ovoideus Dall, 1890, herein re-classified as Ascetoaxinus ovoidea (Dall, 1890). Results obtained from scanning electron microscopy reveal additional anatomical differences, including distinct gill structure, that distinguish A. quatsinoensis from other thyasirids examined. Morphological comparisons of this new species to closely related taxa has resulted in a re-evaluation of the genera Conchocele Gabb, 1866, and Channelaxinus Valentich-Scott and Coan, 2012.


Neuromyelitis optica mimics the morphology of spinal cord tumors.
Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system, that predominantly affects the spinal cord and the optic nerve. Its key features include transverse myelitis, commonly associated with extensive inflammation spanning three or more consecutive vertebral segments. Longitudinal extensive spinal cord lesions can also occur in systemic autoimmune diseases, infections, vascular and metabolic disorders, subsequent to irradiation, intramedullary tumors and paraneoplastic myelopathies. We present a case study of an 8-year-old girl seropositive for antibodies against the aquaporin 4 who displayed longitudinal extensive spinal cord lesions, that was initially misdiagnosed as an intramedullary tumor.


Hypervolemic hemodilution in acute ischemic stroke: the Multicenter Austrian Hemodilution Stroke Trial (MAHST).
Experimental studies suggest a beneficial effect of hemodilution on acute ischemic stroke. This was not proven by previous multicenter trials in the clinical setting. Various reasons have been suggested for the failure of these studies, which we attempted to consider in the Multicenter Austrian Hemodilution Stroke Trial (MAHST). MAHST is a randomized, double-blind, placebo-controlled study of hypervolemic hemodilution (HHD) within 6 hours of a clinically first ischemic stroke localized in the middle cerebral artery territory. The treatment consisted of 10% hydroxyethyl starch 200/0.5 (HES) and was tested against pure rehydration with Ringer's lactate over a period of 5 days. Our primary outcome measure was clinical improvement within 7 days as measured by the Graded Neurologic Scale (GNS). We performed an adaptive interim analysis to reevaluate the study goal after entering half of the projected number of patients (n = 200). At least 600 patients per group would have been required for significant results, and therefore we decided to terminate the trial. Ninety-eight patients received HHD and 102 patients placebo. The baseline characteristics were comparable between both groups. In the HHD group the absolute reduction of the hematocrit was 2.5% on day 2 with a maximum of 3.7% on day 5, which compares with a reduction in the placebo group of 1% and 1.9%, respectively. Intention-to-treat analysis showed no significant difference of the change of the GNS scores between HHD-treated (median, -8.5; 95% confidence interval, -14.2 to -4.0) and placebo-treated patients (median, -6.0; 95% confidence interval, -11.0 to 0.0) on day 7, and GNS scores remained similar in both treatment groups throughout the trial. At 3 months, slightly more HHD patients showed complete independence on the Barthel Index (28 versus 24), and fewer HHD than placebo patients had died (13 versus 17), but these differences were not statistically significant. HHD treatment was not associated with any specific adverse event. Mild HHD is safe but failed to demonstrate a significant beneficial effect over the pure rehydration regimen in patients with acute ischemic stroke.


Structural and Rotational Dynamics of Carbon Dioxide in 1-Alkyl-3-methylimidazolium Bis(trifluoromethylsulfonyl)imide Ionic Liquids: The Effect of Chain Length.
Ionic liquids (ILs) have been proposed as possible carbon dioxide (CO2) capture media; thus, it is useful to understand the dynamics of both the dissolved gas and its IL environment as well as how altering an IL affects these dynamics. With increasing alkyl chain length, it is well-established that ILs obtain a mesoscopic structural feature assigned to polar-apolar segregation, and the change in structure with chain length affects the dynamics. Here, the dynamics of CO2 in a series of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ILs, in which the alkyl group is ethyl, butyl, hexyl, or decyl, were investigated using ultrafast infrared spectroscopy by measuring the reorientation and spectral diffusion of carbon dioxide in the ILs. It was found that reorientation of the carbon dioxide occurs on three time scales, which correspond to two different time scales of restricted wobbling-in-a-cone motions and a long-time complete diffusive reorientation. Complete reorientation slows with increasing chain length but less than the increases in viscosity of the bulk liquids. Spectral diffusion, measured with two-dimensional IR spectroscopy, is caused by a combination of the liquids' structural fluctuations and reorientation of the CO2. The data were analyzed using a recent theory that takes into account both contributions to spectral diffusion and extracts the structural spectral diffusion. Different components of the structural fluctuations have distinct dependences on the alkyl chain length. All of the dynamics are fast compared to the complete orientational randomization of the bulk ILs, as measured with optical heterodyne-detected optical Kerr effect measurements. The results indicate a hierarchy of constraint releases in the liquids that give rise to increasingly slower dynamics.


Optimization of liposomal topotecan for use in treating neuroblastoma.
The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy.


Phase I study of hyperfractionated whole brain irradiation (HWBI) in the treatment of primary cerebral lymphoma.
The poor prognosis for primary cerebral lymphoma following conventional radiation therapy has generally been attributed to high local relapse rates despite initial local control. Hyperfractionated radiation therapy may improve the therapeutic ratio by allowing higher total radiation doses to be prescribed without exceeding the radiation tolerance of the central nervous system (CNS). Eight patients entered a study of hyperfractionated whole brain irradiation (HWBI) between October 1988 and May 1991. The prescribed dose was 64.8 Gy in 54 fractions over 5.5 weeks. All patients were followed clinically and with computed tomographic scanning. Additional investigations to discriminate between lymphoma recurrence and radionecrosis included magnetic resonance imaging (MRI), thallium-201 single photon emission computed tomography (SPECT), and immunocytological examination of the cerebrospinal fluid (CSF). A complete remission as seen on CT scan was achieved in all cases. The overall median survival was 102 weeks. Six patients initially deteriorated neurologically without evidence of tumour recurrence. Three patients have died without evidence of recurrence at 18, 62 and 128 weeks. As of 31 May 1992, three patients remain alive, two with radiation brain injury at 147 and 184 weeks. Treatment toxicity prompted study closure in September 1991. The hyperfractionation regimen used is reported by others to be free from significant morbidity. The pathogenesis of cerebral lymphomas (diffuse disease, angiotropism, subependymal involvement) may adversely affect CNS radiation tolerance.


Stem cell dynamics in mouse hair follicles: a story from cell division counting and single cell lineage tracing.
Understanding tissue stem cells behavior is a prerequisite for elucidating the mechanisms that govern their self-renewal and differentiation. Previously, we provided single cell lineage tracing and proliferation history data (based on H2B-GFP label dilution over time) in mouse hair follicles. We proposed a population deterministic model with symmetric stem cell fate decisions throughout life. Here we provide data suggesting that in hair follicle stem cells the self-renewing divisions within the niche (bulge) are symmetric with respect to localization of daughter cells near the basement membrane, an important niche component. In contrast, when cells migrate from the niche to the differentiating zone where they become short-lived progenitors, their daughter cells can orient themselves asymmetrically relative to the basement membrane. Furthermore, we document the dynamic re-localization of cells within the bulge to accommodate the hair follicle morphological changes through hair cycle. In addition, we provide a method to compute the change in number of cells generated by division from H2B-GFP pulse-chase data, and to estimate the minimum cell loss encountered when the fold change can be experimentally determined. We computed a minimum of 42% of bulge cell loss during one hair cycle, a massive rate of loss previously unrecognized. Finally, we showed that a multipotent population of cells found at the junction zone between hair follicle and epidermis, known to express Lrig1, cycle more rapidly than some other hair follicle compartments.


Herpesvirus-associated acute urticaria: an age matched case-control study.
Acute and recurrent acute urticaria are often associated with multiple factors including infections and recent data suggest a role for herpesviruses. To test the null hypothesis, that is, there is no association of herpesvirus infections with urticaria. Thirty-seven patients between one month and 15 years of age were age matched to 37 controls who were healthy or had mild acute respiratory infections but without urticaria. Patients and controls were followed for 1 to 6 years. Diagnostic studies included DNA detection by real-time PCR for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6). Tests for other infections included adenovirus, parvovirus B 19, respiratory syncytial virus, influenza A, Group A streptococci, rotavirus, and parasites. Specific infections were diagnosed in 26 of 37 cases and among 9 of 37 control children (P=0.0002). Single or concomitant herpesvirus infections occurred in 24 cases and in 4 controls (65% vs 11 %, p=0.0003). Cases had 10 HHV-6 infections, 8 CMV infections, 5 EBV infections, and 4 HSV-1 infections. Herpesvirus infections are associated with acute or recurrent acute urticaria.


Infants with bronchopulmonary dysplasia. Growth pattern and neurologic and developmental outcome.
We evaluate neurodevelopmental and growth outcomes of low-birth-weight infants with bronchopulmonary dysplasia (BPD). Twenty-six cases of BPD (group A) were diagnosed from 244 neonatal survivors with a low birth weight (less than or equal to 1,500 g) born in 1975, 1976, and 1977. During the same period, BPD did not develop in eight infants with a comparable neonatal course (group B) (received oxygen therapy greater than or equal to 21 days). Twenty-five infants who received O2 therapy five or fewer days had a mild clinical course and were considered controls (group C). The BPD infants suffered more asphyxia, respiratory distress syndrome, acidosis, and longer parenteral alimentation and hospitalization than group C infants. Compared with groups B and C, the BPD infants had more respiratory morbidities at 4 and 12 months (P less than .005) and more severe neurodevelopmental sequelae at 2 years.


[Preliminary analysis of retinal gene expression profile of diabetic rat].
Establishing the retinal gene expression profiles of non-diabetic rat and diabetic rat and comparing the profiles in order to analyze the possible genes related with diabetic retinopathy. The whole retinal transcriptional fragments of non-diabetic rat and 8-week diabetic rat were obtained by restriction fragments differential display-PCR (RFDD-PCR). Bioinformatic analysis of retinal gene expression was performed using soft wares, including Fragment Analysis. After comparison of the expression profiles, the related gene fragments of diabetic retinopathy were initially selected as the target gene of further approach. A total of 3639 significant fragments were obtained. By means of more than 3-fold contrast of fluorescent intensity as the differential expression standard, the authors got 840 differential fragments, accounting for 23.08% of the expressed numbers and including 5 visual related genes, 13 excitatory neruotransmitter genes and 3 inhibitory neurotransmitter genes. At the 8th week, the expression of Rhodopsin kinase, beta-arrestin, Phosducinìrod photoreceptor cGMP-gated channel and Rpe65 as well as iGlu R1-4 were down-regulated. mGluRs and GABA-Rs were all up-regulated, whereas the expression of GlyR was unchanged. These results prompt again that the changes in retinal nervous layer of rat have occurred at an early stage of diabetes. The genes expression pattern of visual related genes and excitatory and inhibitory neurotransmitters in rat diabetic retina have been involved in neuro-dysfunctions of diabetic retina.


[Two cases of stage IV gastric cancer responding to chemotherapy with S-1 or UFT].
We report patients with advanced Stage IV gastric cancer responding to chemotherapy with S-1 or UFT. Case 1: The patient was a 59-year-old man with Stage IV gastric cancer because of CY 1. After surgery, chemotherapy with S-1 (100 mg/body/day) was performed for one year and 11 months. At present, 5 years and 5 months after surgery, this patient shows no signs of tumor recurrence. Case 2: The patient was a 68-year-old woman with Stage IV gastric cancer because of P 1. She was treated with 200 mg/day of UFT for one year and 9 months. At present, 5 years after surgery, she shows no signs of tumor recurrence. We considered that the longterm survival of such patients is attributable to chemotherapy with S-1 or UFT. The OPRT activity of the two cases was high, so chemotherapy with S-1 or UFT was thought to be effective for them.


Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.
The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.


Altered cytoskeleton in smooth muscle of aganglionic bowel.
Intestinal motility is under the control of smooth muscle cells, enteric plexus, and hormonal factors. In Hirschsprung disease (HD), the aganglionic colon remains spastic or tonically enhanced and unable to relax. The smooth muscle cell's cytoskeleton consists of proteins or structures whose primary function is to link or connect protein filaments to each other or to the anchoring sites. Dystrophin is a subsarcolemmal protein with a double adhesion property, one between the membrane elements and the contractile filaments of the cytoskeleton and the other between the cytoskeletal proteins and the extracellular matrix. Desmin and vinculin are functionally related proteins that are present in the membrane-associated dense bodies in the sarcolemma of the smooth muscle cells. To examine the distribution of the cytoskeletal proteins in the smooth muscle of the aganglionic bowel. Bowel specimens from ganglionic and aganglionic sections of the colon were collected at the time of pull-through surgery from 8 patients with HD. Colon specimens collected from 4 patients at the time of bladder augmentation acted as controls. Anti-dystrophin, anti-desmin, and anti-vinculin antibodies were used for fluorescein immunostaining using confocal laser scanning microscopy. Moderate to strong dystrophin immunoreactivity was observed at the periphery of smooth muscle fibers in normal bowel and ganglionic bowel from patients with HD, whereas dystrophin immunoreactivity was either absent or weak in the smooth muscle of aganglionic colon. Moderate to strong cytoplasmic immunostaining for vinculin and desmin was seen in the smooth muscle of normal bowel and ganglionic bowel from patients with HD, whereas vinculin and desmin staining in the aganglionic colon was absent or weak. This study demonstrates that the cytoskeletal proteins are abundant in the smooth muscle of normal bowel, but are absent or markedly reduced in the aganglionic bowel of HD. As cytoskeletal proteins are required for the coordinated contraction of muscle cells, their absence may be responsible for the motility dysfunction in the aganglionic segment.


Creatinine index and transthyretin as additive predictors of mortality in haemodialysis patients.
Malnutrition and inflammation are recognized as important predictors of poor clinical outcome in haemodialysis (HD). This study was designed to estimate the relative contribution of known biological markers of inflammation, malnutrition and muscle mass in the prognosis of HD patients. A total of 187 HD patients (100 women, 87 men, median age 66.7 years [22.3-93.5]) were followed-up yearly for 5 years. At baseline, pre-dialysis values of C-reactive protein (CRP), albumin, transthyretin, total HDL- and LDL-cholesterol and triacylglycerol were determined. Estimation of creatinine index (CI) as muscle mass marker was determined by creatinine kinetic modelling using pre- and post-dialysis creatinine values. During the follow-up period, 89 deaths (53 from cardiovascular causes) were observed. After adjustment for age, gender, dialysis vintage, smoking, diabetes mellitus and hypertension, the highest tertile of CRP and lowest tertile of transthyretin and CI were significantly associated with all-cause mortality (relative risk (RR)=1.98 [1.12-3.47], 2.58 [1.48-4.50], 2.71 [1.42-5.19], respectively). In addition, low CI had an additive value to low levels of transthyretin. In contrast, high cholesterol (RR=0.47 [0.27-0.83], P=0.0091) and vitamin E concentrations (RR=0.46 [0.26-0.80], P= 0.006) showed a protective trend for all-cause mortality. In the multivariate analysis, transthyretin appeared as the most predictive biological marker of non-CV mortality (RR=3.78 [1.30-10.96], P=0.014), and CI of CV mortality (RR=2.61 [1.06-6.46], P=0.038), respectively. Discussion. These results confirm that uraemic malnutrition constitutes an important risk factor for mortality in HD. Beyond transthyretin, CI seems to be an additional marker routinely available and monthly determined in HD patients.


Preservation of functioning human thyroid organoids in the scid mouse: II. Biased use of intrathyroidal T cell receptor V genes.
The severe combined immunodeficiency (scid) mouse, which lacks functional B cells and T cells, has proven a useful model for exploring the survival of transplanted human lymphocytes and thyrocytes. In order to further characterize T cell infiltrates in reconstituted sc human thyroid organoids, we examined for the presence of 18 human T cell receptor (hTcR) V alpha and 21 hTcR V beta gene families using polymerase chain reaction (PCR) analysis. Human TcR V gene activity was confirmed by Southern blot analysis of the PCR fragments from all but one of the thyroid organoids, confirming the continued survival of human T cells within the thyroid organoids. However, only 3.5 out of 18 V alpha and 5.9 out of 21 V beta gene families were detected in these human thyroid organoids indicating a marked bias in T cell survival. Sequencing of the V-D-J regions of the amplified TcR fragments showed that approximately 60% of the sequences were representative of clonally expanded T cells. Hence, these passenger T cells exhibited highly biased use of particular TcR V gene families similar to that observed previously in thyroid tissue and intrathyroidal T cell cultures. Furthermore, variations in the V-D-J regions of sequences from similar V gene families indicated that the V gene region was important in T cell selection rather than the CD3 region.


Complex repair of the thoracic aorta with the E-vita open prosthesis.
The treatment of complex aortic pathologies of the thoracic aorta remains a challenging issue in aortic surgery. The'' Frozen elephant trunk'' technique represents a recent development of the classic elephant trunk technique combining endovascular with conventional surgery. Between January 2007 and January 2008, 24 patients were operated on for complex pathologies of the thoracic aorta using the frozen elephant trunk technique with the E-vita open prosthesis. There were 21 male (87.5%) and the mean age was 62.4+/-9.9 years. The majority of patients (N=11) presented type A chronic dissection, 6 (25%) patients had chronic aneurysm of distal aortic arch and 5 (20.8%) type B aortic dissection associated with ascending aorta/aortic arch aneurysm. There were 2 cases of acute aortic dissection (1 type A and 1 type B). Nine patients (37.5%) underwent previous cardiovascular operations. The overall in-hospital mortality was 4.2% (1 patient). None patient developed postoperative stroke and 1 patient suffered from spinal cord ischemia (1 paraparesis, 1 paraplegia). There were 2 cases (8.3%) of renal failure (dialysis), 2 patients (8.3%) had pulmonary complications and 2 patients (8.3%) needed rethoracotomy for bleeding. Five patients (21.7%) required extension of the descending thoracic aorta repair with endovascular treatment for persistent perfusion of dilated false lumen. The Frozen Elephant trunk technique with the new E-vita open prosthesis combines surgical and interventional technologies and it represents a feasible and efficient option in the treatment of complex aortic pathologies. However long term follow up is required.


Spectral properties and classical decays in quantum open systems.
We study the relationship between the spectral properties of diffusive open quantum maps and the classical spectrum of Ruelle-Pollicott resonances. The leading resonances determine the asymptotic time regime for several quantities of interest--the linear entropy, the Loschmidt echo, and the correlations of the initial state. A numerical method that allows an efficient calculation of the leading spectrum is developed using a truncated basis adapted to the dynamics.


Changes in the socio-demographics, risk behaviors, clinical and immunological profile of a cohort of the Puerto Rican population living with HIV: an update of the Retrovirus Research Center (1992-2008).
We describe the changes in the socio demographic, risk behavior, immunological and clinical trends profiles of a cohort HIV patients followed at the Retrovirus Research Center, at baseline and study periods interval by periods intervals: 1992-1997, 1998-2003, and 2004-2008. This is a cross-sectional study of a longitudinal cohort comprised of 4016 HIV/AIDS patients admitted to the RRC since January 1992. Data collected include socio-demographic variables; risk related variables; psychological variables; and clinical variable by periods of study. RESULTS. The most common AIDS defining conditions observed in patients were: Pneumocistis Cariini pneumonia (PCP), toxoplasmosis of brain (TP), and wasting syndrome (WS). Chronic conditions are more prevalent than AIDS-defining conditions in the cohort of patients. Understanding the socio demographic, HIV risk behavior profile; and the immunological and clinical trends among HIV patients is critical for redesigning services and programs oriented in HIV patient care.


Foetus or child? Abortion discourse and attributions of humanness.
Due to moral, religious, and cultural sensibilities, the topic of abortion still gives rise to controversy. The ongoing public debate has become visibly polarized with the usage of the pro-life versus pro-choice rhetoric. The aim of the current research was to investigate whether the language used in abortion discourse can affect people's attitudes by changing their attributions of humanity to unborn. Across three experimental studies we showed that participants who read about a 'foetus', compared to a 'child' declared higher support for elective abortion (Study 1; N = 108), this effect can be explained by greater humanness, as reflected in human nature traits, attributed to the child (vs. the foetus; Study 2; N = 121). The effect is mediated uniquely by attribution of human nature, but not by human uniqueness traits (Study 3; N = 120). These findings serve as a starting point for discussion of the role of language in shaping attitudes on abortion and other morally ambiguous issues.


Use of hormonal contraceptives and HIV acquisition in women: a systematic review of the epidemiological evidence.
Whether or not the use of hormonal contraception affects risk of HIV acquisition is an important question for public health. We did a systematic review, searching PubMed and Embase, aiming to explore the possibility of an association between various forms of hormonal contraception and risk of HIV acquisition. We identified 20 relevant prospective studies, eight of which met our minimum quality criteria. Of these eight, all reported findings for progestin-only injectables, and seven also reported findings for oral contraceptive pills. Most of the studies that assessed the use of oral contraceptive pills showed no significant association with HIV acquisition. None of the three studies that assessed the use of injectable norethisterone enanthate showed a significant association with HIV acquisition. Studies that assessed the use of depot-medroxyprogesterone acetate (DMPA) or non-specified injectable contraceptives had heterogeneous methods and mixed results, with some investigators noting a 1·5-2·2 times increased risk of HIV acquisition, and others reporting no association. Thus, some, but not all, observational data raise concern about a potential association between use of DMPA and risk of HIV acquisition. More definitive evidence for the existence and size of any potential effect could inform appropriate counselling and policy responses in countries with varied profiles of HIV risk, maternal mortality, and access to contraceptive services.


Increased nitrite reductase activity of fetal versus adult ovine hemoglobin.
Growing evidence indicates that nitrite, NO2-, serves as a circulating reservoir of nitric oxide (NO) bioactivity that is activated during physiological and pathological hypoxia. One of the intravascular mechanisms for nitrite conversion to NO is a chemical nitrite reductase activity of deoxyhemoglobin. The rate of NO production from this reaction is increased when hemoglobin is in the R conformation. Because the mammalian fetus exists in a low-oxygen environment compared with the adult and is exposed to episodes of severe ischemia during the normal birthing process, and because fetal hemoglobin assumes the R conformation more readily than adult hemoglobin, we hypothesized that nitrite reduction to NO may be enhanced in the fetal circulation. We found that the reaction was faster for fetal than maternal hemoglobin or blood and that the reactions were fastest at 50-80% oxygen saturation, consistent with an R-state catalysis that is predominant for fetal hemoglobin. Nitrite concentrations were similar in blood taken from chronically instrumented normoxic ewes and their fetuses but were elevated in response to chronic hypoxia. The findings suggest an augmented nitrite reductase activity of fetal hemoglobin and that the production of nitrite may participate in the regulation of vascular NO homeostasis in the fetus.


Associations between connexin37 gene polymorphism and markers of subclinical atherosclerosis: the Cardiovascular Risk in Young Finns study.
Connexin37 (cx37) C1019T polymorphism has been shown to associate with coronary artery disease in different populations. We investigated whether this polymorphism associates with carotid artery intima-media thickness (IMT), carotid artery compliance (CAC) and brachial artery flow mediated dilatation (FMD) - i.e., early ultrasound markers of subclinical atherosclerosis - in a clinically healthy population of young Finnish adults. 1440 individuals from the Cardiovascular Risk in Young Finns study were genotyped and studied using cardiovascular risk factor and ultrasound data obtained in 2001. In linear regression models, no significant association between the cx37 polymorphism and carotid IMT, CAC or brachial artery FMD (ANOVA, p=0.159, 0.151 and 0.547), respectively, was found in the whole population or in women and men separately. The connexin37 C1019T polymorphism is not related with markers of subclinical atherosclerosis in young adults.


Epidermal and urethroid penile cyst.
The authors describe a 74-year-old man who presented with a 2-cm nodule on the ventral face of the penis, showing histologically a cyst lined by both epidermal and urethroid epithelium. The authors discuss the various histological forms of raphe median cysts of the penis.


Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer.
Understanding the molecular mechanisms involved in tumorigenesis and their influence on clinical outcome is providing specific molecular markers for targeted therapy. Activation of tyrosine kinase receptors from the human epidermal growth factor receptor family (EGFR, HER2, HER3, HER4) and the insulin-like growth factor receptor I (IGF-IR) plays a key role in the initiation and progression of breast cancer. HER2 overexpression is a validated therapeutic target, as shown by the clinical efficacy of trastuzumab and lapatinib. However, only 25-30% of patients with HER2-overexpressing tumors respond to single-agent trastuzumab or lapatinib, and resistance develops even in responding patients. Therefore, to optimize therapeutic efficacy, it is urgent to elucidate the complex network of signaling pathways that develop in breast cancer cells. Signaling interactions have been reported between ErbB/HER family members and IGF-IR. As increased IGF-IR signaling has been implicated in trastuzumab resistance, agents targeting HER2, and IGF-IR could be potential therapeutic tools in breast cancers that develop resistance to HER2-directed therapy.


Quantitative analysis of varying profiles of hypoxia in relation to functional vessels in different human glioma xenograft lines.
Tissue oxygenation influences the radiation response of tumors. To further investigate the underlying mechanisms of tumor hypoxia, the spatial distribution of hypoxic cells in relation to the vasculature was studied. In a panel of three human glioma xenograft lines (E2, E102, E106) with different growth characteristics, tumor line-specific patterns of hypoxia (pimonidazole) and (functional) vasculature (Hoechst 33342) were observed. Two of the three glioma lines showed a more homogeneous distribution of perfused vessels (E102 and E106) than the third glioma line (E2). Although all tumors showed hypoxia, the distance at which the steepest part of the gradient of the hypoxia marker was found varied significantly among the different glioma lines. The faster-growing E102 tumors had the longest distance (>300 microm). These results indicate that tumor line-specific factors, rather than vascular geometry alone, may determine the oxygenation status of a tumor. As a consequence, vascular density cannot be used as a surrogate parameter for tumor hypoxia when comparing different tumors. Additional hypoxia and perfusion markers will further improve our understanding of changes in tumor physiology at the microregional level explaining the relationship between the low oxygen levels and the response of tumors to treatment.


Antiepileptic drugs in migraine prophylaxis: state of the art.
Antiepileptic drugs have proven their efficacy in the prophylactic treatment of migraine. Our study comprises a clinical trial that examines the efficacy of gabapentin and topiramate and a description of the pharmacologic characteristics and the efficacy of tiagabine, lamotrigine, levetiracetam and zonisamide. Antiepileptic drugs have multiple modes of action which can explain their efficacy in reducing neuronal excitability which is proven in epilepsy and postulated in migraine. The relationship between epilepsy and migraine has, in fact, been much debated but never convincingly proven. Antiepileptic drugs could be useful in migraine prophylaxis as some of these have determined a reduction in the monthly frequency and intensity of crises in subjects suffering from migraine with and without aura. These are the aims that have been proposed by the U.S. Headache Consortium Evidence-Based Guidelines. Further double-blind placebo-controlled studies are necessary in order to assess their safety and efficacy.


Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure.
The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n = 4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg), increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min) and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome.Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02) and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14) coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems.


Expression of Estrogen Receptor Alpha in Malignant Melanoma.
Features of malignant melanoma (MM) vary in the different geographic regions of the world. This may be attributable to environmental, ethnic, and genetic factors. The aim of this study was to determine the expression of estrogen receptor alpha (ER-α) in MM in Isfahan, Iran. This study was planned as a descriptive, analytical, cross-sectional investigation. During this study, paraffin-embedded tissue blocks of patients with a histopathologic diagnosis of MM was studied for ER-α using immunohistochemistry (IHC). In this study, 38 patients (female/male; 20/18) with a definite diagnosis of malignant cutaneous melanoma and mean age of 52.4 ± 11.2 years were investigated. Using envision IHC staining, there were not any cases with ER-α expression. In confirmation to the most previous studies, expression of ER-α was negative in MM. It is recommended to investigate the expression of estrogen receptor beta and other markers in MM.


Ticks (Acari: Ixodidae) infesting cattle and African buffaloes in the Tsavo conservation area, Kenya.
Several ixodid tick species are shared between domestic cattle and African buffaloes (Syncerus caffer). So too, are a number of tick-borne diseases. The aim of the study was to compare the species composition of ticks that infest cattle and buffaloes utilising the same habitat within the Tsavo Conservation Area, Kenya. To this end, 25 cattle and 62 buffaloes were each opportunistically sampled for ticks on a single occasion in February 2010. Eight species, namely Amblyomma gemma, Amblyomma lepidum, Hyalomma albiparmatum, Hyalomma rufipes, Hyalomma truncatum, Rhipicephalus evertsi evertsi, Rhipicephalus pravus and Rhipicephalus pulchellus infested both cattle and buffaloes. Three species, Rhipicephalus (Boophilus) sp., Rhipicephalus kochi, and Rhipicephalus muehlensi were collected only from cattle, and three species, Hyalomma impeltatum, Rhipicephalus humeralis and Rhipicephalus praetextatus were present only on buffaloes. The attachment sites of the various tick species were also recorded. New locality records for H. impeltatum and H. truncatum and the first confirmed locality record for Rhipicephalus praetextatus sensu stricto in Kenya were documented.


[The basic study of autologous peripheral stem cell transplantation--useful application of KLI and G-CSF].
There has been increasing interest in autologous peripheral stem cell transplantation (APSCT) in the treatment of malignant disease because it is a convenient method and may have a lower risk of tumor cell contamination than autologous bone marrow transplantation (ABMT). Recently, it is reported that the number of peripheral blood stem cells increase during recovery phase of hemopoiesis after chemotherapy, and further increase is reported on the case of treatment with G-CSF. But influences of G-CSF to the residual malignant cells is still unknown. In this report, we have used clonal cell culture and kappa-lambda imaging (KLI) analysis to trace the level of CFU-GM, BFU-E, and malignant B-cell population (mBp) in peripheral blood before and after treatment with rhG-CSF. The peak level of CFU-GM in peripheral blood was a 2-fold increased when rhG-CSF was administered, and this peak appeared 5-7 days earlier than that in the case without rhG-CSF. MBp was detected in bone marrow, however, no mBp was detected before and after treatment with rhG-CSF in peripheral blood. These findings suggest that APSCT is acceptable for this patient in case of minimal bone marrow involvement. And KLI analysis might be an effective method for detecting residual malignant cells in bone marrow and peripheral blood.


Pancreas-specific genes: structure and expression.
Via recombinant DNA technology the mRNA sequence of pancreatic amylase has been cloned and its nucleotide sequence has been determined. The cloned sequence represents 96% of the total length of amylase mRNA; missing are an estimated 75 +/- 30 nucleotides from the 5' end. The amino acid sequence of rat pancreatic amylase was deduced solely from the nucleotide sequence of the mRNA. Unlike other eukaryotic mRNAs, the amylase mRNA has short 5' and 5' untranslated regions, suggesting that long untranslated regions of eukaryotic mRNAs either do not contain extensive functional sequences or that these sequences are incorporated within the amino acid coding region of amylase mRNA. The cloned amylase mRNA sequence was radiolabeled and used as a probe for in situ hybridization. These experiments demonstrate that amylase mRNA is present in all acinar cells but not in other pancreatic cell types. Using the cloned amylase mRNA sequences as a hybridization probe, three nonoverlapping genomic DNA fragments containing amylase gene sequences were isolated. From the similar sequence organization of the three amylase genes visualized by DNA heteroduplex mapping, a consensus structure of a rat amylase gene is proposed. It is an extended gene structure 10 kilobase pairs in length containing the 1547 base pairs of the cloned mRNA coding sequence interrupted by seven intervening sequences ranging from 400-2000 base pairs long. Thus, in nuclear DNA the amylase mRNA coding sequence is disrupted into at least eight segments from 150-300 base pairs long.


Gray-scale ultrasonic properties of the normal and inflamed pancreas.
Eighty-seven examinations of the pancreas in 52 patients with acute or chronic pancreatitis and 31 examinations in 31 normal subjects were reviewed. Demonstration of the portal and splenic veins served as a guidepost to the pancreas. The normal pancreas was indistinguishable from the surrounding tissues in a substantial minority of examinations, and the ultrasonic characteristics of the normal pancreas were quite variable. Acute pancreatitis was found to be characterized by swelling, loss of internal echoes, and loss of distinction between the pancreas and splenic vein. In 50% of patients with chronic inactive pancreatitis, the pancreas could not be identified. Ultrasound should precede endoscopic retrograde cholangiopancreatography whenever a pseudocyst might be present.


The Influence of the Solar Coronal Radiation on Coronal Plasma Structures, I: Determination of the Incident Coronal Radiation.
Coronal structures receive radiation not only from the solar disc, but also from the corona. This height-dependent incident radiation plays a crucial role in the excitation and the ionisation of the illuminated plasma. The aim of this article is to present a method for computing the detailed incident radiation coming from the solar corona, which is perceived at a point located at an arbitrary height. The coronal radiation is calculated by integrating the radiation received at a point in the corona over all of the corona visible from this point. The emission from the corona at all wavelengths of interest is computed using atomic data provided by CHIANTI. We obtain the spectrum illuminating points located at varying heights in the corona at wavelengths between 100 and 912 Å when photons can ionise H or He atoms and ions in their ground states. As expected, individual spectral lines will contribute most at the height within the corona where the local temperature is closest to their formation temperature. As there are many spectral lines produced by many ions, the coronal intensity cannot be assumed to vary in the same way at all wavelengths and so must be calculated for each separate height that is to be considered. This code can be used to compute the spectrum from the corona illuminating a point at any given height above the solar surface. This brings a necessary improvement to models where an accurate determination of the excitation and ionisation states of coronal plasma structures is crucial.


The twenty-year story of a plant-based vaccine against hepatitis B: stagnation or promising prospects?
Hepatitis B persists as a common human disease despite effective vaccines having been employed for almost 30 years. Plants were considered as alternative sources of vaccines, to be mainly orally administered. Despite 20-year attempts, no real anti-HBV plant-based vaccine has been developed. Immunization trials, based on ingestion of raw plant tissue and conjugated with injection or exclusively oral administration of lyophilized tissue, were either impractical or insufficient due to oral tolerance acquisition. Plant-produced purified HBV antigens were highly immunogenic when injected, but their yields were initially insufficient for practical purposes. However, knowledge and technology have progressed, hence new plant-derived anti-HBV vaccines can be proposed today. All HBV antigens can be efficiently produced in stable or transient expression systems. Processing of injection vaccines has been developed and needs only to be successfully completed. Purified antigens can be used for injection in an equivalent manner to the present commercial vaccines. Although oral vaccines require improvement, plant tissue, lyophilized or extracted and converted into tablets, etc., may serve as a boosting vaccine. Preliminary data indicate also that both vaccines can be combined in an effective parenteral-oral immunization procedure. A partial substitution of injection vaccines with oral formulations still offers good prospects for economically viable and efficacious anti-HBV plant-based vaccines.


Metal-Free Transamidation of Secondary Amides via Selective N-C Cleavage under Mild Conditions.
Nonplanar, electronically destabilized amides have emerged as powerful intermediates in organic synthesis. We report a highly selective method for transamidation of common secondary amides under mild, metal-free conditions that relies on transient N-selective functionalization to weaken amidic resonance. The combination of rational modification of the amide bond with nucleophilic addition mechanism, and the thermodynamic collapse of the resultant tetrahedral intermediate constitutes a two-step procedure to accomplish a challenging transamidation of secondary amides under mild conditions.


Finite Lambertian source analysis of concentrators: application to solar reflectors.
The maximum power cast on a collector from a source of finite angular extension by a concentrator of fixed position occurs when the collector sees the concentrator as a Lambertian source. Concentrators not fully meeting this requirement are evaluated using a parameter called the shape quality factor. Lambertian concentrators can be obtained with mirrors but not with lenses of finite n. In many cases they are not ideal, and some rays are cast outside the collector leading to an intercept factor below unity. Among those mirrors with the highest intercept factor, shape inaccuracies reduce this parameter and the shape quality factor to the extent which is analyzed. Rules for effective cost design are given leading to the conclusion that Lambertian concentrators must be used if the collector cost is high, while ideal concentrators should be used if the concentrator cost is high.


SUCCESSFUL FATHERS SIRE SUCCESSFUL SONS.
The theory of sexual selection holds a central role in evolutionary biology. Its key assumption is the heritability of traits associated with reproductive success. Strong indirect evidence supporting this assumption comes from the numerous studies that have identified heritable traits associated with mating success. However, there remain only a handful of studies that have attempted to demonstrate directly that successful fathers have successful sons. We present the results of an experimental study of the mating success and phenotype of male field crickets Gryllus bimaculatus (Orthoptera: Gryllidae) and their offspring. These reveal that sons of successful males obtain significantly more copulations than sons of unsuccessful males. There was no difference in body size of sons of either group, but sons of successful males had significantly longer development times. This may represent a naturally selected cost to traits associated with success that could balance their sexually selected advantages.


Radiation doses potentially received on-board aeroplanes during recent solar particle events.
Because the doses received on-board aeroplanes are now monitored to fulfil legal requirements in some countries, including the European Community, the models to calculate doses received during solar events have left their purely academic status to become a part of operational systems as well. The present work considers parameters of importance to determine the doses received during solar events: spectral characteristics of the solar particles and anisotropy of primary particles and their variations in the course of the Ground Level Enhancement (GLE). Precise determination of both, using all the information available from the worldwide neutron monitor network, being a long process, simpler methods are proposed to calculate rigidity spectrum exponent and to correct the models for anisotropy. A recent GLE of large intensity, having occurred on 20 January 2005, is used both as an example of an important event and because the necessary data were collected within a few days, showing that the above methods, in addition to their own interest, have also an operational potential.


Habitual intake of fruit juice predicts central blood pressure.
Despite a common perception that fruit juice is healthy, fruit juice contains high amounts of naturally occurring sugar without the fibre content of the whole fruit. Frequent fruit juice consumption may therefore contribute to excessive sugar consumption typical of the Western society. Although excess sugar intake is associated with high blood pressure (BP), the association between habitual fruit juice consumption and BP is unclear. The present study investigated the association of fruit juice consumption with brachial and central (aortic) BP in 160 community dwelling adults. Habitual fruit juice consumption was measured using a 12 month dietary recall questionnaire. On the same day, brachial BP was measured and central (aortic) BP was estimated through radial artery applanation. Frequency of fruit juice consumption was classified as rare, occasional or daily. Those who consumed fruit juice daily, versus rarely or occasionally, had significantly higher central systolic BP (F (2, 134) = 6.09, p <0.01), central pulse pressure (F (2, 134) = 4.16, p <0.05), central augmentation pressure (F (2, 134) = 5.98, p <0.01) and central augmentation index (F (2, 134) = 3.29, p <0.05) as well as lower pulse pressure amplification (F (2, 134) = 4.36, p <0.05). There were no differences in brachial BP. Central systolic BP was 3-4 mmHg higher for those who consumed fruit juice daily rather than rarely or occasionally. In conclusion, more frequent fruit juice consumption was associated with higher central BPs.


Professional Identity Formation and the Clinician-Scientist: A Paradigm for a Clinical Career Combining Two Distinct Disciplines.
The clinician-scientist role is critical to the future of health care, and in 2010, the Carnegie Report on Educating Physicians focused attention on the professional identity of practicing clinicians. Although limited in number, published studies on the topic suggest that professional identity is likely a critical factor that determines career sustainability. In contrast to clinicians with a singular focus on clinical practice, clinician-scientists combine two major disciplines, clinical medicine and scientific research, to bridge discovery and clinical care. Despite its importance to advancing medical practice, the clinician-scientist career faced a variety of threats, which have been identified recently by the 2014 National Institutes of Health Physician Scientist Workforce. Yet, professional identity development in this career pathway is poorly understood. This Perspective focuses on the challenges to the clinician-scientist's professional identity and its development. First, the authors identify the particular challenges that arise from the different cultures of clinical care and science and the implications for clinician-scientist professional identity formation. Next, the authors synthesize insights about professional identity development within a dual-discipline career and apply their analysis to a discussion about the implications for clinician-scientist identity formation. Although not purposely developed to address identity formation, the authors highlight those elements within clinician-scientist training and career development programs that may implicitly support identity development. Finally, the authors highlight a need to identify empirically the elements that compose and determine clinician-scientist professional identity and the processes that shape its formation and sustainability.


An examination of social and environmental determinants of secondhand smoke exposure among non-smoking adolescents.
Adolescents are at increased risk of secondhand smoke exposure (SHS) due to the limited control that they have over social and physical environments. Yet, knowledge regarding determinants of SHS among non-smoking adolescents is limited. This study identifies social and environmental factors associated with SHS among non-smoking adolescents. To be included, parents and adolescents (aged 11-17 years) of the Adolescents, Place, and Behavior Study had to have completed surveys between March 2019 and May 2020. Adolescents had to have not reported smoking within the past 30 days and provided a saliva sample assayed for cotinine (≤3 ng/mL). A series of stepwise linear regression models were fit to the data to identify social and environmental determinants of SHS, using log-transformed salivary cotinine. Of the 105 adolescent and parent dyads included, 90.3% were African American, 26.9% of parents reported smoking, 33.3% resided in multi-unit housing, and 67.7% lived in homes where smoking was not permitted. Significant associations were found between parent tobacco use (β=2.56, SE=0.98, p=0.0082) and residing in multi-unit housing (β=1.72, SE=0.86, p=0.0460) with increased log-transformed cotinine levels among non-smoking adolescents. Adolescent age, gender, and race/ ethnicity, parental education, peer tobacco use, the number of adults and children in the home, average number of days of self-reported SHS within public spaces outside of the home, and home smoking policies were not significantly associated with cotinine. Results emphasize the importance of reducing secondhand smoke exposure by reducing parental smoking and altering exposures within social and home environments. Parental tobacco use and residential setting should be considered when developing interventions to reduce secondhand smoke exposure among non-smoking adolescents.


Neratinib for the Treatment of Early-Stage HER2-Positive Breast Cancer.
The treatment of breast cancer has been revolutionized by the development of HER2-targeted treatments for patients who are HER2 positive. The HER2 protein is present at high levels in about 30% of breast cancer patients. These high levels are associated with a greater chance of metastasis, relapse, and decreased survival. The current standard of care for early-stage HER2-positive patients includes treatment with 1 year of trastuzumab therapy. Although trastuzumab has improved outcomes, there is still a 20% chance for tumor recurrence and a 16% chance of death. Neratinib was developed to give patients with early-stage HER2-positive breast cancer an option to increase the disease-free survival rate. The 5-year invasive disease-free survival rate was 90.2% (95% confidence interval = 88.3-91.8) in the neratinib group and 87.7% (95% confidence interval = 85.7-89.4) in the placebo group.


Cis-aconitic anhydride ethyl ester and phenolic compounds from the seeds of Alisma orientale.
From the seeds of Alisma orientale, cis-aconitic anhydride ethyl ester and cis-2,4,5-trihydroxycinnamic acid were isolated, together with nine known phenolic compounds and a megastigmane sesquiterpene. All compounds are reported for the first time from Alisma species.


Pro- and anti-inflammatory cytokines in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the accumulation of inflammatory cells into the synovium and the destruction of joints. Cytokines are important regulators of the synovial inflammation. Some cytokines, such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1, function by promoting inflammatory responses and by inducing cartilage degradation. Other cytokines, such as IL-4, IL-10 and IL-13, function mainly as anti-inflammatory molecules. Although anti-inflammatory cytokines are present in rheumatoid joints, in progressive RA their levels obviously are too low to neutralize the deleterious effects of proinflammatory cytokines. Inhibiting the action of proinflammatory cytokines by using specific cytokine inhibitors or anti-inflammatory cytokines is the basis for new therapies currently tested in patients with RA. Promising results on the use of neutralizing anti-TNF-alpha monoclonal antibodies in the treatment of RA have been reported. The results from a trial using recombinant IL-10 in the treatment of patients with RA are available in the near future and will be important in determining the therapeutic potential of this cytokine.


Molecular Insights Into SARS COV-2 Interaction With Cardiovascular Disease: Role of RAAS and MAPK Signaling.
In December 2019, reports of viral pneumonia came out of Wuhan city in Hubei province in China. In early 2020, the causative agent was identified as a novel coronavirus (CoV) sharing some sequence similarity with SARS-CoV that caused the severe acute respiratory syndrome outbreak in 2002. The new virus, named SARS-CoV-2, is highly contagious and spread rapidly across the globe causing a pandemic of what became known as coronavirus infectious disease 2019 (COVID-19). Early observations indicated that cardiovascular disease (CVD) patients are at higher risk of progression to severe respiratory manifestations of COVID-19 including acute respiratory distress syndrome. Moreover, further observations demonstrated that SARS-CoV-2 infection can induce de novo cardiac and vascular damage in previously healthy individuals. Here, we offer an overview of the proposed molecular pathways shared by the pathogenesis of CVD and SARS-CoV infections in order to provide a mechanistic framework for the observed interrelation. We examine the crosstalk between the renin-angiotensin-aldosterone system and mitogen activated kinase pathways that potentially links cardiovascular predisposition and/or outcome to SARS-CoV-2 infection. Finally, we summarize the possible effect of currently available drugs with known cardiovascular benefit on these pathways and speculate on their potential utility in mitigating cardiovascular risk and morbidity in COVID-19 patients.


Subclassification of BCLC B Stage Hepatocellular Carcinoma and Treatment Strategies: Proposal of Modified Bolondi's Subclassification (Kinki Criteria).
Intermediate stage hepatocellular carcinoma (HCC) is a very heterogeneous tumor in terms of tumor size (>3 cm ∼ over 10 cm), tumor number (4 ∼ over 20) and liver function (Child-Pugh score 5-9). However, transarterial chemoembolization is the only recommended treatment option according to the Barcelona Clinic Liver Cancer (BCLC) staging. Bolondi's subclassification of BCLC B stage is feasible; however, there are several weak points. Therefore, by modifying Bolondi's subclassification, we have proposed a more simplified subclassification, Kinki criteria. The Kinki criteria consist of 2 factors: liver function (Child-Pugh score 5-7 or 8, 9) and tumor status (Beyond Milan and within up-to-7 criteria; IN and OUT). The Kinki criteria classifies BCLC B stage from B1 (Child-Pugh score 5-7 and within up-to-7), B2 (Child-Pugh score 5-7 and beyond up-to-7) and B3 (Child-Pugh score 8, 9 and any tumor status). These criteria are simple and easy to apply to clinical practice. Therefore, these criteria will stratify the heterogeneous population of BCLC B group patient well and give the treatment indication according to each substage. These criteria should be further validated both retrospectively and prospectively.


TRAF7 sequesters c-Myb to the cytoplasm by stimulating its sumoylation.
Small ubiquitin-related modifiers (SUMOs) are proteins that are posttranslationally conjugated to diverse proteins. The c-myb proto-oncogene product (c-Myb) regulates proliferation and differentiation of hematopoietic cells. PIASy is the only known SUMO E3 ligase for c-Myb. Here, we report that TRAF7 binds to c-Myb and stimulates its sumoylation. TRAF7 bound to the DNA-binding domain of c-Myb via its WD40 repeats. TRAF7 has an E3 ubiquitin ligase activity for self-ubiquitination, but TRAF7 also stimulated the sumoylation of c-Myb at Lys-523 and Lys-499, which are the same sites as those used for PIASy-induced sumoylation. TRAF7 inhibited trans-activation induced by wild-type c-Myb, but not by the sumoylation site mutant of c-Myb. The expression of both c-myb and TRAF7 was down-regulated during differentiation of M1 cells. Endogenous TRAF7 localized to both the cytoplasm and nucleus of M1 cells. Consistent with this, significant amounts of sumoylated c-Myb were found in the cytoplasm of M1 cells, whereas nonsumoylated c-Myb was found predominantly in the nucleus. Overexpressed TRAF7 was localized in the cytoplasm of CV-1 cells, and sequestered c-Myb and SUMO1 in the cytosol, whereas PIASy was localized in the nucleus. Thus, TRAF7 negatively regulates c-Myb activity by sequestering c-Myb to the cytosol via sumoylation.


Dynamic changes in numbers and properties of circulating tumor cells and their potential applications.
Circulating tumor cells (CTCs) can be detected in the blood of different types of early or advanced cancer using immunology-based assays or nucleic acid methods. The detection and quantification of CTCs has significant clinical utility in the prognosis of metastatic breast, prostate, and colorectal cancers. CTCs are a heterogeneous population of cells and often different from those of their respective primary tumor. Understanding the biology of CTCs may provide useful predictive information for the selection of the most appropriate treatment. Therefore, CTC detection and characterization could become a valuable tool to refine prognosis and serve as a "real-time biopsy" and has the potential to guide precision cancer therapies, monitor cancer treatment, and investigate the process of metastasis.


Alkalinity modulates a unique suite of genes to recalibrate growth and pH homeostasis.
Alkaline soils pose a conglomerate of constraints to plants, restricting the growth and fitness of non-adapted species in habitats with low active proton concentrations. To thrive under such conditions, plants have to compensate for a potential increase in cytosolic pH and restricted softening of the cell wall to invigorate cell elongation in a proton-depleted environment. To discern mechanisms that aid in the adaptation to external pH, we grew plants on media with pH values ranging from 5.5 to 8.5. Growth was severely restricted above pH 6.5 and associated with decreasing chlorophyll levels at alkaline pH. Bicarbonate treatment worsened plant performance, suggesting effects that differ from those exerted by pH as such. Transcriptional profiling of roots subjected to short-term transfer from optimal (pH 5.5) to alkaline (pH 7.5) media unveiled a large set of differentially expressed genes that were partially congruent with genes affected by low pH, bicarbonate, and nitrate, but showed only a very small overlap with genes responsive to the availability of iron. Further analysis of selected genes disclosed pronounced responsiveness of their expression over a wide range of external pH values. Alkalinity altered the expression of various proton/anion co-transporters, possibly to recalibrate cellular proton homeostasis. Co-expression analysis of pH-responsive genes identified a module of genes encoding proteins with putative functions in the regulation of root growth, which appears to be conserved in plants subjected to low pH or bicarbonate. Our analysis provides an inventory of pH-sensitive genes and allows comprehensive insights into processes that are orchestrated by external pH.


Panel 2: phase II investigations.
At the end of Phase II, a decision must be made as to whether or not the drug should be developed as a therapeutic agent. Such a decision may be based on many criteria in addition to the scientific data derived from the Phase II study. At this point, expert judgment is needed. One should like to assume that if the decision is made to proceed with the increasingly expensive and laborious process of further development, the drug will, barring some completely unforeseen misadventure, ultimately find its way into clinical therapeutics. Phase II studies, therefore, are the most crucial stage in the course of drug development. Planning of these studies requires great care and investigators of the highest caliber should be used for their conduct. The escalating costs of new drug development are resulting in an undesirable imbalance of efforts in the direction of studies characterized more by easily defined end points than by therapeutic needs. Industry, academia, and the FDA must all be concerned with facilitationg studies in areas of most-needed therapeutic advances.


Fermentation data analysis and state estimation in the presence of incomplete mass balance.
A method is developed for identifying measurement errors and estimating fermentation states in the presence of unidentified reactant or product. Unlike conventional approaches using elemental balances, this method employs an empirically determined basis, which can tolerate unidentified reaction species. The essence of this approach is derived from the concept of reaction subspace and the technique of singular value decomposition. It is shown that the subspace determined via singular value decomposition of multiple experimental data provides an empirical basis for identifying measurement errors. The same approach is applied to fermentation state estimation. Via the formulation of the reaction subspace, the sensitivity of state estimates to measurement errors is quantified in terms of a dimensionless quantity, maximum error gain (MEG). It is shown that using the empirically determined subspace, one can circumvent the problem of unidentified reaction species, meanwhile reducing the sensitivity of the estimates.


Significance of cone biopsy margins in the management of patients with cervical neoplasia.
Too many patients in the United States undergo hysterectomy for cervical neoplasia following cone biopsy because too many gynecologists choose not to pay attention to the pathology present at the margins of the cone specimen. In view of the need to improve the management of cervical neoplasia--i.e., to reduce the number of needless hysterectomies--a retrospective study was done to verify the trend in our institution and to evaluate the utilization of cone biopsy to determine the extent of the process. Also, the methods used for procuring the cone sample and for interpreting the results of the biopsy were studied. The present study included 345 patients who underwent a cone biopsy; subsequently, 102 of them had a hysterectomy. Based on the evaluation of the cases in this study, information was obtained about the performance of cone biopsy and the guidelines for determining when a hysterectomy should be performed and when other, less drastic means of eradicating the neoplasia should be considered.


Effects of diaper types on diaper dermatitis associated with diarrhea and antibiotic use in children in day-care centers.
Infants and toddlers in day-care centers have a relatively high frequency of diarrhea and/or oral antibiotic use, and may be at increased risk of developing diaper dermatitis when diapered. A six-month, prospective, double-blind study was conducted in day-care centers in Houston, Texas, to determine the frequency of diarrhea, antibiotic use, and diaper dermatitis in infants and toddlers wearing conventional (cellulose-only core) disposable diapers or disposable diapers with a core of absorbent gelling material (AGM) and cellulose. A questionnaire was administered weekly to the day-care staff to gather health information, and weekly visual examinations were made of children for diaper dermatitis. The frequency of diarrhea was 1.9 episodes per child-year and that of antibiotic use was 3.3 courses per child-year. Infants diapered in disposable diapers with AGM had a significantly (P 0.032) lower mean grade of diaper dermatitis during diarrhea episodes and a lower (P 0.054) mean grade during antibiotic use, compared to those diapered in conventional disposable diapers. There was no significant difference between groups with regard to isolation of Staphylococcus aureus or Candida albicans from superficial skin cultures of the diapered area. The results indicate that diarrhea and antibiotic use occur frequently in children in day-care centers, and that the severity of diaper dermatitis is less in children wearing AGM disposable diapers than those wearing conventional disposable diapers in that setting.


Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding?
Abnormal uterine bleeding is commonly associated with progestin-only contraceptives, including depot medroxyprogesterone acetate (DMPA), and remains the main reason why these agents are discontinued. Matrix metalloproteinases (MMP), enzymes which degrade specific extracellular matrix components, and leukocytes are implicated in menstruation. Alteration in endometrial MMP-9 and leukocytes has been described in users of other progestin-only contraceptives, suggesting a potential role in the pathogenesis of abnormal uterine bleeding. This study describes the immunohistochemical localization of MMP-9, the tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2 and TIMP-3, and leukocytes [CD3+ T lymphocytes, CD68+ macrophages and CD56+ uterine natural killer cells (uNK cells)] in the endometrium of women using DMPA. Comparison is made with perimenstrual endometria from normal cycling women. Similar to the perimenstrual period, an influx of MMP-9 positive cells (identified as neutrophils and CD3+ T cells on the basis of dual immunofluorescence), macrophages and uNK cells was observed in the endometrium of DMPA users. However, significantly more endometrial T lymphocytes were observed in DMPA users. Immunoreactive TIMP, present in all endometrial compartments, demonstrated a significantly decreased immunostaining intensity score in endometrial epithelium (TIMP-1 and TIMP-2), stroma (TIMP-1, TIMP-2 and TIMP-3), endothelium (TIMP-1 and TIMP-2) and vascular smooth muscle (TIMP-1) of DMPA users compared with controls. No correlation was observed between the parameters studied and bleeding patterns reported by subjects. These findings provide additional evidence for the importance of the MMP/TIMP balance in the loss/maintenance of endometrial integrity and in the complex pathological mechanisms involved in the troubling side-effect of menstrual bleeding disturbance.


Influence of an atomistic protrusion at the tip apex on enhancing molecular emission in tunnel junctions: A theoretical study.
Light emission from the gap of a scanning tunneling microscope can be used to investigate many optoelectronic processes at the single-molecule level and to gain insight into the fundamental photophysical mechanisms involved. One important issue is how to improve the quantum efficiency of quantum emitters in the nanometer-sized metallic gap so that molecule-specific emission can be clearly observed. Here, using electromagnetic simulations, we systematically investigate the influence of an atomic-scale protrusion at the tip apex on the emission properties of a point dipole in the plasmonic nanocavity. We found that such an atomistic protrusion can induce strong and spatially highly confined electric fields, thus increasing the quantum efficiency of molecular fluorescence over two orders of magnitude even when its dipole is oriented parallel to the metal surface, a situation occurring in most realistic single-molecule electroluminescence experiments. In addition, our theoretical simulations indicate that due to the lightning rod effect induced by the protrusion in a plasmonic nanocavity, the quantum efficiency increases monotonically as the tip approaches the dipole to the point of contact, instead of being quenched, thus explaining previous experimental observations with ever-enhancing fluorescence. Furthermore, we also examine in detail how the protrusion radius, height, and material affect the protrusion-induced emission enhancement. These results are believed to be instructive for further studies on the optoelectronic properties of single molecules in tip-based plasmonic nanocavities.


An anatomical study of the dorsal and ventral nasal conchal bullae in normal horses: Computed tomographic anatomical and morphometric findings.
Infection of the dorsal nasal conchal bulla and ventral nasal conchal bulla has recently been shown to cause clinical disease in horses, but the anatomy of these 2 structures is poorly documented. To describe the anatomical features, dimensions and relationships to adjacent structures of the dorsal conchal bulla and ventra conchal bulla in normal horses using computed tomography (CT). Descriptive imaging study using cadavers. Computed tomographic images acquired from 60 equine cadaver heads that were shown to be free of sinonasal disease were categorised into 3 age groups (0-5; 6-15; >16 years old). Linear and volumetric measurements and descriptive anatomical assessments of the dorsal conchal bulla and ventral conchal bulla were produced from these CT images and the anatomical relationships between the dorsal conchal bulla and ventral conchal bulla and the adjacent structures, particularly the maxillary cheek teeth, were examined. The associations between bullae dimensions with horse ages and skull dimensions were assessed using linear regression. Mean (range) dorsal conchal bulla measurements were: length 7.5 cm (4.6-14), width 1.9 cm (1.3-2.5), height 2.8 cm (1.8-4), volume 24 cm3 (5.9-50.5). Mean ventral conchal bulla measurements were: length 5.7 cm (2.5-8.5), width 1.6 cm (0.7-2.9), height 2.4 cm (0.8-3.7), volume 15 cm3 (0.4-30). In both dorsal conchal bulla and ventral conchal bulla, there were significant differences in sizes between the different age groups (smaller in younger animals). In the ventral conchal bulla, this was probably related to protrusion of the large dental alveoli of younger horses into the lateral nasal cavity. Measures of bullae size and volume were significantly associated with head size. The anatomical positions (rostro-caudal boundaries) of the dorsal conchal bulla and ventral conchal bulla were closely associated with specific maxillary cheek teeth. Computed tomography was a useful technique to establish the linear and volumetric dimensions of the nasal conchal bullae in normal horses. Both dorsal conchal bulla and ventral conchal bulla sizes increased with animal age. Relatively consistent anatomical relationships were shown between the rostral and caudal limits of the bullae and certain maxillary cheek teeth, which would be of diagnostic value with conventional radiography and act as landmarks in the surgical treatment of nasal bulla disease.


Effect of silver diamine fluoride (SDF) on the dentin-pulp complex: ex vivo histological analysis on human primary teeth and rat molars.
The aim of this study was to determine the effect of SDF on the dentin-pulp complex using two models: teeth after SDF application (ex vivo) and experimental animal molars. A descriptive study was performed using two models. In the first model, primary teeth (ex vivo) with enamel-dentin caries, without pulp involvement and previously treated with 38% SDF, were evaluated by means of two techniques: (a) Scanning Electron Microscopy (SEM) and energy-dispersive X-ray detector (EDS) to determine qualitative and quantitative composition, and (b) brightfield optical microscopy (OM) after decalcification. The second model used laboratory animal molars from 12 male Wistar rats. Standardized enamel-dentin cavities approximately 0.5 mm deep were made the distal fossa of the occlusal face of both first lower molars, to one of which a 38% SDF solution was applied, while the other was used as a control. Histological sections were prepared and dental pulp was evaluated qualitatively in both groups. SEM on ex vivo teeth showed areas of hypermineralization in the intertubular dentin and few blocked tubules, while EDS detected Ag in the center of the lesion (7.34%), its concentration declining at the edges (1.71%), with none in the areas farthest from the lesion. OM showed SDF sealing the tubules only at the site where it had been placed, with limited penetration beneath, the tubules appeared normal and the pulp tissue associated to treated caries showed chronic inflammatory infiltrate and formation of tertiary dentin, with no Ag precipitate. In the experimental animal model, pulp histology was not significantly altered in the molar cavities exposed to SDF. The observations using the different techniques on dental tissues suggest that SDF causes minimal adverse effects. The results of this study may contribute to further studies on the suitability of SDF as a cost-effective strategy for treating caries.


A Highly Convergent and Biomimetic Total Synthesis of Portentol.
An efficient total synthesis of the unusual polyketide portentol is reported. Three boron aldol reactions were used to assemble the linear carbon chain of the natural product, which contains two challenging anti-anti stereotriads. A biomimetic double cyclization cascade, triggered by an oxidation, then afforded portentol and its known dehydration product, anhydroportentol. The biosynthesis of portentol and the biosynthetic relevance of our key step are discussed.


A Plasmid With Conserved Phage Genes Helps Klebsiella pneumoniae Defend Against the Invasion of Transferable DNA Elements at the Cost of Reduced Virulence.
Klebsiella pneumoniae exhibits extensive phenotypic and genetic diversity. Higher plasmid loads in the cell were supposed to play an key role in its genome diversity. Although some plasmids are widely distributed in Kp populations, they are poorly recognized. A plasmid named p2 in strain Kp1604 was predicted to be an intact prophage like Salmonella phage SSU5. However, our study showed that p2 was specifically packaged into membrane vesicles (MVs) rather than phage particles triggered by mitomycin C and subinhibitory concentrations of antibiotics. p2-minus mutant Kp1604Δp2 did not affect MV production. Compared with Kp1604, the capacity of plasmid uptake and the amount of phage burst of Kp1604Δp2 were improved. Moreover, virulence of Kp1604Δp2 also increased. Our results indicated that p2 could contribute to the host defense against the invasion of transferable DNA elements at the cost of reduced virulence. Further study on the mechanism will help us understand how it provides adaptive phenotypes to host evolution.


Push-out bond strength of an experimental self-adhesive resin cement.
The adhesion of fiber posts luted with simplified adhesive systems has been a matter of great interest over the past years. The aim of this study was to assess the post retentive potential of experimental self-adhesive resin cement (EXP) when used alone and in combination with a self-etch adhesive. Fiber posts were placed in endodontically treated teeth and divided into four groups (n = 6) according the luting material, as follows: group 1 (EXP alone); group 2 (EXP used with self-etch adhesive); group 3 (marketed dual-cured cement used with self-etch adhesive); and group 4 (marketed self-adhesive cement). The push-out test was used to assess the retentive strength of fiber posts (expressed in MPa), and specimens were analyzed under a stereomicroscope to determine failure mode. The adhesive interface between the cement and root canal dentin for each group was evaluated using scanning electron microscopy. The post retentive potential of group 1 (EXP) (7.48 ± 4.35 MPa) was comparable with that of marketed cements from group 4 (6.79 ± 3.68 MPa) and group 3 (8.77 ± 4.58 MPa). When EXP was used in combination with self-etch adhesive (group 2), significantly higher push-out bond-strength values were measured (15.87 ± 4.68 MPa) compared with the other groups.


[Pure white cell aplasia (PWCA) with an inhibitor against colony-forming unit of granulocyte-macrophage (CFU-GM)].
We reported here a case of pure white cell aplasia (PWCA). A 23-year-old man was admitted to our hospital in September 1989 because of agranulocytosis, fever, and anal pain. He had no history of toxic-drug exposure or blood transfusion. Laboratory studies were all within the normal range except white blood cell count of 2,300/microliters with no neutrophils and low serum IgA level (28 mg/dl). Bone marrow examination showed hypocellular with erythroid predominance and no granulocyte maturation beyond the myelocyte. Complement-dependent suppression of autologous and heterologous granulocyte-macrophage colony-forming units by the patient's serum could be demonstrated. Though corticosteroid administration was ineffective, neutropenia improved by plasmapheresis. Furthermore, recombinant granulocyte colony stimulating factor (rG-CSF) could release him from persistent bacterial infection of anal fistula by transient improvement of neutropenia. These findings suggest a humoral autoimmune mechanism for the pathogenesis of PWCA and the effectiveness of rG-CSF for the patient with severe infections.


Prevalence of Enamel Markings on Third Molars.
The purpose of this study was to measure the prevalence of enamel markings in routinely extracted third molars. One hundred donated third molars were examined. All had some marking(s). Caries was almost universal; white snowcapping of cusps and ridges was extremely common; pit and valley defects were very common; spots and bands were very common, most were white; horizontal grooves were common; linear enamel hypoplasia, considered to be a true developmental defect, was rare.


Susceptibility to the acute toxicity of acrylonitrile in streptozotocin-induced diabetic rats: protective effect of phenethyl isothiocyanate, a phytochemical CYP2E1 inhibitor.
Diabetes mellitus is a significant global public health issue. The diabetic state not only precipitates chronic disease but also has the potential to change the toxicity of drugs and chemicals. Acrylonitrile (AN) is a potent neurotoxin widely used in industrial products. This study used a streptozotocin (STZ)-induced diabetic rat model to examine the role of cytochrome P450 2E1 (CYP2E1) in acute AN toxicity. The protective effect of phenethyl isothiocyanate (PEITC), a phytochemical inhibitor of CYP2E1, was also investigated. A higher incidence of convulsions and loss of the righting reflex, and decreased rates of survival, as well as elevated CYP2E1 activity, were observed in diabetic rats treated with AN when compared to those in non-diabetic rats, suggesting that diabetes confers susceptibility to the acute toxicity of AN. Pretreatment with PEITC (20-80 mg/kg) followed by AN injection alleviated the acute toxicity of AN in diabetic rats as evidenced by the decreased incidence of convulsions and loss of righting reflex, and increased rates of survival. PEITC pretreatment at 40 and 80 mg/kg decreased hepatic CYP2E1 activity in AN-exposed diabetic rats. PEITC pretreatment (20 mg/kg) increased the glutathione (GSH) content and glutathione S-transferase (GST) activity and further decreased ROS levels in AN-exposed diabetic rats. Collectively, STZ-induced diabetic rats were more sensitive to AN-induced acute toxicity mainly due to CYP2E1 induction, and PEITC pretreatment significantly alleviated the acute toxicity of AN in STZ-induced diabetic rats. PEITC might be considered as a potential effective chemo-preventive agent against AN-induced acute toxicity in individuals with an underlying diabetic condition.


Review of acquired cystic disease-associated renal cell carcinoma with focus on pathobiological aspects.
Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) is a recently established entity. In this article, we introduce the general view of this new entity. Macroscopically, the disease exclusively occurs in ACD and may arise as a dominant mass or non-dominant masses. Histologically, the tumor is characterized by a microcystic pattern, neoplastic cells with an eosinophilic or oncocytic cytoplasm and frequent intratumoral oxalate crystal deposition. Prominent nucleoli of tumor cells are often observed. Immunohistochemically, neoplastic cells are generally positive for AMACR but negative for cytokeratin 7. Ultrastructurally, neoplastic cells contain abundant mitochondria in the cytoplasm. Genetically, the gain of chromosomes 3, 7, 17 and abnormality of the sex chromosome were frequently observed in several studies. In conclusion, ACD-associated RCC may be widely recognized as a distinct entity in the near future because this tumor is morphologically and genetically different from other renal tumor entities that have been previously established.


Diffeomorphic metric surface mapping in subregion of the superior temporal gyrus.
This paper describes the application of large deformation diffeomorphic metric mapping to cortical surfaces based on the shape and geometric properties of subregions of the superior temporal gyrus in the human brain. The anatomical surfaces of the cortex are represented as triangulated meshes. The diffeomorphic matching algorithm is implemented by defining a norm between the triangulated meshes, based on the algorithms of Vaillant and Glaunès. The diffeomorphic correspondence is defined as a flow of the extrinsic three dimensional coordinates containing the cortical surface that registers the initial and target geometry by minimizing the norm. The methods are demonstrated in 40 high-resolution MRI cortical surfaces of planum temporale (PT) constructed from subsets of the superior temporal gyrus (STG). The effectiveness of the algorithm is demonstrated via the Euclidean positional distance, distance of normal vectors, and curvature before and after the surface matching as well as the comparison with a landmark matching algorithm. The results demonstrate that both the positional and shape variability of the anatomical configurations are being represented by the diffeomorphic maps.


Influence of initial conditions on homogeneous nucleation kinetics in a closed system.
The formation of nuclei of a new phase from the supersaturated mother phase in a closed system is studied. The depletion of the mother phase due to phase transition is taken into account. Basic kinetic equations describing such process are solved numerically to determine the number density of nuclei of newly forming phase and nucleation rate. It is shown that in contrary to the standard nucleation model, when the depletion of the mother phase is not taken into account, the initial size distribution of the clusters affects considerably the nucleation process at higher supersaturations. Our model starts with the equilibrium size distribution of clusters up to various cluster sizes in the undercritical region. At lower supersaturation the formation of nuclei is similar to the standard model because of the low depletion of the mother phase. At higher supersaturation, the depletion of the mother phase plays an important role and some extremal value appears at the size distribution of nuclei, which is not observed in the standard model. The extremum in the size distribution is not a consequence of the coalescence process itself, but it is caused rather by the depletion of the mother phase during the phase transformation.


Outcomes following coronary artery bypass surgery in diabetic treatment sub-groups. A propensity matched analysis of >7000 patients over 18 years.
European System for Cardiac Operative Risk Evaluation II incorporates insulin-controlled diabetes whilst omitting tablet-controlled diabetes. Differences in adverse clinical outcomes following coronary artery bypass graft between these groups are poorly established. Therefore, a propensity matched comparison of short and longer term mortality and morbidity in insulin-controlled diabetes, tablet-controlled diabetes and non-diabetic patients was undertaken. Isolated first-time coronary artery bypass graft surgeries between April 1999 and April 2017 were propensity score matched by pre- and intra-operative variables. 8241 patients; 23.5% diabetics and 76.5% non-diabetics. The groups' demographical and clinical characteristics were comparable after matching. Insulin-controlled diabetes patients had significantly higher in-hospital mortality (3.8% vs. 1.7%, p < 0.05), multisystem failure (2.6% vs. 1.8%, p < 0.05), sternal wound infections requiring debridement (3.6% vs. 1.3%, p < 0.05), respiratory complications (25.6% vs. 21.9%, p < 0.05), new dialysis (4.7% vs. 0.9%, p < 0.05) and longer hospital stays (13.5 ± 13.3 vs. 10.6 ± 8.0, p < 0.05) compared to non-diabetic patients.Tablet-controlled diabetes patients had significantly higher strokes (2.9% vs. 1.2, p < 0.05), superficial sternal wound infections (6.7% vs. 5.4%, p < 0.05), respiratory complications (25.7% vs. 22.7%, p < 0.05), new dialysis (1.7% vs. 0.6%, p < 0.05), post-operative atrial fibrillation (37.1% vs. 33.9%, p < 0.05) and readmission with myocardial infarction (22.4% vs. 19.6%, p < 0.05) compared to non-diabetic patients. Diabetic treatment sub-groups are an independent risk factor for sternal wound infection, new dialysis requirement, multisystem failure and readmission with myocardial infarction after isolated first coronary artery bypass graft surgery. The findings suggest the need for better risk stratification of diabetic groups prior to cardiac surgery and for improved cardiovascular risk management post-surgery in tablet-controlled diabetes patients.


An integrated critique of the efficacy of topical mupirocin in preventing catheter-related Staphylococcus aureus infections in peritoneal dialysis clients.
Several epidemiological studies indicate that, for two reasons, Staphylococcus aureus (SA) nasal carriage is a risk factor for developing SA infections in peritoneal dialysis (PD) clients. First, nasal carriage is prevalent in these clients due to the nature of their disease. Second, there is a significant relationship between nasal and hand carriage of the SA organism. Because PD clients require frequent catheter handling to receive therapy, they are at risk for catheter contamination. Two prospective randomized control trials and two prospective cohort trials with historical controls were selected for review. Emphasis was placed on the design feature of a comparison or control group in order to find empirical support for the efficacy of topical mupirocin (Bactroban) as an infection control measure. The four studies selected also used two methods of application, the first application was to the nares and the second was to the catheter exit site. The result of the analysis revealed a weak support for the prophylactic role of topical mupirocin in preventing SA exit-site infections (ESI) in PD clients. Well-controlled prospective, randomized studies with sufficiently large sample sizes to produce statistically and clinically significant results for the prophylactic role of mupirocin are lacking. In light of the analysis, the advocacy of several practice implications involving client education and timely follow-up, staff training, and client comfort are warranted.


New trends in glioma cancer therapy: Targeting Na+ /H + exchangers.
Glioma is the oneof the most prevalent primarybrain tumors. There is a variety of oxidative stresses, inflammatory pathways, apoptosis signaling, and Na+ /H + exchangers (NHEs) involved in the pathophysiology of glioma. Previous studies have indicated a relationship between NHEs and some molecular pathways in glioma. NHEs, including NHE1, NHE5, and NHE9 affect apoptosis, tumor-associated macrophage inflammatory pathways, matrix metalloproteinases, cancer-cell growth, invasion, and migration of glioma. Also, inhibition of NHEs contributes to increased survival in animal models of glioma. Limited studies, however, have assessed the relationship between NHEs and molecular pathways in glioma. This review summarizes current knowledge and evidence regarding the relationship between NHEs and glioma, and the mechanisms involved.